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Platinum Based Chemotherapy or Capecitabine in Treating Patients With Residual Triple-Negative Basal-Like Breast Cancer Following Neoadjuvant Chemotherapy
This randomized phase III trial studies how well cisplatin or carboplatin (platinum based
chemotherapy) works compared to capecitabine in treating patients with remaining (residual)
basal-like triple-negative breast cancer following chemotherapy after surgery (neoadjuvant).
Drugs used in chemotherapy, such as cisplatin, carboplatin and capecitabine, work in
different ways to stop the growth of tumor cells, either by killing the cells, by stopping
them from dividing, or by stopping them from spreading. It is not yet known whether cisplatin
or carboplatin is more effective than capecitabine in treating patients with residual triple
negative basal-like breast cancer.
• ELIGIBILITY CRITERIA FOR SCREENING AND MOLECULAR PROFILING (STEP 0)
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 within 2 weeks
prior to screening
• Female and male patients must have histologically confirmed invasive breast cancer
that meets the following criteria:
• Clinical stage II-III (American Joint Committee on Cancer [AJCC] 7th edition) at
diagnosis, based on initial evaluation by clinical examination and/or breast
imaging; no metastatic disease allowed
• ER- and PR- should meet one of the following criteria:
• =< 10% cells stain positive, with weak intensity score (equivalent to Allred
score =< 3)
• =< 1% cells stain positive, with weak or intermediate intensity score
(equivalent to Allred score =< 3)
• HER2 negative (not eligible for anti-HER2 therapy) will be defined as:
• Immunohistochemistry (IHC) 0, 1+ without in situ hybridization (ISH)
HER2/neu chromosome 17 ratio OR
• IHC 2+ and ISH HER2/neu chromosome 17 ratio non-amplified with ratio less
than 2.0 and if reported average HER2 copy number < 6 signals/cells OR
• ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and
if reported average HER2 copy number < 6 signals/cells without IHC
• NOTE: Patients that originally present with synchronous bilateral tumors are
eligible provided both tumors are TNBC, and at least one of them fulfills
the remainder eligibility criteria of the protocol; multifocal or
multicentric breast cancers are eligible as long as all tumors fulfill
eligibility criteria
• NOTE: Patients that have a discrepancy in ER/PR/HER2 status between original
diagnosis and surgical specimen (if ER/PR/HER2 status were repeated) are not
eligible for study participation (i.e. ER/PR/HER2 has to fulfill above
criteria in both scenarios)
• Patients must have completed neoadjuvant taxane +/- anthracycline; patients must NOT
have received cisplatin or carboplatin or capecitabine as part of their neoadjuvant
therapy regimen
• NOTE: Patients who received preoperative therapy as part of a clinical trial may
enroll
• NOTE: Patients that were not able to complete their planned neoadjuvant
chemotherapy for any reason (i.e. toxicities, etc.) are eligible to participate
as long as no further systemic standard of care therapy is planned by the
treating physician
• Must have completed definitive resection of primary tumor
• Negative margins for both invasive and ductal carcinoma in situ (DCIS) are
desirable, however patients with positive margins may enroll if the treatment
team believes no further surgery is possible and patient has received
radiotherapy; patients with margins positive for lobular carcinoma in situ (LCIS)
are eligible
• Either mastectomy or breast conserving surgery (including lumpectomy or partial
mastectomy) is acceptable
• Sentinel node biopsy either pre or post neoadjuvant chemotherapy (i.e. at the
time of definitive surgery) are allowed; axillary dissection is encouraged in
patients with lymph node involvement, but is not mandatory
• Post neoadjuvant chemotherapy, patients must be found to have residual invasive cancer
in the breast at the time of definitive surgery; residual cancer is defined as a
contiguous focus of residual invasive cancer, in the breast, measuring >= 1 cm in
diameter, and with more than minimal cellularity, as per local pathologist
determination; this is required due to constraints in deoxyribonucleic acid (DNA)
extraction for PAM50 analysis
• NOTE: The presence of ductal carcinoma in situ (DCIS) without invasion does not
qualify as residual invasive disease in the breast
• NOTE: Despite lymph node involvement if residual invasive cancer in the breast is
< 1 cm in diameter patients are not eligible for participation
• Radiotherapy may be given before or after protocol treatment per standard of care
guidelines; when radiotherapy is planned prior to protocol treatment administration,
patients may be registered and screened while receiving radiation
• Post-mastectomy radiotherapy is required for all patients with the following:
• Primary tumor >= 5 cm (prior to neoadjuvant chemotherapy [clinically] or at
the time of definitive surgery) or involvement of 4 or more lymph nodes at
the time of definitive surgery
• For patients with primary tumors < 5 cm or with < 4 involved lymph nodes
prior to neoadjuvant chemotherapy and at the time of definitive surgery,
provision of post-mastectomy radiotherapy is at the discretion of the
treating physician
• Radiation of regional nodal basins is at the discretion of the treating
radiation oncologist
• NOTE: Breast radiotherapy (whole breast or partial) is required for patients who
underwent breast-conserving therapy, including lumpectomy or partial mastectomy
• Hemoglobin (Hgb) > 9.0 g/dL
• Platelets > 100,000 mm^3
• Absolute neutrophil count (ANC) > 1500 mm^3
• Calculated creatinine clearance of > 50 mL/min using the Cockcroft-Gault formula
• Bilirubin =< 1.5 x ULN upper limit of normal (except in patients with documented
Gilbert?s disease, who must have a total bilirubin =< 3.0 mg/dL)
• Aspartate aminotransferase (AST, serum glutamic oxaloacetic transaminase [SGOT]) =<
2.5 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT, serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
ULN
• No history of TNBC invasive breast cancer within 5 years of enrollment, no concurrent
malignancies of any sort
• No clinically significant infections as judged by the treating investigator
• Patients with active >= Common Terminology Criteria for Adverse Events (CTCAE) version
(v.) 4 grade 2 neuropathy are ineligible
• Adjuvant chemotherapy after surgery other than that specified in this protocol is not
allowed; luteinizing hormone-releasing hormone (LHRH) agonists and adjuvant
bisphosphonate or denosumab use is allowed
• Patients must have archived formalin-fixed paraffin-embedded (FFPE) tumor tissue
specimen from the residual disease on the definitive surgical specimen available for
PAM50 analysis for stratification
• Tumor tissue specimen from the definitive surgery has been collected and is ready
to ship to the ECOG-American College of Radiology Imaging Network (ACRIN) Central
Biorepository and Pathology Facility (CBPF) within 21 weeks post-surgery
• The Molecular Diagnostics Laboratory (MDL) at MD Anderson Cancer Center will
perform the PAM50 analysis and notify the ECOG-American College of Radiology
Imaging Network (ACRIN) operations office within three (3) weeks of receipt of
the tumor tissue specimen via secure electronic messaging to the ECOG-ACRIN
database; results will not be reported to the submitting institution
• NOTE: Tissue must be submitted any time during screening period, even if patient
is getting radiation
• NOTE: Every effort should be made to submit the tumor tissue specimen to the
ECOG-ACRIN CBPF immediately
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): No specific timeframe between
registration and randomization needs to be observed, as long as:
• Patients randomized to the chemotherapy arms have their cycle 1/ day 1 (platinum
based or capecitabine) start within 3 weeks (15 working days) following
randomization date
• Randomization occurs no more than 24 weeks from surgery date
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Must have PAM50 analysis by digital
mRNA quantitation on the formalin-fixed paraffin-embedded tumor tissue specimen (FFPE)
of the residual disease in the breast or axilla resected at the time of definitive
surgery completed
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): ECOG performance status 0 or 1 within
2 weeks prior to randomization
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Radiotherapy may be given before or
after protocol treatment. when radiotherapy is planned prior to protocol treatment
administration, patients must have completed adjuvant radiotherapy >= 2 weeks prior to
randomization for protocol therapy, if applicable
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Patients must have completed
treatment with any investigational agent >= 30 days prior to randomization for
protocol therapy, if applicable
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Patients must be randomized within 24
weeks from surgery
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Women must not be pregnant or
breast-feeding; all females of childbearing potential must have a blood test or urine
study within 2 weeks prior to randomization to rule out pregnancy
• A female of childbearing potential is any woman, regardless of sexual orientation
or whether they have undergone tubal ligation, who meets the following criteria:
1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Women of childbearing potential and
sexually active males must be strongly advised to use an accepted and effective method
of contraception or to abstain from sexual intercourse for the duration of their
participation in the study
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Hemoglobin (Hgb) > 9.0 g/dL
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Platelets > 100,000 mm^3
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Absolute neutrophil count (ANC) >
1500 mm^3
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): International normalized ratio (INR)
=< 3 (to be done/tested only for subjects on warfarin)
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Calculated creatinine clearance of >
50 mL/min using the Cockcroft-Gault formula
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Bilirubin =< 1.5 x ULN (except in
patients with documented Gilbert?s disease, who must have a total bilirubin =< 3.0
mg/dL)
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Aspartate aminotransferase (AST,
SGOT) =< 2.5 x ULN
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Alanine aminotransferase (ALT, SGPT)
=< 2.5 x ULN
HER2/Neu Negative, Stage IIA Breast Cancer, Stage IIB Breast Cancer, Stage IIIB Breast Cancer, Estrogen Receptor Negative, Progesterone Receptor Negative, Invasive Breast Carcinoma, Stage IIIA Breast Cancer, Stage IIIC Breast Cancer, Triple-Negative Breast Carcinoma, Stage III Breast Cancer, Stage II Breast Cancer, Breast - Female, Breast - Male
Use of the CA 125 Algorithm for the Early Detection of Ovarian Cancer in Low Risk Women
The goal of this clinical research study is to evaluate a method involving a blood test,
called CA-125, that may be helpful in the early detection of ovarian cancer in women who are
at low risk.
1. Female, >/= 50 years old or less than 75 years old.
2. Postmenopausal (>/= 12 months amenorrhea).
3. Have at least one ovary.
4. Cancer-free and have not received any chemotherapy or radiation therapy for >/=12
months prior to enrolling on this study.
5. Willingness to return for CA 125 blood tests annually or earlier if indicated.
6. Willingness to return to undergo transvaginal ultrasound if indicated.
7. Women need to provide the name of a gynecologist or qualified healthcare professional
willing to provide appropriate follow-up care if indicated
Exclusion Criteria:
1. Female: Less than 50 years old or older than 75 years at the time of enrollment.
2. Psychiatric or psychological or other conditions which prevent a fully informed
consent.
3. Prior removal of both ovaries.
4. Active non-ovarian malignancy.
5. Women who have a history of non-ovarian malignancy will be eligible if they have no
persistent or recurrent disease and have not received treatment for >12 months. If
they are on SERMS (i.e. tamoxifen or aromatase inhibitors) they will not be excluded.
Women maybe undergoing or have had treatment <12 months prior to study entry for basal
cell carcinoma only.
6. High risk for ovarian cancer due to familial predisposition as defined by the
following: a. Known mutation in BRCA1 of BRCA2. b. Two 1st or 2nd degree relatives of
same lineage who have: two ovarian cancers; one ovarian cancer & one pre-menopausal
breast cancer; two pre-menopausal breast cancers; one pre-menopausal & one
post-menopausal breast cancer. (These conditions can also be met using the patient and
one 1st or 2nd degree female relative.) c. Ashkenazi Jewish descent with one 1st
degree or two 2nd degree relatives with pre-menopausal breast or ovarian cancer or
participant has had pre-menopausal breast cancer. d. 1st or 2nd degree male relative
with breast cancer diagnosed at any age. (First degree relative defined as children,
siblings and parents. Second degree relative defined as half-siblings, aunts, uncles,
nieces, nephews, grandparents, and grandchildren.)
7. Hereditary Nonpolyposis Colorectal Cancer (HNPCC)/Lynch Syndrome: known genetic
mutation, presumed HNPCC carrier, Amsterdam criteria.
Behavioral: Questionnaire
Ovarian Cancer, Ovary
Ovarian Cancer, CA 125 Algorithm, Cancer Detection, Questionnaire, Survey
Phase 1 Study of MM-398 Plus Cyclophosphamide in Pediatric Solid Tumors
This is a Phase 1 study of the combination of two drugs: MM-398 and Cyclophosphamide. The
goal is to find the highest dose of MM-398 that can be given safely when it is used together
with the chemotherapy drug Cyclophosphamide.
• Histologically or cytologically-confirmed Ewing sarcoma, rhabdomyosarcoma,
neuroblastoma, or osteosarcoma
• Disease progression after prior therapy in locally advanced or metastatic setting
• Measurable or evaluable disease based on the Response Evaluation Criteria in Solid
Tumors (RECIST v1.1) criteria
• Age 12 months to <21 years
• Adequate bone marrow reserves, hepatic function, and renal function
• Recovered from effects of any prior surgery or cancer therapy
• Patients 18 years or older will provide written consent. A parent or legal guardian of
a patient <18 years of age will provide informed consent and patients 11 to 18 years
of age will provide written assent or as per participating institutional policy.
Exclusion Criteria:
• Clinically significant gastrointestinal disorders
• NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled
blood pressure
• Active infection or unexplained fever
• Known hypersensitivity to any of the components of MM-398 or other liposomal products
• Recent Investigational therapy
• Pregnant or breast feeding; females of child-bearing potential must test negative for
pregnancy at the time of enrollment
Drug: MM-398 (Irinotecan Sucrosofate Liposome Injection) plus cyclophosphamide
Neuroblastoma, Sarcoma, Ewing Sarcoma, Mycosis Fungoides, Rhabdomyosarcoma, Osteosarcoma, Recurrent or Refractory Solid Tumors, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Ear, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Nose, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Uterine (Endometrial), Vulva, Hodgkins Lymphoma, Kaposis sarcoma, Other Hematopoietic, Small Intestine, Soft Tissue
Combination Chemotherapy With or Without Temsirolimus in Treating Patients With Intermediate Risk Rhabdomyosarcoma
This randomized phase III trial studies how well combination chemotherapy (vincristine
sulfate, dactinomycin, cyclophosphamide alternated with vincristine sulfate and irinotecan
hydrochloride or vinorelbine) works compared to combination chemotherapy plus temsirolimus in
treating patients with rhabdomyosarcoma (cancer that forms in the soft tissues, such as
muscle), and has an intermediate chance of coming back after treatment (intermediate risk).
Drugs used work in different ways to stop the growth of tumor cells, either by killing the
cells, by stopping them from dividing, or by stopping them from spreading. Combination
chemotherapy and temsirolimus may stop the growth of tumor cells by blocking some of the
enzymes needed for cell growth. It is not yet known whether chemotherapy plus temsirolimus is
more effective than chemotherapy alone in treating patients with intermediate-risk
rhabdomyosarcoma.
• Feasibility Phase: Patients must be < 21 years of age at the time of enrollment;
please note: the feasibility phase is complete, effective with amendment #1
• Efficacy Phase: Patients must be =< 40 years of age at the time of enrollment
• Patients with newly diagnosed RMS of any subtype, except adult-type pleomorphic, based
upon institutional histopathologic classification, are eligible to enroll on the study
based upon stage, group, and age, as below
• RMS types included under embryonal rhabdomyosarcoma (ERMS) include those classified in
the 1995 International Classification of Rhabdomyosarcoma (ICR) as ERMS (classic,
spindle cell, and botryoid variants), which are reclassified in the 2013 World Health
Organization (WHO) classification as ERMS (classic, dense and botryoid variants) and
spindle cell/sclerosing RMS (encompassing the historical spindle cell ERMS variant and
the newly recognized sclerosing RMS variant); classification of alveolar
rhabdomyosarcoma (ARMS) in the 2013 WHO classification is the same as in the ICR and
includes classic and solid variants
• ERMS
• Stage 1, group III (non-orbit)
• Stage 3, group I/II
• Stage 2/3, group III
• Stage 4, group IV, < 10 years old
• ARMS:
• Stages 1-3, groups I-III
• Specimen Submission: Patients must have sufficient tissue available for the required
biology study
• Lansky performance status score >= 50 for patients =< 16 years of age; Karnofsky
performance status score >= 50 for patients > 16 years of age
• Peripheral absolute neutrophil count (ANC) >= 750/uL
• Platelet count >= 75,000/uL
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• 1 month to < 6 months old: 0.4 mg/dl (male), 0.4 mg/dl (female)
• 6 months to < 1 year old: 0.5 mg/dl (male), 0.5 mg/dl (female)
• 1 to < 2 years old: 0.6 mg/dl (male), 0.6 mg/dl (female)
• 2 to < 6 years old: 0.8 mg/dl (male), 0.8 mg/dl (female)
• 6 to < 10 years old: 1 mg/dl (male), 1 mg/dl (female)
• 10 to < 13 years old: 1.2 mg/dl (male), 1.2 mg/dl (female)
• 13 to < 16 years old: 1.5 mg/dl (male), 1.4 mg/dl (female)
• >= 16 years old: 1.7 mg/dl (male), 1.4 mg/dl (female)
• Patients with an elevated serum creatinine due to obstructive hydronephrosis
secondary to tumor are still eligible; however, patients with urinary tract
obstruction by tumor must have unimpeded urinary flow established via diversion
(i.e. percutaneous nephrostomies or ureteric stents) of the urinary tract
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• All patients and/or their parents or legal guardians must sign a written informed
consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met.
Exclusion Criteria:
• Patients who have previously received temsirolimus, another mTOR inhibitor, or any
other investigational agent
• Patients who have received any chemotherapy (excluding steroids) and/or RT prior to
this enrollment
• Patients with uncontrolled hyperglycemia
• Patients with uncontrolled hyperlipidemia
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation and for
at least 3 months after treatment is completed
• Female patients who are pregnant are not eligible since fetal toxicities or
teratogenic effects have been noted for several of the study drugs; Note: A pregnancy
test is required for female patients of childbearing potential prior to study entry
• Lactating females who plan to breastfeed their infants are not eligible
Inclusion Criteria-Part A:
Subject must meet all of the following applicable inclusion criteria to participate in this
study:
• Patients must have histologically confirmed advanced RCC (any histology). Collecting
duct tumors and tumors originating from the renal pelvis or upper urinary tract are
considered of urothelial origin and are excluded from this protocol.
