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.
CAMPFIRE: A Study of Ramucirumab (LY3009806) in Children and Young Adults With Desmoplastic Small Round Cell Tumor
This study is being conducted to test the safety and efficacy of ramucirumab in combination
with other chemotherapy in the treatment of relapsed, recurrent, or refractory desmoplastic
small round cell tumor (DSRCT) in children and young adults. This trial is part of the
CAMPFIRE master protocol which is a platform to accelerate the development of new treatments
for pediatric and young adult participants with cancer. Your participation in this trial
could last 12 months or longer, depending on how you and your tumor respond.
• Participants must have discontinued all previous treatments for cancer or
investigational agents ≥7 days after the last dose or per the type of previous
treatment as stated in the protocol and must have recovered from the acute effects to
≤Grade 2 for alopecia and decreased tendon reflex and to ≤Grade 1 for all other
effects at the time of enrollment, unless otherwise noted. Consult with the Lilly
clinical research physician or scientist for the appropriate length of time prior to
the first dose of study treatment.
• Participants with relapsed, recurrent, or refractory DSRCT.
• Participants must:
• Have measurable disease by Response Evaluation Criteria in Solid Tumors, Version
(RECIST) 1.1.
• Have received at least one prior line of systemic treatment (including
neoadjuvant and adjuvant chemotherapy). This prior treatment must include
approved therapies for which they are eligible, unless the participant is not a
suitable candidate for the approved therapy.
• Not be eligible for surgical resection at time of enrollment.
• Adequate cardiac function, defined as: Shortening fraction of ≥27% by echocardiogram,
or ejection fraction of ≥50% by gated radionuclide study.
• Adequate blood pressure (BP) control, defined as:
• Participants ≥18 years: Controlled hypertension defined as systolic BP ≤150
millimeters of mercury (mmHg) or diastolic BP ≤90 mmHg where standard medical
management is permitted. Please note that ≥2 serial BP readings should be
obtained and averaged to determine baseline BP.
• Participants <18 years: A BP ≤95th percentile for age, height, and gender
measured as described in National High Blood Pressure Education Program Working
Group (NHBPEPWG) on High Blood Pressure in Children and Adolescents (2004), where
standard medical management is permitted. Please note that ≥2 serial BP readings
should be obtained and averaged to determine baseline BP.
• Adequate hematologic function, as defined as:
• Absolute neutrophil count (ANC): ≥750/microliters (µL) granulocyte-colony
stimulating factor (G-CSF) permitted up to 48 hours prior. Participants with
documented history of benign ethnic neutropenia or other conditions could be
considered with a lower ANC after discussion with and approval from the Lilly
clinical research physician or scientist.
• Platelets: ≥75,000/cubic millimeters. Platelet transfusion permitted up to 72
hours prior.
• Hemoglobin: ≥8 grams per deciliter (g/dL) (≥80 g/liter). Transfusions to increase
the participant's hemoglobin level to at least 8 g/dL are permitted; however,
study treatment must not begin until 7 days after the transfusion, and complete
blood count criteria for eligibility are confirmed within 24 hr of first study
dose.
• Adequate renal function, as defined as:
• Creatinine clearance or radioscope glomerular filtration rate (GFR) ≥60
milliliters/minute/meters squared OR serum creatinine meeting the following
parameters:
• for participants ≥18 years of age serum creatinine ≤1.5×upper limit of
normal (ULN);
• for participants <18 years of age, serum creatinine based on age/gender as
follows: Age 1 to <2 years maximum serum creatinine 0.6, Age 2 to <6 years
maximum serum creatinine 0.8, Age 6 to <10 years maximum serum creatinine
1.0, Age 10 to <13 years maximum serum creatinine 1.2, Age 13 to <16 years
maximum serum creatinine 1.5 for males and 1.4 for females, Age 16 to <18
years maximum serum creatinine 1.7 for males and 1.4 for females.
• Urine protein meeting the following parameters:
• for participants ≥18 years of age: <2+ on dipstick or routine urinalysis. If
urine dipstick or routine analysis indicates proteinuria ≥2+, then a 24-hour
urine must be collected and must demonstrate <2 grams of protein in 24 hours
to allow participation in the study.
• for participants <18 years of age: ≤30 milligrams per deciliter urine
analysis or <2+ on dipstick. If urine dipstick or routine analysis indicates
proteinuria ≥2+, then a 24-hour urine must be collected and must demonstrate
<1 g of protein in 24 hours to allow participation in the study.
• Adequate liver function:
• Total bilirubin: ≤1.5×ULN. Except participants with document history of Gilbert
Syndrome who must have a total bilirubin level of <3.0×ULN.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): ≤2.5×ULN OR
≤5.0×ULN if the liver has tumor involvement.
• The participant has an adequate coagulation function as defined by International
Normalized Ratio ≤1.5 or prothrombin time ≤1.5×ULN, and partial thromboplastin time
≤1.5×ULN if not receiving anticoagulation therapy. For participants receiving
anticoagulants, exceptions to these coagulation parameters are allowed if they are
within the intended or expected range for their therapeutic use. Participants must
have no history of clinically significant active bleeding (defined as within 14 days
of first dose of study drug) or pathological condition that carries a high risk of
bleeding (for example, tumor involving major vessels or known esophageal varices).
• The participant has adequate hematologic and organ function ≤1 week (7 days) prior to
first dose of study drug.
• Female participants of childbearing potential must have a negative urine or serum
pregnancy test within 7 days prior to randomization. Male and female participants must
agree to use highly effective contraception for the duration of the study and up to 3
months following the last dose of ramucirumab and vinorelbine, and 12 months following
the last dose of cyclophosphamide in order to prevent pregnancy.
Exclusion Criteria:
• Participants with severe and/or uncontrolled concurrent medical disease or psychiatric
illness/social situation that in the opinion of the investigator could cause
unacceptable safety risks or compromise compliance with the protocol.
• Participants who have active infections requiring therapy.
• Participants with an active fungal, bacterial, and/or known severe viral
infection including, but not limited to, human immunodeficiency virus (HIV) or
viral (A, B, or C) hepatitis (screening is not required).
• Participants who have had allogeneic bone marrow or solid organ transplant are
excluded.
• Surgery: Participants who have had, or are planning to have, the following invasive
procedures are not eligible:
• Major surgical procedure, laparoscopic procedure, or significant traumatic injury
within 28 days prior to enrollment.
• Central line placement or subcutaneous port placement is not considered major
surgery.
• Core biopsy, fine needle aspirate, and bone marrow biopsy/aspirate are not
considered major surgeries.
• Surgical or other wounds must be adequately healed prior to enrollment.
• Bleeding and thrombosis:
• Participants with evidence of active bleeding or a history of significant (≥Grade
3) bleeding event within 3 months prior to enrollment are not eligible.
• Participants with a bleeding diathesis or vasculitis are not eligible.
• Participants with known or prior history in the prior 3 months of esophageal
varices are not eligible.
• Participants with a history of deep vein thrombosis requiring medical
intervention (including pulmonary embolism) within 3 months prior to study
enrollment are not eligible.
• Participants with a history of hemoptysis or other signs of pulmonary hemorrhage
within 3 months prior to study enrollment are not eligible.
• Cardiac:
• Participants with a history of central nervous system (CNS) arterial/venous
thromboembolic events (VTEs) including transient ischemic attack (TIA) or
cerebrovascular accident (CVA) within 6 months prior to study enrollment are not
eligible.
• Participants with myocardial infarction or unstable angina within the prior 6
months.
• Participants with New York Heart Association Grade 2 or greater congestive heart
failure (CHF).
• Participants with serious and inadequately controlled cardiac arrhythmia.
• Participants with significant vascular disease (eg, aortic aneurysm, history of
aortic dissection).
• Participants with clinically significant peripheral vascular disease.
• Participants who have a history of fistula, gastrointestinal (GI) ulcer or
perforation, or intra-abdominal abscess within 3 months of study enrollment are not
eligible.
• Participants with a history of hypertensive crisis or hypertensive encephalopathy
within 6 months of study enrollment are not eligible.
• Participants who have non-healing wound, unhealed or incompletely healed fracture, or
a compound (open) bone fracture at the time of enrollment are not eligible.
• Participants previously treated and progressed on combination cyclophosphamide and
vinorelbine regimen. Participants who received combination as maintenance therapy,
without progression, would be eligible.
• Participants with a known hypersensitivity to ramucirumab, cyclophosphamide,
vinorelbine or any of the excipients of the medicinal products.
• Hepatic impairment:
• Severe liver cirrhosis Child-Pugh Class B (or worse).
• Cirrhosis with a history of hepatic encephalopathy.
• Clinically meaningful ascites resulting from cirrhosis and requiring ongoing
treatment with diuretics and/or paracentesis.
• History of hepatorenal syndrome.
• The participant has a bowel obstruction, history or presence of inflammatory
enteropathy or extensive intestinal resection (eg, hemicolectomy or extensive small
intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or
chronic diarrhea.
• The participant has a urinary outflow obstruction.
• The participant has Grade 2 hematuria or non-infectious cystitis at the time of
screening.
• Participants with central nervous system (CNS) involvement are ineligible.
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
This clinical trial will evaluate 4 different strategies of chemotherapy schedules in newly
diagnosed participants with metastatic Fusion Positive (alveolar) Rhabdomyosarcoma. The
participant and their physician will choose from: Arm A) a first strike therapy, Arm B) a
first strike-second strike (maintenance) therapy, Arm C) an adaptively timed therapy, and Arm
D) conventional chemotherapy.
