Inclusion Criteria:
1. Patients with locally advanced or metastatic RMC histologically confirmed by expert
pathology review and loss of SMARCB1 staining by immunohistochemistry. Patients with
advanced or metastatic unclassified renal cell carcinoma with medullary phenotype (a
rare SMARCB1 negative RMC variant occurring in individuals without sickle
hemoglobinopathies) are also eligible.
2. Patients will be eligible regardless of whether they have had prior nephrectomy or
still have their primary tumor in-situ.
3. 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 MRI or CT scan. If the patient has had previous radiation to the
marker lesion(s), there must be evidence of progression since the radiation.
4. Patients should be willing to provide a newly obtained fresh core biopsy of a tumor
lesion. Not required if there is a recently obtained fresh specimen on an IRB approved
correlated trial up to 6 weeks (42 days) prior to initiation of treatment on Day 1.
5. Patients can be either naïve for any previous systemic treatment or have had any
number of prior systemic therapies. However, patients must not have received prior
anticancer therapy with antiPD1, anti-PD-L1, anti-CTLA-4, or anti-LAG-3 immune
checkpoint inhibitors.
6. There must be evidence of progression on or after last treatment regimen received.
7. ECOG performance status 0-2. o NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair,
subject is considered to be ambulatory for the purpose of assessing their performance
status.
8. Age (at the time of consent/assent): ≥ 18 years. 9. Consent to MD Anderson companion laboratory protocol 2014-0938. 10. Within 14 days of the first dose of the study drugs (cycle 1 day 1), patients must
have adequate organ and marrow function as defined below:
- - Hemoglobina ≥9 g/dl (treatment allowed)
- Absolute neutrophil countb ≥1,000/µL.
- - total bilirubin ≤ 1.5 mg/dl.
- - AST(SGOT) or ALT (SGPT) ≤ 2.5 X institutional ULN, except in known hepatic
metastasis, wherein may be ≤ 5 x ULN.
- - Serum Creatininec ≤ 1.5 x ULN by gender (as long as patient does not require
dialysis) aMay receive transfusion b Without growth factor support (filgrastim or
pegfilgrastim) for at least 14 days c If creatinine is not <1.5×ULN, then
calculate by Cockcroft-Gault methods or local institutional standard and CrCl
must be >30 mL/kg/1.73 m2 11 INR and PTT ≤ 1.5 x ULN prior to registration for
treatment.
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 registration for treatment.
12 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).
13 Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24
hours prior to the start of the study drug. 14 Women must not be breastfeeding.
15 WOCBP must agree to follow instructions for method(s) of contraception from
the time of registration for treatment for the duration of treatment with study
drug (s) plus 5 half-lives of study drug (s) plus 30 days (duration of ovulatory
cycle) for a total of 5 months post treatment completion. Men must agree to
effective contraception from the time of registration for treatment to 7 months
post last treatment with nivolumab. 16 WOCBP who are continuously not
heterosexually active are exempt from contraceptive requirements. However, WOCBP
must still undergo pregnancy testing as described in these sections.
Exclusion Criteria:
1. 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.
2. Patients currently receiving anticancer therapies or who have received anticancer
therapies (including chemotherapy and targeted therapy) within 2 weeks (14 days) prior
to study Day 1 are excluded. Patients who have completed palliative radiation therapy
more than 14 days prior to the first dose of the combination immunotherapy are
eligible.
3. Patients with persistent grade ≥2 adverse events from prior systemic therapies that
would confound timely detection of immune-related adverse events or otherwise hinder
patient participation in the clinical trial.
4. 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, other than cytoreductive nephrectomy ± retroperitoneal lymph node
dissection, during the course of the study.
5. Patients who have organ allografts.
6. 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. Patientswith 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.
7. Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).
8. Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBVsAg) test or
positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV
antibody test indicating acute or chronic infection. If hepatitis C antibody test is
positive then active infection has to be confirmed by hepatitis C RNA testing for the
patient to be excluded.
9. 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 or
vomiting. Patients with active COVID-19 disease as indicated by a positive polymerase
reaction (PCR) test are excluded.
Patients with previous COVID-19 disease are allowed if ≥30 days from last positive
test, and COVID-19 symptoms have resolved and/or PCR test is now negative. 10. Patients must not have received prior anticancer therapy with anti-LAG-3 immune
checkpoint inhibitors.
11. Patients receiving any concomitant systemic therapy for renal cell cancer are
excluded.
12. Patients must not be scheduled to receive another experimental drug while on this
study.
13. Patients who are on high dose steroid (e.g., > 10mg 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 (eg, from contrast dye allergy) is permitted.
Physiological corticosteroid replacement therapy for adrenal insufficiency is also
permitted.
14. Troponin T (TnT) or I (TnI) > 2 × institutional ULN. Participants with TnT or TnI
levels between > 1 to 2 × ULN will be permitted if a repeat levels within 24 hours are
≤ 1 x ULN. If TnT or TnI levels are between >1 to 2 × ULN within 24 hours, the
participant may undergo a cardiac consultation and be considered for treatment,
following cardiologist recommendation. When repeat levels within 24 hours are not
available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat
levels beyond 24 hours are < 2 × ULN, the participant may undergo a cardiac
consultation and be considered for treatment, following cardiologist recommendation.
Notification of the decision to enroll the participant following cardiologist
recommendation has to be made to the MD Anderson Medical Monitor or designee.
15. Left ventricular ejection fraction (LVEF) assessment with documented LVEF < 50% by
either transthoracic echocardiogram (TTE) or multigated acquisition (MUGA) scan (TTE
preferred test) within 6 months prior to start of study treatment.
16. Active myocarditis, regardless of etiology.
17. Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:
1. Symptomatic congestive heart failure of New York heart Association Class III or
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. 3. Severely impaired lung function as defined as 02 saturation that is 92% or less
at rest on room air. 4. Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN (if unfasted
glucose elevation, treating physician will evaluate per standard of care)
5. 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. 6. Known active or symptomatic viral hepatitis or chronic liver disease.
Uncontrolled adrenal insufficiency. 7. Patients with a history of major psychiatric illness judged unable to fully
understand the investigational nature of the study and the risks associated with
the therapy.
18. 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 nivolumab or relatlimab or that
might affect the interpretation of the results of the study or render the subject at
high risk from treatment complications.
19. Patients should not receive immunization with attenuated live vaccines within one week
(7 days) of registration for treatment or during study period.
a. Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are
live attenuated vaccines, and are not allowed.
20. Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases.
21. Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods as defined above.
22. Any patients who cannot be compliant with the appointments required in this protocol
must not be enrolled in this study.