• Patients must have at least one measurable site of disease, per RECIST 1.1, that has
not been previously irradiated. If the patient has had previous radiation to the
marker lesion(s), there must be evidence of progression since the radiation.
• Archival tissue of a metastatic lesion obtained within 1 year prior to study
registration (within 4 weeks preferred) and tumor tissue from nephrectomy is required
if available. In addition to archival tissue of a metastatic lesion and nephrectomy,
patients must have at least one site of disease (not including bone metastases)
accessible for biopsy. If biopsy/resection of a new lesion or primary tumor and slow
freezing of fresh tissue for single cell RNAseq study (as specified in the CLM) is not
feasible, the subject is not eligible for the study. All biopsies must be core needle
or excisional. Fine needle aspirate is not acceptable. NOTE: The tissue collected from
a surgical resection or multiple core biopsies of either a metastatic lesion or
primary tumor for the slow freezing of fresh tissue after the patient has signed
consent for the study could also be used for collecting the FFPE specimens.
• ECOG performance status 0-2
• Have signed the current approved informed consent form
Patients must have adequate organ function within 14 days prior to study entry as evidenced
by screening laboratory values that must meet the following criteria:
Hematological:
• White blood cell (WBC) ≥ 2000/µL
• Absolute Neutrophil Count (ANC) ≥ 1500/μL
• Platelets (Plt) ≥ 100 x103/μL
• Hemoglobin (Hgb) > 9.0 g/dL (with or without transfusion)
Renal:
• Serum Creatinine ≤ 1.5 x ULN; if creatinine > 1.5, subject must demonstrate CrCl as
outlined below.
• Calculated creatinine clearance ≥ 40 mL/min using Cockcroft-Gault formula
Hepatic:
• Bilirubin ≤ 1.5× upper limit of normal (ULN); Except subjects with Gilbert Syndrome,
who can have total bilirubin < 3.0 mg/dL
• Aspartate aminotransferase (AST) ≤ 3 × ULN
• Alanine aminotransferase (ALT) ≤ 3 × ULN
• Patients should not have received prior systemic therapy for metastatic RCC. Prior
radiotherapy must have been completed at least 2 weeks prior to the administration of
study drug. Patients must be 2 weeks from prior major surgery and 1 week from
pre-treatment biopsy. Prior systemic adjuvant therapy (excluding with PD1 or CTLA4
pathway blockers) is allowed if treatment completed > 12 months previously.
• Women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks
• Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) during screening for
registration purposes. This pregnancy test should be repeated within 24 hours prior to
the start of nivolumab.
• Women must not be breastfeeding
• Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year Men receiving nivolumab and who are sexually
active with WOCBP will be instructed to adhere to contraception for a period of 31
weeks after the last dose of investigational product Women who are not of childbearing
potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men
do not require contraception.
• Be willing and able to comply with this protocol.
Exclusion Criteria:
• Patients are excluded if they have active brain metastases or leptomeningeal
metastases. Subjects with brain metastases are eligible if metastases have been
treated and there is no magnetic resonance imaging (MRI) evidence of progression for 2
weeks of more after treatment is complete and within 28 days prior to the first dose
of nivolumab administration. There must also be no requirement for immunosuppressive
doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2
weeks prior to study drug administration.
• Patients with controlled brain metastases are allowed on protocol if they had solitary
brain metastases that was surgically resected without recurrence or treated with SRS
without progression x 4 weeks.
• Patients should be excluded if they have an active, known or suspected autoimmune
disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes
mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger.
• Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration. Inhaled or
topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents
are permitted in the absence of active autoimmune disease.
• As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab
combinations, drugs with a predisposition to hepatoxicity should be used with caution
in patients treated with nivolumab-containing regimen
• Active infection requiring systemic therapy
• Has any other medical or personal condition that, in the opinion of the site
investigator, may potentially compromise the safety or compliance of the patient, or
may preclude the patient's successful completion of the clinical trial
• Patients should be excluded if they are positive test for hepatitis B virus surface
antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating
acute or chronic infection
• Patients should be excluded if they have known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Allergies and Adverse Drug Reaction
• History of allergy to study drug components
• History of severe hypersensitivity reaction to any monoclonal antibody
• Known additional malignancies within the past 3 years (excluding basal of squamous
cell skin cancers, CIS or localized prostate cancer that has been treated or is being
observed)
Inclusion/Exclusion Criteria- Part B
• Must meet eligibility criteria for initiation of Part A with the exception of being
allowed to have prior nivolumab in Part A of this protocol
• Must have evidence of either RECIST 1.1 defined Disease Progression or Stable Disease
1 year after initiating nivolumab therapy
• Tumor biopsy prior to combination treatment is mandatory. If a biopsy/resection of a
new lesion or primary tumor and slow freezing of fresh tissue for single cell RNAseq
study (as specified in the CLM) is not feasible, the subject is not eligible for the
study. All biopsies must be core needle or excisional. Fine needle aspirate is not
acceptable.
• Must not have had a Grade ≥ 3 irAE on nivolumab monotherapy
• Must not have untreated brain metastases
• Must not have had major surgery or radiation therapy within 14 days of starting study
treatment
• Must not have active autoimmune disease
• Must not have a concurrent medical condition requiring use of systemic corticosteroids
with prednisone >10 mg per day
• Must not have had prior systemic therapy for Stage IV RCC (except for nivolumab as
part of part A of this protocol)
• Prior solid organ or stem cell transplant
Maintenance Chemotherapy With or Without Local Consolidative Therapy in Treating Patients With Stage IV Non-small Cell Lung Cancer
This randomized phase II/III trial studies how well giving maintenance chemotherapy with or
without local consolidation therapy works in treating patients with stage IV non-small cell
lung cancer. Drugs used in maintenance chemotherapy, such as docetaxel, pemetrexed disodium,
erlotinib hydrochloride, and gemcitabine work in different ways to stop the growth of tumor
cells, either by killing the cells, by stopping them from dividing, or by stopping them from
spreading. Local consolidation therapy such as radiation/stereotactic body radiation or
surgery may kill cancer cells left after initial treatment. Giving maintenance chemotherapy
and local consolidation therapy together may work better than maintenance chemotherapy alone
in treating patients with stage IV non-small cell lung cancer.
• Patients must have the psychological ability and general health that permits
completion of the study requirements and required follow up
• Women of childbearing potential and men who are sexually active should be willing and
able to use medically acceptable forms of contraception during the trial and for up to
180 days after completion of all treatment to prevent pregnancy or fathering a child.
• Pathologically proven diagnosis of NSCLC, with metastases (stage IV disease) present
prior to registration; this includes patients newly diagnosed with metastatic disease
or those initially diagnosed and treated for stage I-III NSCLC who ultimately develop
metastases
• Appropriate stage for study entry based on the following diagnostic workup:
• History/physical examination within 30 days prior to registration
• Imaging proof of limited metastatic disease and response to therapy/stable
disease, by at least CT chest through the adrenals or PET/CT within 30 days prior
to registration
• Zubrod performance status 0, 1, or 2 within 30 days prior to registration
• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × upper limit of
normal (ULN) or ≤ 5 × ULN with metastatic liver disease
• Total bilirubin ≤ 1.5 × ULN
• Absolute neutrophil count (ANC) ≥ 500 cells/mm^3
• Creatinine clearance ≥ 45 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal
• Platelets ≥ 50,000 cells/mm^3
• Negative serum pregnancy test within one week prior to registration for females of
childbearing potential
• Patients must have received first-line/induction chemotherapy (4 cycles) and achieved
stable disease or a partial response
• Prior systemic chemotherapy as part of concurrent treatment approach for previously
diagnosed stage III NSCLC, as adjuvant therapy for previously resected NSCLC, or for
other previous cancers is permitted
• Prior radiotherapy for patients with brain metastases prior to enrollment is
acceptable
• Patients must have measurable disease at baseline and 3 or fewer discrete,
extracranial metastatic disease sites that are technically amenable to SBRT
• For de novo stage IV NSCLC patients (patients with metastatic disease at first
presentation), primary disease must be treatable with local therapy in the form of
SBRT or hypofractionated radiation; if the primary disease is found in the peripheral
or central lung parenchyma without nodal disease for instance, SBRT may be employed;
if primary disease is more advanced with involvement of the mediastinum (T4 tumor,
N1-N3 disease, etc.), these volumes should be technically treatable with
hypofractionated radiation
• If primary disease in the thoracic cavity was previously treated with local therapy in
the form of surgery, any local/regional disease recurrence should be technically
treatable with SBRT or hypofractionated radiation after induction systemic therapy
• Patients must be registered within 35 days of administration of the last dose of
first-line/induction systemic therapy
• The patient or a legally authorized representative must provide study-specific
informed consent prior to study entry
• Patients with brain metastases are eligible if these lesions have been previously
treated and the patients have no clinical or radiographic evidence of progression
prior to enrollment
Exclusion Criteria:
• Clinical or radiologic evidence of untreated and/or progressive brain metastases
• Cutaneous metastasis of NSCLC
• Metastatic disease invading the esophagus, stomach, intestines, or mesenteric lymph
nodes if not a candidate for surgery for these lesions
• Prior invasive malignancy (except non-melanomatous skin cancer, low or intermediate
risk prostate cancer, or in situ carcinoma of breast, oral cavity, skin, or cervix)
unless disease free for a minimum of one year
• Metastases located within 3 cm of previously irradiated (< 3Gy per fraction)
structures if if not a candidate for surgery for these lesions and if:
• Spinal cord previously irradiated to > 40 Gy
• Brachial plexus previously irradiated to > 50 Gy
• Small intestine, large intestine, or stomach previously irradiated to > 45 Gy
• Brainstem previously irradiated to > 50 Gy
• Lung previously irradiated with prior V20 Gy > 35%
• Patients receiving targeted therapy (non-cytotoxic systemic therapy) for NSCLC in the
first-line setting
• If a patient has progressed in previous areas of primary disease that received
definitive doses of radiation, these patients would require re-irradiation in previous
high dose anatomic areas and are not eligible for this study
• Patients with malignant pleural effusions that do not resolve after first-line
systemic therapy; patients with pleural effusions that have become too small for
thoracentesis at the time of registration would be permitted on study, indicating a
significant response to first-line chemotherapy
• Patients with more than 3 discrete locations of extra-cranial metastatic disease after
first-line systemic therapy requiring more than 3 SBRT plans to cover these distinct
metastatic disease entities
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of
registration
• Patients who are pregnant or nursing
• Participation in any investigational drug study (excluding non-oncology and/or symptom
management studies) within 4 weeks prior to registration
• Known human immunodeficiency virus (HIV) positive with cluster of differentiation 4
(CD4) count < 200 cells/microliter; note that patients who are HIV positive are
eligible, provided they are under treatment with highly active antiretroviral therapy
(HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to
registration; note also that HIV testing is not required for eligibility for this
protocol
• Patients who received prior non-induction pembrolizumab, patients on chronic steroids
or who have active autoimmune disease for which they received systemic treatment in
the previous 2 years with corticosteroids, disease modifying agents, or
immunosuppressive drugs. Replacement therapy (thyroxine, insulin or physiological
corticosteroid replacement for adrenal or pituitary insufficiency) is allowed.
Patients with active interstitial lung disease or who have a history of pneumonitis
for which they had received glucocorticoids are not eligible
• Prior bevacizumab therapy
Study to Assess Safety and Preliminary Activity of Eribulin Mesylate in Pediatric Participants With Relapsed/Refractory Rhabdomyosarcoma (RMS), Non-rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS) and Ewing Sarcoma (EWS)
This study will be conducted as an assessment of the safety and preliminary activity of
eribulin mesylate in pediatric participants with relapsed/refractory rhabdomyosarcoma (RMS),
non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), or Ewing sarcoma (EWS) to determine whether
each cohort warrants further investigation.
• Age: ≥12 months to <18 years old at the time of informed consent
• Diagnosis: Histologically confirmed rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft
tissue sarcoma (NRSTS) (Grade 2 or 3), or Ewing sarcoma (EWS) which is relapsed or
refractory (failed front line therapy)
• The presence of measurable disease meeting the following criteria:
• At least 1 lesion of ≥1.0 centimeter (cm) in the longest diameter for a non-lymph
node or ≥1.5 cm in the short-axis diameter for a lymph node that is serially
measurable according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
using computerized tomography/magnetic resonance imaging (CT/MRI).
• Lesions that have had radiotherapy must show subsequent radiographic evidence of
increase in size by at least 20% to be deemed a target lesion.
• Therapeutic options: Participant's current disease state must be one for which there
is no known curative therapy or therapy proven to prolong survival with an acceptable
quality of life.
• Performance level: Performance score ≥50%. Karnofsky (for participants >16 years of
age) or Lansky (for participants ≤16 years of age). Participants who are unable to
walk because of paralysis and/or previous surgeries, but who are in a wheelchair, will
be considered ambulatory for the purpose of assessing performance score.
• Participants must have fully recovered from the acute toxic effects of all prior
anticancer therapy and must meet the following minimum duration from prior anticancer
directed therapy prior to study drug administration. If, after the required time
frame, the numerical eligibility criteria are met, eg, blood count criteria, the
participant is considered to have recovered adequately:
• Cytotoxic chemotherapy or other chemotherapy known to be myelosuppressive: ≥21
days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days
if prior nitrosourea).
• Anticancer agents not known to be myelosuppressive (eg, not associated with
reduced platelet or absolute neutrophil count [ANC] counts): ≥7 days after the
last dose of agent.
• Monoclonal antibodies ≥ 3 half-lives must have elapsed from infusion of last dose
of antibody (including checkpoint inhibitors), and toxicity related to prior
antibody therapy must be recovered to Grade ≤1.
• Hematopoietic growth factors: ≥14 days after the last dose of a long-acting
growth factor (eg, Neulasta) or 7 days for a short-acting growth factor. For
agents that have known adverse events (AEs) occurring beyond 7 days after
administration, this period must be extended beyond the time during which AEs are
known to occur. The duration of this interval must be discussed with the sponsor.
• Interleukins, interferons, and cytokines (other than hematopoietic growth
factors): ≥21 days after the completion of interleukins, interferons, or
cytokines (other than hematopoietic growth factors)
• Stem cell infusions (with or without total body irradiation [TBI]): ≥84 days
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell
infusion including donor lymphocyte infusion or boost infusion: ≥84 days after
infusion and no evidence of graft versus host disease (GVHD)
• Autologous stem cell infusion including boost infusion: ≥42 days
• Cellular therapy: ≥42 days after the completion of any type of cellular therapy
(eg, modified T-cells, natural killer cells, dendritic cells, etc)
• Radiation therapy (XRT)/External Beam Irradiation including Protons: ≥14 days
after local XRT; ≥150 days after TBI, craniospinal XRT or if radiation to ≥50% of
the pelvis; ≥42 days if other substantial BM radiation
• Radiopharmaceutical therapy (eg, radiolabeled antibody,
131I-metaiodobenzylguanidine): ≥42 days after systemically administered
radiopharmaceutical therapy.
• Adequate bone marrow function, defined as:
• ANC ≥1.0 × 10^9/Liter (L)
• Platelet count ≥100 × 10^9/L (transfusion independent, defined as not receiving
platelet transfusions within a 7-day period prior to study drug administration)
• Hemoglobin at least 8.0 grams per deciliter (g/dL) at Baseline (blood
transfusions are allowed during the screening period to correct hemoglobin values
less than 8.0 g/dL) Note: As blood transfusions are permitted to meet the
hemoglobin criteria, participants requiring transfusion must not be known to be
refractory to red blood cell or platelet transfusions.
• Adequate renal function, defined as:
• A serum creatinine based on age/gender, derived from the Schwartz formula for
estimating glomerular filtration rate (GFR)
• Or creatinine clearance or GFR ≥50 milliliters per minute (mL/min)/1.73 meters
squared (m^2) based on a 12 or 24 hour urine creatinine collection
• Adequate liver function, defined as:
• Bilirubin (sum of conjugated + unconjugated) ≤1.5 × upper limit of normal (ULN)
for age
• Alanine aminotransferase (ALT) ≤110 units per Liter (U/L). For the purpose of
this study, the ULN for ALT is 45 U/L
• Serum albumin ≥2 g/dL
• Informed consent: All participants and/or their parents or legally authorized
representatives must sign a written informed consent. Assent, when appropriate, will
be obtained according to institutional guidelines. Participants must be willing to
comply with all aspects of the protocol.
Exclusion Criteria:
• Pregnancy, breastfeeding, contraception: Females who are breastfeeding or pregnant at
Screening or Baseline (as documented by a positive beta-human chorionic [β-hCG] or
human chorionic gonadotropin [hCG] test with a minimum sensitivity of 25 International
Units per Liter [IU/L] or equivalent units of β-hCG [or hCG]). A separate baseline
assessment is required if a negative screening pregnancy test was obtained more than
72 hours before the first dose of study drug.
• Females of childbearing potential (all post pubertal females will be considered
to be of childbearing potential unless they have early menopause [amenorrheic for
at least 12 consecutive months, in the appropriate age group, and without other
known or suspected cause] or have been sterilized surgically [ie, bilateral tubal
ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at
least 1 month before dosing]) who:
• Do not agree to use a highly effective method of contraception for the entire
study period and for 6 months after study drug discontinuation, ie:
• Total abstinence (if it is their preferred and usual lifestyle);
• An intrauterine device (IUD) or intrauterine system (IUS);
• A contraceptive implant;
• An oral contraceptive (must be on a stable dose of the same oral hormonal
contraceptive product for at least 4 weeks before dosing with study drug and for
the duration of the study and for 6 months after study drug discontinuation); or
• Do not have a vasectomized partner with confirmed azoospermia.
For sites outside of the European Union (EU), it is permissible that if a highly effective
method of contraception is not appropriate or acceptable to the participant, or the
participant has commenced/adjusted/changed oral hormonal contraceptive product/dose within
4 weeks prior to study drug administration, then the participant must agree to use a
medically acceptable method of contraception, ie, double barrier methods of contraception
such as condoms plus diaphragm or cervical/vault cap with spermicide.