• Participants must have a new histologic diagnosis of rhabdomyosarcoma
• Participants must have FISH, PCR or other molecular confirmation of PAX/FOXO1 fusion
per institutional standards
• Participants must have sufficient tissue (up to 10 unstained FFPE) for correlative
testing
• All participants must have distant metastatic disease; either biopsy positive or PET
avid extranodal or distant nodal lesions determined by the investigator to be
metastatic disease. Patients with a single distant metastatic site that has been
excised prior to study entry are eligible
• No prior systemic chemotherapy
• Participants enrolled to Arm B, maintenance, must be able to take oral
cyclophosphamide. Note: enteral administration of cyclophosphamide is allowable.
• Males and females of reproductive potential may not participate unless they have
agreed to the use of, at minimum, two methods of contraception during and after
treatment or abstinence.
• Women of childbearing potential should adhere to contraception for a period of 4
months after completion of systematic chemotherapy administration
• Men who are sexually active with women of child bearing potential should adhere to
contraception for a period of 4 months after completion of systematic chemotherapy
administration
• All patients and/or their parents or legal guardians must have the ability to
understand and the willingness to sign a written informed consent or assent document.
Exclusion Criteria:
• Participants with regional lymph nodes as the only site of disease are not eligible.
Distant nodal sites alone are eligible
• Participants who are receiving any other investigational agents for rhabdomyosarcoma
are ineligible
• Participants must not be receiving any additional medicines being given for the
specific purpose of treating cancer. Alternative medications including, but not
limited to cannabis based products would not be a reason for exclusion
• Participants are ineligible if they have uncontrolled intercurrent illness including,
but not limited to:
• ongoing or active infection not expected to resolve with current antibiotic plan
• cardiac arrhythmia
• psychiatric illness/social situations that would limit compliance with study
requirements
• Patients who are pregnant or breastfeeding are not eligible because there is no
available information regarding human fetal or teratogenic toxicities. Females of
childbearing potential must have a negative serum or urine pregnancy test within 24
hours of starting protocol therapy.
• Participants who are considered unable to comply with the safety monitoring
requirements of the study are not eligible
Nivolumab or Nivolumab and Azacitidine in Patients With Recurrent, Resectable Osteosarcoma
The purpose of this study is to evaluate the safety and efficacy of nivolumab, or nivolumab
in combination with azacitidine in participants with recurrent, resectable osteosarcoma
• Participants must have had a histologic diagnosis of osteosarcoma at original
diagnosis
• Disease Status: Patients with an isolated pulmonary recurrence of osteosarcoma can be
enrolled on this study.
• Any history of metastatic disease at a site other than lung would make the
patient ineligible for this study.
• The patient's treating team must consider the patient's disease to be resectable
and the patient must be willing to undergo resection of all disease, including
any lung lesion meeting criteria for likely metastatic disease, defined as: 3 or
more lesions ≥ 3 mm in diameter OR a single lesion ≥ 5 mm.
• Patients with bilateral disease are eligible provided their disease is considered
resectable. Resectable pulmonary nodules are defined as nodules that can be
removed without performing a pneumonectomy (e.g., nodules immediately adjacent to
the main stem bronchus or main pulmonary vessels).
• Must have a performance status corresponding to Eastern Cooperative Oncology Group
(ECOG) scores of 0, 1 or 2, using the Karnofsky scale for patients > 16 years of age
and the Lansky scale for patients ≤ 16 years of age
• Prior Therapy: Participants must have fully recovered from the acute toxic effects of
all prior chemotherapy, immunotherapy, or radiotherapy prior to the start of protocol
therapy.
• Participants must have normal organ and marrow function within 7 days of starting
protocol therapy
• All participants and/or their parents or legal guardians must have the ability to
understand and the willingness to sign a written informed consent/assent document
• Additional criteria may apply
Exclusion Criteria:
• Pregnancy or Breast Feeding
• Males and females of reproductive potential may not participate unless they have
agreed to the use of, at minimum, two methods of contraception, with one method being
highly effective and the other method being either highly effective or less effective
as outlined in study protocol documentation
• Concomitant Medications: Patients receiving the following are not eligible:
• Corticosteroids or other immunosuppressive medications
• Patients who are currently receiving other investigational agents or other anti-cancer
therapy
• Intercurrent Illnesses: Patients with uncontrolled intercurrent illness including, but
not limited to:
• Ongoing or active infection
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Cardiac arrhythmia
• Psychiatric illness/social situations that would limit compliance with study
requirements
• Autoimmune disorders: Patients with a history of any Grade autoimmune disorder are not
eligible.
• Asymptomatic laboratory abnormalities (e.g., ANA, rheumatoid factor, altered thyroid
function studies) will not render a patient ineligible in the absence of a diagnosis
of an autoimmune disorder.
• Patients with ≥ Grade 2 hypothyroidism due to history of autoimmunity are not
eligible. Note: Hypothyroidism due to previous irradiation or thyroidectomy will not
impact eligibility
• Allergies: Patients with a history of allergic reactions attributed to compounds of
similar chemical or biologic composition to Nivolumab (e.g., another humanized
antibody) or Azacitidine are not eligible
• Safety and Monitoring: Patients who are considered unable to comply with the safety
monitoring requirements of the study are not eligible
• Patients with known HIV or hepatitis B or C are excluded
• Patients who have received prior solid organ transplantation are not eligible
• Patients who have received prior anti-PD-1 directed therapy (mAb or small molecule)
are not eligible
Drug: Nivolumab, Drug: Azacitidine, Procedure: Post Treatment Surgery
Sarcoma, Osteosarcoma, Soft Tissue, Osteosarcoma in Children, Osteosarcoma Recurrent
Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101)
To evaluate the safety and tolerability of sotorasib administered in investigational regimens
in adult participants with KRAS p.G12C mutant advanced solid tumors.
• Men or women greater than or equal to 18 years old.
• Pathologically documented, locally-advanced or metastatic malignancy with, KRAS p.G12C
mutation identified through molecular testing performed according to in-country
requirements. In the United States, this test must be performed in a Clinical
Laboratory Improvement Amendments (CLIA)-certified laboratory.
Exclusion Criteria:
• Primary brain tumor.
• Spinal cord compression, or untreated, or symptomatic, or active brain metastases, or
leptomeningeal disease from non-brain tumors.
• Myocardial infarction within 6 months of study day 1.
• Gastrointestinal (GI) tract disease causing the inability to take oral medication.
A Study of Avapritinib in Pediatric Patients With Solid Tumors Dependent on KIT or PDGFRA Signaling
This is a Phase 1/2, multicenter, open-label trial of avapritinib in patients aged 2 to less
than 18 years of age with with relapsed/refractory (R/R) solid tumors with mutations
(including non-synonymous point mutations, insertions, and deletions) in KIT or PDGFRA, or
gliomas with the H3K27M mutation, and no available alternative treatment options. This is a
single-arm trial in which all patients will receive avapritinib. The study consists of 2
parts: dose confirmation, safety, and PK (Part 1) and initial efficacy, safety, and PK at the
Part 2 recommended dose (Part 2).
• Patient has confirmed diagnosis of a R/R solid or CNS tumor with a mutation in KIT or
PDGFRA (confirmed by local mutational testing of tumor sample) that has progressed
despite standard therapy and no alternative treatment option is available OR Confirmed
diagnosis of H3K27M mutant glioma that has failed standard therapy or for which no
standard therapy that may convey clinical benefit exists, as judged by the
Investigator.
• Patients with CNS disease should be on a stable dose (≤10% change) of corticosteroids
for at least 7 days prior to first dose of avapritinib, with no plans for dose
escalation.
• Disease extent
1. Part 1: All patients must have at least 1 measurable lesion as defined by RECIST
v1.1 or RANO (for CNS tumors). If radiation therapy has been administered, at
least
1 measurable lesion must not have been irradiated, or must have clearly
progressed since being irradiated.
2. Part 2: At least one measurable lesion as defined by RECIST v1.1 (RANO for CNS
tumors). If radiation therapy has been administered, at least 1 measurable lesion
must not have been irradiated within the previous 12 weeks, or must have clearly
progressed since being radiated (per RANO). For up to 5 patients with H3K27M
mutant gliomas where there is no standard therapy that may convey clinical
benefit as judged by the investigator, progression of disease of a measurable
lesion after irradiation is not required.
• A Lansky (≤16 years of age) or Karnofsky (>16 years of age) score of at least 50. If
the patient is unable to walk due to paralysis, but is mobile in a wheelchair, the
patient is considered ambulatory for the purpose of assessing their performance
status.
• Patient agrees to utilize contraception consistent with local regulations
Exclusion Criteria:
• Patient has any of the following within 14 days before the first dose of study
treatment:
1. Platelet count <75 × 109/L (<100 × 109/L if a CNS tumor).
2. Absolute neutrophil count (ANC) <1.0 × 109/L.
3. Hemoglobin <8.0 g/dL (RBC transfusion ≥14 days before test is permitted to meet
criterion).
4. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × the upper
limit of normal (ULN) for age; except in patients with tumor involvement of the
liver who must not have AST and ALT >5 × ULN for age.
5. Total bilirubin >1.5 mg/dL for age; and in presence of Gilbert's syndrome, total
bilirubin.
> 3 × ULN or direct bilirubin > 1.5 × ULN.
6. Serum creatinine >1.5 × ULN for age.
7. International normalized ratio (INR) or prothrombin time (PT) >ULN (>1.5 × ULN if
on prophylactic reversible anticoagulants).
• Patient has a QT interval corrected using Fridericia's formula (QTcF) >470 msec.
Patient has a familial or personal history of prolonged QT syndrome or Torsades de
pointes.
• Patient has clinically significant, uncontrolled, cardiovascular disease including
congestive heart failure Grade III or IV according to the New York Heart Association
(NYHA) classification; myocardial infarction or unstable angina within the previous 6
months, uncontrolled hypertension (>99th percentile for age), or clinically
significant, uncontrolled arrhythmias, including bradyarrhythmias that may cause QT
prolongation (eg, Type II second degree heart block or third-degree heart block).
