Summary

This phase II trial studies of side effects of cabozantinib and sunitinib malate and to see how well they work in treating participants with variant histology kidney cancer that has spread to other places in the body. Cabozantinib and sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Objectives

PRIMARY OBJECTIVE:
I. To compare the median progression free survival for patients with variant histology renal cell carcinoma randomized to receive treatment with cabozantinib or sunitinib malate (sunitinib).

SECONDARY OBJECTIVES:
I. To compare the median overall survival for patients with variant histology renal cell carcinoma randomized to receive treatment with cabozantinib or sunitinib.
II. To compare the objective response rates for the two treatment arms.
III. To evaluate the adverse event rates for the two treatment arms.

OUTLINE: Participants are randomized to 1 of 2 groups.

GROUP 1: Participants receive cabozantinib orally (PO) once daily (QD) on days 1-42. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

GROUP 2: Participants receive sunitinib malate PO QD on days 1-28. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up every 6 weeks for 1 year, and then every 6 months.

Eligibility

1. The subject has a histologic or cytologic diagnosis of a variant histology renal cell carcinoma including papillary, chromophobe, Xp.11 translocation, undifferentiated, or unclassified which is treatment naive or has previously been treated with one systemic treatment line not containing any vascular endothelial growth factor antibody or vascular endothelial growth factor receptor tyrosine kinase inhibitors. The patient may have received treatment with immune checkpoint therapy including nivolumab as a single agent or nivolumab plus ipilimumab in combination. Previous treatment with mammalian target of rapamycin agents such as temsirolimus or everolimus is acceptable.
2. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 as determined by the investigator.
3. The subject has had an assessment of all known disease sites e.g., by computerized tomography (CT) scan, magnetic resonance imaging (MRI), bone scan as appropriate, within 28 days before the first dose of cabozantinib or sunitinib.
4. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2.
5. Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
6. Absolute neutrophil count (ANC) >= 1500/mm^3 without colony stimulating factor support (obtained within 4 days before the first dose of cabozantinib or sunitinib).
7. White blood cell count >= 2500/mm^3 (>= 2.5 GI/L) (obtained within 4 days before the first dose of cabozantinib or sunitinib).
8. Platelets >=100,000/mm^3 (obtained within 4 days before the first dose of cabozantinib or sunitinib).
9. Hemoglobin >= 9 g/dL (obtained within 4 days before the first dose of cabozantinib or sunitinib); The patient may have had a blood transfusion to meet this criteria
10. Bilirubin =< 1.5 x the upper limit of normal (ULN) (obtained within 4 days before the first dose of cabozantinib or sunitinib). For subjects with known Gilbert’s disease, bilirubin =< 3.0 mg/dL.
11. Serum albumin >= 2.8 g/dl (obtained within 4 days before the first dose of cabozantinib or sunitinib).
12. Serum creatinine =< 2.0 x ULN or calculated creatinine clearance >= 30 mL/min (>= 0.5 mL/sec) (obtained within 4 days before the first dose of cabozantinib or sunitinib) using the Cockcroft-Gault equation.
13. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) =< 3 x upper limit of normal (ULN) (obtained within 4 days before the first dose of cabozantinib or sunitinib). ALP =< 5 x ULN with documented bone metastases.
14. Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol) (obtained within 4 days before the first dose of cabozantinib or sunitinib).
15. The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document.
16. Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s).
17. Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e., females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons.