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About
This randomized phase II trial studies how well nivolumab with or without ipilimumab works in treating patients with gastrointestinal stromal tumor that has spread to other places in the body or cannot be removed by surgery. Monoclonal antibodies, such as nivolumab and ipilimumab, interfere with the ability of tumor cells to grow and spread.
Full description
PRIMARY OBJECTIVES:
I. To assess the response rate of nivolumab alone and in combination with ipilimumab in subjects with metastatic or locally advanced/unresectable gastrointestinal stromal tumor (GIST).
SECONDARY OBJECTIVES:
I. Ascertain the response rate of nivolumab alone and in combination of ipilimumab in subjects with metastatic or locally advanced/unresectable GIST by Choi criteria.
II. Assess the progression-free survival (PFS). III. Ascertain the clinical benefit rate (CBR = complete response [CR] + partial response [PR] and stable disease [SD]) of nivolumab and ipilimumab in refractory/unresectable GIST.
IV. Explore the safety of nivolumab monotherapy and nivolumab and ipilimumab in this population assessed by the frequency and severity of adverse events (AEs).
TERTIARY OBJECTIVES:
I. Compare RR and CBR in patients whose tumors are programmed cell death ligand 1 (PD-L1) positive (+) and PD-L1 negative (-) at baseline.
II. In the patients who are PD-L1 positive, compare RR and CBR in patients with 1% and 5% tumor membrane staining.
III. Determine the baseline mutational load of patients at the start of treatment.
IV. Determine the response to treatment based on the baseline mutation load and baseline GIST mutations.
V. Determine the response rate based on GIST mutational status.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive nivolumab intravenously (IV) over 60 minutes on day 1. Courses repeat every 14 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive nivolumab IV over 30 minutes on day 1 and ipilimumab IV over 30 minutes every 6 weeks. Courses repeat every 14 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically.
Enrollment
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Inclusion criteria
Written informed consent must be obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
Life expectancy > 12 weeks
Histological confirmation of GIST
Mutational testing of patient samples for KIT and platelet-derived growth factor receptor (PDGFR) mutations; (this will not hold up starting therapy, but will be done for all patients lacking up front mutational testing)
Patients must have refused or have evidence of intolerance to or progression on imatinib
This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (i.e., subject has not been randomized / has not been treated); if re-enrolled, the subject must be re-consented
Adequate archival tissue must be available from the prior 3 months to signing consent; if not, an adequate tumor specimen obtained by either excisional biopsy, incisional biopsy or core needle biopsy must be sent to the central pathology lab for evaluation; the material must measure at least 0.8 × 0.1 cm in size or contain at least 100 tumor cells
Measurable tumor lesions according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
Hemoglobin >= 9 g/dL
Absolute neutrophil count >= 1,500/mm^3
Platelet count >= 100,000/mm^3
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 × institutional upper limit of normal (ULN); for subjects with liver metastases, AST or ALT =< 5 × ULN
Bilirubin =< 1.5 × ULN; for subjects with documented/suspected Gilbert's disease, bilirubin =< 3 × ULN
Willingness to provide consent for biopsy samples; tumor biopsies will be required for all subjects, tumor lesions used for biopsy should not be lesions used as RECIST target lesions, unless there are no other lesions suitable for biopsy; if a RECIST target lesion is used for biopsy the lesion must be >= 2 cm in longest diameter
Women of childbearing potential (WOCBP) 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 study drug
Women must not be breastfeeding
Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug (25 days) plus 30 days (duration of ovulatory cycle) for a total of 155 days post-treatment completion
Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of the study drug plus 90 days (duration of sperm turnover) for a total of 215 days post-treatment completion; in addition, male subjects must be willing to refrain from sperm donation during this time
Azoospermic males are exempt from contraceptive requirements; WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements, and still must undergo pregnancy testing as described in this section
Male subjects must be willing to refrain from sperm donation during the entire study and for 5 half-lives of study drug plus 90 days (duration of sperm turnover) after dosing has been completed
At a minimum, subjects must agree to use one highly effective (which have a failure rate of < 1% when used consistently and correctly) OR one less effective method of contraception as listed below:
WOCBP and female partners of male subjects, who are WOCBP, are expected to use one of the highly effective methods of contraception listed below; male subjects must inform their female partners who are WOCBP of the contraceptive requirements of the protocol and are expected to adhere to using contraception with their partner; contraception methods are as follows:
Less effective methods of contraception
Unacceptable methods of contraception
Exclusion criteria
Palliative surgery and/or radiation treatment within 28 days prior to course 1 day 1 (C1D1)
No steroids are permitted within 28 days of C1D1; or doses < 10mg/day prednisone equivalent or levels necessary for physiologic replacement
Women who are of pregnant or breastfeeding
Inability to give informed consent
An inadequate tumor specimen as defined by the local pathologist
History of other malignancies except cured basal cell carcinoma, cutaneous squamous cell carcinoma, melanoma in situ, superficial bladder cancer or carcinoma in situ of the cervix; for other malignancies, must be documented to be free of cancer for >= 2 years; all other cases can be considered on a case by case basis at the discretion of the principal investigator
Any condition that might interfere with the subject's participation in the study, safety, or in the evaluation of the study results
Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study
Prior exposure to any anti-PD-1 or anti-PD-L1 antibody, or any anti-cytotoxic T-lymphocyte-associated protein (CTLA) 4 antibodies
Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment; concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable
Current or prior use of immunosuppressive medication within 28 days before the first dose of nivolumab, with the exceptions of intranasal, topical, and inhaled corticosteroids or systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent (use for brain metastases is not permitted 28 days prior to start of therapy)
Active or prior documented autoimmune disease within the past 3 years
History of organ transplant that requires use of immunosuppressives
Active or prior documented inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis) or a history of primary immunodeficiency
Exposure to any therapeutic agent (investigational or conventional) within 7 days of date of randomization or to any agent for which 5 half lives have not elapsed
Unresolved toxicities from prior anticancer therapy, defined as having not resolved to National Cancer Institute's (NCI's) Common Terminology Criteria for Adverse Events (CTCAE) (NCI CTCAE version [v]4.03) grade 0 or 1, or to levels dictated in the inclusion/exclusion criteria with the exception of alopecia; subjects with irreversible toxicity that is not reasonably expected to be exacerbated by nivolumab may be included (eg, hearing loss) after consultation with the principal investigator
Subjects who active hepatitis B or C, or human immunodeficiency virus (HIV)
Prisoners or subjects who are involuntarily incarcerated; (Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a subject
Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
Primary purpose
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Masking
36 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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