• Patient received the following systemic antineoplastic therapies:
1. Systemic antineoplastic therapy (including experimental therapy within 5
half-lives or 28 days [6 weeks if prior nitrosurea], whichever is shorter).
2. Focal external beam radiotherapy, including stereotactic radiosurgery, within 6
weeks prior to the first dose of avapritinib to either target or non-target
lesions. Systemic radiopharmaceuticals, including nonstereotactic radiosurgery,
within 2 weeks of the first dose of avapritinib (within 6 weeks for patients with
CNS tumors). Craniospinal irradiation within 12 weeks prior to the first dose of
avapritinib.
3. All AEs related to other antineoplastic therapies (eg, systemic antineoplastics,
radiotherapy) must have resolved to Grade ≤1 (Grade ≤2 for peripheral neuopathy
and/or ototoxicity) prior to the first dose of avapritinib.
• Patient has previously received treatment with avapritinib.
• Patient received autologous stem cell transplant (SCT) following myeloablative therapy
or chimeric antigen receptor T cell (CAR-T) therapy within 3 months prior to the first
dose of avapritinib or prior allogeneic SCT within 1 year and no evidence of Grade 1
or greater graft-versus-host disease and no immunosuppressants for graft-versus-host
disease (steroids for primary malignancy being permitted). Patients who received stem
cell reinfusion following nonmyeloablative therapy are eligible once they meet the
peripheral blood count criteria in Exclusion Criterion #1.
• Patient requires on going treatment or has received treatment within 28 days before
the start of avapritinib administration with drugs or foods that are strong CYP3A
inhibitors or inducers or EIAEDs (eg, carbamazepine, phenytoin, phenobarbital, and
primidone). Please refer to Appendix 1 for a list of these drugs and/or foods.
• Patient has had a major surgical procedure within 14 days of the first dose of study
treatment (procedures such as central venous catheter placement, tumor needle biopsy,
and feeding tube placement are not considered major surgical procedures).
• Patient has a history of another primary malignancy that has been diagnosed or
required therapy within 3 years before the first dose of avapritinib. The following
prior malignancies are not exclusionary: completely resected basal cell and squamous
cell skin cancer, curatively treated localized prostate cancer, and completely
resected carcinoma in situ of any site.
• Female subjects of childbearing potential who are unwilling, if not post-menopausal or
surgically sterile, to abstain from sexual intercourse or employ highly effective
contraception from the time of informed consent and for at least 6 weeks after the
last dose of study treatment. Male subjects who are unwilling, if not surgically
sterile, to abstain from sexual intercourse or employ highly effective contraception
from the time of informed consent and for at least 6 weeks after the last dose of
study treatment. Refer to Section 5.4.2 for acceptable methods of contraception.
• Patient is pregnant
• Patient is breastfeeding.
• Patient has prior or ongoing clinically significant illness, medical condition,
surgical history, physical finding, or laboratory abnormality that, in the
Investigator's opinion, could affect the safety of the patient; alter the absorption,
distribution, metabolism, or excretion of the study drug; or impair the assessment of
study results.
• History of thrombosis requiring treatment within the past 6 months.
• Patients who require anticoagulants, with the exception of stable doses of
prophylactic reversible anticoagulants.
• Patients who are unable to swallow tablets (in Part 1) or mini-tablets (in Part 2)
within the sprinkle capsules.
• Patients with a known risk of intracranial bleeding, such as a brain aneurysm that has
not been removed or repaired, or a history of intracranial bleeding within the past
year, or radiographic evidence of hemorrhage on Screening MRI. Exceptions are patients
with primary CNS tumors who are eligible unless CNS bleeding has occurred within 2
weeks of the first dose of avapritinib and patients with punctate hemorrhages <3 mm.
• History of a seizure disorder that is not well controlled on current antiepileptic
medications. EIAEDs carbamazepine, phenytoin, phenobarbital, and primidone are
prohibited.
• Patient is unwilling or unable to comply with scheduled visits, treatment
administration plan, laboratory tests, or other study procedures and study
restrictions
Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1 or SMARCA4 Deficient Tumors
This phase I/II trial studies how well tiragolumab and atezolizumab works when given to
children and adults with SMARCB1 or SMARCA4 deficient tumors that that has either come back
(relapsed) or does not respond to therapy (refractory). SMARCB1 or SMARCA4 deficiency means
that tumor cells are missing the SMARCB1 and SMARCA4 genes, seen with some aggressive cancers
that are typically hard to treat. Immunotherapy with monoclonal antibodies, such as
tiragolumab and atezolizumab, may help the body's immune system attack the cancer, and may
interfere with the ability of tumor cells to grow and spread.
• Patients must be >= 12 months of age at the time of study enrollment. For part A,
patients must be <18 years old at enrollment. For part B, there is no upper age limit
• The Part B (phase 2) cohorts will initially open concurrently with the part A but
will only enroll patients at least 18 years of age. Patients <18 years of age
will be included in the part B cohorts only after the tiragolumab monotherapy
dose has been assessed to be safe in the part A portion
• Patients must have SMARCB1 (INI1) or SMARCA4 deficient tumors verified through
institutional immunohistochemistry (IHC) or molecular confirmation of a pathologic
tumor bi-allelic SMARCB1 (INI1) or SMARCA4 loss or mutation from a Clinical Laboratory
Improvement Act (CLIA) certified lab with the following disease histologies:
• Renal medullary carcinoma
• Malignant rhabdoid tumor (extra-CNS)
• Atypical teratoid rhabdoid tumor (CNS)
• Poorly differentiated chordoma
• Epithelioid sarcoma
• Other SMARCB1 or SMARCA4 deficient tumors
• Note: Documentation of the institutional IHC or molecular testing must be
uploaded via the RAVE system
• Part A: Patients must have either measurable or evaluable disease Part B: Patients
must have either measurable disease per RECIST v1.1 for non-CNS tumors or CNS response
criteria for CNS tumors
• Patients must have relapsed, refractory disease or newly diagnosed disease for which
there is no known curative therapy or therapy proven to prolong survival with an
acceptable quality of life
• Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1 or 2 (Karnofsky/Lansky score of > 50). Use Karnofsky for
patients > 16 years of age and Lansky for patients =< 16 years of age. Note:
Neurologic deficits in patients with CNS tumors must have been stable for at least 7
days prior to study enrollment. 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 have fully recovered from the acute toxic effects of all prior
anti-cancer therapy and must meet the following minimum duration from prior
anti-cancer directed therapy prior to enrollment. If after the required timeframe, the
numerical eligibility criteria are met, e.g., blood count criteria, the patient is
considered to have recovered adequately
• Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive:
See Developmental Therapeutics (DVL) homepage on the Children's Oncology Group
(COG) Members site for commercial and investigational agent classifications. For
agents not listed, the duration of this interval must be discussed with the study
chair and the study-assigned Research Coordinator prior to enrollment
• >= 21 days after the last dose of myelosuppressive chemotherapy (42 days if
prior nitrosourea). Please refer to the table of myelosuppressive/Anticancer
Agents on the COG website:
https://www.cogmembers.org/uploadedFiles/Site/Disc/DVL/Documents/TableOfMyel
osuppressiveAnti-CancerAgents.pdf
• Anti-cancer agents not known to be myelosuppressive (e.g., not associated with
reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the
last dose of agent. See the DVL homepage on the COG Members site for commercial
and investigational agent classifications. For agents not listed, the duration of
this interval must be discussed with the study chair and the study-assigned
Research Coordinator prior to enrollment
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,
and toxicity related to prior antibody therapy must be recovered to grade =< 1
• Hematopoietic growth factors: >= 14 days after the last dose of a long-acting
growth factor (e.g., pegfilgrastim) or 7 days for short acting growth factor. For
agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur
• Interleukins, interferons and cytokines (other than hematopoietic growth
factors): >= 21 days after the completion of interleukins, interferon or
cytokines (other than hematopoietic growth factors)
• Stem cell infusions (with or without total-body irradiation [TBI]):
• Autologous stem cell infusion including boost infusion: >= 30 days
• Cellular therapy: >= 30 days after the completion of any type of cellular therapy
(e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)
• External radiation therapy (XRT)/external beam irradiation including protons: >=
14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation
to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM)
radiation
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, iodine I 131
metaiodobenzylguanidine [131I MIBG]): >= 42 days after systemically administered
radiopharmaceutical therapy
• Patients must not have had prior TIGIT targeting therapy
• Patients must not have received prior therapy with an anti- PD-1, anti-PD-L1,
anti-PD-L2, or anti-CTLA4 agent or with an agent directed to another stimulatory
or co-inhibitory T cell receptor (i.e. OX-40, CD137)
• Patients must not have received live/attenuated vaccine within 30 days of first
dose of treatment
• Patients must not be receiving concomitant systemic steroid medications and > 14
days must have elapsed since last dose of systemic corticosteroid with the
following exceptions:
• The use of physiologic doses of corticosteroids (5 mg/m^2/day up to 10
mg/day of prednisone equivalent) is acceptable
• The use of topical, inhaled, or ophthalmic corticosteroids are acceptable
• The use of acute, low-dose systemic immunosuppressant medication or a
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours
of corticosteroids for a contrast allergy) are acceptable
• Treatment with systemic immunosuppressive medication (including, but not limited
to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor-alpha [TNF-alpha] agents) must have concluded >= 14 days prior to
study enrollment
• For patients with solid tumors without known bone marrow involvement
• Peripheral absolute neutrophil count (ANC) >= 1000/uL (must be performed within 7
days prior to enrollment)
• For patients with solid tumors without known bone marrow involvement
• Platelet count >= 100,000/uL (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment) (must be performed
within 7 days prior to enrollment)
• Patients with known bone marrow metastatic disease will be eligible for study provided
they meet the blood counts above (may receive transfusions provided they are not known
to be refractory to red cell or platelet transfusions). These patients will not be
evaluable for hematologic toxicity
• A creatinine based on age/gender as follows (must be performed within 7 days prior to
enrollment):
• Age; Maximum Serum Creatinine (mg/dL)
• 1 to < 2 years; Male: 0.6; Female: 0.6
• 2 to < 6 years; Male: 0.8; Female: 0.8
• 6 to < 10 years; Male: 1; Female: 1
• 10 to < 13 years; Male: 1.2; Female: 1.2
• 13 to < 16 years; Male: 1.5; Female: 1.4
• >= 16 years; Male: 1.7; Female: 1.4 OR- a 24 hour urine creatinine clearance
>= 70 mL/min/1.73 m^2 (must be performed within 7 days prior to enrollment)
OR- a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2. GFR must be
performed using direct measurement with a nuclear blood sampling method OR
direct small molecule clearance method (iothalamate or other molecule per
institutional standard) (must be performed within 7 days prior to
enrollment)
• Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates
are not acceptable for determining eligibility
• Bilirubin (sum of conjugated + unconjugated or total) =< 1.5 x upper limit of normal
(ULN) for age (must be performed within 7 days prior to enrollment)
• Patients with known Gilbert disease: Total bilirubin < 3 x ULN
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L
(must be performed within 7 days prior to enrollment). For the purpose of this study,
the ULN for SGPT is 45 U/L
• Albumin >= 2 g/dL (must be performed within 7 days prior to enrollment)
• Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled as evidenced by no increase in seizure frequency in the prior 7 days
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] v5)
resulting from prior therapy must be =< grade 2, with the exception of decreased
tendon reflex (DTR). Any grade of DTR is eligible
• International normalized ratio (INR) =< 1.5 (must be performed within 7 days prior to
enrollment)
• Serum amylase =< 1.5 x ULN (must be performed within 7 days prior to enrollment)
• Serum lipase =< 1.5 x ULN (must be performed within 7 days prior to enrollment)
• Grade 1 or lower calcium level
• Note: can have history of hypercalcemia as long as controlled and asymptomatic
Exclusion Criteria:
• Pregnant or breast-feeding women will not be entered on this study due to risks of
fetal and teratogenic adverse events as seen in animal/human studies, OR because there
is yet no available information regarding human fetal or teratogenic toxicities.
Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of
reproductive potential may not participate unless they have agreed to use two
effective methods of birth control, including a medically accepted barrier or
contraceptive method (e.g., male or female condom) for the duration of therapy and at
least 90 days after final dose of tiragolumab and 150 days after final dose of
atezolizumab, whichever is later. Abstinence is an acceptable method of birth control.
• It is not known if atezolizumab or tiragolumab are present in breast milk;
however, IgG immunoglobulins are found in milk. Due to the potential for serious
adverse reactions in the breastfed infant, breastfeeding is not recommended
during therapy and for at least 150 days after the last dose of atezolizumab and
90 days after the last dose of tiragolumab, whichever is later
• Concomitant medications:
• Corticosteroids:
• Patients must not be receiving concomitant systemic steroid medications and
>= 14 days must have elapsed since last dose of systemic corticosteroid with
the following exceptions:
• The use of physiologic doses of corticosteroids (5 mg/m^2/day up to 10
mg/day of prednisone equivalent) is acceptable
• The use of topical, inhaled, or ophthalmic corticosteroids are
acceptable
• The use of acute, low-dose systemic immunosuppressant medication or a
one-time pulse dose of systemic immunosuppressant medication (e.g. 48
hours of corticosteroids for a contrast allergy) are acceptable
• Investigational drugs: Patients who are currently receiving another
investigational drug are not eligible
• Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents
are not eligible
• Systemic immunosuppressive medications (including, but not limited to,
cyclophosphamide, azathioprine, methotrexate, and thalidomide) during study
treatment because these agents could potentially alter the efficacy and safety of
study treatments would not be eligible
• Patients must not have a known hypersensitivity to any component of tiragolumab or
atezolizumab injection
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of
the atezolizumab or tiragolumab formulation
• Patients who have undergone allogeneic bone marrow or stem cell transplant are not
eligible
• Patients with known, untreated CNS metastases will be excluded with the following
exceptions:
• Patients with a history of CNS metastases that have been previously treated may
enroll if sequential imaging shows no evidence for active disease in the CNS
• Patients must not have active autoimmune disease that has required systemic treatment
in the past 12 months, or a documented history of clinically severe autoimmune
disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
Subjects with vitiligo or resolved childhood asthma/atopy are not excluded.
Replacement therapy (e.g. thyroxine, insulin, physiologic corticosteroid replacement
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of
systemic treatment and these patients are eligible
• Patients who have active immune deficiency are not eligible
• Patients who have known active tuberculosis are not eligible
• Hepatitis B or C infection:
• Patients < 18 years old at enrollment, who have known hepatitis B or C
• Patients >= 18 years old at enrollment with:
• Positive hepatitis B surface antigen (HBsAg), OR
• Positive total hepatitis B core antibody (HBcAb) who have a quantitative
hepatitis B virus (HBV) deoxyribonucleic acid (DNA) >= 500 IU/mL, OR
• Positive hepatitis C virus (HCV) antibody with a positive HCV ribonucleic acid
(RNA) test
• Note: For adults (>= 18 years old at enrollment), hepatitis B serology testing is
required to determine eligibility. The HBV DNA test is required only for patients
who have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb
test. For adults (>= 18 years old at enrollment), hepatitis C serology testing is
required to determine eligibility. The HCV RNA test is required only for patients
who have a positive HCV antibody test
• Patients who have a known, recent Epstein-Barr virus (EBV) infection or known history
of chronic, active infection are not eligible
• Patients who have history of or active human immunodeficiency virus (HIV) are not
eligible except patients who are stable on anti-retroviral therapy, have a CD4 count
>= 200/uL, and have an undetectable viral load
• Patients who have significant cardiovascular disease (such as New York Heart
Association class III or IV congestive heart failure, myocardial infarction, or
cerebrovascular accident) within 3 months prior to study enrollment, unstable
arrhythmia, or unstable angina are not eligible
• Patients who have a major surgical procedure, other than for diagnosis, within 4 weeks
prior to study enrollment, or the anticipation of the need for a major surgical
procedure during the study are not eligible
• Patients who have a history of idiopathic pulmonary fibrosis, organizing pneumonia,
drug-induced pneumonitis, idiopathic pneumonitis, or known active pneumonitis are not
eligible. History of radiation pneumonitis in the radiation field is permitted
• Patients who have uncontrolled pleural effusion, pericardial effusion, or ascites
requiring recurrent drainage procedures (once monthly or more frequently) are not
eligible. Patients with indwelling catheters (e.g., PleurX) are allowed
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible
A Study of Repotrectinib in Pediatric and Young Adult Subjects Harboring ALK, ROS1, OR NTRK1-3 Alterations
Phase 1 will evaluate the safety and tolerability at different dose levels of repotrectinib
in pediatric and young adult subjects with advanced or metastatic malignancies harboring
anaplastic lymphoma kinase (ALK), receptor tyrosine kinase encoded by the gene ROS1 (ROS1),
or neurotrophic receptor kinase genes encoding TRK kinase family (NTRK1-3) alterations to
estimate the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) and select the
Pediatric Recommended Phase 2 Dose (RP2D).
Phase 2 will determine the anti-tumor activity of repotrectinib in pediatric subjects with
advanced or metastatic malignancies harboring ALK, ROS1, or NTRK1-3 alterations.
1. Documented genetic ALK, ROS1, or NTRK1-3 alteration (point mutation, fusion,
amplification) as identified by local testing in a Clinical Laboratory Improvement
Amendments (CLIA) laboratory in the US or equivalently accredited diagnostic lab
outside the United States (US) is required.
2. Phase 1: Age <12 years; Phase 2: Age 12- 25 years
3. Prior cytotoxic chemotherapy is allowed.
4. Prior immunotherapy is allowed.
5. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer
therapy to National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) Version 4.03 Grade less than or equal to 1.
6. All subjects must have measurable disease by RECIST v1.1 or Response Assessment in
Neuro-Oncology Criteria (RANO) criteria at time of enrollment.
7. Subjects with a primary CNS tumor or CNS metastases must be neurologically stable on a
stable or decreasing dose of steroids for at least 14 days prior to enrollment.
8. Subjects must have a Lansky (< 16 years) or Karnofsky (≥ 16 years) score of at least
50.
9. Life expectancy greater than or equal to 12 weeks.
10. Adequate hematologic, renal and hepatic function.
Phase 2
Inclusion Criteria:
1. Cohort Specific
Inclusion Criteria:
• Cohort 1: Subjects with NTRK fusion gene positive (NTRK+) advanced solid tumors
(including primary CNS tumors), that are tropomyosin receptor kinase (TRK) TKI
naïve;
• Cohort 2: subjects with NTRK+ advanced solid tumors (including primary CNS
tumors), that are TRK TKI pre-treated;
• Cohort 3: subjects with tumors or ALCL characterized by other ALK/ROS1/NTRK
alterations or NTRK fusions without centrally confirmed measurable disease or not
otherwise eligible for Cohort 1 or 2.
2. Subjects in Cohorts 1 and 2 must have prospectively confirmed measurable disease by
BICR prior to enrollment.
Key Exclusion Criteria (Phase 1 and Phase 2):
1. Subjects with neuroblastoma with only bone marrow disease evaluable by bone marrow
aspiration only.
2. Major surgery within 14 days (2 weeks) of start of repotrectinib treatment. Central
venous access (Broviac, Mediport, etc.) placement does not meet criteria for major
surgery.