• Males who have not had a successful vasectomy (confirmed azoospermia) or if they and
their female partners do not meet the criteria above (ie, not of childbearing
potential or practicing highly effective contraception throughout the study period or
for 3 months after study drug discontinuation). No sperm donation is allowed during
the study period or for 3 months after study drug discontinuation.
•Concomitant medications:
• Corticosteroids: Participants receiving corticosteroids who have not been on a stable
or decreasing dose of corticosteroid for at least 7 days prior to study drug
administration (except when indicated for Central Nervous System [CNS] metastases,
then participants must not have received corticosteroids for at least 28 days)
• Anticancer Agents: participants who are currently receiving other anticancer agents
• Anti-GVHD agents Post-transplant: Participants who are receiving cyclosporine,
tacrolimus or other agents to prevent graft-versus-host disease post bone marrow
transplant
• Strong CYP3A4 inducers/inhibitors
• Received prior therapy with eribulin mesylate
• Any other malignancy that required treatment (except for non-melanoma skin
cancer, or histologically confirmed complete excision of carcinoma in situ),
within 2 years prior to study drug administration
• Has hypersensitivity to eribulin or any of the excipients
• Has a prior history of viral hepatitis (B or C) as demonstrated by positive
serology (presence of antigens) or have an uncontrolled infection requiring
treatment. Participants with a known prior history of hepatitis B or C may be
eligible pending agreement with the sponsor.
• Has > Grade 1 peripheral sensory neuropathy or > Grade 1 peripheral motor
neuropathy graded according to the Modified ("Balis") Pediatric Scale of
Peripheral Neuropathies
• Has cardiac pathology: Participants with known congestive heart failure,
symptomatic or left ventricular (LV) ejection fraction <50% or shortening
fraction <27%
• Participants with congenital long QT syndrome, bradyarrhythmias, or QTc >480 msec
on at least 2 separate electrocardiograms (ECGs).
• Has CNS Disease: Participants with brain or subdural metastases are not eligible
unless the metastases are asymptomatic and do not require treatment or have been
adequately treated by local therapy (eg, surgery or radiotherapy) and have
discontinued the use of corticosteroids for this indication for at least 4 weeks
prior to study drug administration. Confirmation of radiographic stability must
be done by comparing the brain scan (CT or MRI) performed during the Screening
Period, using the same imaging modality, to a brain scan performed earlier (and
following local therapy where applicable). Participants must be clinically
stable. It is not the intention of this protocol to treat participants with
active brain metastases.
Note: CNS imaging is required to confirm eligibility for participants with a known history
of CNS disease.
• Have had or are planning to have the following invasive procedures:
• Major surgical procedure or significant traumatic injury within 28 days prior to
study drug administration
• Laparoscopic procedure or open biopsy within 7 days prior to study drug
administration
• Central line placement or subcutaneous port placement is not considered major
surgery but must be placed at least 2 days prior to study drug administration
• Core biopsy, including bone marrow biopsy, within 2 days prior to study drug
administration
• Fine needle aspirate within 3 days prior to study drug administration
• Has any serious concomitant illness that in the opinion of the investigator(s) could
affect the participant's safety or interfere with the study assessments
• Participants with known human immunodeficiency virus (HIV); due to lack of available
safety data for eribulin therapy in HIV-infected participants
Study of Biomarker-Based Treatment of Acute Myeloid Leukemia
This screening and multi-sub-study Phase 1b/2 trial will establish a method for genomic
screening followed by assigning and accruing simultaneously to a multi-study "Master Protocol
(BAML-16-001-M1)." The specific subtype of acute myeloid leukemia will determine which
sub-study, within this protocol, a participant will be assigned to evaluate investigational
therapies or combinations with the ultimate goal of advancing new targeted therapies for
approval. The study also includes a marker negative sub-study which will include all screened
patients not eligible for any of the biomarker-driven sub-studies.
• Adults, age 60 years or older at the time of diagnosis
• Subjects or their legal representative must be able to understand and provide written
informed consent
• Cohort Inclusion Criteria •Group A: Subjects must have previously untreated acute
myeloid leukemia (AML) according to the WHO classification with no prior treatment
other than hydroxyurea. Prior therapy for myelodysplastic syndrome (MDS),
myeloproliferative syndromes (MPD), or aplastic anemia is permitted but not with
hypomethylating agents.
• Cohort Inclusion Criteria •Group B: Subjects must have relapsed or refractory AML
according to the WHO classification. For study purposes, refractory AML is defined as
failure to ever achieve CR or recurrence of AML within 6 months of achieving CR;
relapsed AML is defined as all others with disease after prior remission. (Group B is
not currently recruiting. Expected to begin recruiting in 3rd quarter 2017.)
Exclusion Criteria:
• Isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement with
AML to enter the study)
• Acute promyelocytic leukemia
• Symptomatic central nervous system (CNS) involvement by AML
• Signs of leukostasis requiring urgent therapy
• Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis
• Patients with psychological, familial, social, or geographic factors that otherwise
preclude them from giving informed consent, following the protocol, or potentially
hamper compliance with study treatment and follow-up
• Any other significant medical condition, including psychiatric illness or laboratory
abnormality, that would preclude the patient participating in the trial or would
confound the interpretation of the results of the trial
A Study of Pembrolizumab and Bavituximab in Patients With Advanced Hepatocellular Carcinoma
This is a non-randomized, open-label, multi-site phase II therapeutic trial of pembrolizumab
and bavituximab in patients with locally advanced HCC. Locally advanced or metastatic HCC is
defined as disease that is not amenable to surgical and/or locoregional therapies. Subjects
must not have received prior systemic therapy for advanced HCC in keeping with the first-line
setting of this study.
• Patient must have a histologically confirmed diagnosis hepatocellular carcinoma; known
fibrolamellar HCC, sarcomatoid HCC or mixed cholangiocarcinoma and HCC will be
excluded
• Locally advanced or metastatic disease
• Patients with locally advanced or metastatic disease must have disease deemed not
amenable to surgical and/or locoregional therapies or patients who have progressed
following surgical and/or locoregional therapies.
• Measurable disease, as defined as lesions that can accurately be measured in at least
one dimension according to RECIST version 1.1 at least 1 cm with contrast enhanced
dynamic imaging (magnetic resonance imaging or computed tomography).
• Child-Pugh Score A
• Age ≥ 18 years
• ECOG Performance score of 0-1
• Life expectancy greater than 6 months
• Following baseline laboratory values:
1. Total bilirubin ≤ 2.0 mg/ml
2. INR ≤ 1.7
3. Hgb ≥ 8.5 g/dl
4. AST, ALT ≤5 times ULN
5. Platelet count ≥ 50,000/mm3
6. Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min
7. Albumin ≥ 2.5 g/dl
8. Absolute neutrophil ≥ 1,500 cells/mm3
• Male and female subjects of child bearing potential must agree to use an adequate
method of contraception for the course of the study through 120 days after the last
dose of study medication
• Women of childbearing potential must have a negative pregnancy test within 72 hours
prior to receiving the first dose of study medication
• Subjects are eligible to enroll if they have non-viral-HCC, or if they have HBV-HCC,
or HCV-HCC defined as follows:
HBV-HCC: Controlled (treated) hepatitis B subjects will be allowed if they meet the
following criteria:
Antiviral therapy for HBV must be given for at least 12 weeks and HBV viral load must be
less than 100 IU/mL prior to first dose of study drug. Subjects on active HBV therapy with
viral loads under 100 IU/ml should stay on the same therapy throughout study treatment.
Subjects who are anti-HBc (+), negative for HBsAg, negative for anti-HBs, and have an HBV
viral load under 100 IU/mL do not require HBV anti-viral prophylaxis.
HCV-HCC: active or resolved HCV infection as evidenced by detectable HCV RNA or antibody.
Patients who have failed HCV therapy as evidenced by detectable HCV RNA will be eligible.
Subjects with chronic infection by HCV who are treated (successfully or treatment failure)
or untreated are allowed on study. In addition, subjects with successful HCV treatment are
allowed as long as there are ≥4 weeks between completion of HCV therapy and start of study
drug.
Successful HCV treatment definition: SVR12.
•Prior therapy is allowed provided the following are met: at least 4 weeks since prior
locoregional therapy including surgical resection, chemoembolization, radiotherapy, or
ablation. Provided target lesion has increased in size by 25% or more or the target lesion
was not treated with locoregional therapy. Patients treated with palliative radiotherapy
for symptoms will be eligible 1 week after treatment as long as the target lesion is not
the treated lesion.
Exclusion Criteria:
• Prior liver transplant;
• Patient who has received previous systemic therapy for HCC;
• Clinically significant, uncontrolled heart disease and/or recent events including any
of the following:
• History of acute coronary syndromes (including myocardial infarction, unstable angina,
coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic
pericarditis within 12 months prior to screening;
• History of documented congestive heart failure (New York Heart Association functional
classification III-IV);
• Documented cardiomyopathy;
• Patient has a left ventricular ejection fraction <40% as determined by MUGA scan or
ECHO (MUGA and ECHO are not required prior to enrollment);
• Known human immunodeficiency virus (HIV) positive (testing not required);
• History of thromboembolic events (including both pulmonary embolism and deep venous
thrombus but not including tumor thrombus) within the last 6 months;
• Hypersensitivity to IV contrast; not suitable for pre-medication;
• Active or fungal infections requiring systemic treatment within 7 days prior to
screening;
• Known history of, or any evidence of, interstitial lung disease or active
non-infectious pneumonitis;
• Evidence of poorly controlled hypertension which is defined as systolic blood pressure
>150 mmHg or diastolic pressure >90 mmHg despite optimal medical management;
• Pre-existing thyroid abnormality with thyroid function that cannot be maintained in
the normal range with medication;
• Active, known, or suspected autoimmune disease with the following exceptions i)
Subjects with vitiligo, type I diabetes mellitus, resolved childhood asthma or atopy
are permitted to enroll; ii) Subjects with suspected autoimmune thyroid disorders may
be enrolled if they are currently euthyroid or with residual hypothyroidism requiring
only hormone replacement.
iii) Subjects with psoriasis requiring systemic therapy must be excluded from enrollment
• Patient has any other concurrent severe and/or uncontrolled medical condition that
would, in the investigator's judgment, cause unacceptable safety risks, contraindicate
patient participation in the study or compromise compliance with the protocol (e.g.
chronic pancreatitis, active untreated or uncontrolled fungal, bacterial, or viral
infections, etc.);
• Patient has any other concurrent severe and/or uncontrolled medical condition that
would, in the investigator's judgment, cause unacceptable safety risks, contraindicate
patient participation in the study or compromise compliance with the protocol (e.g.
chronic pancreatitis, active untreated or uncontrolled fungal, bacterial, or viral
infections, etc.);
• Known history of active bacillus tuberculosis;
• Subjects with a condition requiring systemic treatment with either corticosteroids (>
10 mg/day prednisone equivalent) or other immunosuppressive medications within 14 days
of study administration. Inhaled or topical steroids and adrenal replacement doses >10
mg/day prednisone equivalents are permitted in the absence of autoimmune disease;
• Patient who has received radiotherapy ≤ 4 weeks prior to study entry. Palliative
radiotherapy for symptomatic control is acceptable (if completed at least 2 weeks
prior to study drug administration and no additional radiotherapy for the same lesion
is planned);
• Patient has had major surgery within 14 days prior to starting study drug or has not
recovered from major side effects (tumor biopsy is not considered as major surgery);
• Clinically apparent ascites on physical examination, ascites present on imaging
studies is allowed;
• Patient has a known hypersensitivity to any of the excipients of bavituximab or
pembrolizumab or monoclonal antibody;
• Active gastrointestinal bleeding within previous 2 months;
• History of any condition requiring anti-platelet therapy (aspirin >300 mg/day,
clopidogrel >75 mg/day);
• Prisoners or subjects who are involuntarily incarcerated;
• Symptomatic or clinically active brain metastases;
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after contraception and until the termination of gestation, confirmed by a
positive hCG laboratory test;
• Prior immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2 agents;
• Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection
(anti-HCV Ab(+) and detectable HCV RNA) at study entry.
1. Subjects with a diagnosis of iobenguane avid, relapsed, high-risk neuroblastoma based
on revised INRC criteria who have completed at least one cycle of induction and
consolidation therapy with an INRC criterion of partial response or better, and then
showed new progressive disease (revised INRC criteria progressive disease) as
described in Park, et al. (2017).This may include one or more of the following drugs:
cyclophosphamide or ifosfamide, cisplatin or carboplatin, vincristine, doxorubicin
(adriamycin), etoposide, topotecan, and/or busulfan and melphalan (sometimes used
during stem cell transplant) and/or immunotherapy. (If a subject is symptomatic and
for logistical reasons cannot be treated immediately with 131I-MIBG, 1 to 2 cycles of
"bridging chemotherapy" or immunotherapy will be permitted. If "bridging chemotherapy"
or immunotherapy is applied, approximately 4 weeks will be required for reassessment
of the baseline including tumor assessment.
2. Must be therapeutic 131I-MIBG naive.
3. All soft tissue lesions identified on CT/MRI scans must be iobenguane-avid lesions on
an iobenguane (123I) scan or any non iobenguane avid lesions biopsy proven to be
non-tumor lesions.
4. Adequate cryopreserved autologous peripheral blood stem cells or bone marrow (at least
2 aliquots of 2.0 × 10exp6 CD34/kg at the time of study enrollment).
5. If a man, must agree to use an adequate contraception method as deemed appropriate by
the Investigator (e.g., vasectomy, condoms) or partner using effective contraception
and to not donate sperm during the study and for 90 days after receiving the last dose
of study drug.
6. If a woman of childbearing potential, have a negative serum pregnancy test result
prior to each dosing and, if sexually active, be practicing an effective method of
birth control [e.g., intrauterine device, double-barrier method (i.e., diaphragm, or a
cervical cap) with intravaginal spermicidal foam, cream or gel], or male partner
sterilization throughout the study.
7. Age at study entry ≥1 year.
8. Previous platelet transfusions are permitted, as long as the subject has a platelet
count ≥50,000/μL without transfusion support for at least 1 week.
9. Subjects must have a minimum pulse oximetry measurement of at least 94% at baseline.
10. An absolute neutrophil count ≥750/μL without growth factor for 5 days.
11. Liver function parameter results: total bilirubin ≤1.5 × upper limit of normal for
age, and serum glutamic-pyruvic transaminase (alanine aminotransferase) [SGPT (ALT)]
and serum glutamic-oxaloacetic transaminase (aspartate aminotransferase) [SGOT (AST)]
<3 × upper limit of normal (note that for ALT, the upper limit of normal for all sites
is defined as 45 U/L).
12. Normal thyroid function as measured by T4 and TSH or have abnormal results that are
not considered clinically important by the Investigator or may be receiving
levothyroxine.
13. Cardiac Function: Ejection fraction (≥55%) documented by echocardiogram within 1 month
prior to Visit 1 (baseline).
14. Karnofsky Performance Status (for subjects >16 years of age) or the Lansky Performance
Status Performance Status (for subjects 1 to 16 years of age) ≥50%.
15. Full recovery from the toxic effects of any prior therapy.
Exclusion Criteria:
1. Evidence of non-avid iobenguane lesions on iobenguane (123I) scan including soft
tissue disease on CT/MRI that is not iobenguane-avid.
2. Subjects with primary refractory disease.
3. Subjects within 5 half-lives after any antibody-based immunotherapy, or have not
recovered from effects of any biologic therapy.
4. Subjects that are refractory to the prior treatment regimen.
5. Subjects <12 weeks after myeloablative therapy with autologous stem cell transplant.
6. Subjects who have had an allogeneic stem cell treatment less than 4 months from Visit
1 are excluded. Those who have received allogeneic stem cell treatment more than 4
months from Visit 1 must have recovered and have no active graft versus host disease
(GVHD) to be eligible.
7. History of local radiation therapy within the last 3 months.
8. History of total body irradiation.
9. Subjects do not have adequate renal function defined as adjusted serum creatinine ≥1.5
× upper limit of normal for sex and age.
10. Subjects who are on hemodialysis.
11. Pregnancy or breastfeeding.
12. Significant active infections including active hepatitis B, or hepatitis C infection,
or known infection with human immunodeficiency virus (HIV) (testing for HIV is not
required prior to study entry).
13. Clinically important cardiac, pulmonary, and hepatic impairment.
Drug: 131I-MIBG
Neuroblastoma, Neoplasms, Neuroectodermal Tumors, Brain and Nervous System
A Study of NKTR-262 in Combination With Bempegaldesleukin (NKTR-214) and With Bempegaldesleukin Plus Nivolumab in Patients With Locally Advanced or Metastatic Solid Tumor Malignancies (REVEAL)
Patients will receive intra-tumoral (IT) NKTR-262 in 3-week treatment cycles. During the
Phase 1 dose escalation portion of the trial, NKTR-262 will be combined with systemic
administration of bempegaldesleukin. After determination of the recommended Phase 2 dose
(RP2D) of NKTR-262, between 6 and 18 patients may be enrolled at the RP2D to further
characterize the safety and tolerability profile of the combination of NKTR 262 plus
bempegaldesleukin (doublet) or NKTR 262 plus bempegaldesleukin in combination with nivolumab
(triplet) in Cohorts A and B, respectively. In the Phase 2 dose expansion portion, patients
will be treated with doublet or triplet in the relapsed/refractory setting and earlier lines
of therapy.
• Histologically confirmed diagnosis of a locally advanced (not amenable to curative
therapy such as surgical resection) metastatic cancer of the following histologies:
melanoma (MEL), Merkel cell carcinoma (MCC), triple-negative breast cancer (TNBC),
renal cell carcinoma (RCC), colorectal cancer, head and neck squamous cell carcinoma
(HNSCC), or sarcoma.
• Life expectancy > 12 weeks as determined by the Investigator.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Measurable disease per RECIST 1.1.
• Patients enrolled in Cohorts 1-10, Cohort A, Cohort B and Phase 2 Doublet must be
refractory to all therapies known to confer clinical benefit to their disease.
• Fresh tumor tissue available for cellular characterization and programmed cell death
protein 1 (PD-L1) status.
• Injected lesions (up to two) must be between 20 mm and 90 mm in diameter for IT
injection; lesions must be accessible for baseline and on-treatment biopsies. Any
liver lesion targeted for injection must not exceed 50 mm at the time of injection.
