Search Results
within category "Digestive Systems & Liver Disease"
Here are the studies that match your search criteria. If you are interested in participating, please reach out to the contact listed for the study. If no contact is listed, contact us and we'll help you find the right person.
Phase 1 Dose-escalating Study of MM-398 (Irinotecan Sucrosofate Liposome Injection) Plus Intravenous Cyclophosphamide in Recurrent or Refractory 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
TransMedics (OCS) Liver Trial: Preserving and Assessing Donor Livers for Transplantation (Liver PROTECT)
A prospective, phased-pivotal, international randomized trial to evaluate the effectiveness
of the OCS™ Liver to preserve and assess donor livers intended for transplantation.
• Registered male or female primary Liver transplant candidate
• Age ≥18 years old
• Signed: 1) written informed consent document and 2) authorization to use and disclose
protected health information
Exclusion Criteria:
• Acute, fulminant liver failure
• Prior solid organ or bone marrow transplant
• Chronic use of hemodialysis or diagnosis of chronic renal failure, defined as chronic
serum creatinine of >3 mg/dl for >2 weeks and/or requiring hemodialysis
• Multi-organ transplant
• Ventilator dependent
• Dependent on > 1 IV inotrope to maintain hemodynamics
Device: OCS™ Liver System, Other: Control
Liver Transplantation, Liver Preservation for Transplant
1. Must have given written informed consent (signed and dated)
2. Participated in a PBC study with seladelpar
3. Females of reproductive potential must use at least one barrier contraceptive and a
second effective birth control method during the study and for at least 90 days after
the last dose. Male subjects who are sexually active with female partners of
reproductive potential must use barrier contraception and their female partners must
use a second effective birth control method during the study and for at least 90 days
after the last dose
Exclusion Criteria:
Exclusion criteria are only applicable for subjects with a seladelpar interruption greater
than 4 weeks prior to Day 1 of this study and for subjects who participated in CB8025-21838
irrespective of seladelpar interruption.
1. Treatment-related adverse event (AE) leading to seladelpar discontinuation in a
previous PBC study with seladelpar (MBX-8025)
2. A medical condition, other than PBC, that in the investigator's opinion would preclude
full participation in the study or confound its results (e.g., cancer)
3. AST or ALT above 3 × the upper limit of normal (ULN)
4. Total bilirubin above 2 × ULN
5. MELD score ≥ 12. For subjects on anticoagulation medication, evaluation of the
baseline INR, in concert with any current dose adjustments in anti-coagulant
medications, will be taken into account when calculating this score. This will be done
in consultation with the medical monitor.
6. Evidence of advanced PBC as defined by the Rotterdam criteria: albumin below 1× the
lower limit of normal (LLN) AND total bilirubin above 1 × ULN)
7. eGFR ≤45 mL/min/1.73 m2 (calculated by MDRD formula)
8. Auto-immune hepatitis
9. Primary sclerosing cholangitis
10. Known history of alpha-1-antitrypsin deficiency
11. Known history of chronic viral hepatitis
12. For females, pregnancy or breast-feeding
13. Use of colchicine, methotrexate, azathioprine, or long-term use of systemic steroids
(e.g. prednisone, prednisolone, budesonide) (>2 weeks) within 2 months prior to
Screening
14. Current use of fibrates or use of fibrates within 3 months prior to Screening
15. Current use of obeticholic acid or use of obeticholic acid within 3 months prior to
Screening
16. Use of an experimental or unapproved treatment for PBC within 3 months prior to
Screening
17. History of malignancy diagnosed or treated, actively or within 2 years, or active
evaluation for malignancy; localized treatment of squamous or non-invasive basal cell
skin cancers and cervical carcinoma in-situ is allowed if appropriately treated prior
to Screening
18. Treatment with any other investigational therapy or medical device within 30 days or
within 5 half-lives, whatever is longer, prior to Screening
19. Any other condition(s) that would compromise the safety of the subject or compromise
the quality of the clinical study, as judged by the Investigator
20. Immunosuppressant therapies (e.g., cyclosporine, tacrolimus, anti-TNF or other
immunosuppressive biologics)
21. Other medications that effect liver or GI functions such as absorption of medications
or the roux-en-y gastric bypass procedure may be prohibited and should be discussed
with the medical monitor on a case-by-case basis
22. Positive for:
1. Hepatitis B, defined as the presence of hepatitis B surface antigen
2. Hepatitis C, defined as the presence of hepatitis C virus ribonucleic acid (RNA)
3. Human immunodeficiency virus (HIV) antibody
23. Active COVID-19 infection during screening
A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001) (LIBRETTO-001)
This is an 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 participants with advanced solid tumors, including
rearranged during transfection (RET)-fusion-positive solid tumors, medullary thyroid cancer
(MTC) and other tumors with RET activation.
For Phase 1:
• Participants with a locally advanced or metastatic solid tumor that:
• Has progressed on or is intolerant to standard therapy, or
• For which 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 multikinase inhibitors (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) greater than or equal to (≥) 40 percent (%) (age less than [<] 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: Participants 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 participants with evidence of a RET gene
alteration in tumor
• 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:
• Cohorts 1-4 without measurable disease
• MCT not meeting the requirements for Cohorts 3 or 4
• 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: Participants who otherwise are eligible for Cohorts 1, 2 or 5 who
discontinued another RET inhibitor may be eligible with prior Sponsor approval
• Cohort 7: Participants with a histologically confirmed stage IB-IIIA NSCLC and a RET
fusion; determined to be medically operable and tumor deemed resectable by a thoracic
surgical oncologist, without prior systemic treatment for NSCLC
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: Participants
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 2 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 participants 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 Common Terminology Criteria
for Adverse Events (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. Participants 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) greater than (>) 470 milliseconds
(msec)
• Participants with implanted pacemakers may enter the study without meeting QTc
criteria due to nonevaluable measurement if it is possible to monitor for QT
changes.
• Participants with bundle branch block may be considered for study entry if QTc is
appropriate by a formula other than Fridericia's and if it is possible to monitor
for QT changes.
• Required treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or
inducers and certain prohibited concomitant medications
• Phase 2 Cohort 7 (neoadjuvant treatment): Participant must not have received prior
systemic therapy for NSCLC.
Drug: LOXO-292
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, neo-adjuvant treatment in early stage NSCLC
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.
The rationale of this clinical trial is to assess the feasibility of selective non-operative
management for locally advanced rectal cancer using dose-escalated ultra-fractionated short
course radiation therapy interdigitated with chemotherapy. We believe delivering short course
radiotherapy over a prolonged interval, at escalated doses and with concurrent chemotherapy
may be feasible and allow for improved clinical response.
1. At least 18 years of age. Both men and women and members of all races and ethnic
groups will be included.
2. Willing and able to provide written informed consent
3. Pathologic diagnosis of rectal adenocarcinoma
4. T3-4 and/or N+ disease per AJCC 8th edition
5. No prior treatment for rectal adenocarcinoma
6. Eastern Cooperative Group (ECOG) performance status of 0-2.
7. Laboratory values supporting acceptable organ and marrow function within 30 days of
eligibility confirmation. Defined as follows:
• WBC ≥ 3,000/mL;
• ANC WBC ≥ 1,000/mL;
• PLT ≥ 75,000/mL;
• T Bili ≤ 1.5 x upper limit of normal (ULN);
• AST/ALT ≤ 2.5 x ULN;
• Creatinine not above ULN, or creatinine clearance >50 mL/min/1.73 m2 for
participants with creatinine levels above institutional normal.
8. All men, as well as women of child-bearing potential must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) starting with
the first dose of study therapy through 90 days after the last dose of study drugs.
Should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately.
A female of child-bearing potential is any woman (regardless of sexual orientation, marital
status, 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).
Exclusion Criteria:
1. Distant nodal disease (retroperitoneal nodes) including inguinal nodes, or any
metastatic disease by CT.
2. Prior RT to the pelvis.
3. Uncontrolled comorbid illness or condition including congestive heart failure,
unstable angina, cardiac arrhythmia, or psychiatric illness that would limit
compliance with the study requirements.
4. Psychiatric illness/social situations that would limit consenting and compliance with
study requirements.
5. Participants who are pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants
Radiation: Ultrafractionated radiotherapy for rectal cancer
Rectal Cancer, Rectum
Rectal Cancer,T3-4 or N+
UT Southwestern; Parkland Health & Hospital System
Testicular Tissue Cryopreservation for Fertility Preservation
Testicular tissue cryopreservation is an experimental procedure where a young boy's
testicular tissue is retrieved and frozen. This technique is reserved for young male patients
who are not yet producing mature sperm, with the ultimate goal that their tissue may be used
in the future to restore fertility when experimental techniques emerge from the research
pipeline.
• Be male at any age.
• Be scheduled to undergo surgery, chemotherapy, drug treatment and/or radiation for the
treatment or prevention of a medical condition or malignancy with risk of causing
permanent and complete loss of subsequent testicular function.
• Or, have a medical condition or malignancy that requires removal of all or part of one
or both testicles.
• Have newly diagnosed or recurrent disease. Those who were not enrolled at the time of
initial diagnosis (i.e., patients with recurrent disease) are eligible if they have
not previously received therapy that is viewed as likely to result in complete and
permanent loss of testicular function.
• Have two testicles if undergoing elective removal of all or part of a testicle for
fertility preservation only. Note: removal of both testicles will limit fertility
preservation options.
• Sign an approved informed consent and authorization permitting the release of personal
health information. The patient and/or the patient's legally authorized guardian must
acknowledge in writing that consent for specimen collection has been obtained, in
accordance with institutional policies approved by the U.S. Department of Health and
• Consent for serum screening tests for infectious diseases [HIV-1, HIV-2, Hepatitis B,
Hepatitis C], to be performed at the time of testicular tissue harvesting.
• Undergo a full history and physical examination and obtain standard pre-operative
clearance (based on the most recent ACC/AHA Guideline for Perioperative Cardiovascular
Evaluation for Noncardiac Surgery) as determined by their primary surgeon.
• Participating in long term follow-up is a requirement of the protocol.
Exclusion Criteria:
• Diagnosed with psychological, psychiatric, or other conditions which prevent giving
fully informed consent.
• Diagnosed with an underlying medical condition that significantly increases their risk
of complications from anesthesia and surgery.
Procedure: Testicular biopsy
Lymphoma, Sarcoma, Cancer, Mycosis Fungoides, Brain and Nervous System, Other, Eye and Orbit, Anklylosing Spondylitis, Anus, Bones and Joints, Breast - Male, Carcinoid Tumor, Cardiovascular, Colon, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Nose, Other Digestive Organ, Other Endocrine System, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Leukemia, Other, Hodgkins Lymphoma, Heart, Leukemia, Not Otherwise Specified, Lymphoid Leukemia, Myeloid and Monocytic Leukemia, Non-Hodgkins Lymphoma, Other Hematopoietic, Small Intestine, Soft Tissue, Unknown Sites, Ill - Defined Sites, Autoimmune Disorders
Testing the Addition of an Anti-Cancer Immunotherapy Drug, Avelumab, to Gemcitabine and Carboplatin Chemotherapy Prior to Surgery in Muscle Invasive Urinary Tract Cancer vs. Surgery Alone in Patients Who Are Not Able to Receive Cisplatin Therapy (SWOG GAP TRIAL)
This phase II trial studies the effect of avelumab, gemcitabine and carboplatin before
surgery compared with surgery alone in treating patients with muscle invasive bladder or
upper urinary tract cancer who are not able to receive cisplatin therapy. Immunotherapy with
monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer,
and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs,
such as gemcitabine and carboplatin, 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. Giving avelumab together with gemcitabine and carboplatin before surgery may work
better in lowering the chance of muscle invasive urinary tract cancer growing or spreading,
in patients who cannot receive cisplatin therapy compared to surgery alone.
• Participants must have one of the following:
• Histologically documented muscle-invasive bladder carcinoma (MIBC) from
transurethral resection of bladder tumor (TURBT) within 56 days prior to
registration
• Histologically confirmed high grade upper tract urothelial carcinoma (UTUC)
within 56 days prior to registration, with invasion confirmed by either a mass on
cross-sectional imaging or a tumor directly visualized during upper urinary tract
endoscopy within 56 days prior to registration
• Participants diagnosed with mixed urothelial carcinoma and variant histology
within 56 days prior to registration may be eligible if the majority (> 50%) of
the tumor consists of urothelial carcinoma. Participants with pure non-urothelial
variant histologies or any small cell histology are not eligible
• Participants must have clinical stage T2-T4aN0M0 bladder or upper tract cancer
confirmed by radiologic staging (computed tomography [CT] scan/magnetic resonance
imaging [MRI] abdomen and pelvis, and CT scan/x-ray of the chest) within 56 days prior
to registration
• Participants must have a bone scan within 56 days prior to registration if they have
bone pain or elevated serum alkaline phosphatase
• Participants must have a bimanual examination under anesthesia within 56 days prior to
registration
• Participants must not have received prior systemic chemotherapy, immunotherapy or
radiotherapy for the treatment of muscle invasive bladder cancer (MIBC) or upper tract
urothelial carcinoma (UTUC). Other prior pelvic radiotherapy is allowed if it does not
preclude surgery (radical cystectomy, nephroureterectomy or ureterectomy, based on
location of primary tumor). Prior intravesical therapy is allowed
• Participants must not have received immunosuppressive medication within 14 days prior
to registration, with the exception of intranasal, inhaled, topical steroids, or local
steroid injections (e.g., intra-articular injection) systemic corticosteroids at
physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
• Participants must be >= 18 years of age
• Participants must have Zubrod performance status 0-2
• Participants must have history and physical examination within 28 days prior to
registration
• Participants must be surgical candidates as deemed by the local site oncologic surgeon
within 28 days prior to registration. This must be clearly documented
• Participants must have a serum creatinine =< the institutional upper limit of normal
(IULN) OR measured OR calculated creatinine clearance >= 30 mL/min using the
Crockroft-Gault Formula. This specimen must have been drawn and processed within 28
days prior to registration
• Participants must be deemed cisplatin-ineligible based on greater than or equal to 1
of the following:
• Zubrod performance status = 2
• Creatinine clearance (calculated by Crockroft-Gault formula or measured) 30 to <
60 ml/min,
• Neuropathy > grade 1
• Hearing loss > grade 1
• Congestive heart failure > grade 2
• Hemoglobin >= 9.0 g/dL (within 28 days prior to registration)
• Absolute neutrophil count >= 1,500/mcL (within 28 days prior to registration)
• Platelets >= 100,000/mcL (within 28 days prior to registration)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 days
prior to registration)
• Aspartate aminotransferase (AST) =< 2.5 x institutional ULN (within 28 days prior to
registration)
• Alanine aminotransferase (ALT) =< 2.5 x institutional ULN (within 28 days prior to
registration)
• Participants with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification and be class
2B or better
• Participants with known human immunodeficiency virus (HIV) must be on effective
anti-retroviral therapy and have undetectable viral load at their most recent viral
load test and within 6 months prior to registration
Exclusion Criteria:
• Participant must not have any other prior malignancy except for the following:
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,
prostate cancer Gleason score =< 3+4 in active surveillance, adequately treated stage
I or II cancer from which the participant is currently in complete remission, or any
other cancer from which the participant has been disease free for two years
• Participants must not be pregnant or nursing due to the risk of harm to a fetus or
nursing infant. Women/men of reproductive potential must have a negative serum or
urine pregnancy test within 28 days prior to registration and must have agreed to use
an effective contraceptive method. A woman is considered to be of "reproductive
potential" if she has had menses at any time in the preceding 12 consecutive months.
In addition to routine contraceptive methods, "effective contraception" also includes
heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect
of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or
bilateral tubal ligation. However, if at any point a previously celibate participant
chooses to become heterosexually active during the time period for use of
contraceptive measures outlined in the protocol, he/she is responsible for beginning
contraceptive measures
• Participants must not have a history of active primary immunodeficiency
• Participants must not have a history of or active autoimmune or inflammatory disorder,
with the exception of vitiligo, alopecia, hypothyroidism (stable on hormone
replacement), or chronic skin condition that does not require systemic therapy
Bladder Carcinoma Infiltrating the Muscle of the Bladder Wall, Stage II Bladder Cancer AJCC v8, Infiltrating Renal Pelvis and Ureter Urothelial Carcinoma
Niraparib in the Treatment of Patients With Advanced PALB2 Mutated Tumors
The purpose of this study is to further evaluate the efficacy and safety of niraparib in
patients with locally advanced or metastatic solid tumors and a pathogenic or likely
pathogenic tumor PALB2 (tPALB2) mutation.
• Participants must be at least 18 years of age or older.
• Participants must have a histologically or cytologically confirmed diagnosis of
locally advanced or metastatic solid tumor(s).
• Participants must have tested positive for a pathogenic or likely pathogenic tPALB2
gene mutation using a CLIA-certified laboratory as described in the Next-Generation
Sequencing (NGS) Laboratory Manual.
• Participants who have stable and asymptomatic Central Nervous System (CNS) disease
must be receiving a stable (for at least 7 days) or decreasing corticosteroid dose at
the time of study entry.
• Participants must submit fresh or archived (collected within 24 months of enrollment)
Formalin-Fixed Paraffin-Embedded (FFPE) tumor sample to the central laboratory for
post-enrollment confirmation of tPALB2 status.
• Participants must have received all standard therapies appropriate for their tumor
type and stage of disease or, in the opinion of the Investigator, the patient would be
unlikely to tolerate or derive clinically meaningful benefit from appropriate standard
of care therapy, or the participant has no satisfactory alternative treatments.
Exclusion Criteria:
• Participants have other active concomitant malignancy that warrants systemic,
biologic, or hormonal therapy.
• Participants who have ovarian or prostate cancer.
• Participants who have variants of undetermined significance (VUS), but not pathogenic
variants of PALB2, at the time of screening.
• Participants who relapsed while receiving platinum based therapy in the
adjuvant/curative setting.
• Participants progressing within 14-18 weeks while receiving platinum based therapy in
the metastatic setting.
• Participants who have received Poly (ADP-ribose) polymerase (PARP) inhibitor(s) in
prior lines of treatment.
• Participants with leptomeningeal disease, carcinomatous meningitis, symptomatic brain
metastases, or radiologic signs of CNS hemorrhage.
• Participants with germline or somatic BRCA1 or BRCA2 mutations.
• Participant has systolic blood pressure (BP) over 140 mmHg or diastolic BP over 90
mmHg, despite optimal medical therapy.
• Participants have previously or are currently participating in a treatment study of an
investigational agent within 3 weeks of the first dose of therapy preceding the study.
• Participants have received prior systemic cytotoxic chemotherapy, biological therapy,
or hormonal therapy for cancer, or received radiation therapy within 3 weeks of the
first dose therapy preceding the study.
Drug: Niraparib
Endometrial Cancer, Esophageal Cancer, Melanoma, Pancreatic Cancer, Metastatic Cancer, Head and Neck Cancer, Solid Tumor, Breast - Female, Colon, Corpus Uteri, Esophagus, Lung/Thoracic, Melanoma, skin, Other Urinary, Pancreas, Breast Tumor, Colon Tumor, Malignant, Lung Tumor, Urologic Cancer, Locally Advanced Solid Tumor
PALB2, Solid Tumor, Metastatic Solid Tumor, Locally Advanced Solid Tumor, Advanced Solid Tumor, Local Solid Tumor, PALB2 Mutation, Niraparib, tPALB2, tPALB2 Mutation, Pathogenic tumor, Lung Tumor, Breast Tumor, Colon Tumor, Zejula, Pancreatic Cancer, Urologic Cancer, Melanoma, Metastatic Cancer, Head and Neck Cancer, Endometrial Cancer, Esophageal Cancer
The iCat2, GAIN (Genomic Assessment Informs Novel Therapy) Consortium Study
This research study is evaluating the use of specialized testing of solid tumors including
sequencing. The process of performing these specialized tests is called tumor profiling. The
tumor profiling may result in identifying changes in genes of the tumor that indicate that a
particular therapy may have activity. This is called an individualized cancer therapy (iCat)
recommendation. The results of the tumor profiling and, if applicable, the iCat
recommendation will be returned.
• Age -- Age ≤ 30 years at time of initial qualifying solid tumor diagnosis
• Diagnosis -- Histologic diagnosis of solid malignancy (excluding brain tumors and
lymphoma) that meets at least one of the following criteria:
• Refractory, defined as tumor progression after initiation of standard first line
therapy without having achieved a prior partial or complete remission OR Biopsy
proven residual disease at the completion of planned standard initial front-line
therapy.
• Recurrent, defined as tumor progression after achieving a prior partial or
complete remission
• Newly diagnosed high risk disease, defined as having an expected event free
survival of < 50% at 2 years.
• Lacks definitive diagnosis or classical genomic findings after histologic review
and standard molecular testing (rare tumor group).
• Examples include (eligibility not limited to these examples):
• Histology typically associated with a fusion in which fusion is not detected.
• Ewing-like sarcoma
• Undifferentiated sarcoma
• Inflammatory myofibroblastic tumor without ALK fusion
• Infantile fibrosarcoma without NTRK fusion
• Specimen Samples
• Sufficient tumor specimen available to meet the minimum requirements for
profiling from diagnosis or progression / recurrence
--- OR
• Surgery / biopsy planned as part of clinical care that is anticipated to yield
sufficient material to meet the minimum requirements for profiling; OR
• Patient has already had molecular profiling and patient has not yet started
matched targeted therapy based on the report .
Exclusion Criteria:
• No Therapy Planned
-- Patients who have declined further anticancer therapy will be excluded.
• Performance Status
-- Patients with Lansky (age < 16 years) or Karnofsky (age ≥16 years) score < 50 will
be excluded.
• Life Expectancy -- Patients with anticipated life expectancy < 3 months will be
excluded.
Genetic: Genetic testing and GAIN report
Sarcoma, Pediatric Solid Tumor, Brain and Nervous System, Other, Eye and Orbit, Anklylosing Spondylitis, Anus, Bones and Joints, Breast - Female, Breast - Male, Carcinoid Tumor, 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, Heart, Kaposis sarcoma, Small Intestine, Soft Tissue, Ill - Defined Sites
Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery
This partially randomized phase II/III trial studies how well, in combination with surgery,
cisplatin and combination chemotherapy works in treating children and young adults with
hepatoblastoma or hepatocellular carcinoma. Drugs used in chemotherapy, such as cisplatin,
doxorubicin, fluorouracil, vincristine sulfate, carboplatin, etoposide, irinotecan,
sorafenib, gemcitabine and oxaliplatin, 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. Giving combination chemotherapy may kill more tumor cells than one type of
chemotherapy alone.
• Patients in Group F must have a body surface area (BSA) >= 0.6 m^2
• Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age; patients who are unable to walk because of
paralysis, but who are up in a wheelchair, will be considered ambulatory for the
purpose of assessing the performance score
• Patients must be newly diagnosed with histologically-proven primary pediatric hepatic
malignancies including hepatoblastoma or hepatocellular carcinoma, except as noted
below; patients with a diagnosis of hepatocellular neoplasm, not otherwise specified,
should be classified and treated per hepatoblastoma treatment arms; note that rapid
central pathology review is required in some cases; please note: all patients with
histology as assessed by the institutional pathologist consistent with pure small cell
undifferentiated (SCU) HB will be required to have testing for INI1/SMARCB1 by
immunohistochemistry (IHC) according to the practices at the institution
• Patients with histology consistent with pure SCU must have positive INI1/SMARCB1
staining
• For all Group A patients, WDF status as determined by rapid review will be used to
further stratify patients to Group A1 or A2
• For Groups B, C and D, rapid review is required if patients are either >= 8 years
of age or have an alphafetoprotein (AFP) =< 100 at diagnosis
• For all Groups E and F patients, rapid central pathology review is required
• In emergency situations when a patient meets all other eligibility criteria and has
had baseline required observations, but is too ill to undergo a biopsy safely, the
patient may be enrolled without a biopsy
• Clinical situations in which emergent treatment may be indicated include, but are
not limited to, the following circumstances:
• Anatomic or mechanical compromise of critical organ function by tumor (e.g.,
respiratory distress/failure, abdominal compartment syndrome, urinary
obstruction, etc.)
• Uncorrectable coagulopathy
• For a patient to maintain eligibility for AHEP1531 when emergent treatment is
given, the following must occur:
• The patient must have a clinical diagnosis of hepatoblastoma, including an
elevated alphafetoprotein (AFP), and must meet all AHEP1531 eligibility
criteria at the time of emergent treatment
• Patient must be enrolled on AHEP1531 prior to initiating protocol therapy; a
patient will be ineligible if any chemotherapy is administered prior to
AHEP1531 enrollment
• Note: If the patient receives AHEP1531 chemotherapy emergently PRIOR to
undergoing a diagnostic biopsy, pathologic review of material obtained in the
future during either biopsy or surgical resection must either confirm the
diagnosis of hepatoblastoma or not reveal another pathological diagnosis to be
included in the analysis of the study aims
• Patients may have had surgical resection of the hepatic malignancy prior to
enrollment; all other anti-cancer therapy for the current liver lesion is prohibited
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60
mL/min/1.73 m^2 or
• A serum creatinine based on age/gender as follows:
• Age: maximum serum creatinine (mg/dL)
• 1 month to < 6 months: 0.4 (male and female)
• 6 months to < 1 year: 0.5 (male and female)
• 1 to < 2 years: 06 (male and female)
• 2 to < 6 years: 0.8 (male and female)
• 6 to < 10 years: 1 (male and female)
• 10 to < 13 years: 1.2 (male and female)
• 13 to < 16 years: 1.5 (male), 1.4 (female)
• >= 16 years: 1.7 (male), 1.4 (female)
• Total bilirubin =< 5 x upper limit of normal (ULN) for age
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 10 x upper limit of normal (ULN) for age
• Shortening fraction of >= 28% by echocardiogram (for patients on
doxorubicin-containing regimens [Groups C, D, E2, and F] assessed within 8 weeks prior
to study enrollment) or
• Ejection fraction of >= 47% by echocardiogram or radionuclide angiogram (for patients
on doxorubicin-containing regimens [Groups C, D, E2, and F] assessed within 8 weeks
prior to study enrollment)
• Group F patients only: QT/corrected QT (QTc) interval =< 450 milliseconds for males
and =< 470 milliseconds for females (assessed within 8 weeks prior to study
enrollment)
• Normal pulmonary function tests (including diffusion capacity of the lung for carbon
monoxide [DLCO]) if there is clinical indication for determination (e.g. dyspnea at
rest, known requirement for supplemental oxygen) (for patients receiving chemotherapy
[Groups A, B, C, D, E2, F]); for patients who do not have respiratory symptoms or
requirement for supplemental oxygen, pulmonary function tests (PFTs) are NOT required
• 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:
• Prior chemotherapy or tumor directed therapy (i.e. radiation therapy, biologic agents,
local therapy (embolization, radiofrequency ablation, and laser); therefore, patients
with a pre-disposition syndrome who have a prior malignancy are not eligible
• Patients who are currently receiving another investigational drug
• Patients who are currently receiving other anticancer agents
• Patients with uncontrolled infection
• Patients who previously received a solid organ transplant, other than those who
previously received an orthotopic liver transplantation (OLT) as primary treatment of
their hepatocellular carcinoma
• Patients with hypersensitivity to any drugs on their expected treatment arm
• Group C: Patients who have known deficiency of dihydropyrimidine dehydrogenase (DPD)
• Group D:
• Patients with chronic inflammatory bowel disease and/or bowel obstruction
• Patients with concomitant use of St. John's wort, which cannot be stopped prior
to the start of trial treatment
• Group F:
• Patients with peripheral sensitive neuropathy with functional impairment
• Patients with a personal or family history of congenital long QT syndrome
• These criteria apply ONLY to patients who may receive chemotherapy (all groups other
than Group E1):
• 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
• Note for Group F: patients of childbearing potential should use effective
birth control during treatment with sorafenib and for at least 2 weeks after
stopping treatment
Comparing the Outcome of Immunotherapy-Based Drug Combination Therapy With or Without Surgery to Remove the Kidney in Metastatic Kidney Cancer, the PROBE Trial (PROBE)
This phase III trial compares the effect of adding surgery to a standard of care
immunotherapy-based drug combination versus a standard of care immunotherapy-based drug
combination alone in treating patients with kidney cancer that has spread to other places in
the body (metastatic). Immunotherapy with monoclonal antibodies, such as nivolumab,
ipilimumab, pembrolizumab, and avelumab, may help the body's immune system attack the cancer,
and may interfere with the ability of tumor cells to grow and spread. Axitinib may stop the
growth of tumor cells by blocking some of the enzymes needed for cell growth. Surgery to
remove the kidney, called a nephrectomy, is also considered standard of care; however,
doctors who treat kidney cancer do not agree on its benefits. It is not yet known if the
addition of surgery to an immunotherapy-based drug combination works better than an
immunotherapy-based drug combination alone in treating patients with kidney cancer.