3. Known active infections (bacterial, fungal, viral including HIV positivity).
4. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut
syndrome) or other malabsorption syndromes that would impact drug absorption.
5. Any of the following cardiac criteria:
• Mean resting corrected QT interval (ECG interval measured from the onset of the
QRS complex to the end of the T wave) for heart rate (QTc) > 480 msec obtained
from three ECGs, using the screening clinic ECG machine-derived QTc value
• Any clinically important abnormalities in rhythm, conduction, or morphology of
resting ECG (e.g., complete left bundle branch block, third degree heart block,
second degree heart block, PR interval > 250 msec)
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, congenital long QT syndrome, family history of long
QT syndrome, or any concomitant medication known to prolong the QT interval
6. Peripheral neuropathy of CTCAE ≥grade 2.
7. Subjects being treated with or anticipating the need for treatment with strong CYP3A4
inhibitors or inducers.
A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors (LIBRETTO-121)
This is an open-label, multi-center Phase 1/2 study of oral LOXO-292 in pediatric
participants with an activating rearranged during transfection (RET) alteration and an
advanced solid or primary CNS tumor.
• Advanced or metastatic solid or primary CNS tumor which has failed standard of care
therapies
• Evidence of an activating RET gene alteration in the tumor and/or blood
• Measurable or non-measurable disease
• Karnofsky (participants 16 years and older) or Lansky (participants younger than 16)
performance score of at least 50
• Participant with primary CNS tumors or cerebral metastases must be neurologically
stable for 7 days prior and must not have required increasing doses of steroids within
the last 7 days
• Adequate hematologic, hepatic and renal function.
• Ability to receive study drug therapy orally or via gastric access
• Willingness of men and women of reproductive potential to observe conventional and
effective birth control
Exclusion Criteria:
• Major surgery within two weeks prior to planned start of LOXO-292
• Clinically significant, uncontrolled cardiac, cardiovascular disease or history of
myocardial infarction within 6 months prior to planned start of LOXO-292
• Active uncontrolled systemic bacterial, viral, fungal or parasitic infection
• Clinically significant active malabsorption syndrome
• Pregnancy or lactation
• Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e. the participant
required a modification to current thyroid medication in the 7 days before start of
LOXO-292)
• Uncontrolled symptomatic hypercalcemia or hypocalcemia
• Known hypersensitivity to any of the components of the investigational agent, LOXO-292
or Ora-Sweet® SF and OraPlus®, for participants who will receive LOXO-292 suspension
• Prior treatment with a selective RET inhibitor(s) (including investigational selective
RET inhibitor[s])
• Diagnosis of EBV+ disorder
• Eastern Cooperative Oncology Group performance status <= 3 for participants aged >= 16
years; Lansky score >= 20 for participants from 1 year to < 16 years
• Adequate organ function test results, unless organ dysfunction is considered to be due
to the underlying EBV-associated disease by the investigator
Cohort-specific
Inclusion Criteria:
• For participants with PID LPD:
• Newly diagnosed or relapsed/refractory LPD confirmed by biopsy-proven EBV+ LPD or
positive cerebrospinal fluid (CSF) cytology with or without radiographically
measurable intracranial disease with EBV detected in CSF
• Participant must have systemic measurable disease and/ or CNS measurable disease
• Definitive therapy (eg, allogeneic HCT, gene therapy) for the underlying PID is
planned
• Participants with newly diagnosed disease should be ineligible for standard
first-line therapy for EBV+ LPD, as determined by the investigator
• For participants with AID LPD:
• Newly diagnosed or relapsed/refractory LPD confirmed by biopsy-proven EBV+ LPD or
positive CSF cytology, with or without radiographically measurable intracranial
disease, with EBV detected in CSF
• Participant must have systemic measurable disease and/ or CNS measurable disease
• Participants who are human immunodeficiency virus positive (HIV+) must meet both
of the following criteria: Have an HIV viral load assessed by reverse
transcription-polymerase chain reaction (RT-PCR) below the lower limit of
detection and CD4 >= 50 cells/μL within 6 months prior to the first dose of
tabelecleucel
• Participants with newly diagnosed disease should be ineligible for standard
first-line therapy for EBV+ LPD, as determined by the investigator
• For participants with CNS PTLD:
• Newly diagnosed or relapsed/refractory EBV+ CNS PTLD histologically confirmed by
biopsy-proven EBV+ CNS PTLD or positive CSF cytology with or without
radiographically measurable intracranial disease with EBV detected in CSF
• Participant may have systemic and CNS disease or CNS disease only
• Participants with newly diagnosed disease should be ineligible for standard
first-line therapy for EBV+ LPD, as determined by the investigator
• For participants with EBV+ PTLD, where standard first line therapy (rituximab and/or
chemotherapy) is not appropriate, including CD20-negative disease:
• Newly diagnosed, biopsy-proven EBV+ PTLD
• Ineligible for standard first-line therapy for EBV+ PTLD, as determined by the
investigator
• Participants must have systemic disease measurable per Lugano Classification
criteria, except when contraindicated or mandated by local practice, then MRI may
be used.
• For participants with sarcoma, including LMS:
• Newly diagnosed or failed systemic first-line therapy for EBV+ sarcoma.
Participants with newly diagnosed disease should be ineligible for standard
first-line therapy for EBV+ sarcoma, as determined by the investigator.
• Biopsy-proven EBV+ sarcoma
• Measurable disease using diagnostic PET/CT and/or MRI following RECIST 1.1
criteria
• For participants with CAEBV:
• Newly diagnosed or previously treated CAEBV
• Detectable EBV viremia on at least 2 occasions at a minimum of 90 days apart
• At least 3 active clinical findings (per Kimura H, et al. Front Immunol.
2017;8:1867) as: Fever >= 38.5°C; splenomegaly, lymphadenopathy, and/or
hepatomegaly; cytopenia affecting at least 2 or 3 lineages in the peripheral
blood (hemoglobin < 9 g/dL, platelets < 100 × 10^3/mL, neutrophils < 1 ×
10^3/mL); hypogammaglobulinemia; hemophagocytosis; hepatitis; neuropathy; rash;
and hydroa vacciniforme
• For participants with EBV+ viremia with HLH:
• Newly diagnosed or previously treated EBV+ viremia with HLH
• A molecular diagnosis consistent with HLH-2004 trial (per Henter JI, et al.
Pediatr Blood Cancer. 2007;48:124-31) OR 5 or more of the clinical symptoms (per
Jordan MB, et al. Blood. 2011;118:4041-4052): Fever >= 38.5°C; splenomegaly;
cytopenia affecting at least 2 or 3 lineages in the peripheral blood (hemoglobin
< 9 g/dL, platelets < 100 × 10^3/mL, neutrophils < 1 × 10^3/mL);
hypertriglyceridemia (fasting >= 265 mg/dL) and/or hypofibrinogenemia (<= 150
mg/dL); hemophagocytosis in bone marrow, spleen, lymph nodes, or liver; low or
absent natural killer cell (NK-cell) activity; ferritin >= 500 ng/mL; and
elevated soluble CD25
Exclusion Criteria:
• Burkitt, T-cell (except in the setting of HLH), natural killer/T-cell lymphoma/LPD,
Hodgkin, or transformed lymphoma
• Serious known active infections, defined as ongoing uncontrolled adenovirus infection
or infections requiring systemic therapy at the time of enrollment
• Suspected or confirmed Grade >= 2 acute graft-versus-host disease (GvHD) per the
Center for International Blood and Marrow Transplant Research (CIBMTR) consensus
grading system or extensive chronic GvHD per National Institutes of Health (NIH)
consensus criteria at the time of the enrollment
• Need for vasopressor or ventilatory support
• Prior therapy (in order of increasing washout period) prior to enrollment as:
• Within 4 weeks or 5 half-lives (whichever is shorter) for any investigational
product and/ or any chemotherapy (systemic or intrathecal), targeted small
molecule therapy, or antibody/biologic therapy. Note: prior anti-CD20 antibody
use is permitted within the washout period if a subsequent disease response
assessment indicates disease progression
• Within <= 8 weeks for cellular therapies (EBV-CTLs, chimeric antigen receptor
therapies directed at T cells or T-cell subsets, donor lymphocyte infusion, other
CTLs); and/or therapies which could impact tabelecleucel function (anti-thymocyte
globulin, alemtuzumab)
• Unwilling to use protocol specified contraceptive methods
• Women who are pregnant or breastfeeding
• Ongoing need for daily steroids of > 0.5 mg/kg prednisone or glucocorticoid
equivalent, ongoing methotrexate, or extracorporeal photopheresis (protocol-specified
dexamethasone is permitted and concludes by the time of enrollment)
• For participants with PID LPD or AID LPD: history of prior allogeneic HCT or solid
organ transplant
Biological: Tabelecleucel
Sarcoma, Leiomyosarcoma, Stem Cell Transplant Complications, Lymphoproliferative Disorders, Solid Organ Transplant Complications, Allogeneic Hematopoietic Cell Transplant, Brain and Nervous System, Epstein-Barr Virus (EBV)-Associated Diseases, EBV+ Lymphoproliferative Disease With Primary Immunodeficiency (PID LPD), EBV+ Lymphoproliferative Disease With Acquired (Non-congenital) Immunodeficiency (AID LPD), EBV+ Posttransplant Lymphoproliferative Disease in Central Nervous System (CNS PTLD), EBV+ Post-transplant Lymphoproliferative Disease (EBV+ PTLD), EBV+ Sarcomas, Chronic Active Epstein-Barr Virus (CAEBV), Chronic Active Epstein-Barr Virus With Hemophagocytic Lymphohistiocytosis (HLH), Lymphohistiocytosis, Hemophagocytic
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
A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1)
Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the
maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose
(RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an
ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
Midazolam DDI substudy will examine effect of of repotrectinib on CYP3A induction.
