Phase 2 Study of Combination Tivozanib and Nivolumab in Advanced Non-Clear Cell Renal Cell Carcinoma

Inclusion Criteria:

1. Patients with histologically or cytologically confirmed metastatic non-clear cellrenal cell carcinoma of papillary, chromophobe, oncocytic neoplasms, unclassified,or not otherwise specified (NOS) as clear cell. Medullary carcinoma of the kidneyand collecting duct tumors are NOT allowed

2. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

3. Up to 1 systemic line of therapy (either monotherapy or combination) including priorimmunotherapy (anti-PD1, PD-L1, or CTLA-4) and multi-tyrosine kinase inhibitors innon-metastatic or metastatic setting is allowed. A washout period of 5 half lives or 21 days, whichever one is shorter, will be required for patients that have receivedprevious systemic therapy.

4. Age ≥18 years.

5. Eastern Cooperative Oncology Group (ECOG) Appendix 1 performance status ≤2 (Karnofsky ≥60%).

6. Patients must have adequate organ and marrow function as defined below:

7. absolute neutrophil count ≥1,000/mcL

8. platelets ≥100,000/mcL

9. total bilirubin ≤ institutional upper limit of normal (ULN)

10. AST ≤3 × institutional ULN

11. (ALT) ≤3 × institutional ULN

12. creatinine ≤1.5 × institutional ULN

13. eGFR ≥30 ml/min

14. Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load.

15. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated.

16. Patients with treated brain metastases (at least 4 weeks have passed from treatment)are eligible if follow-up brain imaging after central nervous system (CNS)-directedtherapy shows no evidence of progression.

17. Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate CNS specific treatment is not required and is unlikely to be requiredduring the first cycle of therapy.

18. Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial.

19. Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better.

20. The effects of combination tivozanib and nivolumab on the developing human fetus areunknown. For this reason and because tyrosine kinase inhibitors and immunotherapyagents as well as other therapeutic agents used in this trial are known to beteratogenic, women of child-bearing potential (WOCBP) and men must agree to useadequate contraception (hormonal or barrier method of birth control; abstinence)prior to study entry and for the duration of study participation. (refer to MDAPolicy CLN 1114) This includes all female patients, between the onset of menses (asearly as 8 years of age) and 55 years unless the patient presents with an applicableexclusionary factor which may be one of the following:

• Postmenopausal (no menses in greater than or equal to 12 consecutive months).

• History of hysterectomy or bilateral salpingo-oophorectomy.

• Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausalrange, who have received Whole Pelvic Radiation Therapy).

• History of bilateral tubal ligation or another surgical sterilizationprocedure. Approved methods of birth control are as follows: Hormonalcontraception (i.e. birth control pills, injection, implant, transdermal patch,vaginal ring), Intrauterine device, Tubal Ligation or hysterectomy,Subject/Partner post vasectomy, Implantable or injectable contraceptives, andcondoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drugwashout period is an acceptable practice; however periodic abstinence, the rhythmmethod, and the withdrawal method are not acceptable methods of birth control.Should a woman become pregnant or suspect she is pregnant while she or her partneris participating in this study, she should inform her treating physicianimmediately.

14. Men treated or enrolled on this protocol must also agree to use adequatecontraception prior to the study, for the duration of study participation, and 4months after completion of combination tivozanib and nivolumab administration.

15. Participants or their legally acceptable representative (LAR) must have signed anddated an IRB/IEC approved written informed consent form in accordance withregulatory and institutional guidelines. This must be obtained before theperformance of any protocol related procedures that are not part of normalparticipant care.

Exclusion Criteria:

1. Prior tivozanib therapy.

2. Prior nivolumab therapy.

3. Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia.

4. Patients who are receiving any other investigational agents.

5. History of allergic reactions attributed to compounds of similar chemical orbiologic composition to tivozanib or nivolumab.

6. Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolicblood pressure > 100 mmHg on 2 or more antihypertensive medications, documented on 2consecutive measurements taken at least 2 hours apart. Anti-hypertensives must nothave been increased 30 days prior to enrollment.

7. History of autoimmune disorders except for the following:

8. Patients with vitiligo or alopecia

9. Hypothyroidism (e.g. following Hashimoto syndrome) that is stable on thyroidhormone replacement

10. Any chronic skin condition that does not require systemic therapy

11. Patients without active autoimmune disease requiring treatment in the last 3years may be included after consultation with study MDA lead PrincipalInvestigator

12. Active human immunodeficiency virus (HIV) infection unless patients are on effectiveanti-retroviral therapy with undetectable viral load within 6 months.

13. Has evidence of any other medical conditions, psychiatric condition, physicalexamination or laboratory findings that may interfere with the planned treatment,affect subject compliance or place the subject at high risk from treatment-relatedcomplications in the opinion of the local principal investigator (PI).

14. Current systemic corticosteroid use greater than prednisone 10 mg daily orequivalent.

15. Pregnant women are excluded from this study because tivozanib and nivolumab areagents with the potential for teratogenic or abortifacient effects. Because there isan unknown but potential risk for adverse events in nursing infants secondary totreatment of the mother with tivozanib and nivolumab, breastfeeding should bediscontinued if the mother is treated with tivozanib and nivolumab.

16. Receiving concomitant CYP3A inducers.