• STEP 1 REGISTRATION: Participants must have a histologically proven diagnosis of clear
cell or non-clear cell renal cell carcinoma. Participants with collecting duct
carcinoma histology are not eligible. Participants with multifocal or bilateral tumors
are eligible
• STEP 1 REGISTRATION: Participants must have primary tumor in place
• STEP 1 REGISTRATION: Participants must have the following scans performed, showing
clinical evidence of measurable or non-measurable metastatic disease:
• Computed tomography (CT) scan of the chest (can be performed without contrast if
CT contrast cannot be given)
• CT of abdomen and pelvis with contrast OR magnetic resonance imaging (MRI) of the
abdomen and pelvis with or without contrast
Scans must be performed within the following timeframes:
• Treatment naive participants must have scans documenting metastatic disease completed
within 90 days prior to study registration
• Previously treated participants must have scans documenting metastatic disease
completed within 90 days prior to first dose of systemic treatment
• STEP 1 REGISTRATION: Participants with symptomatic metastases may have received
palliative radiotherapy or receive palliative radiotherapy after registration
• STEP 1 REGISTRATION: Participants must have no clear contraindications to
nephrectomy
• STEP 1 REGISTRATION: Participants must be offered the opportunity to participate
in specimen bank. With participant consent, specimens must be collected and
submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System
• STEP 1 REGISTRATION: Participants must be informed of the investigational nature
of this study and must sign and give informed consent in accordance with
institutional and federal guidelines
• STEP 1 REGISTRATION: As part of the Oncology Patient Enrollment Network (OPEN)
registration process the treating institution's identity is provided in order to
ensure that the current (within 365 days) date of institutional review board
approval for this study has been entered in the system
• STEP 2 REGISTRATION: Participants must have at least one of the following scans
performed 12 weeks (+/- 2 weeks) after starting pre-randomization treatment
• CT scan of the chest (can be performed without contrast if CT contrast cannot be
given)
• CT of abdomen and pelvis with contrast OR MRI of the abdomen and pelvis with or
without contrast Scans must be performed within 28 days prior to randomization.
Response should be assessed by comparing with a CT or MRI of the chest, abdomen and
pelvis obtained prior to starting pre-randomization treatment. Participants with
complete response in all metastatic sites are not eligible to randomize to Step 2
• STEP 2 REGISTRATION: Participants must have one of the following objective statuses
after 12 weeks of pre-randomization treatment
• Stable disease
• Partial response
• The treating investigator believes the patient is deriving clinical benefit from
systemic therapy AND have Zubrod performance status 0-1
• STEP 2 REGISTRATION: Participants must plan to continue the immune-based therapy
received during pre-randomization treatment
• STEP 2 REGISTRATION: Participants must be randomized on or between the 11th and
14th week of protocol-directed pre-randomization treatment therapy
• STEP 2 REGISTRATION: Participants must have received at least one of the minimum
amounts of immunotherapy:
• 2 infusions of nivolumab + 1 infusion of ipilimumab
• 2 infusions of pembrolizumab
• 2 infusions of avelumab
• STEP 2 REGISTRATION: Participants must have a planned surgery date within 42 days
of randomization
• STEP 2 REGISTRATION: Participants must be a surgical candidate as determined by
study urologist. The urology consult should be done within 42 days prior to
randomization
• STEP 2 REGISTRATION: Participants must have a complete physical examination and
medical history within 28 days prior to randomization
• STEP 2 REGISTRATION: Participants must have a Zubrod performance status of 0-1
within 28 days prior to randomization
• STEP 2 REGISTRATION: Total bilirubin =< institutional upper limit of normal (ULN)
(within 28 days prior to randomization)
• STEP 2 REGISTRATION: Aspartate aminotransferase (AST)/alanine aminotransferase
(ALT) =< 3 x institutional upper limit of normal (ULN) (within 28 days prior to
randomization)
• STEP 2 REGISTRATION: Serum creatinine =< 1.5 x the institutional upper limit of
normal (IULN) OR measured OR calculated creatinine clearance >= 50 mL/min using
the Cockcroft-Gault Formula) (must have been drawn and processed within 28 days
prior to randomization)
Exclusion Criteria:
• STEP 1 REGISTRATION: Participants must not have known active brain metastases.
Participants with previously treated brain metastases are eligible if participant has
no neurologic signs or symptoms suggestive of brain metastasis. Brain imaging studies
are not required. If brain imaging studies are performed, they must be negative for
disease
• STEP 1 REGISTRATION: Participants must not have received the following prior treatment
of metastatic renal cell carcinoma:
• Treatment naive participants must not have received any prior lines of systemic
therapy for metastatic renal cell carcinoma beyond the line intended as part of
protocol therapy
• Previously treated participants must not have received any systemic therapy for
metastatic renal cell carcinoma beyond the one regimen received off protocol as
specified in Step 1 pre-randomization treatment
• STEP 1 REGISTRATION: Participants must not have received more than the following
amounts protocol-directed pre-randomization treatment:
• Treatment naive participants must not have received any pre-randomization
treatment.
• Previously treated participants must not be planning to receive any additional
treatment prior to Step 2 randomization, and must not have received more than the
following amounts of pre-randomization treatment:
• 4 infusions of nivolumab
• 4 infusions of ipilimumab
• 4 infusions of pembrolizumab
• 7 infusions of avelumab
• STEP 1 REGISTRATION: Participants must not have received immunotherapy for any cancer
within the following timeframes:
• Treatment naive participants must not have received any immunotherapy within a
year of registration
• Previously treated participants must not have received any other immunotherapy
within a year of the start of off protocol specified pre-randomization treatment
• STEP 1 REGISTRATION: Participants must not have a solitary kidney and not have a
transplanted kidney
• STEP 1 REGISTRATION: No other prior malignancy is allowed except for the following:
adequately treated basal cell or squamous cell skin cancer, any in situ or T1 cancer,
adequately treated stage I or II cancer from which the participant is currently in
complete remission, or any other cancer from which the participant has been disease
free for at least two years
• STEP 1 REGISTRATION: Participants must not have been previously diagnosed with a
medical condition that makes them ineligible for immune based combination therapy or
nephrectomy
• STEP 2 REGISTRATION: Participants must not show progression in the primary tumor.
Participants who are considered to have pseudo progression are allowed
• STEP 2 REGISTRATION: Participants must not have known active brain metastases.
Participants with previously treated brain metastases are eligible if participant has
no neurologic signs or symptoms suggestive of brain metastasis. Brain imaging studies
are not required. If brain imaging studies are performed, they must be negative for
disease
• STEP 2 REGISTRATION: No other prior malignancy is allowed except for the following:
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,
adequately treated stage I or II cancer from which the participant is currently in
complete remission, or any other cancer from which the participant has been disease
free for two years
Procedure: Cytoreductive Nephrectomy, Drug: Active Comparator
Metastatic Renal Cell Carcinoma, Metastatic Clear Cell Renal Cell Carcinoma, Stage IV Renal Cell Cancer AJCC v8, Kidney
Study to Investigate the Efficacy and Safety of Dupilumab in Pediatric Patients With Active Eosinophilic Esophagitis (EoE) (EoE KIDS)
The Primary objective is to demonstrate the efficacy of dupilumab treatment compared with
placebo in pediatric patients with active eosinophilic esophagitis (EoE) based on histologic
improvement meeting validated histologic criteria.
The Secondary objectives are:
- To demonstrate the efficacy of dupilumab compared to placebo in pediatric patients with
active EoE after 16 weeks of treatment as assessed by endoscopic visual measurements of
disease activity using the Eosinophilic Esophagitis-Endoscopic Reference Score
(EoE-EREFS) and histologic abnormalities as measured by the EoE Histology Scoring System
(EoE-HSS)
- To evaluate the safety, tolerability, and immunogenicity of dupilumab treatment for up
to 16 weeks in pediatric patients with active EoE
- To evaluate the effects of dupilumab on transcriptomic signatures associated with EoE
and type 2 inflammation
- To study the effects of dupilumab on the type 2 inflammation gene expression signature
- To evaluate the concentration-time profile of functional dupilumab in serum in this
population
- To assess efficacy of long-term (52 weeks) dupilumab treatment
- To assess safety, tolerability, and immunogenicity of long-term (52 weeks) dupilumab
treatment
- To evaluate the impact of dupilumab treatment on EoE signs and symptoms
• A documented diagnosis of eosinophilic esophagitis (EoE)
• Baseline endoscopic biopsies with a demonstration on central reading of
intraepithelial eosinophilic infiltration
Key
Exclusion Criteria:
• Body weight <5 kg or ≥60 kg at screening
• Other causes of esophageal eosinophilia
• Active Helicobacter pylori
• History of Crohn's disease, ulcerative colitis, celiac disease, or prior esophageal
surgery
• Any esophageal stricture unable to be passed with a standard, diagnostic, upper
endoscope or any critical esophageal stricture that requires dilation at screening
• Treatment with swallowed topical corticosteroids within 8 weeks prior to baseline
standard of care endoscopy
• History of bleeding disorders or esophageal varices that, in the opinion of the
investigator, would put the patient at undue risk for significant complications from
an endoscopy procedure
• Active parasitic infection or suspected parasitic infection
• Known or suspected immunodeficiency disorder
NOTE: Other protocol defined inclusion/exclusion criteria apply.
Effects of Hypoglossal Nerve Stimulation on Cognition and Language in Down Syndrome and Obstructive Sleep Apnea
This study is a prospective, single-arm study conducted under a common implant and follow-up
protocol. The objective will be to follow fifty-seven (57) adolescents and young adults
(10-21 years of age), with Down syndrome, moderate to severe sleep apnea, and
post-adenotonsillectomy, for 12 months after undergoing implant of the Inspire Upper Airway
Stimulation (UAS) System. The study is being conducted in order to evaluate objective change
in cognition and expressive language after implant and therapy with the Inspire UAS System.
• Diagnosis of Down syndrome
• Age 10-21 years
• Prior adenotonsillectomy
• Severe OSA (AHI > 10, AHI < 50, no more than 25% AHI attributable to central events)
based on prior in-lab PSG performed after adenotonsillectomy and within 18 months of
enrollment
• Approval from at least two of the three physician reviewers based upon the results of
a routine drug-induced sleep endoscopy (DISE) having occurred within 12 months of
enrollment
• Subjects must have either tracheotomy or be ineffectively treated with CPAP due to
non-compliance, discomfort, un-desirable side effects, persistent symptoms despite
compliance use, or refusal to use the device
• Children and their parents/guardians must be willing to have stimulation hardware
permanently implanted, and be willing to participate in follow-up visits,
postoperative PSG, and questionnaire completion
• Children's parents/guardians must complete a questionnaire confirming that their child
is capable of communicating feelings of pain or discomfort. They must also confirm
they are able to assess their child for adverse effects related to device implantation
• Children and their parents/guardians must be proficient in English
Exclusion Criteria:
• Body mass index (BMI) above the 95th percentile for subject's age
• Circumferential airway collapse at the level of the velopharynx observed during DISE
• Other medical conditions resulting in medical instability (eg. congestive heart
failure, recent open heart surgery, immunosuppression, or chronic lung disease or
aspiration)
• Presence of another medical condition requiring future magnetic resonance imaging
(MRI) of the chest
• Patients with another implantable device which could interact unintentionally with the
Inspire system
• Any contraindication for general anesthesia
• History of bleeding or clotting disorders and those on blood thinning or NSAID
medications for the week prior to implantation surgery. Subjects will be asked to
refrain from the use of NSAIDS for two weeks after implantation or any revision
surgeries
• Subject is currently taking muscle relaxant medication
• Life expectancy less than 12 months
• Subject's inability to communicate pain or discomfort to their caretaker/parent, based
on parental or investigator assessment
• Nonverbal candidates will be excluded due to an inability to complete testing
procedures including expressive language sampling
• Subjects with a co-occurring diagnosis of autism spectrum disorder
• Subjects that have a positive β-HCG
• Subjects deemed unfit for participation by the investigator for any other reason
Device: Inspire Upper Airway Stimulation (UAS) System
Obstructive Sleep Apnea, Down Syndrome, Ear, Nose, Throat
A Phase 2b Study in Subjects With Alcoholic Hepatitis to Evaluate Safety and Efficacy of DUR-928 Treatment (AHFIRM)
This is a randomized, double-blind, placebo-controlled, phase 2b clinical Trial evaluating
Safety and Efficacy of DUR-928 (an experimental medication) in Patients with Alcoholic
Hepatitis (AH).
