Sitravatinib and Nivolumab in Treating Patients With Advanced or Metastatic Kidney Cancer

PRIMARY OBJECTIVES:

I. To determine the toxicities (defined as a grade 3 or 4 National Cancer Institute [NCI]
non-hematologic or hematologic adverse event, within 12 weeks from treatment initiation), and
efficacy (defined as achieving complete remission, partial remission, or stable disease
within 6 weeks) of sitravatinib (MGCD516) when administered orally (PO) daily in combination
with standard dose nivolumab 240 mg/kg every 2 weeks.

SECONDARY OBJECTIVES:

I. To estimate the overall survival (OS), progression-free survival (PFS) times, objective
response rates (ORR), and quality of life (QOL) of patients with advanced clear cell renal
cell cancer (RCC) treated with the combination of MGCD516 and nivolumab.

II. Evaluate potential biomarkers for patient stratification and treatment response,
including genetic analysis, serum cytokines and chemokines, as well as tumor antigen-specific
immune responses, such as antibody and T cell responses, as surrogates for anti-tumor
activity.

OUTLINE:

Patients receive sitravatinib PO once daily (QD) on days 1-14 and receive nivolumab
intravenously (IV) over 60 minutes on day 1 starting course 2. Courses repeat every 14 days
for courses 1-6 and then every 28 days for subsequent courses in the absence of disease
progression or unacceptable toxicity. Patients who receive at least 6 infusions of nivolumab
with no dose limiting toxicities (DLTs), may then receive nivolumab every 4 weeks.

After completion of study treatment, patients are followed up at 30 days and then every 3
months.

Inclusion Criteria:

- Patients with histologically or cytologically confirmed metastatic/advanced clear cell
RCC, or RCC with a clear cell component, who have received 1 or 2 prior
anti-angiogenic therapy regimens (+/- cytokine therapy with interleukin-2 or
interferon-alfa) in the advanced or metastatic setting; examples of anti-angiogenic
agents include, but are not limited to, sorafenib, sunitinib, pazopanib, axitinib, and
bevacizumab

- There must be evidence of progression on or after last treatment regimen received and
within 6 months of enrollment

- Patients must have at least one measurable site of disease, defined as a lesion that
can be accurately measured in at least one dimension (longest diameter to be recorded)
and measures >= 15 mm with conventional techniques or >=10 mm with more sensitive
techniques such as magnetic resonance imaging (MRI) or spiral computed tomography (CT)
scan; if the patient has had previous radiation to the marker lesion(s), there must be
evidence of progression since the radiation

- Karnofsky performance status >= 70

- Hemoglobin >= 9 g/dl (treatment allowed) within 14 days prior to study entry

- Absolute neutrophil count >= 1,500/uL within 14 days prior to study entry

- Platelets >= 100,000/uL within 14 days prior to study entry

- Total bilirubin =< 1.5 mg/dl within 14 days prior to study entry

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) or
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
institutional upper limit of normal (ULN), except in known hepatic metastasis, wherein
may be < 5 x ULN within 14 days prior to study entry

- Serum creatinine =< 1.5 x ULN (as long as patient does not require dialysis); a) may
receive transfusion b) if creatinine is not < 1.5 x ULN, then calculate by
Cockcroft-Gault methods or local institutional standard and creatinine clearance
(CrCl) must be >= 40 mL/kg/1.73 m^2 within 14 days prior to study entry

- International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 x
ULN within 14 days prior to study entry; therapeutic anticoagulation with warfarin is
allowed if target INR =< 3 on a stable dose of warfarin or on a stable dose of low
molecular weight (LMW) heparin for > 2 weeks (14 days) at the time of enrollment

- Female patients of childbearing potential (not postmenopausal for at least 12 months
and not surgically sterile) must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[HCG]) within 14 days before study entry; pregnancy test must be repeated if performed
> 14 days before starting study drug

- Women must not be breastfeeding

- Patients with a history of major psychiatric illness must be judged (by the treating
physician) able to fully understand the investigational nature of the study and the
risks associated with the therapy

- Patients with controlled brain metastases are allowed on protocol if they had solitary
brain metastases that was surgically resected or treated with radiosurgery or gamma
knife, without recurrence or edema for 1 month (4 weeks)

Exclusion Criteria:

- Patients must not have any other malignancies within the past 2 years except for in
situ carcinoma of any site, or adequately treated (without recurrence post-resection
or post-radiotherapy) carcinoma of the cervix or basal or squamous cell carcinomas of
the skin or active non-threatening second malignancy that would not, in the
investigator's opinion, potentially interfere with the patient's ability to
participate and/or complete this trial; examples include but not limited to:
urothelial cancer grade Ta or T1, adenocarcinoma of the prostate treated by active
surveillance

- Patients currently receiving anticancer therapies or who have received anticancer
therapies within 2 weeks (14 days) from enrollment into this study (including
chemotherapy and targeted therapy) are excluded; also, patients who have completed
palliative radiation therapy more than 14 days prior to the first dose of MGCD516 are
eligible

- Patients, who have had a major surgery or significant traumatic injury (injury
requiring > 4 weeks [28 days] to heal) within 4 weeks (28 days) of start of study
drug, patients who have not recovered from the side effects of any major surgery
(defined as requiring general anesthesia) or patients that are expected to require
major surgery during the course of the study

- Patients who have been previously treated with mTOR inhibitors such as everolimus and
temsirolimus, or with c-MET inhibitors such as cabozantinib

- Patients who have organ allografts

- Known or suspected autoimmune disease; patients with a history of inflammatory bowel
disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders
such as rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic
lupus erythematosus or autoimmune vasculitis (e.g., Wegener's granulomatosis) are
excluded from this study; patients with a history of Hashimoto's thyroiditis only
requiring hormone replacement, type I diabetes, or psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external trigger
are allowed to participate

- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS)

- Any underlying medical condition, which in the opinion of the investigator, will make
the administration of study drug hazardous or obscure the interpretation of adverse
events, such as a condition associated with frequent diarrhea, uncontrolled nausea,
vomiting, malabsorption syndrome or small bowel resection that may significantly alter
the absorption of MGCD516

- Patients must not have received prior anticancer therapy with any immune checkpoint
inhibitors such as anti-CLTA-4, anti-PD1, or anti-PD-L1

- Patients receiving any concomitant systemic therapy for renal cell cancer are excluded

- Patients must not be scheduled to receive another experimental drug while on this
study

- Patients who are on high dose steroid (e.g., > 10 mg prednisone daily or equivalent)
or other more potent immune suppression medications (e.g., infliximab); topical,
inhaled, intra-articular, ocular, or intranasal corticosteroids (with minimal systemic
absorption) are allowed; a brief course (=< 48 hours) of systemic corticosteroids for
prophylaxis (e.g., from contrast dye allergy) is permitted

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as: symptomatic
congestive heart failure of New York Heart Association class III or IV; unstable
angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6
months of start of study drug, serious uncontrolled cardiac arrhythmia or any other
clinically significant cardiac disease; severely impaired lung function as defined as
oxygen (O2) saturation that is 88% or less at rest on room air; uncontrolled diabetes
as defined by blood glucose > 200 mg/dl (11.1 mmol/l); systemic fungal, bacterial,
viral, or other infection that is not controlled (defined as exhibiting ongoing
signs/symptoms related to the infection and without improvement) despite appropriate
antibiotics or other treatment; liver disease such as cirrhosis or chronic active
hepatitis; positive test for hepatitis B virus (HBV) using HBV surface antigen (HBV
sAg) test or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid
(RNA) or HCV antibody test indicating acute or chronic infection

- Patients must not have history of other diseases, metabolic dysfunction, physical
examination finding, or clinical laboratory finding giving reasonable suspicion of a
disease or condition that contraindicates the use of MGCD516 or nivolumab or that
might affect the interpretation of the results of the study or render the subject at
high risk from treatment complications

- Patients should not receive immunization with attenuated live vaccines within one week
(7 days) of study entry or during study period

- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods; if barrier contraceptives
are being used, these must be continued throughout the trial by both sexes; hormonal
contraceptives are not acceptable as a sole method of contraception; (women of
childbearing potential must have a negative urine or serum pregnancy test within 14
days prior to study entry; pregnancy test must be repeated if performed > 14 days
before administration of MGCD516)

- Any patients who cannot be compliant with the appointments required in this protocol
must not be enrolled in this study

- Concurrent therapy with medications known to significantly prolong the QT interval
and/or associated with increased risk for Torsade de Pointes arrhythmia; the principal
investigator (PI) is the final arbiter in questions related to eligibility

- Patients with left ventricular ejection fraction (LVEF) < 40%