Nivolumab With or Without Ipilimumab in Treating Patients With Gastrointestinal Stromal Tumor That Is Metastatic or Cannot Be Removed by Surgery

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.

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:

- Progestogen only hormonal contraception associated with inhibition of
ovulation

- Hormonal methods of contraception including oral contraceptive pills
containing combined estrogen + progesterone, vaginal ring, injectables,
implants and intrauterine devices (IUDs) such as Mirena

- Nonhormonal IUDs, such as ParaGard

- Bilateral tubal occlusion

- Vasectomised partner with documented azoospermia 90 days after procedure

- Intrauterine hormone-releasing system (IUS)

- Complete abstinence

- Less effective methods of contraception

- Diaphragm with spermicide

- Cervical cap with spermicide

- Vaginal sponge with spermicide

- Male or female condom with or without spermicide

- Progestogen-only oral hormonal contraception, where inhibition of ovulation
is not the primary mode of action

- Unacceptable methods of contraception

- Periodic abstinence (calendar, symptothermal, post-ovulation methods)

- Withdrawal (coitus interruptus)

- Spermicide only

- Lactation amenorrhea method (LAM)

Exclusion Criteria:

- Palliative surgery and/or radiation treatment within 28 days prior to course 1 day 1
(C1D1)

- Localized therapy of non-target lesions is allowed

- 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

- NOTE: subjects with active, known or suspected autoimmune disease such as
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune
condition only requiring hormone replacement, psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external
trigger are permitted to enroll

- 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