1. Able to provide written informed consent (either from subject or subject's legally
acceptable representative).
2. Onset of jaundice within prior 8 weeks.
3. Average daily consumption of >40 (females) or >60 (males) grams of alcohol for 6
months or longer, with < 8 weeks of abstinence before the onset of jaundice.
4. The determination of AH may be based on typical serum chemistry (as determined by
local laboratory) or liver biopsy at any time during the current episode of AH:
• Serum total bilirubin > 3.0 mg/dL
• 50 < AST < 400 IU/L
• ALT < 400 IU/L
• AST/ALT > 1.5
5. Maddrey discriminant function (MDF) ≥ 32 assuming a control prothrombin time of 12
seconds.
6. Model for End-stage Liver Disease (MELD) score: 21-30.
7. Liver biopsy is not required, but may be used to confirm the diagnosis of AH at the
Investigator's discretion. Biopsy, if used as a diagnostic criterion, must have
occurred during the current episode.
8. Male or female subjects 18 years of age or older.
9. Subjects must agree to use effective methods to prevent pregnancy while participating
in the study.
10. Subjects must agree to participate in an alcohol abstinence support program
recommended by the local institution's addiction specialists.
Exclusion Criteria:
1. Subjects taking systemic corticosteroids for a duration exceeding 8 days in the 30
days prior to screening.
2. Subjects experiencing or considered at high risk for alcohol withdrawal seizures or
delirium tremens.
3. Active infection (such as spontaneous bacterial peritonitis [SBP], urinary tract
infection [UTI], bacteremia, acute viral hepatitis, uncontrolled HIV, and active SARS
CoV2 infection).
4. Serum creatinine >2.5 mg/dL.
5. Subjects undergoing continuous veno-venous hemodialysis (CVVH).
6. Uncontrolled gastrointestinal bleeding.
7. A history of pre-admission refractory ascites defined as more than 4 paracenteses in
the previous 8 weeks despite diuretic therapy.
8. Liver biopsy (if carried out) with findings not compatible with AH.
9. Stage ≥3 hepatic encephalopathy by West Haven criteria.
10. Any severe concomitant cardiovascular, renal, endocrine, pulmonary, psychiatric
disorder, or multi-organ failure.
11. Other concomitant cause(s) of liver disease.
12. Any active malignancy or any malignancy diagnosed within the last five years other
than curable skin cancer (basal cell or squamous cell carcinomas).
13. Positive Urine Drug Screen (amphetamines, barbiturates, benzodiazepines, cocaine and
opiates) except THC and prescription medications.
14. Existing or intended pregnancy or breast feeding.
15. Participation in another interventional clinical trial within 30 days of Screening.
16. History of organ transplantation, other than a corneal transplant.
17. Underlying diseases that, in the opinion of the site investigator, might be
complicated or exacerbated by proposed treatments or might confound assessment of
study drug.
Drug: DUR-928 30 mg, Drug: DUR-928 90 mg, Drug: Placebo+ Standard of Care (SOC)
Abatacept in Immune Checkpoint Inhibitor Myocarditis (ATRIUM)
The primary aim is to test whether abatacept, as compared to placebo, is associated with a
reduction in major adverse cardiac events (MACE) among participants hospitalized with
myocarditis secondary to an immune checkpoint inhibitor (ICI). The primary outcome, MACE, is
a composite of first occurrence of cardiovascular death, non-fatal sudden cardiac arrest,
cardiogenic shock, significant ventricular arrythmias, significant bradyarrythmias, or
incident heart failure.
1. Must have provided informed consent in a manner approved by the Investigator's
Institutional Review Board (IRB) prior to any study-related procedure being performed.
If a participant is unable to provide informed consent due to his/her medical
condition, the participant's legally authorized representative may consent on behalf
of the study participant, as permitted by local law and institutional Standard
Operating Procedures;
2. Aged greater than or equal to 18 years at the time of informed consent;
3. Recent use of an FDA-approved immune checkpoint inhibitor (ICI, defined as
administered an immune checkpoint inhibitor ≤ 6 months of myocarditis diagnosis),
alone or in combination with other cancer therapies (i.e. chemotherapy, radiation
therapy or targeted therapy). The FDA-approved ICI could be given as part of a
clinical trial but not in combination with a new investigational agent which may cause
myocarditis;
4. A diagnosis of myocarditis.
5. Hospitalized at the time of randomization;
6. On 1000 mg of solumedrol per day for myocarditis or with an intent to initiate 1000 mg
of solumedrol per day for myocarditis within 24 hours of first administration of study
drug;
7. Serum evidence of ongoing myocardial injury: Serum evidence of ongoing myocardial
injury will be defined as an institutional troponin (either conventional or
high-sensitivity troponin I or T, using the standard institutional assay) with a value
that is ≥5 times the upper limit of the reference standard normal for that
institution. The troponin assay may be adjusted based on sex depending on
institutional standards. This value of troponin of ≥5 times above the institutional
upper limits of normal value must be noted within 10 days prior to potential
randomization. The 10-day period can be in the outpatient or inpatient setting. For
example, a participant with a troponin value that on one occasion was ≥5 times the
upper limits of institutional normal in the 10-day window prior to potential
randomization (whether in the inpatient or outpatient setting), but later decreases
below that threshold, typically due to starting corticosteroids, would still be
considered eligible;
8. The following laboratory parameters, not older than 48 hours at the time of
randomization, and measured as part of usual care:
• Total white blood cell (WBC) count >2,500/μl
• Absolute neutrophil count (ANC) >1,500/μL
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <20 times the
upper limit of the institutional normal ranges;
9. Women of childbearing potential (i.e., not postmenopausal, or surgically sterilized)
must have a negative highly sensitive urine or serum pregnancy test prior to
randomization. Participating women of childbearing potential must be willing to
consistently use effective methods of contraception from screening until at least 90
days after administration of the last dose of study drug. Participating men must also
be willing to consistently use effective methods of contraception from screening until
at least 90 days after administration of the last dose of study drug; and
10. Must be willing and able to abide by all study requirements and restrictions.
Exclusion Criteria:
1. Must not have experienced any of the following (as defined in the section on the
primary endpoint) in the 30-day period prior to randomization:
• A sudden cardiac arrest
• Cardiogenic shock as defined. A significant bradyarrhythmia (Mobitz type II
second degree atrioventricular block or third degree (complete) atrio-ventricular
(AV) block, for which an intervention with a temporary or permanent pacemaker is
completed or recommended).
• A significant tachyarrhythmia (ventricular fibrillation of any duration or
sustained ventricular tachycardia (>30 seconds, >120 beats per minute); or a
ventricular tachyarrhythmia requiring intervention.
2. Recent (≤2 month) exposure to abatacept or belatacept.
3. Concurrent or recent (≤2 month) use of the following non-corticosteroid
immunosuppressive therapies prior to randomization: mycophenolate, JAK STAT inhibitors
(including but not limited to upadacitinib, tofacitinib, baricitinib, and filgotinib),
tacrolimus, anti-thymocyte globulin, alemtuzumab, infliximab, and plasma exchange. The
use of intravenous immunoglobulin is permitted prior to randomization and during study
treatment.
4. Currently enrolled in another interventional study utilizing systemic agents for the
management of ICI-related toxicities.
5. Female who is pregnant, breastfeeding, or is considering becoming pregnant during the
study or for approximately 90 days after the last dose of study drug.
6. Male who is considering fathering a child or donating sperm during the study or for
approximately 30 days after the last dose of study drug.
7. Any active, chronic, or recurrent viral infection that, based on the investigator's
clinical assessment, makes the participant an unsuitable candidate for the study.
These may include hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or
disseminated (even a single episode) herpes zoster, and disseminated (even a single
episode) herpes simplex. Active HBV and HCV are defined as: HBV: hepatitis B surface
antigen (HBs Ag) positive (+) or detected sensitivity on the HBV deoxyribonucleic acid
(DNA) polymerase chain reaction (PCR) qualitative test for Hepatitis B core antibody
(HBc Ab) positive (+) participants; HCV: HCV ribonucleic acid (RNA) detectable in any
participant with anti-HCV antibody (HCV Ab). Patients with active Covid-19 infection
will be excluded. This is defined as the period of ongoing symptoms in the setting of
a positive Covid-19 test, or until 10 days after symptom onset and after resolution of
fever for at least 24 hours, without the use of fever-reducing medications.
8. Known active tuberculosis (TB), history of incompletely treated TB, suspected or known
extrapulmonary TB, suspected or known systemic bacterial or fungal infections;
9. Receipt of any live vaccine within four weeks prior to the first dose of study drug,
or expected need of live vaccination during study participation including at least 90
days after the last dose of IV study drug.
10. Any medical condition that could interfere with, or for which the treatment might
interfere with, the conduct of the study or interpretation of the study results, or
that would, in the opinion of the Investigator, increase the risk of the participant
by participating in the study.
11. Any factors that, in the Investigator's opinion, are likely to interfere with study
procedures, such as history of noncompliance with scheduled appointments.
Drug: Abatacept plus, Drug: Placebo
Cancer, 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, Rectum, Stomach, Thyroid, Urinary Bladder, Small Intestine, Soft Tissue, Unknown Sites, Myocarditis Acute
PREA, PK And Safety PASS Study Of IV Pantoprazole In Pediatric Subjects
The purpose of this study is to characterize the pharmacokinetics (PK) and safety of
intravenous (IV) pantoprazole in patients 1 to 16 years old who are candidates for acid
suppression therapy.
• Subjects aged 1 to 16 years who in the judgment of the investigator are candidates for
gastric acid suppression therapy (ie, those with a presumptive diagnosis of GERD, a
clinical diagnosis of suspected GERD, symptomatic GERD, or endoscopically proven GERD)
and whom the investigator judges would need to receive IV PPI therapy for at least 4
days.
• Body weight > 5th percentile for age.
• Y-site or dedicated IV line for administration of pantoprazole sodium.
• Expected survival for at least 30 days.
• Fertile male and female subjects of childbearing potential at risk for pregnancy must
agree to use a highly effective method of contraception throughout the study and for
at least 28 days after the last dose of assigned treatment. Female subjects of
non-childbearing potential must be premenarchal, have undergone hysterectomy with
bilateral oophorectomy, have medically confirmed ovarian failure, or achieved
post-menopausal status.
Exclusion Criteria:
• Participation in other studies involving investigational drug(s) or treatment with an
investigational drug within 30 days or 5 half lives prior to study entry and/or during
study participation.
• Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgment of the investigator, would make the subject
inappropriate for entry into this study.
• Pregnant females; breastfeeding females; fertile male subjects, and female subjects of
childbearing potential who are unwilling or unable to use a highly effective method of
contraception for the duration of the study and for at least 28 days after last dose
of investigational product.
• Serum CK levels >3x ULN.
• Known history of HIV or clinical manifestations of AIDS.
• Known hypersensitivity to PPIs or to any substituted benzimidazole or to any of the
excipients.
• History of treatment with any PPI within 2 days (48 hours) before investigational
product dosing on Day 1.
• Use of H2RAs, sucralfate, misoprostol, or prokinetic agents, and bismuth preparations
within 1 day (24 hours) before investigational product dosing on Day 1.
• Any disorder requiring chronic (every day) use of warfarin, carbamazepine, or
phenytoin, methotrexate, atazanavir or nelfinavir, clopidogrel, and potent inhibitors
and inducers of CYP2C19.
• Chronic (daily) use of glucocorticoids. Steroid inhalers and topical steroids may be
used.
• Active malignancy of any type, or history of a malignancy (Subject with a history of
malignancies that have been surgically removed or eradicated by irradiation or
chemotherapy and who have no evidence of recurrence for at least 5 years before
Screening are acceptable).
• ALT or BUN >2.0 ULN or estimated creatinine >1.5 X ULN for age or any other laboratory
abnormality considered by the Investigator to be clinically significant within 14 days
before Screening.
• In the Investigator's opinion, a chronic condition (eg, diabetes, epilepsy), which is
either not stable or well controlled and may interfere with the conduct of the study.
• History of sensitivity to heparin or heparin induced thrombocytopenia.
Drug: IV pantoprazole
Gastroesophageal Reflux Disease
candidate for acid suppression therapy, presumptive diagnosis of GERD, clinical diagnosis of suspected GERD, symptomatic GERD, endoscopically proven GERD
1. Have histologically confirmed advanced or metastatic castration-resistant prostate
cancer, bladder cancer, melanoma, non-small cell lung cancer, pancreatic cancer,
colorectal cancer, gastric cancer, esophageal cancer, ovarian cancer, and head neck
squamous cell carcinoma.
Or,
Have histologically confirmed metastatic pancreatic adenocarcinoma. Recurrent
unresectable pancreatic cancer is acceptable as long as the treatment is first-line.