• Demonstrated adequate organ function within 14 days of Cycle 1 Day 1 (C1D1).
Key
Exclusion Criteria:
• Use of an investigational agent or an investigational device within 21 days before
administration of first dose of study drug(s).
• Patients treated with prior interleukin-2 (IL-2).
• Patients who have been previously treated with a toll-like receptor (TLR) agonist
(excluding topical agents) and patients who have received experimental cancer
vaccines.
• Patients who have received systemic interferon (IFN)α within the previous 6 months
prior to enrollment to the study.
• Other active malignancy, except non-melanomic skin cancer
• Evidence of clinically significant interstitial lung disease or active, noninfectious
pneumonitis.
• Prior surgery or radiotherapy within 14 days of initiating study drug(s). Patients
must have recovered from all radiation-related toxicities, not required
corticosteroids and have not had radiation pneumonitis.
• Prolonged Fridericia's corrected QT interval (QTcF) > 450 ms for men and > 470 ms for
women at Screening.
History of unstable or deteriorating cardiac disease within the previous 6 months prior to
screening including but not limited to the following:
• Unstable angina or myocardial infarction.
• Congestive heart failure (NYHA Class III or IV).
• Uncontrolled clinically significant arrhythmias.
• Patients with a history of any retinal disorders (e.g., retinal detachment, diabetic
retinopathy, retinal hemorrhage, macular degeneration).
• Uveal melanoma will be excluded
• Patients with tumor that invade the superior vena cava or other major blood vessels.
Additional general and tumor specific inclusion and exclusion criteria will apply.
Letrozole in Post-Menopausal Patients With Operable Hormone-Sensitive Breast Cancer
A short pre-surgical non-therapeutic trial involving postmenopausal women with newly
diagnosed eR+, HeR2-negative operable breast cancers. After undergoing a core needle biopsy
for tissue acquisition, study participants will take a 7- to 56-day (1-8 weeks) course of
letrozole in accordance with standard of care. They will then undergo definitive surgical
resection of their primary tumor (mastectomy vs lumpectomy) as per standard of care
guidelines.
1. Eligibility waivers are not permitted. Subjects must meet all of the inclusion and
exclusion criteria to be registered to the study. Study treatment may not begin until
a subject is registered.
2. Patients must provide informed written consent
3. ECOG performance status 0-1.
4. Clinical stage operable I, II or III invasive mammary carcinoma, which is ER-positive
by IHC and HER2-negative by Herceptest (0 or 1+) or not amplified by FISH as per
routine clinical testing Patients who have measurable residual tumor at the primary
site Patients who will undergo surgical treatment with either segmental resection or
total mastectomy
5. Measurable tumor i. Measurable disease: a mass that can be reproducibly measured by
physical exam and calipers or ultrasound and is at least 1 cm in size
6. The pathology report from the initial diagnosis has been reviewed by either UTSW or
Parkland Hospital, Department of Pathology and meets eligibility criteria. Available
core biopsies from the time of diagnosis have been requested. These may include the
paraffin block or sections from the paraffin-embedded tumor blocks.
7. Post-menopausal female subjects ≥18 years of age, as defined by any of the following:
• Subjects at least 55 years of age;
• Subjects under 55 years of age and amenorrhoeic for at least 12 months or
follicle-stimulating hormone (FSH) values ≥40 IU/L and estradiol levels ≤40 pg/mL
(140 pmol/L) or in postmenopausal ranges per local or institutional reference
ranges;
• Prior bilateral oophorectomy or prior radiation castration with amenorrhea for at
least 6 months.
• (There is no upper age limit for enrollment to this study)
8. No prior chemotherapy for this primary breast cancer.
9. Patients with a prior history of contralateral breast cancer are eligible if they have
no evidence of recurrence of their initial primary breast cancer.
10. Women may have been taking tamoxifen or raloxifene as a preventive agent prior to
study entry but must have discontinued the drug for at least 21 days prior to study
enrollment.
11. Subjects must have ended hormone replacement therapy (HRT) (e.g., conjugated estrogens
tablets, USP, [Premarin]), at least 7 days prior to receiving the first dose of
randomized therapy.
12. Patients must have adequate hepatic and renal function. All tests must be obtained
less than 4 weeks from study entry. This includes:
1. Creatinine <1.5X upper limits of normal
2. Bilirubin, SGOT, SGPT <1.5X upper limits of normal
13. Able to swallow and retain oral medication
Exclusion Criteria:
1. Patients with locally advanced disease who are candidates for other preoperative
chemotherapy at the time of initial evaluation. This may include patients with locally
advanced disease such as:
• Inflammatory breast cancer (T4d)
• Fixed axillary lymph node metastases (N2)
• Metastasis to ipsilateral internal mammary node (N3)
2. Locally recurrent breast cancer
3. Evidence of distant metastatic disease (i.e. lung, liver, bone, brain, etc.)
4. Serious medical illness that in the judgment of the treating physician places the
patient at high risk of operative mortality.
5. Severe uncontrolled malabsorption condition or disease (i.e. grade II/III diarrhea,
severe malnutrition, short gut syndrome)
6. Dementia, altered mental status, or any psychiatric condition that would prohibit the
understanding or rendering of informed consent.
7. Use of an investigational drug within 30 days or 5 half-lives, whichever is longer,
preceding the first dose of letrozole.
A Study of Abiraterone Acetate Plus Prednisone With or Without Abemaciclib (LY2835219) in Participants With Prostate Cancer (CYCLONE 2)
This study is being done to see how safe and effective abemaciclib is when given together
with abiraterone acetate plus prednisone in participants with metastatic castration resistant
prostate cancer. Prednisolone may be used instead of prednisone per local regulation.
• Histologically confirmed adenocarcinoma of the prostate.
• Metastatic prostate cancer documented by positive bone scan and/or measurable soft
tissue metastatic lesions by CT or magnetic resonance imaging (MRI).
• Progressive disease at study entry demonstrated during continuous androgen-deprivation
therapy (ADT)/post orchiectomy defined as one or more of the following:
• PSA progression
• Radiographic progression per Response Evaluation Criteria in Solid Tumors
(RECIST)1.1 for soft tissue and/or per Prostate Cancer Working Group 3 (PCWG3)
for bone, with or without PSA progression
• Be able and willing to undergo mandatory tumor biopsy of at least one metastatic site.
• Have adequate organ function.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
Exclusion Criteria:
• Prior therapy with cytochrome P450 (CYP)17 inhibitors.
• Prior treatment with abemaciclib or any cyclin-dependent kinase (CDK) 4 & 6
inhibitors.
• Prior cytotoxic chemotherapy for metastatic castration resistant prostate cancer
(participants treated with docetaxel in the metastatic hormone-sensitive prostate
cancer [mHSPC] are eligible), prior radiopharmaceuticals for prostate cancer, or prior
enzalutamide, apalutamide, darolutamide or sipuleucel-T. Participants who had prior
radiation or surgery to all target lesions.
• Currently enrolled in a clinical study involving an investigational product.
• Gastrointestinal disorder affecting the absorption or ability to swallow large pills.
• Clinically significant heart disease, active or chronic liver disease, moderate/severe
hepatic impairment (Child-Pugh Class B and C).
Basket Study of Neratinib in Participants With Solid Tumors Harboring Somatic HER2 or EGFR Exon 18 Mutations (SUMMIT)
This is an open-label, multicenter, multinational, Phase 2 basket study exploring the
efficacy and safety of neratinib as monotherapy or in combination with other therapies in
participants with HER (EGFR, HER2) mutation-positive solid tumors.
• Provide written informed consent
• Histologically confirmed cancers for which no curative therapy exists
• Documented HER2 or EGFR exon 18 mutation
• Participants must agree and commit to use appropriate methods of contraception as
outlined in the protocol
• At least one measurable lesion, defined by RECIST v1.1
Exclusion Criteria:
• Participants harboring ineligible somatic HER2 mutations
• Prior treatment with any HER2-directed tyrosine kinase inhibitor (e.g., lapatinib,
afatinib, dacomitinib, neratinib) is excluded with the following exception: patients
with EGFR exon 18 mutated NSCLC who may have received afatinib, osimertinib, or other
pan HER or EGFR TKIs remain eligible
• Participants who are receiving any other anticancer agents
• Symptomatic or unstable brain metastases
• Women who are pregnant or breast-feeding
There are additional inclusion and exclusion criteria. The study center will determine if
criteria for participation are met.
A Study of Nivolumab in Participants With Hepatocellular Carcinoma Who Are at High Risk of Recurrence After Curative Hepatic Resection or Ablation (CheckMate 9DX)
This study will investigate if nivolumab will improve recurrence-free survival (RFS) compared
to placebo in participants with HCC who have undergone complete resection or have achieved a
complete response after local ablation, and who are at high risk of recurrence
For more information regarding Bristol Myers Squibb Clinical Trial participation, please
visit www.BMSStudyConnect.com
Inclusion Criteria:
• Participants with a first diagnosis of HCC who have undergone a curative resection or
ablation
• Participants are eligible to enroll if they have non-viral related-HCC, or if they
have HBV-HCC, or HCV-HCC
• Child-Pugh Score 5 or 6
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
Exclusion Criteria:
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
• Any evidence of tumor metastasis or co-existing malignant disease
• Participants previously receiving any prior therapy for HCC, including loco-regional
therapies
• Participants who have undergone a liver transplant or those who are in the waiting
list for liver transplantation
• Participants who have received a live/attenuated vaccine within 30 days of
randomization (eg, varicella, zoster, yellow fever, rotavirus, oral polio and measles,
mumps, rubella [MMR]).
Other protocol defined inclusion/exclusion criteria could apply
Phase 1/2 Study of LOXO-292 in Patients With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001)
This is a Phase 1/2, open-label, first-in-human study designed to evaluate the safety,
tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of selpercatinib
(also known as LOXO-292) administered orally to patients with advanced solid tumors,
including RET-fusion-positive solid tumors, medullary thyroid cancer (MTC) and other tumors
with RET activation.
For Phase 1
• Patients with a locally advanced or metastatic solid tumor who:
• have progressed on or are intolerant to standard therapy, or
• no standard therapy exists, or in the opinion of the Investigator, are not
candidates for or would be unlikely to tolerate or derive significant clinical
benefit from standard therapy, or
• decline standard therapy
• Prior MKIs with anti-RET activity are allowed.
• A RET gene alteration is not required initially. Once adequate PK exposure is
achieved, evidence of RET gene alteration in tumor and/or blood is required as
identified through molecular assays, as performed for clinical evaluation.
• Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as
appropriate to tumor type.
• Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 or Lansky Performance
Score (LPS) ≥ 40% (age < 16 years) with no sudden deterioration 2 weeks prior to the
first dose of study treatment.
• Adequate hematologic, hepatic and renal function.
• Life expectancy of at least 3 months.
For Phase 2
As for phase 1 with the following modifications:
•For Cohort 1 (up to 250 patients): Subjects must have received prior standard therapy
appropriate for their tumor type and stage of disease, or in the opinion of the
Investigator, would be unlikely to tolerate or derive clinical benefit from appropriate
standard of care therapy.
• Cohorts 1 and 2: enrollment will be restricted to patients with evidence of a RET gene
alteration in tumor.
• Cohorts 1 and 2: at least one measurable lesion as defined by RECIST 1.1 or RANO, as
appropriate to tumor type and not previously irradiated.
• Cohorts 3 and 4: Enrollment closed.
• Cohort 5: (up to 200 patients):
• Cohorts 1 and 2 without measurable disease;
• MTC syndrome spectrum cancers (e.g., MTC, pheochromocytoma), cancers with
neuroendocrine features/differentiation, or poorly differentiated thyroid cancers
with other RET alteration/activation may be allowed with prior Sponsor approval;
• cfDNA positive for a RET gene alteration not known to be present in a tumor
sample.
• Cohort 6 (up to 50 patients):
• Patients who otherwise are eligible for Cohorts 1, 2 or 5 who discontinued
another RET inhibitor due to intolerance may be eligible with prior Sponsor
approval.
Key Exclusion Criteria (Phase 1 and Phase 2):
• Phase 2 Cohorts 1 and 2: an additional known oncogenic driver.
• Cohorts 3 and 4: Enrollment closed.
• Cohorts 1, 2 and 5: prior treatment with a selective RET inhibitor
Notes:
Patients otherwise eligible for Cohorts 1, 2, and 5 who discontinued another selective RET
inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval.
•Investigational agent or anticancer therapy (including chemotherapy, biologic therapy,
immunotherapy, anticancer Chinese medicine or other anticancer herbal remedy) within 5
half-lives or 2 weeks (whichever is shorter) prior to planned start of LOXO-292
(selpercatinib). In addition, no concurrent investigational anti-cancer therapy is
permitted.
Note:
Potential exception for this exclusion criterion will require a valid scientific
justification and approval from the Sponsor.
• Major surgery (excluding placement of vascular access) within 4 weeks prior to planned
start of LOXO-292 (selpercatinib).
• Radiotherapy with a limited field of radiation for palliation within 1 week of planned
start of LOXO-292 (selpercatinib), with the exception of patients receiving radiation
to more than 30% of the bone marrow or with a wide field of radiation, which must be
completed at least 4 weeks prior to the first dose of study treatment.
• Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of
starting study treatment with the exception of alopecia and Grade 2, prior
platinum-therapy related neuropathy.
• Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated
spinal cord compression. Patients are eligible if neurological symptoms and CNS
imaging are stable and steroid dose is stable for 14 days prior to the first dose of
LOXO-292 (selpercatinib) and no CNS surgery or radiation has been performed for 28
days, 14 days if stereotactic radiosurgery [SRS].
• Clinically significant active cardiovascular disease or history of myocardial
infarction within 6 months prior to planned start of LOXO-292 (selpercatinib) or
prolongation of the QT interval corrected (QTcF) > 470 msec.
• Required treatment with certain strong CYP3A4 inhibitors or inducers and certain
prohibited concomitant medications.
Drug: LOXO-292 (selpercatinib)
Lymphoma, Non-Small Cell Lung Cancer, Colon Cancer, Medullary Thyroid Cancer, Any Solid Tumor, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Esophagus, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Stomach, Thyroid, Urinary Bladder, Hodgkins Lymphoma, Small Intestine, Soft Tissue
LOXO-292, KIF5B-RET, M918T, CCDC6-RET, RET-PTC1, NCOA4-RET, RET-PTC, RET-PTC3, RET-PTC4, PRKAR1A-RET, RET-PTC2, GOLGA5-RET, RET-PTC5, ERC1-RET, KTN1-RET, RET-PTC8, HOOK3-RET, PCM1-RET, TRIM24-RET, RET-PTC6, TRIM27-RET, TRIM33-RET, RET-PTC7, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1-RET, BCR-RET, FGRF1OP-RET, RFG8-RET, RET-PTC9, ACBD5-RET, MYH13-RET, CUX1-RET, KIAA1468-RET, FRMD4A-RET, SQSTM1-RET, AFAP1L2-RET, PPFIBP2-RET, EML4-RET, PARD3-RET, G533C, C609F, C609G, C609R, C609S, C609Y, C611F, C611G, C611S, C611Y, C611W, C618F, C618R, C618S, C620F, C620R, C620S, C630R, C630Y, D631Y, C634F, C634G, C634R, C634S, C634W, C634Y, K666E, E768D, L790F, V804L, V804M, A883F, S891A, R912P, CLIP1-RET, Y806C, RET fusion, RET alteration, RET mutation, RET rearrangement, RET translocation, Neoplasms by Site, Neoplasms, Non-Small Cell Lung Cancer, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Cancer of Lung, Cancer of the Lung, Lung Cancer, Neoplasms, Lung, Neoplasms, Pulmonary, Pulmonary Cancer, Pulmonary Neoplasms, Respiratory Tract Neoplasms, Lung Diseases, Respiratory Tract Diseases, Carcinoma, Bronchogenic, Bronchial Neoplasms, Medullary Thyroid Cancer, Papillary Thyroid Cancer, Thyroid Diseases, Thyroid Neoplasms, Cancer of the Thyroid, Cancer of Thyroid, Neoplasms, Thyroid, Thyroid Ademona, Thyroid Cancer, Thyroid Carcinoma, Endocrine System Diseases, Endocrine Gland Neoplasms, Head and Neck Neoplasms, Thoracic Neoplasms, CNS tumor, Primary CNS tumor, Cancer of Colon, Cancer of the Colon, Colon Cancer, Colon Neoplasms, Colonic Cancer, Neoplasms, Colonic, Malignant tumor of Breast, Mammary Cancer, Mammary Carcinoma, Human, Mammary Neoplasm, Human, Neoplasms, Breast, Tumors, Breast, Human Mammary Carcinoma, Malignant Neoplasm of Breast, Breast Carcinoma, Breast Tumors, Cancer of the Breast, Breast Neoplasms, Breast Cancer, RET Inhibitor, MTC, NSCLC, selpercatinib
MEDI9447(Oleclumab) Pancreatic Chemotherapy Combination Study
The objective of this study is to evaluate the safety, tolerability, and antitumor activity
of oleclumab (MEDI9447) in combination with or without durvalumab plus chemotherapy in
subjects with metastatic pancreatic cancer.
1. Age ≥ 18
2. Written and signed informed consent must be obtained
3. ECOG Performance Status 0 or 1
4. Weight ≥ 35 kg
5. Subjects must have histologically or cytologically, confirmed pancreatic
adenocarcinoma:
Cohort A: Subjects with previously untreated metastatic pancreatic adenocarcinoma (1st
line metastatic disease) not previously treated with systemic therapies.
Cohort B: Subjects with metastatic pancreatic adenocarcinoma previously treated with
gemcitabine-based chemotherapy (without exposure to 5-FU, capecitabine, oxaliplatin)
2nd line metastatic disease
6. Subjects must have at least 1 measurable lesion according to RECIST v1.1
7. All subjects must consent to providing archival tumor specimens
Exclusion Criteria:
1. Receipt of any conventional or investigational anticancer therapy within 21 days or
palliative radiotherapy within 14 days prior to the scheduled first dose of study
treatment.