Phase 2 will determine the confirmed Overall Response Rate (ORR) as assessed by Blinded
Independent Central Review (BICR) of repotrectinib in each subject population expansion
cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene
rearrangement. The secondary objective will include the duration of response (DOR), time to
response (TTR), progression-free survival (PFS), overall survival (OS) and clinical benefit
rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor a
ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
solid tumor (including primary CNS tumors) (Stage IV, American Joint Committee on
Cancer v.7) that harbors an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement by
protocol specified tests.
2. ECOG PS 0-1.
3. Age ≥18 (or age ≥ 20 of age as required by local regulation).
4. Capability to swallow capsules intact (without chewing, crushing, or opening).
5. At least 1 measurable target lesion according to RECIST version 1.1. CNS-only
measurable disease as defined by RECIST version 1.1 is allowed.
6. Prior cytotoxic chemotherapy is allowed.
7. Prior immunotherapy is allowed.
8. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer
therapy to National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) Version 4.03 Grade less than or equal to 1.
9. Patients with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
specified criteria.
10. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L);
Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
clearance Within normal limits or > 40 mL/min; Total serum bilirubin < 1.5 × ULN;
Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present
Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are
present; Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or
without supplementation
11. Life expectancy ≥ 3 months.
PHASE 2 Key Inclusion Criteria
1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
solid tumor (including primary CNS tumors) that harbors a ROS1, or NTRK1-3 gene
fusion.
2. Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based
local testing using either:
1. a next-generation sequencing (NGS) or quantitative polymerase chain reaction
(qPCR) test will be accepted to determine molecular eligibility.
• Adequate tumor tissue needs to be sent to the Sponsor designated central
diagnostic laboratory for retrospective confirmation by a central diagnostic
laboratory test selected by the Sponsor.
OR
2. a fluorescence in situ hybridization (FISH) test AND prospective confirmation of
fusion status by a central diagnostic laboratory test selected by the Sponsor
PRIOR to enrollment will be accepted to determine molecular eligibility.
• Adequate tumor tissue must be sent to the Sponsor designated central
diagnostic laboratory for prospective confirmation by a central diagnostic
laboratory test selected by the Sponsor PRIOR to enrollment.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
4. Age ≥12 (or age ≥ 20 as required by local regulation).
5. Willing and able to provide written institutional review board (IRB)/institutional
ethics committee-approved Informed Consent or an Assent signed by a parent or legal
guardian for subjects age 12 to 17.
6. At least 1 measurable target lesion according to RECIST (v1.1) prospectively confirmed
by Blinded Independent Central Radiology Review (BICR), selected by Sponsor, PRIOR to
enrollment. Subjects with CNS-only measurable disease ≥10 mm as defined by RECIST
(v1.1) are eligible.
7. Subjects with advanced solid tumors harboring ROS1, NTRK1, NTRK2, or NTRK3
rearrangement will be assigned into 6 distinct expansion (EXP) cohorts provided all
inclusion and exclusion criteria are met.
i. EXP-1: ROS1 TKI-naïve ROS1+ NSCLC ii. EXP-2: 1 Prior ROS1 TKI and 1 Platinum based
chemo ROS1+ NSCLC iii. EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) iv.
EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) v. EXP-5: TRK TKI-naïve NTRK+
solid tumors vi. EXP-6: TRK TKI-pretreated NTRK+ solid tumors
8. Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
specified criteria.
9. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L);
Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
clearance > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases
(ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline
phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present;
Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or without
supplementation
10. Life expectancy ≥ 3 months.
Key Exclusion Criteria PHASE 1 and PHASE 2
1. Concurrent participation in another therapeutic clinical trial.
2. Symptomatic brain metastases or leptomeningeal involvement.
3. History of previous cancer, except for squamous cell or basal-cell carcinoma of the
skin, or any in situ carcinoma that has been completely resected, requiring therapy
within the previous 2 years.
4. Major surgery within 4 weeks of start of repotrectinib treatment. Radiation therapy
(except palliative to relieve bone pain) within 2 weeks of study entry. Palliative
radiation (≤10 fractions) must have been completed at least 48 hours prior to study
entry
5. Clinically significant cardiovascular disease (either active or within 6 months prior
to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery
bypass graft, symptomatic congestive heart failure (New York Heart Association
Classification Class ≥ II), cerebrovascular accident or transient ischemic attack,
symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac
dysrhythmias of NCI CTCAE grade ≥2
6. Any of the following cardiac criteria:
Mean resting corrected QT interval (ECG interval measured from the onset of the QRS
complex to the end of the T wave) for heart rate (QTcF) > 470 msec obtained from 3
ECGs, using the screening clinic ECG machine-derived QTc value Any clinically
important abnormalities in rhythm, conduction or morphology of resting ECG (e.g.,
complete left bundle branch block, third degree heart block, second degree heart
block, PR interval > 250 msec) Any factors that increase the risk of QTc prolongation
or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT
syndrome, family history of long QT syndrome, or any concomitant medication known to
prolong the QT interval.
7. Known active infections (bacterial, fungal, viral including HIV positivity).
8. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut
syndrome) or other malabsorption syndromes that would impact drug absorption.
9. Peripheral neuropathy of CTCAE ≥grade 2.
10. History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4
interstitial fibrosis or interstitial lung disease including a history of pneumonitis,
hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease,
obliterative bronchiolitis, and pulmonary fibrosis. Subjects with history of prior
radiation pneumonitis are not excluded.
Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
This Pediatric MATCH screening and multi-sub-study phase II trial studies how well treatment
that is directed by genetic testing works in pediatric patients with solid tumors,
non-Hodgkin lymphomas, or histiocytic disorders that have progressed following at least one
line of standard systemic therapy and/or for which no standard treatment exists that has been
shown to prolong survival. Genetic tests look at the unique genetic material (genes) of
patients' tumor cells. Patients with genetic changes or abnormalities (mutations) may benefit
more from treatment which targets their tumor's particular genetic mutation, and may help
doctors plan better treatment for patients with solid tumors or non-Hodgkin lymphomas.
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients must be >= 12 months and
=< 21 years of age at the time of study enrollment
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients with recurrent or
refractory solid tumors, including non-Hodgkin lymphomas, histiocytoses (e.g.
langerhans cell histiocytosis [LCH], juvenile xanthogranuloma [JXG], histiocytic
sarcoma), and central nervous system (CNS) tumors are eligible; patients must have had
histologic verification of malignancy at original diagnosis or relapse except in
patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with
pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers
including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG); in cases where
patient enrolls prior to histologic confirmation of recurrent disease, patient is
ineligible and should be withdrawn from study if histology fails to confirm
recurrence; please note: Patients with Hodgkin lymphoma and plexiform neurofibroma are
not eligible
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Tumor Testing Requirement: Tumor
sample availability requirement for stage 1 of Pediatric MATCH (patients enrolled from
start of study in July 2017 through 12/31/21); Patients must have an formalin-fixed
paraffin-embedded (FFPE) tumor sample available for MATCH study testing from a biopsy
or surgery that was performed at any point after initial tumor recurrence/progression,
or be planned to have a procedure to obtain such a sample that is considered to be of
potential benefit by the treating clinicians; a tumor sample from a clinically
performed diagnostic (pre-treatment) biopsy will be acceptable for enrollment onto
Pediatric MATCH only for children with high-grade gliomas of the brainstem (diffuse
intrinsic pontine gliomas) or thalamus
• Please note: Samples that have been decalcified using standardly utilized
acid-based decalcification methods are not generally suitable for MATCH study
testing; the nucleic acids will have been degraded in the decalcification process
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Tumor molecular profiling report
availability requirement for Stage 2 of Pediatric MATCH (patients enrolled starting
2022): In stage 2 of the study, no tumor samples will be submitted for centralized
clinical tumor profiling; instead, a tumor molecular profiling report from a College
of American Pathologists (CAP)/ Clinical Laboratory Improvements Amendments
(CLIA)-approved testing laboratory must be submitted for review by the Molecular
Review Committee (MRC)
• This molecular profiling must have been performed on a tumor sample that was
obtained at any point after initial tumor recurrence/progression and must be
accompanied by a pathology report for the same tumor specimen; a molecular
profiling report for a diagnostic (pre-treatment) tumor sample will be acceptable
for enrollment onto Pediatric MATCH only for children with high-grade gliomas of
the brainstem (diffuse intrinsic pontine gliomas) or thalamus. In the event that
molecular profiling reports are available from multiple timepoints, the most
recent report should be prioritized for study submission
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Karnofsky >= 50% for patients >
16 years of age and Lansky >= 50 for patients =< 16 years of age); note: neurologic
deficits in patients with central nervous system (CNS) tumors must have been stable
for at least 7 days prior to study enrollment; 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
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients must have
radiographically measurable disease; measurable disease based on imaging obtained less
than or equal to 56 days prior to enrollment; patients with neuroblastoma who do not
have measurable disease but have metaiodobenzylguanidine (MIBG) positive (+) evaluable
disease are eligible; measurable disease in patients with CNS involvement is defined
as any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance
imaging (MRI) or computed tomography (CT)
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or
positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or CSF
• Previously radiated lesions that have not demonstrated clear progression
post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: NOTE: patient does not need to meet all
subprotocol criteria at time of enrollment onto the APEC1621SC screening protocol, but
will need to meet all criteria prior to enrollment on any assigned treatment
subprotocol. Patients must be enrolled onto a subprotocol within 2 weeks (14 days) of
treatment assignment
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Karnofsky >= 50% for patients > 16 years
of age and Lansky >= 50 for patients =< 16 years of age); Note: neurologic deficits in
patients with CNS tumors must have been stable for at least 7 days prior to study
enrollment; 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
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of treatment with subprotocol
specified therapy, the patients must have radiographically measurable disease;
patients with neuroblastoma who do not have measurable disease but have MIBG+
evaluable are eligible; measurable disease in patients with CNS involvement is defined
as any lesion that is at minimum 10 mm in one dimension on standard MRI or CT
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or
positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or CSF
• Previously radiated lesions that have not demonstrated clear progression
post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for
RECIST 1.1
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of enrollment onto a
subprotocol, the following general criteria for initiation of therapy will be
required:
• Patients must have fully recovered from the acute toxic effects of all prior
anticancer therapy and must meet the following minimum duration from prior
anticancer directed therapy prior to enrollment to the subprotocol; if after the
required timeframe, the numerical eligibility criteria are met, e.g. blood count
criteria, the patient is considered to have recovered adequately
• Cytotoxic chemotherapy or other anticancer agents known to be
myelosuppressive: for agents not listed, the duration of this interval must
be discussed with the study chair and the study-assigned research
coordinator prior to enrollment >= 21 days after the last dose of cytotoxic
or myelosuppressive chemotherapy (42 days if prior nitrosourea)
• Anticancer agents not known to be myelosuppressive (e.g. not associated with
reduced platelet or absolute neutrophil counts [ANC]): >= 7 days after the
last dose of agent; for agents not listed, the duration of this interval
must be discussed with the study chair and the study-assigned research
coordinator prior to enrollment
• Antibodies: >= 21 days must have elapsed from infusion of last dose of
antibody, and toxicity related to prior antibody therapy must be recovered
to grade =< 1
• Corticosteroids: If used to modify immune adverse events related to prior
therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Hematopoietic growth factors: >= 14 days after the last dose of a
long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth
factor; for agents that have known adverse events occurring beyond 7 days
after administration, this period must be extended beyond the time during
which adverse events are known to occur; the duration of this interval must
be discussed with the study chair and the study-assigned research
coordinator
• Interleukins, interferons and cytokines (other than hematopoietic growth
factors): >= 21 days after the completion of interleukins, interferon or
cytokines (other than hematopoietic growth factors)
• Stem cell infusions (with or without total-body irradiation [TBI]):
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any
stem cell infusion including donor lymphocyte infusion (DLI) or boost
infusion: >= 84 days after infusion and no evidence of graft versus
host disease (GVHD)
• Autologous stem cell infusion including boost infusion: >= 42 days
• Cellular therapy: >= 42 days after the completion of any type of cellular
therapy (e.g. modified T cells, natural killer (NK) cells, dendritic cells,
etc.)