2. Have not received any approved chemotherapy, except in the adjuvant setting.
Exclusion Criteria:
1. Subject was using immunosuppressive medications within 14 days before Screening with
the exception of topical (intranasal, inhaled, and local injection), systemic
(prednisone equivalent 10 mg/day or less), or as needed for hypersensitivity reactions
such as computed tomography (CT) scan premedication.
2. Subject has active infections or other serious underlying significant medical illness,
abnormal and clinically significant laboratory findings or psychiatric illness/social
situation.
3. Subject is using a pacemaker, implantable cardiac defibrillator, neurostimulator,
cochlear implants, cochlear implants, or other electronic medical equipment.
4. Subject has documented immunodeficiency or organ transplant.
5. Subject has an untreated central nervous system disease, leptomeningeal disease or
cord compression.
6. Subject has a history, or presence, of significant cardiovascular diseases; including
uncontrolled hypertension, clinically relevant cardiac arrhythmia, unstable angina or
myocardial infarction within 6 months before randomization, congestive heart failure >
New York Heart Association Class II, severe peripheral vascular disease, corrected QT
(QTc) prolongation >470 msec, clinically significant pericardial effusion.
7. Subject has a history or presence of documented inflammatory bowel disease.
8. Subject is known to be positive for human immunodeficiency virus infection.
-
Linerixibat Long-term Safety and Tolerability Study
This is an open-label, non-comparator, global, multi-center, long-term safety study for
evaluating safety and tolerability of linerixibat in participants with cholestatic pruritus
in primary biliary cholangitis (PBC) who participated in a prior eligible clinical trial with
linerixibat. Participants will be administered with 90 milligrams (mg) linerixibat orally
twice daily. The total daily dose will not exceed 180 mg total daily dose. The effect of
linerixibat on measures of quality of life and health-related quality of life in the study
population will also be assessed. The duration of the study will be approximately four years
until study end and the total duration of study participation will vary by participant
depending upon time of entry relative to study end in their respective country. Approximately
75 participants will be enrolled in this study.
• Participant must be 18 to 80 years of age inclusive, at the time of signing the
informed consent in the participant's parent trial BAT117213 (NCT01899703) or 201000
(NCT02966834)
• Participants with a diagnosis of PBC and a history of associated pruritus as evidenced
by randomization into a prior eligible linerixibat clinical trial.
• Participants must have completed the main treatment period in a prior eligible
linerixibat clinical trial.
• Male or female; Contraceptive use by women should be consistent with local regulations
regarding the methods of contraception for those participating in clinical studies.
Contraception by male participants or male partners of female participants is not
required in this protocol.
• A female participant is eligible to participate if she is not pregnant or
breastfeeding, and at least one of the following conditions applies:
1. is not a woman of childbearing potential (WOCBP) or
2. is a WOCBP and using a contraceptive method that is highly effective (with a
failure rate of <1 percent [%] per year), with low user dependency, as described
during the intervention period and for at least 4 weeks, after the last dose of
study intervention. The investigator should evaluate the effectiveness of the
contraceptive method in relationship to the first dose of study intervention;
3. a WOCBP must have a negative highly sensitive pregnancy test (urine or serum as
required by local regulations) within 24 hours before the first dose of study
intervention;
4. if a urine test cannot be confirmed as negative (e.g., an ambiguous result), a
serum pregnancy test is required. In such cases, the participant must be excluded
from participation if the serum pregnancy result is positive.
5. The investigator is responsible for review of medical history, menstrual history,
and recent sexual activity to decrease the risk for inclusion of a woman with an
early undetected pregnancy.
• Capable of giving signed informed consent as described in which includes compliance
with the requirements and restrictions listed in the informed consent form (ICF) and
in this protocol.
Exclusion Criteria:
• Screening total bilirubin >2x upper limit of normal (ULN). Total bilirubin >2x ULN is
acceptable if bilirubin is fractionated and direct bilirubin <35%.
• Screening ALT or AST >6x ULN.
• Screening eGFR <45 milliliters per minute per 1.73 square meter (mL/min/1.73m^2) based
on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
• History or presence of hepatic decompensation (e.g., variceal bleeds, encephalopathy
or ascites).
• Presence of actively replicating viral hepatitis B or C (HBV, HCV) infection and/or
confirmed hepatocellular carcinoma or biliary cancer.
• Recent or current clinically significant diarrhea in the Investigator's medical
opinion.
• Current symptomatic cholelithiasis or inflammatory gallbladder disease is
exclusionary. Participants with history of cholecystectomy >=3 months before screening
may be eligible for enrollment.
• Current diagnosis or previous diagnosis of colorectal cancer.
• Any current medical condition (e.g. psychiatric disorder, senility or dementia), which
may affect the participant's ability to comply with the protocol specified procedures.
• Use of Obeticholic acid: within 8 weeks prior to the date of the screening visit and
may not restart until after the end of the study or study withdrawal.
• Administration of any other ileal bile acid transporter (IBAT) inhibitor in the 1
month prior to screening.
• Current enrollment or participation in any other clinical study (except for 201000)
involving an investigational study treatment within 8 weeks prior to the screening
visit.
• QT interval corrected (QTc) >480 millisecond (msec): A QTc >480 msec (12-lead
electrocardiogram [ECG]) at screening is exclusionary.
• History of regular alcohol consumption within 6 months of the study defined as an
average weekly intake of >21 units for males or >14 units for females. One unit is
equivalent to 8 grams (g) of alcohol: a half-pint (~240 milliliter [mL]) of beer, 1
glass (125 mL) of wine or 1 measure (25 mL) of spirits.
Testing the Use of the Usual Chemotherapy Before and After Surgery for Removable Pancreatic Cancer
This phase III trial compares perioperative chemotherapy (given before and after surgery)
versus adjuvant chemotherapy (given after surgery) for the treatment of pancreatic cancer
that can be removed by surgery (removable/resectable). Chemotherapy drugs, such as
fluorouracil, irinotecan, leucovorin, and oxaliplatin, 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. Giving chemotherapy before and after surgery (perioperatively)
may work better in treating patients with pancreatic cancer compared to giving chemotherapy
after surgery (adjuvantly).
PRE-REGISTRATION:
• Pathology: Histologic or cytologic proof of pancreatic adenocarcinoma or adenosquamous
carcinoma
• TNM Stage: Tx-4, N0-1, M0 (M0 disease does not include spread to distant lymph nodes
and organs)
• Resectable Primary Tumor: Local radiographic reading must be consistent with
resectable disease defined as the following on 1) arterial and venous phase
contrast-enhanced abdominal/pelvic CT scan or abdominal/pelvic magnetic resonance
imaging (MRI) scan and 2) chest CT:
• No involvement or abutment of the celiac artery, common hepatic artery, superior
mesenteric artery, or replaced right hepatic artery (if applicable)
• Less than 180 degree interface between tumor and vessel wall of the portal vein
or superior mesenteric vein, and patent portal vein/splenic vein confluence
• No evidence of metastatic disease
• Measurable disease or non-measurable disease o Non-measurable disease is defined as
cytologic or histologic confirmation of adenocarcinoma of adenosquamous carcinoma by
fine needle aspiration or core-biopsy of the pancreas without measurable disease by
radiographic imaging
REGISTRATION:
• Confirmation of resectable disease by real-time central imaging review by the Alliance
Imaging Core Lab at Imaging and Radiation Oncology Core (IROC) Ohio
• Determined to be appropriate candidate for curative-intent pancreatectomy by surgeon
intending to perform the resection
• No prior radiation therapy, chemotherapy, targeted therapy, investigational therapy,
or surgery for pancreatic cancer
• Not pregnant and not nursing, because this study involves an agent that has known
genotoxic, mutagenic, and teratogenic effects.
• Therefore, for women of childbearing potential only, a negative pregnancy test done =<
14 days prior to registration is required
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Total Neuropathy Score < 2
• Absolute neutrophil count (ANC) >= 1,500/uL
• Platelet count >= 100,000/uL
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (If obstructive jaundice is
present, then biliary drainage must be initiated and total bilirubin =< 3.0)
• Creatinine =< 1.5 x ULN OR calculated (Calc.) creatinine clearance >= 30 mL/min
(Calculated using the Cockcroft-Gault equation)
• No known Gilbert's Syndrome or known homozygosity for UGAT1A1*28 polymorphism
• No comorbid conditions that would prohibit curative-intent pancreatectomy
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this
study. Patients on strong CYP3A4 inhibitors must discontinue the drug prior to
registration
• Chronic concomitant treatment with strong inducers of CYP3A4 is not allowed on this
study. Patients on strong CYP3A4 inducers must discontinue the drug prior to
registration
Comparison of Chemotherapy Before and After Surgery Versus After Surgery Alone for the Treatment of Gallbladder Cancer
This phase II/III trial compares the effect of adding chemotherapy before and after surgery
versus after surgery alone (usual treatment) in treating patients with stage II-III
gallbladder cancer. Chemotherapy drugs, such as gemcitabine and cisplatin, 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. Giving chemotherapy before surgery may make the
tumor smaller; therefore, may reduce the extent of surgery. Additionally, it may make it
easier for the surgeon to distinguish between normal and cancerous tissue. Giving
chemotherapy after surgery may kill any remaining tumor cells. This study will determine
whether giving chemotherapy before surgery increases the length of time before the cancer may
return and whether it will increase a patient's life span compared to the usual approach.
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0-1
• Patient must have histologically-confirmed T2 or T3 gallbladder cancer discovered
incidentally at the time of or following routine cholecystectomy for presumed benign
disease
• NOTE: Patients with histologically-confirmed Tis, T1a, T1b, or T4 tumors are not
eligible
• Patient must have undergone initial cholecystectomy within 12 weeks prior to
randomization
• Patient must have the ability to understand and the willingness to sign a written
informed consent document
• Leukocytes >= 3,000/mcL (obtained =< 28 days prior to randomization)
• Absolute neutrophil count >= 1,500/mcL (obtained =< 28 days prior to randomization)
• Platelets >= 100,000/mcL (obtained =< 28 days prior to randomization)
• Total bilirubin =< institutional upper limit of normal (ULN) except in patients with
Gilbert's syndrome. Patients with Gilbert's syndrome are eligible if direct bilirubin
< 1.5 x ULN of the direct bilirubin (obtained =< 28 days prior to randomization)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
institutional ULN (obtained =< 28 days prior to randomization)
• Serum creatinine =< institutional ULN OR creatinine clearance >= 50 mL/min/1.73 m^2
(Based on Cockcroft Gault estimation) (obtained =< 28 days prior to randomization)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months of randomization are eligible for
this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
• Patients with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association functional classification. To be
eligible for this trial, patients should be class 2B or better
Exclusion Criteria:
• Patient must not have any evidence of metastatic disease or inoperable loco-regional
disease based on high-quality, preoperative, cross-sectional imaging (computed
tomography [CT] or magnetic resonance imaging [MRI]) of the chest, abdomen, and pelvis
(C/A/P) obtained within 6 weeks prior to randomization, defined as
• No radiographic evidence of distant disease (M1 disease)
• No radiographic evidence of tumor invasion into multiple extrahepatic organs (T4
disease)
• No radiographic evidence of distant lymph node involvement (celiac, para-aortic,
para-caval lymph nodes)
• No evidence of new-onset ascites
• Soft tissue thickening within or in direct communication with the gallbladder
fossa, peri-portal lymph node involvement, involvement of one extrahepatic organ,
and other disease within the confines of what constitutes 'localized resectable'
disease are allowable
• Women must not be pregnant or breast feeding due to the potential harm to unborn fetus
and possible risk for adverse events in nursing infants with the treatment regimens
being used. All females of child bearing potential must have a serum or urine
pregnancy test to rule out pregnancy within 14 days prior to randomization. A female
of childbearing potential is defined as any woman, regardless of sexual orientation or
whether they have undergone tubal ligation, who meets the following criteria: 1) has
achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral
oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer
therapy does not rule out childbearing potential) for at least 24 consecutive months
(i.e., has had menses at any time in the preceding 24 consecutive months)
• Women of childbearing potential and sexually active males must not expect to conceive
or father children by being strongly advised to use accepted and effective method(s)
of contraception or to abstain from sexual intercourse for the duration of their
participation in the study
Stage III Gallbladder Cancer AJCC v8, Stage IIIA Gallbladder Cancer AJCC v8, Stage IIIB Gallbladder Cancer AJCC v8, Liver, Stage II Gallbladder Cancer AJCC v8, Stage IIA Gallbladder Cancer AJCC v8, Stage IIB Gallbladder Cancer AJCC v8
UT Southwestern; Parkland Health & Hospital System
A Multi-center Trial to Evaluate Multiple Regimens in Metastatic Pancreatic Cancer
Precision Promise is a multi-center, seamless Phase 2/3 platform trial designed to evaluate
multiple regimens in metastatic pancreatic cancer.
Primary Objectives
- To compare each investigational arm versus standard of care (SOC) for superiority in
overall survival in 1st and/or 2nd line metastatic pancreatic cancer patients and
determine which, if any, patients benefit from each investigational arm.
Secondary Objectives
- To determine short and long-term safety signals of each investigational arm in
pancreatic cancer patients vs. SOC.
- To determine progression-free survival (PFS) for each investigational arm vs. SOC.
- Rates of overall response, CR, and PR; duration of overall response, CR or PR (whichever
occurs first).
- Rate of clinical benefit; duration of clinical benefit.
Inclusion Criteria
A subject will be eligible to participate in Precision PromiseSM if all the below inclusion
criteria are met:
• Age ≥ 18 years
• Histologically or cytologically confirmed metastatic pancreatic ductal adenocarcinoma
(PDAC) and eligible for treatment in the first line or second line settings.
