PRIMARY OBJECTIVE:
I. To determine the objective response rate (ORR) and disease control rate (DCR) at 24 weeks of sitravatinib 100 milligrams (mg) by mouth (PO) daily plus nivolumab 480 mg intravenously (IV) every 4 weeks in patients with metastatic renal cell carcinoma (mRCC) who progress on prior PD-1 or PD-L1 immune checkpoint inhibitors (CPIs), cabozantinib, or lenvatinib, as defined by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
SECONDARY OBJECTIVES:
I. To estimate the overall survival (OS), progression-free survival (PFS), duration of response (DOR), and 1-year OS of sitravatinib plus nivolumab in the same population.
II. To determine the safety, tolerability, and impact on health-related quality of life of sitravatinib plus nivolumab in patients with mRCC who progress on PD-1/PD-L1 CPIs, cabozantinib, or lenvatinib as defined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
EXPLORATORY OBJECTIVE:
I. To assess how the immune landscape, transcriptome, and genome change after contemporary first-line treatment via tumor tissue biopsy obtained at time of enrollment, 4 weeks after treatment with sitravatinib plus nivolumab, and at time of progression, as well as blood sample collection.
OUTLINE:
Patients receive sitravatinib PO once daily (QD) and nivolumab IV over 30 minutes on day 1. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up 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 lines of
treatment in the advanced or metastatic setting, and the most recent treatment must
include a PD-1 or PD-L1 CPI, cabozantinib, or lenvatinib. Examples of acceptable prior
regimens include: nivolumab plus ipilimumab (cohort A), pembrolizumab plus axitinib,
avelumab plus axitinib, or VEGF-targeted monotherapy followed by nivolumab monotherapy
(cohort B), or cabozantinib or lenvatinib with or without everolimus, received alone
sequentially before PD-1/PD-L1 inhibitors, or in combination with CPIs (cohort C)
- There must be evidence of progression on or after treatment (at any point after
completing prior therapy) with a PD-1/PD-L1-containing regimen as the last treatment
received 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
- Age >= 18 years
- Hemoglobin >= 9 g/dl (treatment allowed)
- May receive transfusion
- Absolute neutrophil count >= 1,000/uL
- Platelets >= 75,000/uL
- Total bilirubin =< 1.5 mg/dL
- For patients with Gilbert's disease, total bilirubin should =< 3 mg/dL (=< 51.3
umol/L)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or
alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X
institutional upper limit of normal (ULN), except in known hepatic metastasis, wherein
may be < 5 x ULN
- Serum Creatinine =< 1.5 x ULN (as long as patient does not require dialysis)
- 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
- Institutional normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 x
ULN prior to study entry. Therapeutic anticoagulation is permitted if: on a stable
dose of low molecular weight heparin (LMWH) for > 2 weeks (14 days) at the time of
enrollment or on a direct oral anticoagulant (DOAC) for > 2 weeks at 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]) 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, 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 sitravatinib
are eligible
- Patients who had a major surgery or significant traumatic injury (injury requiring >
28 days to heal) within 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 with a prior history of grade 3 or worse immune-related adverse events
attributed to CPIs (PD-1, PD-L1, or CTLA-4), except endocrine adverse events with
appropriate hormone replacement or asymptomatic amylase/lipase elevations
- Active or prior documented autoimmune disease, as follows:
- Inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis)
- Interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis that
required steroid treatment, or any evidence of clinically active ILD.
- Other medically important autoimmune disease within 2 years before first dose of
study treatment. Note: Patients with type 1 diabetes, vitiligo, Graves' disease
requiring only hormone replacement, residual hypothyroidism requiring only
hormone replacement, or psoriasis or Sjogren's syndrome not requiring systemic
treatment are permitted
- Immunocompromising conditions, as follows:
- Known acute or chronic human immunodeficiency virus (HIV) infection
- History of primary immunodeficiency
- History or allogeneic transplant
- Current or prior use of immunosuppressive medication within 28 days before the
first dose of study treatment, with the exception of topical, ocular, intranasal,
and inhaled corticosteroids, or systemic corticosteroids at an equivalent dose =<
10 mg of prednisone daily
- 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 sitravatinib
- 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 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 02 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 sitravatinib 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 a patient can become
pregnant or father a child, appropriate birth control methods, including a
double-barrier method (2 methods at the same time), are required while on study and
for 23 weeks (females) or 31 weeks (males) after you stop receiving the study drugs.
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 sitravatinib)
- 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