• X-ray therapy (XRT)/External Beam Irradiation including Protons: >= 14 days
after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to
>= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM)
radiation; note: radiation may not be delivered to "measurable disease"
tumor site(s) being used to follow response to subprotocol treatment
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42
days after systemically administered radiopharmaceutical therapy
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: For patients with solid tumors without
known bone marrow involvement:
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment)
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients with known bone marrow
metastatic disease will be eligible for study provided they meet the blood counts (may
receive transfusions provided they are not known to be refractory to red cell or
platelet transfusions); these patients will not be evaluable for hematologic toxicity
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Creatinine clearance or radioisotope
glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on
age/gender as follows:
• Age: 1 to < 2 years; maximum serum creatinine (mg/dL): male 0.6; female 0.6
• Age: 2 to < 6 years; maximum serum creatinine (mg/dL): male 0.8; female 0.8
• Age: 6 to < 10 years; maximum serum creatinine (mg/dL): male 1; female 1
• Age: 10 to < 13 years; maximum serum creatinine (mg/dL): male 1.2; female 1.2
• Age: 13 to < 16 years; maximum serum creatinine (mg/dL): male 1.5; female 1.4
• Age: >= 16 years; maximum serum creatinine (mg/dL): male 1.7; female 1.4
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Bilirubin (sum of conjugated +
unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Serum glutamate pyruvate transaminase
(SGPT) (alanine transferase [ALT]) =< 135 U/L (for the purpose of this study, the ULN
for SGPT is 45 U/L)
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients must be able to swallow intact
capsules/tablets, unless otherwise specified in the subprotocol to which they are
assigned
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Agent specific limitations on prior
therapy will be included with specific treatment subprotocols
Exclusion Criteria:
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Pregnant or breast-feeding women will not
be entered on this study due to risks of fetal and teratogenic adverse events as seen
in animal/human studies, or because there is currently no available information
regarding human fetal or teratogenic toxicities; pregnancy tests must be obtained in
females who are post-menarchal; males or females of reproductive potential may not
participate unless they have agreed to use an effective contraceptive method
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Concomitant medications
• Corticosteroids: at the time of consent and enrollment to regimen specific
subprotocols, patients receiving corticosteroids who have not been on a stable or
decreasing dose of corticosteroid for at least 7 days prior to enrollment to the
subprotocol will not be eligible; if used to modify immune adverse events related
to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Investigational drugs: patients must meet criteria for prior therapy at the time
of consent and enrollment to a subprotocol; other investigational agents may not
be administered to patients while they are receiving study drug as part of a
subprotocol
• Anticancer agents: patients must meet criteria for prior therapy at the time of
consent and enrollment to a subprotocol; other investigational agents may not be
administered to patients while they are receiving study drug as part of a
subprotocol
• Anti-GVHD agents post-transplant: patients who are receiving cyclosporine,
tacrolimus or other agents to prevent graft-versus-host disease post bone marrow
transplant are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have an uncontrolled
infection are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have had a prior solid organ
transplant are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Additional agent specific criteria will
be included with specific treatment subprotocols
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
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 [18F]FLT PET/CT as an Early Predictor of Outcome in Pediatric Solid Tumors
The experimental [18F]FLT-PET/CT will be completed before initiation of chemotherapy at
either diagnosis or initiation of salvage chemotherapy at relapse and prior to the third
cycle (or month) of chemotherapy. Laboratory analysis and correlative radiology, as directed
per clinical care based on the primary diagnosis, are required within 30 days of the baseline
[18F]FLT PET/CT. Follow-up will comprise 24 months of standard practice treatment and follow
up.
• Patients with histologically confirmed solid tumor malignancies with residual tumors
present that require standard of care chemotherapy for a minimum number of cycles. All
anatomical sites and all tumor histologies are eligible including central nervous
system tumors. Both newly diagnosed and/or newly relapsed patients are eligible.
• Patients ages 8 •25 years
• In the opinion of the investigator, patients must be thought to be able to lie still
for imaging without sedation for 20 •30 minutes.
• Patients must have a performance status of > 50% (Lansky or Karnofsky).
• Patients of childbearing potential must have a negative urine or serum pregnancy test
as per institution's standard of care within 7 days prior to [18F]FLT PET/CT imaging.
• Ability to understand and the willingness to sign a written informed consent/assent.
Exclusion Criteria:
• Patients with known allergic or hypersensitivity reactions to previously administered
radiopharmaceuticals of similar chemical or biologic composition to [18F]FLT
• Newly diagnosed subjects who had prior chemotherapy or radiotherapy before enrollment
in the study. Relapsed patients are eligible prior to starting their relapsed
chemotherapy regimen if they meet the other eligibility criteria.
• Subjects for whom chemotherapy is not a standard of care primary therapy option.
• Patients who are pregnant or breast-feeding.
• Patients with no residual tumor (i.e. complete resection at diagnosis or relapse).
Drug: [18F]FLT-PET/CT
Sarcoma, Solid Tumor, Brain and Nervous System, Eye and Orbit, Anus, 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, Ovary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Uterine (Endometrial), Vulva, Small Intestine, Soft Tissue
Nivolumab in Treating Patients With Autoimmune Disorders and Advanced, Metastatic, or Unresectable Cancer
This phase Ib trial studies the side effects of nivolumab and to see how well it works in
treating patients with autoimmune disorders and cancer that has spread to other places in the
body or cannot removed by surgery. Immunotherapy with monoclonal antibodies, such as
nivolumab, may help the body's immune system attack the cancer, and may interfere with the
ability of tumor cells to grow and spread.