• Acceptable histologies include adenosquamous carcinoma, mucinous adenocarcinoma,
hepatoid carcinoma, medullary carcinoma, signet ring cell carcinoma, undifferentiated
carcinoma, and undifferentiated carcinoma with osteoclast-like-cells, and
adenocarcinoma. Pancreatic neuroendocrine tumors (PNET) are excluded.
• Radiographically measurable disease of at least one site by computed tomography (CT)
scan or magnetic resonance imaging (MRI) as defined by Response Evaluation Criteria In
Solid Tumors (RECIST) 1.1. Imaging results must be obtained within the 21-day window,
prior to randomization.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Adequate organ function (lab results must be obtained within the 21-day window prior
to randomization)
• Absolute neutrophil count ≥ 1500/mm3
• Hemoglobin ≥ the lower limit of normal (LLN) or 9g/dL
• Platelets ≥ 100,000/mm3
• Serum creatinine ≤ 1.0 x upper limit normal (ULN), or calculated creatinine
clearance ≥ 50 mL/min (Cockcroft Gault)
• Albumin ≥ 3.0 g/dL
• Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)
and/or alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT)
≤ 2.5 x ULN (up to ≤ 5 x ULN in presence of liver metastasis).
• Total bilirubin ≤ 1.5 x ULN
• INR ≤ 1.5 x ULN (up to ≤ 2 x ULN for subjects on anticoagulation therapy).
• Subjects must be willing to provide protocol-mandated tissue and blood samples for
diagnostic and research purposes as a condition of enrollment into the trial.
• Able to swallow pills, capsules or tablets.
• Able to adhere to study visit schedule and other protocol requirements.
• Females of childbearing potential [defined as a sexually mature woman who (1) has not
undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy
(the surgical removal of both ovaries) or (2) has not been naturally postmenopausal
for at least 24 consecutive months (i.e., has had menses at any time during the
preceding 24 consecutive months)] must:
• Have a negative serum or urine pregnancy test (β-human chorionic gonadotropin
[β-hCG]) as verified by the study doctor within 14 days prior to randomization.
• Commit to complete abstinence from heterosexual contact or agree to use medical
doctor-approved contraception throughout the study without interruption while
receiving study treatment and for at least 6 months following last dose of study
treatment.
• Males must practice complete abstinence or agree to use a condom (even if he has
undergone a successful vasectomy) during sexual contact with a pregnant female or a
female of childbearing potential while participating in the study, during dose
interruptions and for at least 6 months following last dose of study treatment.
• HIV-infected subjects on effective anti-retroviral therapy are eligible if the most
recent viral load test performed within six months of screening (based on medical
chart review) is negative. If this is not the case, an HIV viral load test should be
performed at screening and be negative (i.e., undetectable).
• HBV-infected subjects are eligible if the most recent viral load test performed within
six months of screening (based on medical chart review) is negative. If this is not
the case, an HBV viral load test should be performed at screening and be negative
(i.e., undetectable).
• Subjects with a history of hepatitis C virus (HCV) infection must have been treated
and cured. Subjects with HCV infection who are currently on treatment are eligible if
the most recent viral load test performed within six months of screening (based on
medical chart review) is negative. If this is not the case, an HCV viral load test
should be performed at screening and be negative (i.e., undetectable).
• Subjects with a history of brain metastases are eligible provided they show evidence
of stable lesions (and no new lesions) with no evidence of tumor progression for at
least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and
brain imaging (MRI or CT) during the screening period. In addition, any neurological
symptoms that developed either as a result of the brain metastases or their treatment,
must have returned to baseline or resolved. Any steroids administered as part of this
therapy must be completed > 7 days prior to the first dose of trial therapy.
• No known leptomeningeal disease.
• Subjects with a prior or concurrent malignancy whose natural history does not have the
potential to interfere with the safety or efficacy assessment of the investigational
regimen are eligible. Subjects receiving any active therapy for a concurrent secondary
malignancy are excluded.
• Subjects with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using New York Heart Association Functional Classification. To be eligible
for this trial, subjects should be Class 2 or better. Class 2 is defined as slight
limitation of physical activity, in which ordinary physical activity leads to fatigue,
palpitation, or dyspnea; the person is comfortable at rest.
• Understands the nature of the study and has agreed to participate by voluntarily
signing the IRB approved informed consent.
Exclusion Criteria
A subject will not be eligible to participate in Precision PromiseSM if any of the
following criteria are met:
• Received any anti-cancer systemic therapy within 21 days (or 5 half-lives, whichever
is shorter,) prior to randomization.
• Has had major surgery within 14 days prior to enrollment.
• History of known allergy or hypersensitivity to any of the study treatments or any of
their excipients or contraindication to any of the study treatments as outlined in the
local prescribing information (e.g., United States Prescribing Information [USPI]).
• Pre-existing peripheral neuropathy > Grade 1, as defined by CTCAE V 4.03.
• Known active tuberculosis infection.
• Serious, non-healing wound, ulcer, or bone fracture.
• The inability to swallow pills, capsules or tablets.
• Receiving any active therapy for a concurrent secondary malignancy. Subjects with a
prior or concurrent malignancy whose natural history and/or management does not have
the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible.
• History of interstitial lung disease, history of slowly progressive dyspnea and
unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, and
pulmonary hypersensitivity pneumonitis.
• QTc > 450 msec if male and QTc > 470 msec if female.
• Uncontrolled or severe cardiac disease (history of unstable angina, myocardial
infarction, coronary stenting, or bypass surgery within the prior 6 months),
symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia
[including atrial flutter/fibrillation].
• Subjects with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using New York Heart Association Functional Classification. Subjects worse
than Class 2 are excluded. Class 2 is defined as slight limitation of physical
activity, in which ordinary physical activity leads to fatigue, palpitation, or
dyspnea; the person is comfortable at rest.
• Active, uncontrolled infections (bacterial, viral, or fungal infection(s)) requiring
systemic therapy, defined as ongoing signs/symptoms related to the infection without
improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment
(i.e., subjects must be afebrile for > 48 hours off antibiotics).
• Active, known or suspected autoimmune disease, including systemic lupus erythematosus,
Hashimotos thyroiditis, scleroderma, polyarteritis nodosa or autoimmune hepatitis.
o Subjects with type I diabetes mellitus, hypothyroidism requiring only hormone
replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring
systemic treatment, or conditions not expected to recur in the absence of an external
trigger are eligible to participate.
• Receiving immunosuppressive or myelosuppressive medications that would, in the opinion
of the Investigator, increase the risk of serious neutropenic complications. Subjects
receiving replacement therapy of 10 mg of prednisone (or the equivalent hydrocortisone
dose) per day are eligible.
• Receipt of live vaccines within 30 days prior to the first dose of study treatment or
while on active treatment within the trial. (examples of live vaccines include, but
are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever,
rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are
generally killed virus vaccines and are permitted. However, intranasal influenza
vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not permitted).
• Any significant medical condition, laboratory abnormality or psychiatric illness that
would limit the subject's ability to comply with study requirements.
• Subjects that discontinued previous treatment for pancreatic adenocarcinoma due to a
treatment-related ≥ Grade 3 toxicity.
• For toxicity ≤ Grade 3, AE(s) must resolve to Grade 1 or baseline in order to be
considered eligible for this trial.
• Subjects that have received allogenic bone marrow or solid organ transplants are
excluded.
Drug: Gemcitabine combined with nab-paclitaxel, Drug: Dose -mFOLFIRINOX, Drug: Dose - Pamrevlumab combined with gemcitabine and nab-paclitaxel, Drug: Dose- Canakinumab and Spartalizumab combined with nab-paclitaxel and gemcitabine, Drug: Drug: Dose -SM-88
Study Evaluating the Safety and Efficacy of Semaglutide, and the Fixed-Dose Combination of Cilofexor and Firsocostat, Alone and in Combination, in Participants With Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH)
The primary objective of this study is to evaluate whether the combination of semaglutide
(SEMA) with the fixed-dose combination (FDC) of cilofexor/firsocostat (CILO/FIR) causes
fibrosis improvement and Nonalcoholic Steatohepatitis (NASH) resolution in participants with
compensated cirrhosis due to NASH.
• Liver biopsy consistent with cirrhosis (F4) due to NASH in the opinion of the central
reader. In participants who have never had a liver biopsy, a screening liver biopsy
may be performed
• Screening laboratory parameters as determined by the study central laboratory:
• Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m^2, as calculated by
the Modification of Diet in Renal Disease (MDRD) equation
• HbA1c ≤ 10%
• INR ≤ 1.4, unless due to therapeutic anticoagulation
• Platelet count ≥ 125,000/uL
• Alanine Aminotransferase (ALT) < 5 x ULN
• Serum albumin ≥ 3.5 g/dL
• Serum Alkaline Phosphatase (ALP) ≤ 2 x ULN
• BMI ≥ 23 kg/m^2 at screening
Key
Exclusion Criteria:
• Prior history of decompensated liver disease, including ascites, hepatic
encephalopathy (HE), or variceal bleeding
• Child-Pugh (CP) score > 6 at screening, unless due to an alternative etiology such as
Gilbert's syndrome or therapeutic anticoagulation
• Model for End-stage Liver Disease (MELD) score > 12 at screening, unless due to an
alternative etiology such as therapeutic anticoagulation
• Other causes of liver disease based on medical history and/or central reader review of
liver histology, including but not limited to: alcoholic liver disease, autoimmune
disorders (eg, primary biliary cholangitis, primary sclerosing cholangitis, autoimmune
hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron
overload, or alpha-1-antitrypsin deficiency
• Chronic HBV infection (HBsAg positive), or Chronic HCV infection (HCV antibody and HCV
RNA positive). Participants cured of HCV infection less than 2 years prior to the
screening visit are not eligible
• History of liver transplantation
• Current or prior history of hepatocellular carcinoma (HCC)
• Men who habitually drink greater than 21 units/week of alcohol or women who habitually
drink greater than 14 units/week of alcohol (one unit is equivalent to 12 oz/360 mL of
beer, a 4 oz/120 mL glass of wine, or 1 oz/30 mL of hard liquor).
• For individuals on vitamin E regimen ≥ 800 IU/day, or pioglitazone, dose must be
stable, in the opinion of the investigator for at least 180 days prior to the
historical or screening liver biopsy
• For individuals on medications for diabetes, dose must be stable, in the opinion
of the investigator, for at least 90 days prior to the historical or screening
liver biopsy
• History of type 1 diabetes
• Treatment with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in the period
from 90 days prior to the screening visit and for individuals with a qualifying
historical liver biopsy, for 90 days prior to the date of the historical liver biopsy
• For participants who have not completed a series of an authorized COVID-19 vaccination
regimen prior to screening, a positive result for COVID-19 on SARS-CoV-2 RT-PCR test
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Study of TT-00420 Tablet as Monotherapy and Combination Therapy in Patients With Advanced Solid Tumors
This is a Phase Ib/II, multicenter, open-label study to evaluate the safety and preliminary
efficacy of TT-00420 tablet, as monotherapy or in combination regimens, in patients with
advanced solid tumors.
1. ≥ 18 years of age
2. Histopathological or cytologically documented locally advanced or metastatic solid
tumors who have no available standard therapeutic treatment options
3. At least one measurable lesion as defined by RECIST V1.1 criteria for solid tumors
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Adequate organ function confirmed at screening and within 10 days of initiating
treatment, as evidenced by:
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
• Hemoglobin (Hgb) ≥ 8 g/dl
• Platelets (plt) ≥ 75 x 10^9/L
• AST/SGOT and ALT/SGPT ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5.0 x ULN if liver
metastases are present
• Total bilirubin ≤ 1.5 x ULN
• Calculated creatinine clearance ≥ 50 mL/min (Cockcroft Gault formula)
6. Negative pregnancy test within 72 hours before starting study treatment in all
premenopausal women and women < 12 months after the onset of menopause
7. Must agree to take sufficient contraceptive methods to avoid pregnancy during the
study and until at least 6 months after ceasing study treatment
8. Able to sign informed consent and comply with the protocol
Exclusion Criteria:
1. Women who are pregnant or lactating
2. Women of child-bearing potential (WOCBP) who do not use adequate birth control
3. Patients with any hematologic malignancy, including leukemia (any form), lymphoma, and
multiple myeloma
4. Patients with a history of primary central nervous system tumors or carcinomatous
meningitis.
5. Patients with the following mood disorders as judged by the Investigator or a
psychiatrist:
• Medically documented history of or active major depressive episode, bipolar
disorder (I or II), obsessive-compulsive disorder, schizophrenia; a history of
suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm
to others)
• ≥ CTCAE grade 3 anxiety
6. Impaired cardiac function or significant diseases, including but not limited to any of
the following:
• left ventricular ejection fraction (LVEF) < 45% as determined by multigated
acquisition (MUGA) scan or echocardiogram (ECHO)
• Congenital long QT syndrome
• QTcF ≥ 480 msec on screening ECG
• Unstable angina pectoris ≤ 3 months prior to starting study drug
• Acute myocardial infarction ≤ 3 months prior to starting study drug
7. Patients with:
• unresolved diarrhea ≥ CTCAE grade 2, or
• impairment of gastrointestinal (GI) function, or
• GI disease that may significantly alter the absorption of TT-00420
8. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,
uncontrolled hypertension, uncontrolled hypertriglyceridemia, or active or
uncontrolled infection) that could cause unacceptable safety risks or compromise
compliance with the protocol
9. Patients who have received chemotherapy, targeted therapy, or immunotherapy ≤ 4 weeks
(6 weeks for nitrosourea or mitomycin-C) prior to starting study drug or who have not
recovered from side effects of such therapy
10. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field
radiation for palliation ≤ 2 weeks prior to starting study drug or who have not
recovered from side effects of such therapy
11. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or
who have not recovered from side effects of such therapy
12. Patients who have been treated with any hematopoietic colony-stimulating growth
factors (e.g., G-CSF, GM-CSF) ≤ 4 weeks prior to starting study drug.