2. Prior receipt of any immune-related therapy
3. Concurrent enrollment in another therapeutic clinical study. Enrollment in
observational studies will be allowed
4. Subjects with a history of venous thrombosis within the past 3 months
5. Subjects with prior history of myocardial infarction, transient ischemic attack, or
stroke in the last 3 months prior to start of treatment
6. Active or prior documented autoimmune or inflammatory disorders within the past 3
years prior to the start of treatment
7. Other invasive malignancy within 2 years.
8. Any history of leptomeningeal disease or cord compression.
9. Current or prior use of immunosuppressive medication within 14 days prior to the first
dose
Nivolumab With or Without Varlilumab in Treating Patients With Relapsed or Refractory Aggressive B-cell Lymphomas
This phase II trial studies how well nivolumab with or without varlilumab works in treating
patients with aggressive B-cell lymphomas that have come back (recurrent) or do not respond
to treatment (refractory). Immunotherapy with monoclonal antibodies, such as varlilumab and
nivolumab, may help the body's immune system attack the cancer, and may interfere with the
ability of tumor cells to grow and spread.
• Patients must have a histopathologically confirmed diagnosis of an aggressive B-cell
non-Hodgkin lymphoma that is recurrent or refractory to standard therapy
• For the purpose of this study, aggressive B-cell NHL will be deemed any lymphoma
belonging to one of the following groups according to the 2016 revision of the World
Health Organization (WHO) classification of lymphoid neoplasms
• For the purposes of stratification, diagnoses are grouped into 2 categories:
• Category A
• Burkitt lymphoma
• Burkitt-like lymphoma with 11q aberration
• High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6
rearrangements
• High-grade B-cell lymphoma, not otherwise specified (NOS)
• Category B
• Diffuse large B-cell lymphoma (DLBCL), NOS
• Diffuse large B-cell lymphoma (DLBCL), NOS; germinal center B-cell type
• Diffuse large B-cell lymphoma (DLBCL), NOS; activated B-cell type
• Large B-cell lymphoma with IRF4 rearrangement
• T-cell/histiocyte-rich large B-cell lymphoma
• Primary DLBCL of the central nervous system (CNS)
• Primary cutaneous DLBCL, leg type
• Epstein-Barr virus (EBV)+ DLBCL, NOS
• EBV+ mucocutaneous ulcer
• DLBCL associated with chronic inflammation
• Lymphomatoid granulomatosis
• Primary mediastinal (thymic) large B-cell lymphoma
• Intravascular large B-cell lymphoma
• ALK+ large B-cell lymphoma
• Plasmablastic lymphoma
• Primary effusion lymphoma
• Human herpesvirus (HHV)-8+ DLBCL, NOS
• B-cell lymphoma, unclassifiable, with features intermediate between
DLBCL and classical Hodgkin lymphoma
• Patients must have measurable disease, defined as at least one lesion that is > 15 mm
(1.5 cm) in the longest axis on cross-sectional imaging and measurable in two
perpendicular dimensions per computed tomography (spiral computed tomography [CT]),
positron emission tomography (PET)-CT or magnetic resonance imaging (MRI)
• Patients must have disease that has relapsed after or is refractory to at least 2
lines of standard therapy; the remaining standard treatment options are unlikely to be
effective in the opinion of the treating physician, or patient is felt to be
ineligible for such therapies or the patient refuses such therapies; patients who have
undergone autologous stem cell transplant are eligible as long as they meet all other
criteria
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy of greater than 12 weeks
• White blood cell (WBC) >= 2000/mm^3 (within 14 days of registration)
• Absolute neutrophil count (ANC) >= 1500/mm^3 (within 14 days of registration)
• Platelet count >= 100,000/mm^3 (within 14 days of registration)
• Hemoglobin > 9.0 g/dL (within 14 days of registration)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except patients with Gilbert
Syndrome, who can have total bilirubin < 3.0 mg/dL) (within 14 days of registration)
• Aspartate transaminase (aspartate aminotransferase [AST]) =< 2.5 x ULN (within 14 days
of registration)
• Calculated creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault
formula) (within 14 days of registration)
• Females of child bearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[HCG])
• Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
• Patient has received chemotherapy, targeted agent, or radiotherapy within 4 weeks or
at least 5 half-lives, whichever is longer, prior to registration
• Palliative (limited-field) radiation therapy is permitted, if all of the following
criteria are met:
• Repeat imaging demonstrates no new sites of bone metastases
• The lesion being considered for palliative radiation is not a target lesion
• Patient has received immunotherapy (including monoclonal antibodies) within 4 weeks
prior to registration
• Patients who have not recovered to grade 1 or less from any adverse events due to
agents administered more than 4 weeks earlier (excluding alopecia)
• Patients who are receiving any other investigational agents
• Patients should be excluded if they have had prior treatment with an anti-PD-1,
anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug
specifically targeting T-cell co-stimulation or immune checkpoint pathways
• Patients who have received autologous stem cell transplant (ASCT) =< 12 weeks prior to
the first dose of study drug
• Patients with a prior history of allogeneic stem cell or solid organ transplantation
• Patients with evidence of active disease in the central nervous system (CNS) defined
as either the presence of active lesions on MRI obtained within 4 weeks of
registration or progressive neurological decline
• Patients with primary CNS lymphoma who develop systemic recurrence following
standard therapy may be included as long as no active CNS disease is present at
the time or enrollment; similarly, patients with secondary involvement of the CNS
from a systemic lymphoma may be included as long as the CNS disease has been
optimally treated and they demonstrate no evidence of active CNS disease
• History of allergic reactions attributed to compounds of similar chemical or biologic
composition to CDX-1127 (varlilumab) and/or nivolumab
• History of severe hypersensitivity reaction to any monoclonal antibody
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
• Pregnant women are excluded from this study because CDX-1127 (varlilumab) and
nivolumab are agents with the potential for teratogenic or abortifacient effects;
because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with CDX-1127 (varlilumab) or nivolumab,
breastfeeding should be discontinued if the mother is treated with CDX-1127
(varlilumab) or nivolumab
• Patients with human immunodeficiency virus (HIV) are eligible for the study provided
they meet the other protocol criteria in addition to the following:
• Undetectable HIV load by standard polymerase chain reaction (PCR) clinical assay
within 60 days prior to registration
• Absolute CD4 count of >= 200 mm^3 within 60 days prior to registration
• Willing to maintain adherence to combination antiretroviral therapy
• No history of acquired immunodeficiency syndrome (AIDS) defining condition (other
than lymphoma or CD4 cell count < 200 mm^3)
• Likely to have near normal lifespan if not for the presence of
relapsed/refractory lymphoma
• Patients with evidence of hepatitis B virus (HBV) are eligible provided
there is minimal hepatic injury and the patient has undetectable HBV on
suppressive HBV therapy; patient must be willing to maintain adherence to
HBV therapy
• Patients with previously treated and eradicated hepatitis C virus (HCV) who
have minimal hepatic injury are eligible
• Patients with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including systemic corticosteroids, should be excluded; these include but are not
limited to patients with a history of immune related neurologic disease, multiple
sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia
gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE),
connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's,
ulcerative colitis, hepatitis; and patients with a history of toxic epidermal
necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be
excluded because of the risk of recurrence or exacerbation of disease; patients with
vitiligo, endocrine deficiencies including thyroiditis managed with replacement
hormones including physiologic corticosteroids are eligible; patients with rheumatoid
arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with
topical medication and patients with positive serology, such as antinuclear antibodies
(ANA), anti-thyroid antibodies should be evaluated for the presence of target organ
involvement and potential need for systemic treatment but should otherwise be eligible
• Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,
residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger (precipitating event)
• Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration; inhaled or
topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents
are permitted in the absence of active autoimmune disease; patients are permitted to
use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids
(with minimal systemic absorption); physiologic replacement doses of systemic
corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents; a brief
course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for
treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction
caused by contact allergen) is permitted
• Patients who have had evidence of active or acute diverticulitis, intra-abdominal
abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are
known risk factors for bowel perforation should be evaluated for the potential need
for additional treatment before coming on study
• Patients with other active malignancy =< 3 years prior to registration for which
active treatment is required must be excluded; patients with composite lymphomas that
have a non-B-cell component must be excluded EXCEPTIONS: Non-melanotic skin cancer or
carcinoma-in-situ of the cervix
Biological: Nivolumab, Drug: Varlilumab
Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, Recurrent Diffuse Large B-Cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Plasmablastic Lymphoma, ALK-Positive Large B-Cell Lymphoma, Burkitt-Like Lymphoma With 11q Aberration, Diffuse Large B-Cell Lymphoma Activated B-Cell Type, Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation, Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type, EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, EBV-Positive Mucocutaneous Ulcer, Intravascular Large B-Cell Lymphoma, Large B-Cell Lymphoma With IRF4 Rearrangement, Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System, Primary Effusion Lymphoma, Recurrent B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymphoma, Recurrent B-Cell Non-Hodgkin Lymphoma, Recurrent Burkitt Lymphoma, Recurrent Lymphomatoid Granulomatosis, Refractory B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymphoma, Refractory B-Cell Non-Hodgkin Lymphoma, Refractory Burkitt Lymphoma, High Grade B-Cell Lymphoma, Not Otherwise Specified, Lymphoid Leukemia, HHV8-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, High Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements, Recurrent High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Recurrent High Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements, Recurrent Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type, Recurrent T-Cell/Histiocyte-Rich Large B-Cell Lymphoma, Refractory High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Refractory High Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements, Refractory Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type, Refractory T-Cell/Histiocyte-Rich Large B-Cell Lymphoma, Recurrent Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Refractory Primary Mediastinal (Thymic) Large B-Cell Lymphoma
Atezolizumab Before and/or With Chemoradiotherapy in Immune System Activation in Patients With Node Positive Stage IB2, II, IIIB, or IVA Cervical Cancer
This phase I trial studies how well atezolizumab before and/or with standard of care
chemoradiotherapy works in immune system activation in patients with stage IB2, II, IIIB, or
IVA cervical cancer that has spread to the lymph nodes. Immunotherapy with monoclonal
antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and
may interfere with the ability of tumor cells to grow and spread. Giving atezolizumab before
and/or with chemoradiotherapy may lower the chance of tumors growing or spreading.
• Patients with histologically confirmed newly diagnosed advanced cervical cancer
(squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma):
Federation of Gynecology and Obstetrics (FIGO) clinical stages IB2/IIA with positive
para-aortic nodes, or FIGO clinical stages IIB/IIIB/IVA with positive pelvic or
para-aortic lymph nodes (PALN). Pelvic or PALN nodal status confirmed by PET/CT scan
or fine needle biopsy or extra peritoneal biopsy or laparoscopic biopsy. The PALN must
be inferior to the T12/L1 interspace
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Leukocytes >= 2,500/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL (> 50,000 for patients with hematologic malignancies)
• Hemoglobin >= 8 g/dL (can be transfused with red blood cells pre-study)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients
with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x ULN (AST and/or ALT =< 5 x ULN for patients with liver involvement)
• Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for patients with documented liver
involvement or bone metastases)
• Creatinine clearance =< 1.5 mg/dL to receive weekly cisplatin
• Patients whose serum creatinine is between 1.5 and 1.9 mg/dL are eligible for
cisplatin if there is no hydronephrosis and the estimated creatinine clearance
(CCr) is >= 30 ml/min. For the purpose of estimating the CCr, the formula of
Cockcroft and Gault for females should be used
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
=< 1.5 x ULN (this applies only to patients who do not receive therapeutic
anticoagulation; patients receiving therapeutic anticoagulation, such as
low-molecular-weight heparin or warfarin, should be on a stable dose)
• Patient does not have a known allergy to cisplatin or compounds of similar biologic
composition
• Patient is not actively breastfeeding (or has agreed to discontinue breastfeeding
before the initiation or protocol therapy)
• Thyroid-stimulating hormone (TSH) within normal limits or normal free T4 in those with
abnormal TSH
• Ability to understand and the willingness to sign a written informed consent document
• Patients positive for human immunodeficiency virus (HIV) are allowed on study, but
HIV-positive patients must have:
• A stable regimen of highly active anti-retroviral therapy (HAART)
• No requirement for concurrent antibiotics or antifungal agents for the prevention
of opportunistic infections
• A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
polymerase chain reaction (PCR)-based tests
Exclusion Criteria:
• Patients who have received prior radiation therapy to the pelvis or abdominal cavity,
PALN radiation, or previous therapy of any kind for this malignancy or pelvic, PALN,
or abdominal radiation for any prior malignancy
• Patients with PALN nodal metastasis above the T12/L1 interspace
• Patients who had a radical hysterectomy with positive PALNs are not eligible
• Patients with prior allogeneic bone marrow transplantation or prior solid organ
transplantation
• Patients previously treated with systemic anticancer therapy (e.g., chemotherapy,
targeted therapy, immunotherapy) within 3 years prior to entering the study
• Treatment with systemic immunosuppressive medications (including, but not limited to,
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1
• Patients who have received acute, low dose, systemic immunosuppressant
medications (e.g., a one-time dose of dexamethasone for nausea or steroids as CT
scan contrast premedication) may be enrolled
• The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
for patients with orthostatic hypotension or adrenocortical insufficiency is
allowed
• Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins
• Patients requiring treatment with a RANKL inhibitor (e.g., denosumab) who cannot
discontinue it before treatment with atezolizumab
• Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; cirrhosis; fatty liver; and inherited liver disease
• Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
[antibody to hepatitis B core antigen] antibody test) are eligible
• Patients positive for hepatitis C virus (HCV) antibody
• History or risk of autoimmune disease, including but not limited to systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
thyroid disease, vasculitis, or glomerulonephritis
• Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
replacement hormone are eligible
• Patients with controlled type 1 diabetes mellitus on a stable insulin regimen or
type 2 diabetes mellitus are eligible
• Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would
be excluded) are permitted provided that they meet the following conditions:
• Patients with psoriasis must have a baseline ophthalmologic exam to rule out
ocular manifestations
• Rash must cover less than 10% of body surface area (BSA)
• Disease is well controlled at baseline and only requiring low potency
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
• No acute exacerbations of underlying condition within the last 12 months
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,
retinoids, biologic agents, oral calcineurin inhibitors; high potency or
steroids)
• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan. History of radiation pneumonitis in the radiation field
(fibrosis) is permitted
• Patients with active tuberculosis (TB) are excluded
• Severe infections within 4 weeks prior to cycle 1, day 1, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia
• Signs or symptoms of infection within 2 weeks prior to cycle 1, day 1
• Received intravenous (IV) antibiotics within 2 weeks prior to cycle 1, day 1. Patients
receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection
or chronic obstructive pulmonary disease) are eligible
• Major surgical procedure within 28 days prior to cycle 1, day 1 or anticipation of
need for a major surgical procedure during the course of the study
• Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or
anticipation that such a live, attenuated vaccine will be required during the study
and up to 5 months after the last dose of atezolizumab
• Influenza vaccination should be given during influenza season only (approximately
October to March). Patients must not receive live, attenuated influenza vaccine
within 4 weeks prior to cycle 1, day 1 or at any time during the study
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
• Severe, active co-morbidity defined as follows:
• Current (within 28 days of cycle 1, day 1) signs and/or symptoms of bowel
obstruction
• Patients who require parental hydration and/or nutrition
• Patients who require drainage gastrostomy tube
• Evidence of bleeding diathesis or clinically significant coagulopathy
• Serious, non-healing or dehiscing wound, active ulcer or untreated bone fracture
• History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within 1
month of study enrollment
• Significant cardiovascular or cerebrovascular disease including:
• Uncontrolled hypertension (systolic blood pressure [SBP] >= 150; diastolic blood
pressure [DBP] >= 90)
• History of myocardial infarction within 6 months
• Unstable angina
• New York Heart Association functional classification II, III or IV
• Baseline ejection fraction =< 50% as assessed by echocardiogram or multigated
acquisition scan (MUGA)
• Cerebral vascular accident (CVA) or transient ischemic attack (TIA) within 6
months
• Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
peripheral arterial thrombosis) within 6 months
• History of abdominal/pelvic or tracheoesophageal fistula or gastrointestinal
perforation and/or abscess within 6 months prior to initiation of treatment
• If patients are of child-bearing potential and do not agree to use two forms of birth
control then they are ineligible
• Patients who have had a hysterectomy or are planning to have an adjuvant hysterectomy
following radiation as part of their cervical cancer treatment are ineligible
• Patients scheduled to be treated with adjuvant consolidation chemotherapy at the
conclusion of their standard chemoradiation
• Pregnant women are excluded from this study because radiation therapy has the
potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with atezolizumab, breastfeeding should be discontinued if the mother is
treated with atezolizumab
• Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for the 5 months (150 days) after the last
dose of the study agent. Should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her
treating physician immediately
• Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Use of
bisphosphonate therapy for other reasons (e.g. osteoporosis) is allowed
• Patients with known primary central nervous system (CNS) malignancy or CNS metastases
are excluded
• Patients with a prior known history of vesicovaginal, enterovaginal or colovaginal
fistula
A Study of Zolbetuximab (IMAB362) Plus CAPOX Compared With Placebo Plus CAPOX as First-line Treatment of Subjects With Claudin (CLDN) 18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (GLOW)
The purpose of this study is to evaluate the efficacy of zolbetuximab plus capecitabine and
oxaliplatin (CAPOX) compared with placebo plus CAPOX (as first-line treatment) as measured by
Progression Free Survival (PFS).
This study will also evaluate efficacy, safety and tolerability of zolbetuximab, as well as
its effects on quality of life. Pharmacokinetics (PK) of zolbetuximab and the immunogenicity
profile of zolbetuximab will be evaluated as well.
• A female subject is eligible to participate if she is not pregnant (negative serum
pregnancy test at screening; female subjects with elevated serum beta human chorionic
gonadotropin (βhCG) and a demonstrated non-pregnant status through additional testing
are eligible) and at least 1 of the following conditions applies:
• Not a woman of childbearing potential (WOCBP)
• WOCBP who agrees to follow the contraceptive guidance throughout the treatment
period and for 6 months after the final study treatment administration
• Female subject must agree not to breastfeed starting at screening and throughout the
study period, and for 6 months after the final study treatment administration.