• Patients can have either histologically confirmed malignancy that is radiologically
evaluable and metastatic or unresectable, or have a malignancy for which a PD-1/PD-L1
inhibitor has been approved in the adjuvant setting. Eligible tumor types include
solid tumors and malignancies in which there is known evidence of clinical activity
for single agent PD-1 or PD-L1 antibodies. Nivolumab is Food and Drug Administration
(FDA)-approved for the treatment of melanoma, non-small cell lung cancer (NSCLC),
Merkel cell cancer, bladder cancer, renal cell carcinoma (RCC), gastric cancer,
hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer, Hodgkin
lymphoma (HL), metastatic small cell lung cancer (SCLC), and any solid tumor with
microsatellite instability (MSI)-high status confirmed. Patients with HL are eligible
but must follow standard response criteria. Additional tumor types may be eligible on
a case by case basis upon discussion with principal investigator (PI). Patients
enrolling on the trial for adjuvant use will be restricted to those with histology for
which a PD-1/PD-L1 inhibitor has been approved in the adjuvant setting including but
not limited to NSCLC, melanoma, RCC, cervical cancer, and bladder cancer
• Patients who have previously received other forms of immunotherapy (high-dose [HD]
IL-2, IFN, CTLA-4) are allowed. Patients must not have received cytokine immunotherapy
for at least 4 weeks before nivolumab administration. Patients who have received prior
anti-CTLA4 will be allowed and the washout period is 6 weeks
• Age >= 18 years; children are excluded from this study but may be eligible for future
pediatric phase 1 combination trials
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Karnofsky >=
60)
• Life expectancy of greater than 12 weeks
• Leukocytes >= 1,000/mcL
• Absolute neutrophil count >= 500/mcL
• Platelets >= 50,000/mcL
• Total bilirubin =< 2 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 5 x institutional ULN or < 8 x institutional ULN for patients with liver metastases
or an autoimmune disease that is contributing to the elevation of these values
• Creatinine ULN OR glomerular filtration rate (GFR) >= 30 mL/min (if using the
Cockcroft-Gault formula)
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral
therapy with undetectable viral load within 6 months are eligible for this trial
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be
undetectable on suppressive therapy if indicated
• If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV
viral load
• Patients with new or progressive brain metastases (active brain metastases) or
leptomeningeal disease are eligible if the treating physician determines that
immediate central nervous system (CNS) specific treatment is not required and is
unlikely to be required for at least 4 weeks (or scheduled assessment after the first
cycle of treatment), and a risk-benefit analysis (discussion) by the patient and the
investigator favors participation in the clinical trial
• The effects of nivolumab on the developing human fetus are unknown. For this reason,
women of child-bearing potential (WOCBP) and men 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. WOCBP receiving nivolumab will be
instructed to adhere to contraception for a period of 5 months after the last dose of
investigational product. Men receiving nivolumab and who are sexually active with
WOCBP will be instructed to adhere to contraception for a period of 7 months after the
last dose of investigational product. Women of childbearing potential must have a
negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent
units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of
nivolumab. Women must not be breastfeeding. Women who are not of childbearing
potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic
men) do not require contraception. WOCBP is defined as any female who has experienced
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral
oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12
months of amenorrhea in a woman over 45 in the absence of other biological or
physiological causes. In addition, women under the age of 55 must have a documented
serum follicle stimulating hormone (FSH) level less than 40 mIU/mL. These durations
have been calculated using the upper limit of the half-life for nivolumab (25 days)
and are based on the protocol requirement that WOCBP use contraception for 5
half-lives plus 30 days, and men who are sexually active with WOCBP use contraception
for 5 half-lives plus 90 days. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she (or the
participating partner) should inform the treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document
• Patients with more than one autoimmune disease are eligible. The treating physician
would determine which autoimmune disease is dominant and the patient would be treated
under that specific cohort
Exclusion Criteria:
• Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events (AEs) due to agents administered more than 4 weeks
earlier have not resolved or stabilized. Palliative (limited-field) radiation therapy
(RT) is permitted (2 week washout from start of treatment), if all of the following
criteria are met:
• Repeat imaging demonstrates no new sites of bone metastases
• The lesion being considered for palliative radiation is not a target lesion
• Patients with prior therapy with an anti-PD-1 or anti-PD-L1
• Patients with prior allogeneic hematologic transplant
• Patients who are receiving any other anticancer investigational agents
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
• Patients who have had evidence of active or acute diverticulitis, intra-abdominal
abscess, gastrointestinal (GI) bleeding, obstruction, and abdominal carcinomatosis
which are known risk factors for bowel perforation should be evaluated for the
potential need for additional treatment before coming on study. For the IBD (UC and
CD) cohort, an endoscopic assessment, disease activity index, and disease specific
inclusion/exclusion criteria will substitute for these factors in determining
eligibility with the exception of abdominal carcinomatosis, which should prompt
further evaluation
Olanzapine Versus Megestrol Acetate for the Treatment of Loss of Appetite Among Advanced Cancer Patients
This phase III trial compares the effects of olanzapine versus megestrol acetate in treating
loss of appetite in patients with cancer that has spread to other places in the body
(advanced). Olanzapine may stimulate and increase appetite. This study aims to find out if
olanzapine is better than the usual approach (megestrol acetate) for stimulating appetite and
preventing weight loss.
• Women and men of reproductive potential should agree to use an appropriate method of
birth control throughout their participation in this study due to the teratogenic
potential of the therapy utilized in this trial. Appropriate methods of birth control
include abstinence, oral contraceptives, implantable hormonal contraceptives or double
barrier method (diaphragm plus condom)
• Diagnosis of advanced cancer
• Patient-reported 2-month weight loss of at least 5 pounds (2.3 kilograms) and/or
physician-estimated caloric intake of less than 20 calories/kilogram of body weight
per day
• The patient must perceive loss of appetite and/or weight as a problem; and have an
appetite score of 4 or worse on the "Please rate your appetite…." question that
requires a patient response on a 0-10 numeric rating scale
• Not receiving ongoing tube feedings or parenteral nutrition at the time of
registration
• Not currently using systemic adrenal steroids (with the exception of short-term
dexamethasone within 3 days of chemotherapy for control of chemotherapy side effects)
• No use of androgens, progesterone analogs, or other appetite stimulants within the
past month
• Patient should not have poorly controlled hypertension or congestive heart failure at
registration
• Patient should not have an obstruction of the alimentary canal, malabsorption, or
intractable vomiting (defined as vomiting more than 3 times per day over the preceding
week)
• Not currently using olanzapine for another medical condition or had previously used
olanzapine for chronic nausea or for any pre-existing psychotic disorder
• Patient should not have had a previous blood clot at any time in the past
• No history of poorly controlled diabetes
• No symptomatic leptomeningeal disease or known brain metastases as these patients may
have difficulty taking oral medications
• No history of hypersensitivity to olanzapine or megestrol acetate
• No COVID-19 infection in the past that, in the opinion of the treating physician, had
left patients with compromised taste, which has not resolved at the time of
registration
• Not pregnant and not nursing, because this study involves an investigational agent
whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn
are unknown. Therefore, for women of childbearing potential only, a negative urine or
serum pregnancy test done =< 14 days prior to registration is required
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
• Estimated life expectancy of 3 months or longer
• Serum creatinine =< 2.0 mg/dL
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x upper limit
of normal (ULN)
• Fasting glucose > 1410 mg/dl
• Granulocytes > 1000/hpf
• No treatment with another antipsychotic agent, such as risperidone, quetiapine,
clozapine, butyrophenone within 30 days of enrollment
• In order to complete the mandatory patient-completed measures, participants must be
able to speak and/or read English or Spanish. Sites seeking to enroll Spanish-speaking
patients should have access to Spanish speaking staff on site or through the use of a
translation service to be able to conduct the informed consent discussion in Spanish,
and to conduct the weekly phone calls
Exclusion Criteria:
• Psychiatric illness which would prevent the patient from giving informed consent
• Medical condition such as uncontrolled infection (including human immunodeficiency
virus [HIV]), uncontrolled diabetes mellitus or cardiac disease which, in the opinion
of the treating physician, would make this protocol unreasonably hazardous for the
patient
• Patients who cannot swallow oral formulations of the agents
• Patients with impaired decision-making capacity (such as with a diagnosis of dementia
or memory loss) are not eligible for this study
• No presence of a hormone-sensitive tumor, such as breast, endometrial, or prostate
cancer (this exclusion criterion is intended to circumvent any confounding
antineoplastic effects of megestrol acetate)
A Study of LOXO-783 in Patients With Breast Cancer/Other Solid Tumors (PIKASSO-01)
The main purpose of this study is to learn more about the safety, side effects, and
effectiveness of LOXO-783. LOXO-783 may be used to treat breast cancer and other solid tumors
that have a change in a particular gene (known as the PIK3CA gene). Participation could last
up to 36 months (3 years) and possibly longer if the disease does not get worse.
• Have advanced breast cancer or another solid tumor with the presence of a PIK3CA
H1047R mutation (or other Sponsor and SRC-approved, activating PIK3CA mutations other
than H1047R mutation)
• Have adequate archival tumor tissue sample available or be approved by the Sponsor for
enrollment if no tumor sample is available.
• Have stopped all cancer treatment and have recovered from the major side effects
• Have adequate organ function, as measured by blood tests
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
scale
• Patients must have
• Measurable disease
--- Patients with non-breast tumor types must have at least 1 measurable lesion
• Non-measurable bone disease (at least one bone lesion in breast cancer patients
only)
• For patients with an ER+ breast cancer diagnosis:
• If female, must be postmenopausal
• If male, must agree to use hormone suppression
• Phase 1a:
-- Dose escalation and backfill patients:
• Advanced solid tumor
• Patients may have had up to 5 prior regimens for advanced disease
• Phase 1b:
• Part A:
• ER+/HER2- advanced breast cancer
• Patients may have had up to 2 prior regimens for advanced disease
• Prior cyclin dependent kinase (CDK)4/6 inhibitor therapy required
• Part B:
• ER+/HER2- advanced breast cancer
• Patients may have had up to 2 prior regimens for advanced disease.
• Part C:
• ER+/HER2- advanced breast cancer
• Patients may have had up to 5 prior regimens for advanced disease.
---- Prior CDK4/6 inhibitor therapy required.
• Have a diagnosis of diabetes mellitus Type 2
• Part D:
• Advanced breast cancer
• Patients may have had up to 5 prior regimens for advanced disease.
• Part E:
• Advanced solid tumor
• Patients may have had up to 3 prior regimens for advanced disease
Exclusion Criteria:
• Medical Conditions
• Colorectal cancer
• Endometrial cancers with specific concurrent oncogenic alterations
• A history of known active or suspected
• Diabetes mellitus Type 1 or
• Diabetes mellitus Type 2 requiring antidiabetic medication (Phase 1a and all
parts of Phase 1b except Part C).
• Serious concomitant systemic disorder
• Known or suspected history of untreated or uncontrolled central nervous system (CNS)
involvement.
• Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection, or
other clinically significant active disease process
• Prior exposure to PI3K/AKT/mTOR inhibitor(s), except in certain circumstances
Breast Cancer, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, 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, Kaposis sarcoma, Small Intestine, Soft Tissue, Unknown Sites
Stereotactic Radiosurgery (SRS) Dose-Escalation Study 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
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