13. Patients who are currently receiving treatment with therapeutic doses of warfarin
sodium or any other coumarin-derivative anticoagulants
14. Patients who have received systemic corticosteroids ≤ 2 weeks prior to starting study
drug or who have not recovered from the side effects of such treatment.
15. Patients who are currently receiving treatment with strong CYP3A inhibitors or
inducers ≤ 2 weeks prior to starting study drug.
16. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not
mandatory; patients with well controlled HIV might be enrolled)
17. Known history of active infection with Hepatitis B or Hepatitis C
18. Has received a live-virus vaccination within 30 days of planned first dose
19. Inability to swallow or tolerate oral medication
20. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that, in the opinion of the investigator, might confound the results of the trial,
interfere with the patient's safe participation and compliance in the trial.
Prostate Cancer, Sarcoma, Gastric Cancer, Bladder Cancer, Cholangiocarcinoma, Gallbladder Cancer, Thyroid Cancer, Triple Negative Breast Cancer, HER2-negative Breast Cancer, Advanced Solid Tumor, Breast - Female, Breast - Male, Lung/Thoracic, Other Digestive Organ, Other Skin, Other Urinary, Prostate, Stomach, Thyroid, Small Intestine, Small-cell Lung Cancer
Evaluation of Co-formulated Pembrolizumab/Quavonlimab (MK-1308A) Versus Other Treatments in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Cancer (CRC) (MK-1308A-008)
The purpose of this study is to assess the efficacy and safety of co-formulated
pembrolizumab/quavonlimab versus other treatments in participants with MSI-H or dMMR
Metastatic Stage IV Colorectal Cancer.
• Has a histologically confirmed diagnosis of Stage IV CRC adenocarcinoma (as defined by
American Joint Committee on Cancer [AJCC] version 8)
• Has locally confirmed dMMR/MSI-H
• Has a life expectancy of at least 3 months
• Female participants are eligible to participate if not pregnant or breastfeeding, and
not a woman of childbearing potential (WOCBP), or if a WOCBP then uses a contraceptive
method that is highly effective or is abstinent on a long-term and persistent basis,
during the intervention period and for at least 120 days after the last dose of study
intervention
• Has measurable disease per RECIST 1.1 as assessed by the site and verified by BICR
• Submit an archival (within 5 years of Screening) or newly obtained tumor tissue sample
that has not been previously irradiated; formalin-fixed, paraffin embedded (FFPE)
blocks are preferred to slides.
• Has adequate organ function
Cohort A:
•Has been previously treated for their disease and radiographically progressed per RECIST
1.1 on or after or could not tolerate standard treatment, which must include all of the
following agents if approved and locally available in the country where the participant is
randomized:
• Fluoropyrimidine, irinotecan and oxaliplatin (capecitabine is acceptable as equivalent
to fluorouracil in prior therapy)
• With or without an anti-vascular endothelial growth factor (VEGF) monoclonal antibody
(e.g., bevacizumab)
• At least one of the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies
(cetuximab or panitumumab) for rat sarcoma viral oncogene homolog (RAS) wild-type
participants with left-sided tumors. Prior EGFR therapy is optional for patients with
right sided RAS Wild-type (WT) tumors.
Cohort B:
•Has untreated Stage IV dMMR/MSI-H CRC with no prior chemotherapy or immunotherapy for
this disease
Exclusion Criteria:
• Has received prior therapy with an agent directed to another stimulatory or
coinhibitory T-cell receptor
• Has received prior systemic anticancer therapy including investigational agents within
4 weeks before the first dose of study intervention
• Has not recovered adequately from a surgery procedure, and/or has any complications
from a prior surgery before starting study intervention
• Has received prior radiotherapy within 2 weeks of start of study intervention
• Has received a live or live-attenuated vaccine within 30 days before the first dose of
study intervention
• Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks before the first dose of
study intervention
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study medication
• Has a known additional malignancy that is progressing or has required active treatment
within the past 2 years
• Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab, quavonlimab, favezelimab,
vibostolimab, MK-4830, and/or any of their excipients
• Has an active autoimmune disease that has required systemic treatment in past 2 years
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
drugs)
• Has a history of (noninfectious) pneumonitis that required steroids or has current
pneumonitis
• Has a history of acute or chronic pancreatitis
• Has neuromuscular disorders associated with an elevated creatine kinase
• Has urine protein ≥1 gram/24 hours
• Has an active infection requiring systemic therapy (e.g., tuberculosis, known viral or
bacterial infections, etc.)
• Has a known history of Human Immunodeficiency Virus (HIV) infection
• Concurrent active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] positive
and/or detectable Hepatitis B Virus [HBV] deoxyribonucleic acid [DNA]) and Hepatitis C
virus (defined as anti-HCV antibody positive and detectable HCV ribonucleic acid [RNA]
infection
• Has clinically significant cardiac disease, including unstable angina, acute
myocardial infarction within 6 months from Day 1 of study intervention administration,
or New York Heart Association Class III or IV congestive heart failure. Medically
controlled arrhythmia stable on medication is permitted.
• Has present or progressive accumulation of pleural, ascitic, or pericardial fluid
requiring drainage or diuretic drugs within 2 weeks before randomization/allocation
• Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participant's
participation for the full duration of the study, or is not in the best interest of
the participant to participate, in the opinion of the treating investigator
• Has a known psychiatric or substance abuse disorder that would interfere with the
participant's ability to cooperate with the requirements of the study
• Has had an allogenic tissue/solid organ transplant
Stereotactic Radiosurgery (SRS) for Brain Metastasis (SRS)
SRS dose escalation for brain metastases in radiation-naïve patients will establish true
tolerable doses, which may exceed the current standard doses. This may lead to an improvement
in local control, patient survival, and/or quality-of life.
Inclusion Criteria
1. Biopsy-proven non-hematopoietic malignancy, except for small cell lung cancer, germ
cell cancer, or unknown primary tumor.
2. Radiographic evidence by MRI (or by CT scan with CT contrast if ineligible or
intolerant of MRI) of brain metastasis. (If patient is unable to tolerate MRI
contrast, an MRI without contrast is acceptable if lesions are visible)
3. All brain metastases must be outside the brain stem (midbrain, pons and medulla).
4. Patient must have 10 or less brain metastases.
5. The maximum diameter of any lesion must be less than or equal to 3.0 cm.
6. Previous treatment with surgery, radiation, chemotherapy, immunotherapy or any
targeted agents are allowed provided that:
• Radiation was not to the brain.
• Surgery to the brain was > 7 days prior to SRS and there remains at least one
additional brain metastasis that can be targeted with SRS
7. Age ≥ 18 years.
8. ECOG Performance Score of 2 or better/Karnofsky Performance Status score of 50-60 or
better.
9. All men, as well as women of child-bearing potential must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation. Should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately.
A female of child-bearing potential is any woman (regardless of sexual orientation,
marital status, 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).
Medically acceptable birth control (contraceptives) includes:
• Approved hormonal contraceptives (such as birth control pills, patch, or ring:
Depo-Provera, Implanon), or
• Barrier methods (such as a condom or diaphragm) used with a spermicide (a
substance that kills sperm)
10. Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria
1. Patients had craniotomy and surgery to the brain within 7 days from the date of SRS.
2. Patients with leptomeningeal metastasis.
NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive
CSF cytology and/or equivocal radiologic or clinical evidence of leptomeningeal
involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal
enhancement by imaging (MRI) would be considered to have LMD even in the absence of
positive CSF cytology, unless a parenchymal lesion can adequately explain the
neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally
symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would
not be considered to have LMD. In that patient, CSF sampling is not required to
formally exclude LMD, but can be performed at the investigator's discretion based on
level of clinical suspicion.
3. Patients with a contraindication to both MRI (with or without contrast) and CT scan
(with contrast)
4. Patients with life expectancy < 3 months.
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 the opinion of the
investigator, would limit compliance with study requirements.
6. Subjects must not be pregnant or nursing at the time of SRS treatment due to the
potential for congenital abnormalities and the potential of this regimen to harm
nursing infants.
Radiation: Stereotactic Radiosurgery
Brain Neoplasms, Adult, Malignant, Lymphoma, Sarcoma, Multiple Myeloma, Brain and Nervous System, Other, Eye and Orbit, Anklylosing Spondylitis, Anus, Bones and Joints, Breast - Female, Breast - Male, Cardiovascular, 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, Lymphoid Leukemia, Small Intestine, Soft Tissue
UT Southwestern; Parkland Health & Hospital System
Study of the Efficacy and Safety of Lonafarnib / Ritonavir With and Without Pegylated Interferon -Alfa-2a (D-LIVR)
Two LNF-containing regimens will be evaluated in the D-LIVR Phase 3 study: (1) LNF/RTV/PEG
IFN-alfa-2a and (2) LNF/RTV. Each of these arms will have efficacy endpoints that measure
clinical benefit with regard to viral suppression and alanine aminotransferase (ALT)
normalization. For each LNF-containing regimen, a composite endpoint of EOT (48 weeks)
virologic response and ALT normalization will be used. Virologic response will be defined as
a 2 log10 IU/mL reduction from baseline.
1. Chronic HDV infection for at least 6 months in duration, documented by a positive HDV
antibody test and HDV RNA ≥ 500 IU/mL.
Note: All genotypes of HDV permitted.
2. Demonstrable suppression of HBV DNA following at least 12 weeks of anti-HBV
nucleos(t)ide treatment with entecavir or tenofovir prior to initiating therapy.
3. Serum ALT > 1.3 x upper limit of the normal range (ULN) and < 10 x ULN.
4. Baseline liver biopsy demonstrating evidence of chronic hepatitis.
5. ECGs demonstrating no acute ischemia or clinically significant abnormality.
6. Normal dilated retinal examination.
Exclusion Criteria:
General Exclusions
1. Previous use of LNF within 12 months.
2. Current or previous history of decompensated liver disease.
3. Co-infected with human immunodeficiency virus or hepatitis C virus (HCV) by detectable
HIV RNA and HCV RNA, respectively.
4. Evidence of significant portal hypertension.
5. Current evidence or history of ascites requiring diuretics or paracentesis, or hepatic
encephalopathy.
6. History of hepatocellular carcinoma.
7. Patients with any of the following:
• Current eating disorder
• Evidence of alcohol substance use disorder.
• Drug abuse within the previous 6 months before screening.
8. Prior history or current evidence of any of the following:
• Immunologically mediated disease,
• Retinal disorder or clinically relevant ophthalmic disorder,
• Any malignancy within 5 years before screening,
• Cardiomyopathy or significant ischemic cardiac or cerebrovascular disease,
• Chronic pulmonary disease,
• Pancreatitis or colitis,
• Severe or uncontrolled psychiatric disorder.
9. Other significant medical condition that may require intervention during the study.
10. Any condition that may impact proper absorption.
11. Therapy with an immunomodulatory agent, IFN-α (eg, IFN alfa-2a or IFN-alfa-2b, or
pegylated IFN-alfa-2a or alfa 2b), cytotoxic agent, or chronic systemic
corticosteroids within 12 months of screening.
12. Use of heparin or warfarin.
13. Systemic antibiotics, antifungals, or antivirals for treatment of active infection
other than HBV.
14. Receipt of systemic immunosuppressive therapy.
15. History or evidence for any intolerance or hypersensitivity to LNF, RTV, PEG
IFN-alfa-2a, tenofovir or entecavir.
Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors
A study to learn about safety and find out maximum tolerable dose of palbociclib given in
combination with chemotherapy (temozolomide with irinotecan or topotecan with
cyclophosphamide) in children, adolescents and young adults with recurrent or refractory
solid tumors (phase 1). Phase 2 to learn about the efficacy of palbociclib in combination
with irinotecan and temozolomide when compared with irinotecan and temozolomide alone in the
treatment of children, adolescents, and young adults with recurrent or refractory Ewing
sarcoma (EWS).
Inclusion:
1. Histologically confirmed relapsed or refractory solid tumor as follows:
• For dose escalation and dose determination parts: Histologically confirmed
relapsed or refractory solid tumor (including CNS tumors but not lymphomas).
Patients with Diffuse Intrinsic Pontine Glioma do not require histological only
radiographic confirmed relapse to enroll.
• For dose expansion and tumor specific cohorts: Histologically confirmed relapsed
or refractory solid tumor including but not limited to EWS, rhabdoid tumor,
rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Patients with Diffuse
Intrinsic Pontine Glioma do not require histological only radiographic confirmed
relapse to enroll. EWS is not eligible for TOPO and CTX tumor-specific cohorts.
• For randomized Phase 2 part: Histologically confirmed Ewing sarcoma at diagnosis
or at relapse, with presence of EWSR1-ETS or FUS-ETS rearrangement.
Histopathology confirmation of both EWSR1-ETS or FUS-ETS rearrangement partners
is required OR availability of formalin fixed paraffin embedded (FFPE) tumor
tissue sample for central testing. Patient must have relapsed or have refractory
disease and at least evaluable disease in at least one site other than bone
marrow that can be followed by imaging.
2. Age ≥2 and <21 years at the time of study entry.
3. Lansky performance status ≥50% for patients ≤16 years of age, or Eastern Cooperative
Oncology Group (ECOG) 0, 1 or 2 for patients >16 years of age.
4. Adequate bone marrow function.
• Absolute neutrophil count ≥1000/mm3;
• Platelet count ≥100,000/mm3 (transfusion independent, no platelet transfusion in
past 7 days prior study entry);
• Hemoglobin ≥8.5 g/dL (transfusion allowed).