• Female subject must not donate ova starting at screening and throughout the study
period, and for 6 months after the final study treatment administration.
• A male subject with female partner(s) of childbearing potential:
• must agree to use contraception during the treatment period and for 6 months
after the final study treatment administration.
• A male subject must not donate sperm during the treatment period and for 6 months
after the final study treatment administration.
• Male subject with a pregnant or breastfeeding partner(s) must agree to remain
abstinent or use a condom for the duration of the pregnancy or time partner is
breastfeeding throughout the study period and for 6 months after the final study
treatment administration.
• Subject has histologically confirmed diagnosis of Gastric or GEJ adenocarcinoma.
• Subject has radiologically confirmed locally advanced unresectable or metastatic
disease within 28 days prior to randomization.
• Subject has radiologically evaluable disease (measurable and/or non-measurable disease
according to RECIST 1.1), per local assessment, ≤ 28 days prior to randomization. For
subjects with only 1 evaluable lesion and prior radiotherapy ≤ 3 months before
randomization, the lesion must either be outside the field of prior radiotherapy or
have documented progression following radiation therapy.
• Subject's tumor expresses CLDN18.2 in ≥ 75% of tumor cells demonstrating moderate to
strong membranous staining as determined by central IHC testing.
• Subject has a HER2-negative tumor as determined by local or central testing on a
gastric or GEJ tumor specimen.
• Subject has ECOG performance status 0 or 1.
• Subject has predicted life expectancy ≥ 12 weeks.
• Subject must meet all of the following criteria based on the centrally or locally
analyzed laboratory tests collected within 14 days prior to randomization. In case of
multiple central laboratory data within this period, the most recent data should be
used to determine eligibility.
• Hemoglobin (Hb) ≥ 9 g/dl. Subjects requiring transfusions are eligible if they
have a post-transfusion Hgb ≥ 9 g/dL.
• Absolute Neutrophil Count (ANC) ≥ 1.5x10^9/L
• Platelets ≥ 100x10^9/L
• Albumin ≥ 2.5 g/dL
• Total Bilirubin ≤ 1.5 x upper limit of normal (ULN) without liver metastases (or
< 3.0 x ULN if liver metastases are present)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
without liver metastases (or ≤ 5 x ULN if liver metastases are present)
• Estimated creatinine clearance ≥ 30 mL/min
• Prothrombin time/international normalized ratio (PT/INR) and partial
thromboplastin time (PTT) ≤ 1.5 x ULN (except for subjects receiving
anticoagulation therapy)
Exclusion Criteria:
• Subject has received prior systemic chemotherapy for locally advanced unresectable or
metastatic gastric or GEJ adenocarcinoma. However, subject may have received either
neo-adjuvant or adjuvant chemotherapy as long as it was completed at least 6 months
prior to randomization.
• Subject has received radiotherapy for locally advanced unresectable or metastatic
gastric or GEJ adenocarcinoma ≤ 14 days prior to randomization and has not recovered
from any related toxicity.
• Subject has received treatment with herbal medications or other treatments that have
known antitumor activity within 28 days prior to randomization.
• Subject has received systemic immunosuppressive therapy, including systemic
corticosteroids within 14 days prior to randomization. Subjects using a physiologic
replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day
of hydrocortisone or up to 10 mg per day of prednisone), receiving a single dose of
systemic corticosteroids or receiving systemic corticosteroids as premedication for
radiologic imaging contrast use are allowed.
• Subject has received other investigational agents or devices within 28 days prior to
randomization.
• Subject has prior severe allergic reaction or intolerance to known ingredients of
zolbetuximab or other monoclonal antibodies, including humanized or chimeric
antibodies.
• Subject has known immediate or delayed hypersensitivity, intolerance or
contraindication to any component of study treatment.
• Subject has prior severe allergic reaction or intolerance to any component of CAPOX.
• Subject has known dihydropyrimidine dehydrogenase (DPD) deficiency.
• Subject has a complete gastric outlet syndrome or a partial gastric outlet syndrome
with persistent/recurrent vomiting.
• Subject has significant gastric bleeding and/or untreated gastric ulcers that exclude
the subject from participation.
• Subject has a known history of a positive test for human immunodeficiency virus (HIV)
infection or known active hepatitis B (positive hepatitis B surface antigen (HBs Ag))
or C infection. NOTE: Screening for these infections should be conducted per local
requirements.
• For subjects who are negative for HBs Ag, but hepatitis B core antibody (HBc Ab)
positive, an HB deoxyribonucleic acid (DNA) test will be performed and if
positive, the subject will be excluded.
• Subjects with positive hepatitis C virus (HCV) serology, but negative HCV
ribonucleic acid (RNA) test are eligible.
• Subjects treated for HCV with undetectable viral load results are eligible.
• Subject has an active autoimmune disease that has required systemic treatment within
the past 3 months prior to randomization.
• Subject has active infection requiring systemic therapy that has not completely
resolved within 7 days prior to randomization.
• Subject has significant cardiovascular disease, including any of the following:
• Congestive heart failure (defined as New York Heart Association Class III or IV),
myocardial infarction, unstable angina, coronary angioplasty, stenting, coronary
artery bypass graft, cerebrovascular accident (CVA) or hypertensive crisis within
6 months prior to randomization.
• History of clinically significant ventricular arrhythmias (i.e., sustained
ventricular tachycardia, ventricular fibrillation or Torsades de Pointes
• QTc interval > 450 msec for male subjects; QTc interval > 470 msec for female
subjects
• History or family history of congenital long QT syndrome
• Cardiac arrhythmias requiring anti-arrhythmic medications (Subject with rate
controlled atrial fibrillation for > 1 month prior to randomization are
eligible).
• Subject has a history of central nervous system (CNS) metastases and/or carcinomatous
meningitis from gastric/GEJ cancer..
• Subject has known peripheral sensory neuropathy > grade 1 unless the absence of deep
tendon reflexes is the sole neurological abnormality.
• Subject has had a major surgical procedure ≤ 28 days prior to randomization.
• Subject is without complete recovery from a major surgical procedure ≤ 14 days
prior to randomization.
• Subject has psychiatric illness or social situations that would preclude study
compliance.
• Subject has another malignancy for which treatment is required.
• Subject has any concurrent disease, infection, or co-morbid condition that interferes
with the ability of the subject to participate in the study, which places the subject
at undue risk or complicates the interpretation of data.
• Stratum I
• Patients must be less than 18 years of age at the time of diagnosis.
• Patients must have histological verification of the diagnosis of Langerhans cell
histiocytosis according to the criteria described in Section 6.1
• Signed informed consent form
• Stratum II
• Patients of Stratum I who have:
• Progressive disease (AD worse) in non-risk organs after 6 weeks (Initial Course
• AD intermediate or worse in non-risk organs or AD better in risk organs after 12
weeks (Initial Course 2)
• Disease progression (AD worse) in non-risk organs at any time during continuation
treatment
• Active disease at the end of Stratum I treatment
• Disease reactivation in non-risk organs at any time after completion of Stratum I
treatment
• Stratum III
• Patients from Stratum I who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD
intermediate in risk organs after week 12 (after Initial Course 2).
• Presence of unequivocally severe organ dysfunction at the above mentioned
evaluation points (hematological dysfunction, liver dysfunction, or both of them)
as
• Hb <70 g/L (<7.0 g/dl) and/or transfusion dependency
• PLT <20 x109/L (20,000/μL) and/or transfusion dependency (both criteria have
to be fulfilled) AND/OR
• Liver dysfunction (or digestive involvement with protein loss)
• Total protein <55 g/L or substitution dependency
• Albumin <25 g/L or substitution dependency (at least one of the two criteria
to be fulfilled)
• Stratum IV
• Patients from Stratum I or Stratum III who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD
intermediate in risk organs after week 12 (after Initial Course 2) of Stratum I
OR
• AD worse after the 2nd and 3rd 2-CdA/Ara-C course, and those AD worse or AD
intermediate after the 4th 2-CdA/Ara-C course of Stratum III AND
• Presence of unequivocally severe organ dysfunction at the above mentioned
evaluation points (hematological dysfunction, liver dysfunction, or both of them)
as defined in Table XI (see Section 10.3.1).
• Informed consent: All patients or their legal guardians (if the patient is <18
years of age) must sign an Ethics or institutional Review Board approved consent
form indicating their awareness of the investigational nature and the risks of
this study. When appropriate, younger patients will be included in all
discussions in order to obtain assent.
• Adequate organ function: Patients should have adequate hepatic, renal, cardiac
and pulmonary function to undergo reduced intensity HCT based upon local
institutional guidelines, or at a minimum meet requirements noted in eligibility
checklist Appendix A-VIII_1. However, significant hepatic and pulmonary
dysfunction, if secondary to underlying LCH disease activity, will not exclude
patients from protocol enrollment and should be discussed with the National PI
Coordinator and the Coordinating Principal Investigator.
• Stratum V
• All patients with verified diagnosis of LCH and MRI findings consistent with
ND-CNSLCH irrespective of previous treatments (also those not registered to other
Strata ofLCH-IV).
• Patients with isolated tumorous CNS-LCH (including isolated DI with mass lesion
in the hypothalamus-pituitary axis). In patients with already established
diagnosis of LCH and radiologic finding of CNS lesions compatible with LCH, a
biopsy of the lesion is not obligatory. In all other cases a biopsy of the lesion
is needed for inclusion into the study
• Stratum VI
-- Patients with newly diagnosed SS-LCH and localization other than "multifocal
bone",isolated tumorous CNS lesion, or isolated "CNS-risk" lesion.
• Stratum VII -- All patients registered in LCH IV (regardless of treatment) as long as
consent for longterm follow-up has not been withheld.
Exclusion Criteria:
• Stratum I
• Pregnancy (patients of child-bearing age must be appropriately tested before
chemotherapy)
• LCH-related permanent consequences (e.g. vertebra plana, sclerosing cholangitis,
lung fibrosis, etc.) in the absence of active disease
• Prior systemic therapy
• Stratum II
• Patients with progressive disease in risk organs
• Permanent consequences (e.g. sclerosing cholangitis, lung fibrosis, etc.) without
evidence of active LCH in the same organ or in any other locations
• No written consent of the patient or his/her parents or legal guardian
• Stratum III
• The presence of any of the following criteria will exclude the patient from the
study:
• Isolated sclerosing cholangitis without evidence of active hepatic LCH as the
only evidence of risk organ involvement.
• Inadequate renal function as defined by serum creatinine > 3x normal for age
• Stratum IV
• Pulmonary failure (requiring mechanical ventilation) not due to active LCH.
• Isolated liver sclerosis or pulmonary fibrosis, without active LCH.
• Uncontrolled active life-threatening infection.
• Decreased renal function with a GFR of less than 50ml/1.73m2/min.
• Pregnancy or active breast feeding
• Failure to provide signed informed consent
• Stratum VI
• Patients with SS-LCH who have an isolated tumorous CNS lesion (they are eligible
for Stratum V),
• Patients with isolated "CNS-risk" or multifocal bone lesions (they are eligible
for Stratum I, Group 2)
Phase II Concurrent Durvalumab and Radiotherapy for for Stage III Non-Small Cell Lung Cancer
Single arm, Phase II trial of concurrent Durvalumab (MEDI 4736) and radiotherapy followed by
consolidative Durvalumb (MEDI 4736) for Stage III Non-Small Cell Lung Cancer (NSCLC)
1.1 Pathologically (histologically or cytologically) proven diagnosis of NSCLC with,
medically inoperable (or patients who refuse resection) stage IIIA or stage IIIB disease
(AJCC 8th edition);
1.1.1 Inoperable Stage IIIA disease is defined by multiple and/or bulky N2 mediastinal
lymph nodes on computed tomography (CT) scan such that, in the opinion of the treating
investigator, the patient was not a candidate for surgical resection.
1.1.2 N2 disease must have been documented by biopsy, or at a minimum by fluorodeoxyglucose
positron emission tomography (PET) or CT if nodes were more than 2 cm in short axis
diameter.
1.1.3 T4 disease is often considered resectable at the discretion of a thoracic surgeon.
Patients with T4N0 or T4N1 disease can be enrolled if their case is reviewed by a thoracic
surgeon and felt to be unresectable or if they are either medically inoperable or refuse
surgery.
1.1.4 Stage IIIB patients have N3 or T4N2 status. N3 status must have been documented by
the presence of a contralateral (to the primary tumor) mediastinal lymph node or
supraclavicular or scalene lymph node proven by biopsy, or at a minimum by
fluorodeoxyglucose uptake on PET or more than 2 cm in short axis diameter on CT scan.
Patients with disease extending into the cervical region (defined as disease extending
above cricoid cartilage) are not eligible.
1.2 Appropriate stage for study entry based on the following diagnostic workup:
1.2.1 History/physical examination, including documentation of height, weight and vital
signs, within 30 days prior to registration;
1.2.2 CT scan with IV contrast (CT scan without contrast acceptable if IV contrast is
medically contraindicated) of the lung and upper abdomen through the adrenal glands within
60 days prior to registration (recommended within 30 days prior to registration);
1.2.3 MRI of the brain with contrast (or CT with contrast if MRI is medically
contraindicated) within 60 days prior to registration; note: the use of intravenous
contrast is required for the MRI or CT (unless medically contra-indicated).
1.2.4 Whole-body FDG-PET/CT within 60 days prior to registration;
1.3 Age ≥ 18 years;
1.4 Life expectancy ≥ 12 weeks
1.5 Zubrod Performance Status of 0-1 within 30 days prior to registration;
1.6 Adequate respiratory function within 180 days prior to registration defined as follows:
FEV1 > 1.2 liters; DLCO ≥ 50% predicted;
1.7 Patients with post-obstructive pneumonia are eligible provided they no longer require
intravenous antibiotics at registration;
1.8 Patients with a pleural effusion that is transudative, cytologically negative and
non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed
within a reasonable field of radiotherapy; if pleural fluid is too small a volume to
effectively sample by thoracentesis and does not show increased metabolic activity on
CT/PET imaging, the patient will be remain eligible.
1.9 Allowable type and amount of prior therapy
1.10 Adequate organ and marrow function as defined below
1.10.1 Absolute neutrophil count >1.5 × 109/L
1.10.2 Platelet count >100 × 109/L
1.10.3 Baseline or post-transfusion Hemoglobin ≥9.0 g/dL
1.10.4 Serum bilirubin≤ 1.5x upper limit of normal (ULN). This will not apply to patients
with confirmed Gilbert's syndrome, who will be allowed in consultation with their
physician.
1.10.5 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5x ULN.
1.10.6 Measured creatinine clearance (CL) >40 mL/min or calculated CL >40 mL/min as
determined by Cockcroft-Gault (using actual body weight);
Males:
Creatinine CL = Weight (kg) × (140 •Age) (mL/min) 72 × serum creatinine (mg/dL)
Females:
Creatinine CL = Weight (kg) × (140 •Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL)
1.11 Negative serum pregnancy test within three days prior to registration for women of
childbearing potential.
1.12 Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for the
duration of study participation, and for 90 days following completion of therapy. Should a
woman become pregnant or suspect she is pregnant while participating in this study, she
should inform her treating physician immediately.
1.12.1 A female of child-bearing potential is any woman (regardless of sexual orientation,
having undergone a tubal ligation, or remaining celibate by choice) who meets the following
criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has
had menses at any time in the preceding 12 consecutive months).
1.12.2 Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have been
amenorrheic for 12 months without an alternative medical cause. The following age-specific
requirements apply:
• Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal treatments
and if they have luteinizing hormone and follicle-stimulating hormone levels in the
post-menopausal range for the institution or underwent surgical sterilization
(bilateral oophorectomy or hysterectomy).
• Women ≥50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
1.13 Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria:
2.1 Definitive clinical or radiologic evidence of metastatic disease;
2.2 Subjects may not be receiving any other investigational agents for the treatment of the
cancer under study.
2.3 Current invasive malignancy (except non-melanomatous skin cancer, localized bladder and
prostate cancer). Carcinoma in situ of the breast, oral cavity, or cervix are permissible
regardless of timing;
2.4 Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields. For example, patients with prior breast radiotherapy treatments
would likely be excluded;
2.5 Prior systemic treatment with chemotherapy, targeted therapy or an anti-PD-1,
anti-PD-L1 including durvalumab, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or
drug specifically targeting T-cell costimulation or immune checkpoint pathways for NSCLC;
2.6 A condition requiring systemic treatment with either corticosteroids (> 10 mg daily
prednisone equivalents) or other immunosuppressive medications within 7 days of study drug
administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily
prednisone equivalents are permitted in the absence of active autoimmune disease;
2.7 Severe, active co-morbidity defined as follows:
2.7.1 Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
acceptable.
2.7.2 Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis,
hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone
replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but only after
consultation with the study physician
• Patients with celiac disease controlled by diet alone
2.7.3 Active infection including tuberculosis, hepatitis B, hepatitis C.
2.7.4 History of allogenic organ transplantation.
2.7.5 History of symptomatic or previously established interstitial lung disease;
2.7.6 History of severe hypersensitivity reaction to any monoclonal antibody or allergy to
study drug components;
2.7.7 Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
30 days after the last dose of IP.
2.8 Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that, in the opinion of the
investigator, would limit compliance with study requirements.
2.9 Pregnancy, nursing females, or women of childbearing potential and men who are sexually
active and not willing/able to use medically acceptable forms of contraception; this
exclusion is necessary because the treatment involved in this study may be significantly
teratogenic.
2.10 Patients whose radiation treatment plans are likely to encompass a volume of whole
lung receiving ≥ 35% of lung volume. V20s up to 37% will be permitted and viewed as a minor
deviation, provided that the treating radiation oncologist believes this level of exposure
is within patient tolerance.
2.11 Planned radiation cardiac dose V50 >25%.
Radiation: Thoracic RT and Durvalumab, Drug: Consolidative Durvalumab
Hyperpolarized Carbon 13-Based Metabolic Imaging to Detect Radiation-Induced Cardiotoxicity
Patients enrolled in the study will receive standard of care adjuvant or definitive breast,
chest wall or thoracic radiation therapy.Cardiac mitochondrial dysfunction is a hallmark of
radiation-induced cardiac injury. Reactive oxygen species (ROS) produced by ionizing
radiation cause oxidation of mitochondrial proteins and alter oxidative phosphorylation and
pyruvate metabolism(5). The goal of this study is to detect early changes in the
mitochondrial metabolism in situ as a marker for subclinical radiation-induced
cardiotoxicity.