5. Adequate renal function: Serum creatinine level based on age/gender must within
protocol specified limits.
6. Adequate liver function, including:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
≤2.5 × upper limit of normal (ULN) or ≤5 × ULN for age, if attributable to
disease involvement of the liver;
• Total bilirubin ≤1.5 × ULN for age, unless the patient has documented Gilbert's
syndrome.
7. Patients enrolled to Phase 1 portion of the study and tumor specific cohorts must have
measurable disease as defined by RECIST version 1.1 or modified RANO criteria for CNS
disease or INRC for neuroblastoma. Patients with EWS enrolled to Phase 2 portion of
the study are eligible with evaluable disease (eg, bone only disease with no soft
tissue component).
8. Recovered to CTCAE Grade ≤1, or to baseline, from any non-hematological acute
toxicities of prior surgery, chemotherapy, immunotherapy, radiotherapy,
differentiation therapy or biologic therapy, with the exception of alopecia.
9. Serum/urine pregnancy test (for all girls ≥8 years of age) negative at screening and
at the baseline visit.
Exclusion:
1. Phase 1 and tumor specific cohorts: For palbociclib with IRN and TMZ combination,
prior treatment with a CDK4/6 inhibitor or progression while on treatment with an
IRN-containing regimen that includes TMZ. Patients who have received the combination
of IRN and TMZ and did not progress while on these medications are eligible. For
patients enrolling in the palbociclib with TOPO and CTX combination, prior treatment
with a CDK4/6 inhibitor or progression while on treatment with a TOPO-containing
regimen that includes CTX. Patients who have received the combination of TOPO and CTX
and did not progress while on these medications are eligible. Phase 2 portion: prior
treatment with a CDK4/6 inhibitor or progression while on treatment with an
IRN-containing or TMZ-containing regimen. Patients who have received IRN and/or TMZ
and did not progress while on these medications are eligible.
2. Prior intolerability to IRN and/or TMZ plus/minus palbociclib with IRN and TMZ
combination and prior intolerability to TOPO and/or CTX for TOPO and CTX combination.
3. Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers. Patients who are
receiving strong uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) inhibitors
within 12 days of Cycle 1 Day 1 (C1D1) are not eligible for the palbociclib with IRN
and TMZ combination. Patients who are receiving strong UGT1A1 inhibitors within 12
days of C1D1 are eligible for the palbociclib with TOPO and CTX combination (See
Section 5.7.1 for list of products.)
4. Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for
nitrosoureas.
5. Prior irradiation to >50% of the bone marrow (see Appendix 9).
6. Participation in other studies involving investigational drug(s) within 2 weeks or 5
half lives, whichever is longer, prior to study entry.
7. Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line
placement are not considered major surgeries.
8. For IRN and TMZ with/without palbociclib combinations: known or suspected
hypersensitivity to palbociclib, IRN and/or TMZ. For combination of palbociclib with
TOPO and CTX: known or suspected hypersensitivity to palbociclib, TOPO and/or CTX.
9. Patients with known symptomatic brain tumors or brain metastases and require steroids,
unless they have been on a stable or on a decreasing steroid dose for >14 days.
10. Patients with previously diagnosed brain metastases are eligible if they have
completed their prior treatment and have recovered from the acute effects of radiation
therapy or surgery prior to study entry for these metastases for at least 14 days post
radiation and 4 weeks post-surgery and are neurologically stable.
11. Hereditary bone marrow failure disorder.
12. QTc >470 msec.
13. History of clinically significant or uncontrolled cardiac disease, including:
• History of or active congestive heart failure; if patient had congestive heart
failure resolve and >1 year from resolution, patient will be considered eligible;
• Clinically significant ventricular arrhythmia (such as ventricular tachycardia,
ventricular fibrillation or Torsades de Pointes);
• Diagnosed or suspected congenital or acquired prolonged QT syndrome;
• Need for medications known to prolong the QT interval;
• Uncorrected hypomagnesemia or hypokalemia because of potential effects on the QT
interval;
• Left ventricular ejection fraction <50% or shortening fraction <28%.
14. Recent or ongoing clinically significant gastrointestinal disorder that may interfere
with absorption of orally administered drugs (eg, gastrectomy).
15. Severe acute or chronic medical or laboratory test abnormality that may increase the
risk associated with study participation or investigational product administration or
may interfere with the interpretation of study results, and in the judgment of the
Investigator, would make the patient inappropriate for entry into this study.
16. Investigator site staff members directly involved in the conduct of the study and
their family members, site staff members otherwise supervised by the investigator, or
patients who are Pfizer employees, including their family members, directly involved
in the conduct of the study.
Neuroblastoma, Sarcoma, Solid Tumors, Ewing Sarcoma, Medulloblastoma, Diffuse Intrinsic Pontine Glioma, Rhabdomyosarcoma, Rhabdoid Tumor, 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, 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, Kaposis sarcoma, Small Intestine, Soft Tissue, Ill - Defined Sites
Lower-Dose Chemoradiation in Treating Patients With Early-Stage Anal Cancer, the DECREASE Study
This phase II trial studies how well lower-dose chemotherapy plus radiation (chemoradiation)
therapy works in comparison to standard-dose chemoradiation in treating patients with
early-stage anal cancer. Drugs used in chemotherapy, such as mitomycin, fluorouracil, 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. Radiation therapy
uses high-energy x-rays to kill tumor cells and shrink tumors. Giving chemotherapy with
radiation therapy may kill more tumor cells. This study may help doctors find out if
lower-dose chemoradiation is as effective and has fewer side effects than standard-dose
chemoradiation, which is the usual approach for treatment of this cancer type.
• Patient must have histologically proven T1-2N0M0 invasive anal canal or anal margin
squamous cell carcinoma with tumors measuring =< 4 cm within 4 weeks prior to
randomization. This may include tumors of non-keratinizing histology such as basaloid,
transitional cell or cloacogenic histology. Patients with T1N0M0 anal margin squamous
cell carcinoma who underwent surgical excision with negative margins are not eligible
• Patients who are human immunodeficiency virus (HIV)-negative must not have lymph nodes
that are radiographically-concerning for cancer involvement using computed tomography
(CT) and positron emission tomography (PET)/CT-based criteria. Measurable disease is
not required
• Patients who are HIV-negative and do not have lymph nodes classified as lymph
node positive, but are felt to be borderline for cancer involvement must undergo
central imaging review
• NOTE: Patients requiring central imaging review will be pre-registered to
Arm S. Upon central confirmation of no lymph node involvement, eligible
patients may proceed to randomization on Step 1
• Patients will be considered to be lymph node (LN) positive and thereby not
eligible in this study if the lymph nodes meet any of the following criteria:
• Mesorectal, presacral, internal iliac or obturator LN with:
• Short axis measuring > 5 mm based on CT / magnetic resonance imaging
(MRI) OR
• Morphologic features of irregular border or central necrosis if
assessed on MRI and LN measures > 3 mm OR
• Fludeoxyglucose F-18 (FDG) uptake > blood pool (Deauville 3-5) based on
PET/CT
• External Iliac and common Iliac:
• Short-axis measuring > 1 cm based on CT / MRI OR
• Morphologic features of irregular border or central necrosis based on
CT / MRI OR
• FDG uptake > blood pool (Deauville 3-5) based on PET/CT
• Inguinal LN (superficial and deep) meeting any of the following criteria will be
ineligible unless an FNA is performed and resulting cytology is negative.
• Morphologic features of irregular border or central necrosis based on CT /
MRI
• FDG uptake > liver (Deauville 4) based on PET/CT.
• Patients who are HIV-negative and have inguinal lymph nodes that do not meet
the above criteria must undergo fine needle aspiration and have negative
histology to be eligible.
• Patients who are HIV-positive must have
• A CD4 count >= 300
• Confirmation of no lymph node involvement by central real-time review of imaging
• NOTE: Patients will be pre-registered to Arm S. Upon central confirmation of
no lymph node involvement, eligible patients may proceed to randomization on
Step 1
• Patient must have Eastern Cooperative Oncology Group (ECOG) •American College of
Radiology Imaging Network (ACRIN) performance status of 0-2
• Patient must have no history of prior radiation or chemotherapy for this malignancy
• Patient must not have had prior potentially curative surgery (i.e. abdominal-perineal
resection) for carcinoma of the anus
• Patients with excisional biopsy procedure are eligible provided there was tumor
involvement of the anal canal and/or anal verge prior to resection
• Patient must not be receiving any other standard anti-cancer therapy or experimental
agent concurrently with the study drugs
• Patient must not have intercurrent illness including, but not limited to, ongoing or
active infection or psychiatric/social situations that, in the judgement of the
investigator, would limit compliance with study requirements
• Patient must not have had significant cardiovascular disease including myocardial
infarction, unstable angina, stroke, transient ischemic attack, symptomatic coronary
artery disease, symptomatic congestive heart failure, or uncontrolled cardiac
arrhythmia within 6 months of randomization
• Patient must not have a history of a different malignancy unless they have been
disease-free for at least 2 years and are deemed by the investigator to be at low risk
of recurrence
• Individuals with the following cancers are eligible if diagnosed and treated
within the past 5 years: cervical cancer in situ and basal cell or squamous cell
carcinoma of the skin
• Patient must not have active autoimmune or connective disease
• Patients who are on anti-coagulation with warfarin within 2 weeks prior to
registration and are considering the use of capecitabine, must use an alternative
anti-coagulant
• NOTE: Low molecular weight heparin is permitted provided the patient's
prothrombin time (PT)/international normalized ratio (INR) is < 1.5
• Patients who will receive capecitabine and are on Dilantin for a seizure disorder must
have Dilantin levels checked weekly
• Hemoglobin > 10 g/dL (within 2 weeks prior to registration)
• Platelets >= 100,000/mm^3 (within 2 weeks prior to registration)
• Absolute neutrophil count >= 1500/mm^3 (within 2 weeks prior to registration)
• Serum creatinine must be < 1.5 X upper limit of normal (ULN), or calculated creatinine
clearance must be > 60 ml/min (within 2 weeks prior to registration)
• Total bilirubin must be < 2 X ULN (within 2 weeks prior to registration)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 X institutional
ULN (within 2 weeks prior to registration)
• Albumin >= 3.0 g/dL (within 2 weeks prior to registration)
• Women must not be pregnant or breast-feeding because the study treatment administered
may cause harm to an unborn fetus or breastfeeding child. All females of childbearing
potential must have a blood test or urine study within 2 weeks prior to registration
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 achieved menarche at some point, 2) has not undergone a
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal
(amenorrhea following cancer therapy does not rule out childbearing potential) for at
least 24 consecutive months (i.e., has had menses at any time in the preceding 24
consecutive months)
• Women of childbearing potential and sexually active males must be strongly advised to
use accepted and effective method(s) of contraception or to abstain from sexual
intercourse for the duration of their participation in the study and for at least 6
months after the completion of treatment
Comparing Two Treatment Combinations, Gemcitabine and Nab-Paclitaxel With 5-Fluorouracil, Leucovorin, and Liposomal Irinotecan for Older Patients With Pancreatic Cancer That Has Spread
This phase II trial compares two treatment combinations: gemcitabine hydrochloride and
nab-paclitaxel, or fluorouracil, leucovorin calcium, and liposomal irinotecan in older
patients with pancreatic cancer that has spread to other places in the body (metastatic).
Drugs used in chemotherapy, such as gemcitabine hydrochloride, nab-paclitaxel, fluorouracil,
leucovorin calcium, and liposomal irinotecan, 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. This study may help doctors find out which treatment combination is better at
prolonging life in older patients with metastatic pancreatic cancer.
• Newly diagnosed untreated metastatic adenocarcinoma of the pancreas. However, previous
surgery, adjuvant chemotherapy and/or radiation therapy will be allowed, provided
radiation therapy is completed at least 2 weeks prior to registration and adjuvant
therapy was administered more than 6 months prior to registration. Patients with the
following histology are excluded: acinar cell; adenosquamous carcinoma
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Patient is an English speaker with the ability to understand and complete the informed
consent and questionnaires
• Leukocytes >= 3,000/mcL (obtained within 4 weeks of registration)
• Absolute neutrophil count >= 1,500/mcL (obtained within 4 weeks of registration)
• Platelets >= 100,000/mcL (obtained within 4 weeks of registration)
• Total bilirubin =< institutional upper limit of normal (ULN) (obtained within 4 weeks
of registration)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN (obtained within 4 weeks of registration)
• Creatinine =< institutional ULN unless data exists supporting safe use at lower kidney
function values, no lower than 30 mL/min/1.73 m^2 (obtained within 4 weeks of
registration)
• Glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2 unless data exists supporting
safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 (obtained
within 4 weeks of registration)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months of registration are eligible for
this protocol. HIV positive (+) patients who are on ritonavir or/and cobicistat-based
regimen must be switched to alternative anti-retroviral therapy (ART)
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
• Male patients must agree not to father children while on study
• Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association functional classification. To be
eligible for this protocol, patients should be class 2B or better
• Patients must have measurable disease and scans must be done within 4 weeks of
registration
• Patients classified to have mild-moderate abnormalities in any of the domains
evaluated in the screening geriatric assessment and are classified as "vulnerable" are
eligible. Patients classified without any abnormalities ("fit") or with severe
cognitive/functional impairment or high co-morbidity score ("frail") on the screening
geriatric assessment are ineligible
• Patients must agree not to take any medications or substances that are strong
inhibitors or inducers of CYP3A4. Those who are randomized to liposomal irinotecan
treatment arm should avoid drugs that are UGT1A1 inhibitors