• Tissue diagnosis of benign or malignant tumor of the breast (left-sided only) or
thorax
1. Stage I to III
2. ECOG performance status 0-1
3. The patient must be deemed an appropriate candidate for adjuvant ordefinitive
radiation therapy with or without regional nodal irradiation
4. Radiation therapy planning should be CT scan-based using 3D conformal
radiotherapy (3D-CRT), intensity modulated radiotherapy (IMRT) or volumetric arc
therapy (VMAT).
5. Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry,
for the duration of study participation, and for 90 days following completion of
therapy. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician
immediately.
5.1 A female of child-bearing potential is any woman (regardless of sexual
orientation, having undergone a tubal ligation, or remaining celibate by choice)
who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months
(i.e., has had menses at any time in the preceding 12 consecutive months).
5.2. A female of postmenopausal status is defined as patients over 60 or greater
OR patients age 50-59 who meet the following criteria:
• s/p bilateral oophorectomy, OR
• with intact uterus without menses in the past 12 months OR,
• with biochemical confirmation of post-menopausal status (estradiol in the
menopausal range based on local laboratory criteria)
6. Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria:
1. Prior thoracic radiation therapy
2. Neoadjuvant, adjuvant or prior HER-2 directed therapy
3. Subjects may not be receiving any investigational agents for the treatment of the
cancer under study.
4. Tissue expander placement after mastectomy
5. Diagnosis of connective tissue disorders, including systemic lupus erythematosis,
scleroderma, or dermatomyositis
6. Known metastases
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that, in the opinion of the
investigator, would limit compliance with study requirements
8. eGFR <30
9. Any contraindication to MRI (including, but not limited to metal implants and devices
contraindicated at 3T, breast tissue expanders, non-MR compatible IV port,
claustrophobia)
10. History of psychiatric or addictive disorders that would preclude obtaining informed
consent
11. Subjects must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.
Diagnostic Test: [1-13C]pyruvate along with MRI imaging
Thoracic Cancer, Breast - Female, Cardiovascular, Heart, Left Sided Breast Cancer
A Study to Investigate Blinatumomab in Combination With Chemotherapy in Patients With Newly Diagnosed B-Lymphoblastic Leukemia
This phase III trial studies how well blinatumomab works in combination with chemotherapy in
treating patients with newly diagnosed, standard risk B-lymphoblastic leukemia or
B-lymphoblastic lymphoma with or without Down syndrome. Monoclonal antibodies, such as
blinatumomab, may induce changes in the body's immune system and may interfere with the
ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as vincristine,
dexamethasone, prednisone, prednisolone, pegaspargase, methotrexate, cytarabine,
mercaptopurine, doxorubicin, cyclophosphamide, and thioguanine, work in different ways to
stop the growth of cancer cells, either by killing the cells, by stopping them from dividing,
or by stopping them from spreading. Leucovorin decreases the toxic effects of methotrexate.
Giving monoclonal antibody therapy with chemotherapy may kill more cancer cells. Giving
blinatumomab and combination chemotherapy may work better than combination chemotherapy alone
in treating patients with B-ALL. This trial also assigns patients into different chemotherapy
treatment regimens based on risk (the chance of cancer returning after treatment). Treating
patients with chemotherapy based on risk may help doctors decide which patients can best
benefit from which chemotherapy treatment regimens.
• All B-ALL patients must be enrolled on APEC14B1 and consented to Eligibility Screening
(Part A) prior to treatment and enrollment on AALL1731. APEC 14B1 is not a requirement
for B-LLy patients. B-LLy patients may directly enroll on AALL1731.
• Age at diagnosis:
• Patients must be >= 365 days and < 10 years of age (B-ALL patients without DS).
• Patients must be >= 365 days and =< 31 years of age (B-ALL patients with DS).
• Patients must be >= 365 days and =< 31 years of age (B-LLy patients with or
without DS).
• B-ALL patients without DS must have an initial white blood cell count < 50,000/uL
(performed within 7 days prior to enrollment).
• B-ALL patients with DS are eligible regardless of the presenting white blood cell
count (WBC) (performed within 7 days prior to enrollment).
• Patient has newly diagnosed B-cell ALL, with or without Down syndrome: > 25% blasts on
a bone marrow (BM) aspirate;
• OR if a BM aspirate is not obtained or is not diagnostic of B-ALL, the diagnosis
can be established by a pathologic diagnosis of B-ALL on a BM biopsy;
• OR a complete blood count (CBC) documenting the presence of at least 1,000/uL
circulating leukemic cells;
• OR patient has newly diagnosed B-cell LLy Murphy stages I or II, with or without
Down syndrome.
• Note: For B-LLy patients with tissue available for flow cytometry, the criterion
for diagnosis should be analogous to B-ALL. For tissue processed by other means
(i.e., paraffin blocks), the methodology and criteria for immunophenotypic
analysis to establish the diagnosis of B-LLy defined by the submitting
institution will be accepted (diagnostic biopsy for B-LLy must be performed
within 14 days prior to enrollment).
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met.
• All patients and/or their parents or legal guardians must sign a written informed
consent.
Exclusion Criteria:
• Patient must not have secondary ALL that developed after treatment of a prior
malignancy with cytotoxic chemotherapy. Note: patients with Down syndrome with a prior
history of transient myeloproliferative disease (TMD) are not considered to have had a
prior malignancy. They would therefore be eligible whether or not the TMD was treated
with cytarabine.
• With the exception of steroid pretreatment or the administration of intrathecal
cytarabine, patients must not have received any prior cytotoxic chemotherapy for
either the current diagnosis of B ALL or B LLy or for any cancer diagnosed prior to
initiation of protocol therapy on AALL1731.
• For patients receiving steroid pretreatment, the following additional exclusion
criteria apply:
• Non-DS B-ALL patients must not have received steroids for more than 24 hours in
the 2 weeks prior to diagnosis without a CBC obtained within 3 days prior to
initiation of the steroids.
• DS and non-DS B-LLy patients must not have received > 48 hours of oral or IV
steroids within 4 weeks of diagnosis.
• Patients who have received > 72 hours of hydroxyurea.
• B-ALL patients who do not have sufficient diagnostic bone marrow submitted for
APEC14B1 diagnostic testing and who do not have a peripheral blood sample submitted
containing > 1,000/uL circulating leukemia cells.
• Patient must not have acute undifferentiated leukemia (AUL).
• Non-DS B-ALL patients with central nervous system [CNS]3 leukemia (CNS status must be
known prior to enrollment).
• Note: DS patients with CNS3 disease are eligible but will be assigned to the
DS-High B-ALL arm. CNS status must be determined based on a sample obtained prior
to administration of any systemic or intrathecal chemotherapy, except for steroid
pretreatment.
• Non-DS B-ALL patients with testicular leukemia. (Note: DS patients with testicular
disease are eligible but will be assigned to the DS-High B-ALL arm).
• For LLy patients, the following additional exclusion criteria apply:
• T-Lymphoblastic Lymphoma.
• Morphologically unclassifiable lymphoma.
• Absence of both B-cell and T-cell phenotype markers in a case submitted as
lymphoblastic lymphoma.
• CNS positive disease or testicular involvement.
• M2 (5% •25% blasts) or M3 (> 25% blasts) marrow.
• Patients with known Charcot-Marie-Tooth disease.
• Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL,
regardless of blast immunophenotype.
• Patients requiring radiation at diagnosis.
• Female patients who are pregnant since fetal toxicities and teratogenic effects have
been noted for several of the study drugs. A pregnancy test is required for female
patients of childbearing potential.
• Lactating females who plan to breastfeed their infants.
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation.
Efficacy & Safety of rAd-IFN Administered With Celecoxib & Gemcitabine in Patients With Malignant Pleural Mesothelioma (INFINITE)
This study will evaluate intrapleural administration of Adenovirus-Delivered Interferon
Alpha-2b (rAd-IFN) in combination with Celecoxib and Gemcitabine in patients with
histologically confirmed Malignant Pleural Mesothelioma (MPM) who have failed a minimum of 1
treatment regimen and a maximum of 2 treatment regimens, 1 of which must have been an
anti-folate and platinum combination regimen.
Eligible patients will be randomized 1:1 to either:
1. Treatment group: rAd-IFN + Celecoxib followed by Gemcitabine
2. Control group: Celecoxib followed by Gemcitabine
Patients randomized to the treatment group will receive rAd-IFN administered into the pleural
space via an Intrapleural catheter (IPC) or similar intrapleural device on study Day 1.
The primary objective of this study is to compare the overall survival (OS) associated with
rAd IFN, when administered with celecoxib and gemcitabine, versus that associated with
celecoxib and gemcitabine alone for the treatment of patients with MPM
Inclusion Criteria
Patients who meet all of the following criteria will be eligible to participate in the
study:
1. Aged 18 years or older at the time of consent;
2. Able to give informed consent;
3. Has a confirmed histological diagnosis of MPM with histological type epithelioid or
biphasic (if biphasic, histology must be predominantly [50%] epithelioid).
Histological diagnosis of MPM will be confirmed centrally using specimens or slides
from tumor specimens obtained at the time of initial presentation or a subsequent
procedure. Central confirmation of diagnosis with immunohistochemistry will be
performed, and independent central confirmation will be required for study entry;
4. Measurable disease, per modified Response Evaluation Criteria in Solid Tumors [RECIST]
1.1 (see Section 7) for pleural mesothelioma;
5. Has received a minimum of 1 treatment regimen and a maximum of 2 treatment regimens,
which may have been chemotherapeutic and/or immunotherapeutic treatment regimens for
MPM which included at least 1 anti-folate and platinum combination regimen;
• Adjuvant or neoadjuvant therapy represent 1 line of therapy each;
• Patients who have undergone primary surgical resection and/or radiation therapy
to the pulmonary site are eligible to participate. For clarity, surgical
resection and/or radiation therapy to the pulmonary site are not exclusionary and
are not considered a line of therapy;
• Treatment that is split between pre-surgical resection and post-surgical
resection and is the same regimen will be counted as 1 regimen. Patients meeting
this condition should be discussed with the Medical Monitor prior to including
the patient in the study;
6. Has a pleural space accessible for IPC or similar device insertion. Patients with a
previously inserted IPC or similar device may be enrolled, and the pre-existing IPC or
similar device can be used for vector administration as long as it is functional and
has no evidence of local infection;
7. Life expectancy 12 weeks in the judgement of the Investigator;
8. Eastern Cooperative Oncology Group (ECOG) status of 1 or 0;
9. Female and male patients:
• Female patients of childbearing potential must have a negative pregnancy test
upon entry into this study and agree to use a highly effective method of
contraception from Screening until 1 month after the last dose of gemcitabine;
• Highly effective methods of contraception that result in a low failure rate
(i.e., <1% per year) when used consistently and correctly include combined
(estrogen and progestogen containing) hormonal contraception associated with
inhibition of ovulation (oral, intravaginal, or transdermal),
progestogen-only hormonal contraception associated with inhibition of
ovulation (oral, injectable, or implantable), intrauterine device,
intrauterine hormone-releasing system, bilateral tubal occlusion,
vasectomized partner, or sexual abstinence;
• True abstinence, when in line with the preferred and usual lifestyle of the
patient, is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of study
participation and for 1 month after the last dose of gemcitabine. The
reliability of sexual abstinence needs to be evaluated in relation to the
duration of the clinical study and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, and
post-ovulation method) and withdrawal are not acceptable methods of
contraception; and
• Female patients of non-childbearing potential must be either postmenopausal (no
menstrual period for a minimum of 12 months) or surgically sterile upon entry
into the study;
• Male patients must be either surgically sterile or agree to use a double-barrier
contraception method from Screening until 6 months after the last dose of
gemcitabine; o Where available and in accordance with local practice, male
patients must be advised to seek further advice regarding cryoconservation of
sperm prior to gemcitabine treatment due to the possibility of infertility after
therapy with gemcitabine; and
10. Adequate laboratory values at Screening:
• Hemoglobin 9 g/dL;
• White blood cell count 3500/µL;
• Absolute neutrophil count 1500/µL;
• • Platelet count 100,000/µL;
• International normalized ratio (INR) and activated partial thromboplastin time
(aPTT) below the upper limit of normal (ULN). It is expected that patients
receiving anticoagulation therapy will not have INR and aPTT results that fall
within normal limits. It is not intended to exclude these patients and,
therefore, medical discretion is permitted for patients who have clinically
acceptable results in regards to their current concomitant anticoagulant therapy;
• Aspartate aminotransferase (AST) 3 × ULN;
• Alanine aminotransferase (ALT) 3 × ULN;
• Total bilirubin 2 × ULN;
• Estimated glomerular filtration rate (calculated using the Modification of Diet
in Renal Disease study equation [see Appendix B]) 50 mL/min/1.73 m2; and
• Serum albumin 2.5 g/dL.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from participation in the
study:
1. Is "treatment-naïve" (i.e., has not received at least 1 anti-folate and platinum
combination regimen);
2. Has previously received 3 or more lines of systemic chemotherapeutic or
immunotherapeutic treatment. Treatment that is split between pre-surgical resection
and post-surgical resection and is the same regimen will be counted as 1 regimen.
Patients meeting this condition should be discussed with the Medical Monitor prior to
including the patient in the study;
3. Has previously received treatment with gemcitabine;
4. Has stage IV extrathoracic metastatic disease;
5. Inadequate pulmonary function of clinical significance as per Investigator review;
6. Clinically significant pericardial effusion (i.e., as judged by the Investigator
and/or requiring drainage) detected by computed tomography (CT) scan at Screening.
Standard of care CT scans completed within 2 weeks prior to Screening may be used in
place of the Screening CT scan on a case by-case basis as agreed with the Medical
Monitor;
7. Prior therapy(ies), if applicable, must be completed according to the criteria below
prior to vector administration:
• Cytotoxic chemotherapy, at least 21 days from last dose;
• Non-cytotoxic chemotherapy (e.g., small molecule inhibitor), at least 14 days
from last dose;
• Monoclonal antibody, at least 30 days from last dose;
• Non-antibody immunotherapy (e.g., tumor vaccine), at least 42 days from last
dose;
• Radiotherapy, at least 14 days from last local site radiotherapy;
• Hematopoietic growth factor, at least 14 days from last dose; or
• Study drug, 30 days or 5 half-lives, whichever is longer, from last dose;
8. Patient previously treated with IFNs (e.g., for chronic active hepatitis);
9. Suspected/known hypersensitivity to IFN-α2b or rAd-IFN (including any of its
excipients);
10. Known hypersensitivity to celecoxib (including any of its excipients) or sulfonamides;
11. Known hypersensitivity to gemcitabine (including any of its excipients);
12. Impaired cardiac function or clinically significant cardiac disease including the
following:
• New York Heart Association class III or IV congestive heart failure;
• Myocardial infarction within the last 12 months; and
• Patients known to have impaired left ventricular ejection fraction per
institutional standards and of clinical significance as per Investigator review;
13. Women who are pregnant or breastfeeding;
14. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, depression, or psychiatric illness/social situations within the last 12
months;
15. Patients with active, known, or suspected auto-immune disease or a syndrome that
requires systemic or immunosuppressive agents (oral prednisolone or equivalent at a
dose of 10 mg per day is permitted); NOTE: patients with vitiligo, residual
hypothyroidism due to auto immune disease only requiring hormone replacement,
psoriasis not requiring systemic treatment, or conditions not expected to recur in the
absence of an external trigger are permitted to enroll;
16. History of asthma, acute rhinitis, nasal polyps, angioneurotic edema, urticaria, or
other allergic type reactions after taking acetylsalicylic acid or NSAIDs, including
COX-2 inhibitors;
17. History of ulcer disease or gastrointestinal bleeding;
18. Uncontrolled or poorly controlled hypertension (i.e., blood pressure >160/100 mmHg)
requiring 3 or more anti-hypertensive drugs;
19. Heart rate corrected QT interval using Fridericia's formula >470 ms on resting 12-lead
electrocardiogram (ECG);
20. Patients receiving lithium;
21. Any significant disease which, in the opinion of the Investigator, would place the
patient at increased risk of harm if he/she participated in the study;
22. History of a prior malignancy for which treatment was completed <2 years prior to
Screening or for which the patient has continued evidence of disease, or concurrent
malignancy that is clinically unstable and requires tumor-directed treatment;
23. Has a congenital or acquired immunodeficiency, including patients with known history
of infection with human immunodeficiency virus;
24. Has both serum albumin 2.5 to 3.5 g/dL and total bilirubin >1.5 ULN;
25. History of clinically significant inflammatory bowel disease requiring systemic
(parenteral) immunosuppressive therapy within 5 years prior to Screening; or
26. History of galactose intolerance, Lapp lactase deficiency, or glucose-galactose
malabsorption.
Clinical Trial to Evaluate CT053 in Patients With Relapsed and/or Refractory Multiple Myeloma (LUMMICAR STUDY 2)
A phase 1b, open label, multi-center, Clinical Study of Chimeric Antigen Receptor T Cells
targeting BCMA in patients with relapsed and or refractory multiple myeloma.
1. Voluntarily signed consent;
2. Age of ≥ 18 and ≤ 80 years;
3. Received sufficient prior lines of myeloma therapy;
4. Received treatment with at least one proteasome inhibitor, one IMiD and daratumumab.
5. The patients should have measurable disease per IMWG definition.
6. Estimated life expectancy > 12 weeks;
7. ECOG performance score 0-1;
8. Patients should have reasonable CBC counts, renal and hepatic functions;
9. Sufficient venous access for leukapheresis collection, and no other contraindications
to leukapheresis;
10. Women of childbearing age must undergo a serum pregnancy test with negative results
before screening, and are willing to use effective and reliable method of
contraception for at least 6 months after T cell infusion;
11. Men must be willing to use effective and reliable method of contraception for at least
6 months after T cell infusion.
Exclusion Criteria:
1. Pregnant or lactating women;
2. HIV, active hepatitis C virus (HCV), or active hepatitis B virus (HBV) infection;
3. Any uncontrolled active infection;
4. AEs from previous treatment that have not recovered;
5. Patients who have had anti-BCMA therapy;
6. Patients who have graft versus host disease (GvHD);
7. Patients have received stem cell transplantation less than 12 weeks before
leukapheresis;
8. Patients have received any anti-cancer treatment before leukapheresis;
9. Patients have received steroids before leukapheresis or lymphodepletion;
10. Patients have plasma cell leukemia, Waldenström macroglobulinemia, POEMS
(polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin
changes) syndrome or clinically significant symptomatic immunoglobulin light chain
(AL) amyloidosis with evidence of end-organ damage;
11. Patients have been administered live attenuated vaccine before leukapheresis or
lymphodepletion;
12. Patients allergic to Flu, Cy, tocilizumab, dimethyl sulfoxide (DMSO) or CT053 CAR BCMA
T cell;
13. Patients have clinical significant cardiac conditions that researchers believe that
participating in this clinical trial may endanger the health of the patients;
14. Patients have clinical significant pulmonary conditions;
15. Patients are known to have active autoimmune diseases including but not limited to
psoriasis, rheumatoid arthritis and other needs of long-term immunosuppressive
therapy;
16. Patients with second malignancies in addition to MM are not eligible;
17. Patients have central nervous system (CNS) metastases or CNS involvement;
18. Patients have significant neurologic disorders;
19. Patients are unable or unwilling to comply with the requirements of clinical trial;
20. Patients have received major surgery prior to leukapheresis or prior to
lymphodepletion.
Safety and Efficacy Study of IMSA101 in Refractory Malignancies
Open-label, dose escalation (Phase I) and dose expansion (Phase IIA) study of patients
receiving intra-tumoral IMSA101 alone or in combination with an immune checkpoint inhibitor
(ICI) (Phase I and II)
1. Signed informed consent and mental capability to understand the informed consent
2. Male or female patients > 18 years of age
3. Histologically or cytologically documented locally advanced or metastatic solid tumor
malignancies refractory to or otherwise ineligible for treatment with standard-of-care
agents/regimens, including but not limited to:
• Malignant melanoma
• Hormone receptor negative breast cancer
• Gastro-esophageal cancer
• Non-small cell lung cancer
• Head and neck cancer
• Hepatoma
• Renal cell carcinoma
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
5. Evaluable or measurable disease as follows:
• A minimum of 3 RECIST-evaluable lesions: one that is suitable for injection and
biopsied; one non-injected that will be biopsied for abscopal effect; and one
measurable lesion that will be followed for response only.
• Injectable tumors shall be accessed by intralesional (cutaneous) or percutaneous
injection only, including those lesions that are visible, palpable, or detectable
by standard radiographic or ultrasound methods. Neither surgical procedures nor
endoscopically-guided injections including those to endobronchial, endoluminal,
or endosinusial spaces shall be allowed. While no anatomic locations are required
or disallowed, lesions selected for intratumoral injection must, in the opinion
of the investigator:
• Not be immediately adjacent to blood vasculature or other physiologic landmarks
in such a way that will accrue undue safety risk to the patient
• Have longest diameter ≥ 10 mm and ≤ 50 mm
• Be fully efficacy evaluable per RECIST v1.1 criteria
6. Life expectancy > 3 months (Phase I) and > 6 months (Phase IIA)
7. ECG without evidence of clinically meaningful conduction abnormalities or active
ischemia as determined by the investigator
8. Acceptable organ and marrow function as defined below:
• Absolute neutrophil count > 1,500 cells/μL
• Platelets > 50,000 cells/μL
• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine transaminase (ALT) ≤ 2.5 times ULN. If
liver metastases are present, AST/ALT < 5 times ULN
• Serum creatinine < 1.5 mg/dL and a measured creatinine clearance ≥ 50 mL/min
using the Cockcroft-Gault formula
• Prothrombin time (PT)/partial thromboplastin time (PTT) ≤ 1.5 times ULN
9. Women of child-bearing potential (defined as a female who has experienced menarche and
who has not undergone successful surgical sterilization (hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy) or is not postmenopausal (defined as
amenorrhea for at least 12 consecutive months with an appropriate clinical profile at
the appropriate age, e.g., greater than 45 years) must have a negative serum pregnancy
test prior to first dose of study drug
10. Male and female patients with reproductive potential must agree to use two forms of
highly effective contraception throughout the study
11. Phase I combination only: Demonstrated RECIST stable disease through ≥ 4 consecutive
cycles of an approved PD-1 or PD-L1 targeted ICI with no Grade ≥ 3 CTCAE events
considered by the investigator to be drug-related.
Exclusion Criteria:
1. Anti-cancer therapy within 4 weeks or < 5 half-lives of the first dose of study drug.
2. Failure to recover to Grade 1 or less from clinically significant AEs due to prior
anti-cancer therapy.
3. Known untreated brain metastases or treated brain metastases that have not been stable
(scan showing no worsening of central nervous system (CNS) lesion[s] and no
requirement of corticosteroids) ≥ 4 weeks prior to study enrollment
4. Baseline prolongation of QT/QTc interval (QTc interval > 470)
5. Uncontrolled intercurrent illness (including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations) that in opinion of the
investigator would limit compliance with study requirements
6. Women who are pregnant or breastfeeding
7. Phase I combination only: Prior tumor progression through PD-1 or PD-L1 targeted ICI
therapy.
NIMBUS: Nivolumab Plus Ipilimumab in Metastatic Hypermutated HER2-negative Breast Cancer
This research study is studying a drug combination of nivolumab and ipilimumab as a possible
treatment for hypermutated HER2 negative breast cancer.
The drugs involved in this study are:
- Nivolumab (Opdivo ®)
- Ipilimumab (Yervoy ®)
• Participants must have histologically or cytologically confirmed invasive breast
cancer, with metastatic disease. Participants without pathologic or cytologic
confirmation of metastatic disease should have unequivocal evidence of metastasis from
physical examination or radiologic evaluation.
• Breast cancer must be HER2-negative by IHC or non-amplified as determined by the
current ASCO-CAP criteria. If patient has more than one histological result, the most
recent one will be usedfor inclusion. Participants may be ER/PR positive or negative.
• Patients must harbor tumors with total mutational burden (TMB) of at least 9 mutations
per megabase assessed by a cancer-gene panel containing more than 300 genes, and
performed in a CLIA verified laboratory. Tests like Foundation One, Oncopanel (DFCI),
or IMPACT (MSKCC) are acceptable for including patients on this trial.
• Participants must have measurable disease by RECIST version 1.1.
• Participants must agree to undergo a research biopsy, if tumor is safely accessible,
at baseline and at day 29 cycle 1 (+14 scheduling window). Previously collected
archival tissue will be obtained on all participants. Participants for whom
newly-obtained samples cannot be provided (e.g. inaccessible or participant safety
concern) may submit an archived specimen (block or if not possible, 20 unstained
slides).
• Prior chemotherapy: Participants may have received 0-3 prior chemotherapeutic regimens
for metastatic breast cancer and must have been off treatment with chemotherapy for at
least 14 days prior to study treatment initiation.
• Patients with hormone receptor positive breast cancer must have progressed on at least
one prior line of endocrine therapy in the metastatic setting or have disease
recurrence while on adjuvant endocrine therapy.
• Participants should also be adequately recovered from acute toxicities of prior
treatment, with the exception of alopecia and peripheral sensory neuropathy.
• Prior biologic therapy: Patients must have discontinued all biologic therapy at least
14 days prior to study treatment initiation.
• Prior radiation therapy: Patients may have received prior radiation therapy in either
the metastatic or early-stage setting. Radiation therapy must be completed 14 days
prior to study treatment initiation.
• In all cases, there must be no ongoing complications from prior radiotherapy.
• The subject is ≥18 years old.
• ECOG performance status ≤1(Karnofsky ≥70%, see Appendix A).
• Participants must have normal organ and marrow function as defined below:
• absolute neutrophil count ≥1,000/mcL
• platelets ≥100,000/mcL
• hemoglobin ≥ 8 g/dl
• total bilirubin ≤1.5 × institutional upper limit of normal (ULN) (or ≤ 2.0 x ULN
in patients with documented Gilbert's Syndrome)
• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN or (≤ 3 × institutional ULN for
participants with documented liver metastases)
• creatinine ≤1.5 × institutional ULN OR creatinine clearance ≥ 40 mL/min (using
Cockcroft-Gault formula) for participants with creatinine levels above
institutional ULN.
• Female subjects of childbearing potential must have a negative pregnancy test (serum
or urine) at screening.
• Childbearing potential is defined as: participants who have not reached a
postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause
other than menopause) and has not undergone surgical sterilization (removal of ovaries
and/or uterus).
• Female and male participants of childbearing potential must agree to use an adequate
method of contraception. For women, contraception is required starting with the first
dose of study medication through 150 days (5 months) after the last dose of study
medication. For men who are sexuall active with women of childbearing potential,
contraception is required starting with the first dose of study medication for a
period of 7 months after the last dose of nivolumab. Examples of contraceptive methods
with a failure rate of < 1% per year include bilateral tubal ligation, male
sterilization, established and proper use of hormonal contraceptives that inhibit
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration
of the clinical trial and the preferred and usual lifestyle of the patient. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and
withdrawal are not acceptable methods of contraception.
• Participants on bisphosphonates may continue receiving bisphosphonate therapy during
study treatment. Initiation of bisphosphonate or RANKL agent is allowed on study.
• The participant is capable of understanding and complying with the protocol and has
signed the informed consent document.
Exclusion Criteria:
• Major surgery within 2 weeks before the first dose of study treatment.
• Concurrent administration of other anti-cancer therapy within 14 days of starting
protocol therapy and during the course of this study.
• The participant has received another investigational agent within 14 days of the first
dose of study drug.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody.
• Known brain metastases that are untreated, symptomatic, or require therapy to control
symptoms. Participants with a history of treated central nervous system (CNS)
metastases are eligible. Treated brain metastases are defined as those having no
evidence of progression for ≥ 2 weeks after treatment, and no ongoing requirement for
corticosteroids, as ascertained by clinical examination and brain imaging (magnetic
resonance imaging or CT scan) completed during screening. Subject must be either off
corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily (or equivalent)
for at least 7 days prior to first study treatment. Treatment for brain metastases may
include whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate
by the treating physician. Participants with CNS metastases treated by neurosurgical
resection or brain biopsy performed within 28 days before study treatment initiation
will be excluded.
• The subject has uncontrolled, significant intercurrent or recent illness. Individuals
with a history of different malignancy are ineligible except for the following
circumstances. Individuals with a history of other malignancies are eligible if they
have been disease-free for at least 3 years or are deemed by the investigator to be at
low risk for recurrence of that malignancy.
• Participant has an active infection requiring IV antibiotics at initiation of study
therapy.
• Patient has a medical condition that requires chronic systemic steroid therapy or on
any other form of immunosuppressive medication. For example, participants with
autoimmune disease that requires systemic steroids or immunosuppression agents should
be excluded. Replacement therapy (eg., thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
not considered a form of systemic treatment.
• Subjects with current pneumonitis, or requiring supplementary O2 therapy.
• The participant is known to be positive for human immunodeficiency virus (HIV),
HepBsAg, or HCV RNA. HIV-positive participants on combination antiretroviral therapy
are ineligible
• Participants with any other active malignancy requiring concurrent intervention.
• Known hypersensitivity to any of the components of ipilimumab or nivolumab.
• The participant has received a live vaccine within 28 days prior to the first dose of
trial treatment and while participating in the trial. Examples of live vaccines
include, but are not limited to, the following: measles, mumps, rubella,
varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. The use of the
inactivated seasonal influenza vaccine (Fluzone®) is allowed.
• The participant is pregnant or breastfeeding.
Durvalumab vs Placebo Following Stereotactic Body Radiation Therapy in Early Stage Non-small Cell Lung Cancer Patients (PACIFIC-4)
This is a Phase III, randomized, placebo-controlled, double-blind, multi-center study
assessing the efficacy and safety of durvalumab versus placebo following SoC SBRT in patients
with unresected clinical Stage I/II lymph node-negative (T1 to T3N0M0) NSCLC.
1. Age ≥18 years
2. Histologically or cytologically documented Stage I to II NSCLC, with clinical Stage
I/II lymph node-negative (T1 to T3N0M0) disease and planned to receive definitive
treatment with SBRT. Patients may be medically inoperable or are medically operable
and refusing surgery or choosing to have SBRT (Stereotactic Body Radiation Therapy) as
definitive therapy
3. Completion of SoC SBRT as definitive treatment prior to randomization
4. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) PS of 0, 1,
or 2
5. Life expectancy of at least 12 weeks
6. Body weight >30 kg
7. Tumor sample required
8. Adequate organ and marrow function required
9. Patients with central or peripheral lesions are eligible
10. Staging studies must be done within 8 weeks before randomization
Key
Exclusion Criteria:
1. Mixed small cell and non-small cell cancer histology
2. History of allogeneic organ transplantation
3. History of another primary malignancy with exceptions
4. History of active primary immunodeficiency
5. Any unresolved toxicity National Cancer Institute (NCI) CTCAE Grade ≥2 from SBRT
(Stereotactic Body Radiation Therapy)
Drug: Durvalumab, Other: Placebo
Carcinoma, Non-Small-Cell Lung, Lung/Thoracic
NSCLC, Double- Blind, PD-L1, MEDI4736, Durvalumab, PFS, OS
APVO436 is being studied in this Phase 1/1b, open-label, multi-center, dose-escalation study
to evaluate the safety, pharmacokinetic/pharmacodynamic and clinical activity of APVO436
monotherapy in: 1) patients with AML that have relapsed on prior therapy or are refractory to
therapy and are not candidates for intensive chemotherapy or transplant, and 2) patients with
MDS that have > 5% blasts in the bone marrow or blasts in the peripheral blood who have also
failed prior therapy with an hypomethylating agent (HMA).
The primary objective of the Phase 1 part of the study is to determine the recommended dose
of APVO436 administered intravenously to patients with AML or MDS. The primary objective of
the Phase 1b part of the study is to evaluate the clinical activity of APVO436 in patients
with AML or MDS.
1. Signed informed consent. Consent must be obtained prior to any study-related
procedure.
2. Age ≥ 18 years
3. Histologically confirmed AML or MDS:
1. AML •relapsed or refractory AML and refuses or is not a candidate for intensive
chemotherapy (due to prior failure or not eligible due to expected intolerance)
or allogeneic transplant
2. MDS •relapsed or refractory MDS with > 5% blasts in the marrow or any blasts in
the peripheral blood. Patients must have failed prior treatment with an HMA
(azacitidine, decitabine, or other HMA agent); failure is defined as intolerance
to HMA, lack of response [no complete remission (CR) by at least 6 cycles], or
have IWG-defined progressive disease during or after treatment with an HMA.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
5. Life expectancy of > 2 months in the Investigator's opinion
6. White blood cells (WBC) ≤ 25,000 cells/mm3 (may receive hydroxyurea to bring WBC count
down prior to and during the first cycle of treatment with study drug if necessary)
7. Creatinine ≤ 2 × upper limit of normal (ULN)
8. Adequate liver test parameters: total bilirubin < 2.5 × ULN (if disease related or
secondary to Gilbert's disease, then total bilirubin < 3.5 mg/dL), aspartate
aminotransferase (AST), and alanine aminotransferase (ALT) < 3 × ULN
9. Prothrombin time (PT) / international normalized ratio (INR) and partial
thromboplastin time (PTT) < 1.5 × ULN
10. Patients and partners of childbearing potential must be willing to use adequate
contraception during the study and for 2 months after last study drug administration.
Adequate contraception means less than 1% chance of pregnancy may occur with proper
use of the method(s).
Exclusion Criteria:
1. Any central nervous system (CNS) (cerebral/meningeal) disease related to underlying
malignancy
2. History of seizures
3. Acute promyelocytic leukemia
4. Prior anti-CD123 therapy outside of this study
5. Any clinically significant graft-versus-host disease (GVHD) secondary to prior
allogenic transplant. Patients must be >90 days from transplant and have been on no
immunosuppressive therapy for >30 days. Topical corticosteroids for minor skin rash
(<5% body surface area) is acceptable. Prior solid organ transplant is acceptable
provided the patient is on no immunosuppressive therapy.
6. Any therapy or experimental treatment for MDS or AML within 7 days of the first dose
of study drug. Must have recovered to Grade ≤ 1 from any Grade 2 to 4 toxicity from
previous treatment. The use of hydroxyurea is acceptable and does not exclude the
patient.
7. Active, uncontrolled infection requiring systemic therapy. If the infection is
controlled or has resolved, maintenance and/or prophylactic systemic antimicrobials
are permitted.
8. Major surgery within 3 weeks prior to first dose of study drug
9. Known to be positive for HIV, hepatitis B virus surface antigen (HBsAg), hepatitis B
core antibody (HBcAb), or hepatitis C virus (HCV)
10. Pregnant or breast feeding
11. Any other active systemic malignancies. Exceptions: noninvasive non-melanoma skin
cancer, in situ carcinoma, cervical intraepithelial neoplasia, and breast or prostate
cancer that is well controlled with anti-hormonal therapy
12. Any current autoimmune disorder requiring immunosuppressive therapy
13. Requires more than a replacement dose of corticosteroids (i.e., > 10 mg/day of
prednisone or equivalent)
14. Any uncontrolled medical condition, including but not limited to:
1. Symptomatic congestive heart failure ≥ Class III (New York Heart Association
Functional Classification)
2. Uncontrolled hypertension
3. Unstable angina
4. Myocardial infarction within previous 6 months
5. Clinically significant arrhythmias not controlled by medication
6. Uncontrolled metabolic disorders such as hypercalcemia
15. Substance use disorder, psychiatric, cognitive, or any other condition that, in the
opinion of the Investigator, would pose a risk to the patient's safety, may compromise
the patient's ability to understand and comply with the protocol or provide informed
consent, or interfere with the study evaluation
16. Any difficulty complying with protocol requirements that may increase the risk
associated with study participation or study drug administration, or may cause a
safety concern for the patient