Cabozantinib, Nivolumab, and Ipilimumab for the Treatment of Metastatic Non-clear Cell Renal Cell Cancer
18 Years and older, Male and Female
19-789 (primary)
NCI-2020-11407
Summary
This phase II trial studies the effect of cabozantinib, nivolumab, and ipilimumab for the treatment of non-clear cell renal cell cancer (kidney cancer) that has spread to other places in the body (metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. The purpose of this trial is to assess whether cabozantinib, nivolumab, and ipilimumab in combination are safe and effective (how well the drug works) in slowing down the growth of kidney cancer.
Objectives
PRIMARY OBJECTIVE:
I. To determine the objective response rate (ORR) of cabozantinib combined with nivolumab plus ipilimumab in patients with non-clear cell renal cell carcinoma (nccRCC), defined as the percentage of patients with partial (PR) or complete response (CR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
SECONDARY OBJECTIVES:
I. To determine the duration of response to cabozantinib, nivolumab and ipilimumab in patients with advanced nccRCC.
II. To determine the progression-free survival (PFS) of patients with advanced nccRCC treated with cabozantinib, nivolumab and ipilimumab.
III. To determine the overall survival (OS) of patients with advanced nccRCC treated with cabozantinib, nivolumab and ipilimumab.
IV. To determine ORR, PFS and OS of patients with advanced nccRCC treated with cabozantinib, nivolumab and ipilimumab, according to pre-specified subgroups (these groups are not used for stratification purposes):
IVa. Histological subtypes (papillary versus non-papillary; presence of sarcomatoid differentiation [yes/no]).
IVb. International metastatic renal cell carcinoma database (IMDC) risk groups (favorable versus intermediate versus poor).
IVc. Lines of previous therapy (treatment naïve versus previously treated).
IVd. PD-L1 expression on tumor and immune cells (positive versus negative).
V. To assess the safety of cabozantinib combined with nivolumab and ipilimumab in patients with advanced nccRCC according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
VI. To assess the impact of cabozantinib, nivolumab and ipilimumab on quality of life in patients with advanced nccRCC, using the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI)-19 and the Brief Fatigue Inventory (BFI) to be assessed with each computed tomography (CT) scan.
EXPLORATORY OBJECTIVES:
I. To evaluate heterogeneity of immune markers and molecular features between archival tumor tissue and fresh tumor samples collected at baseline.
II. To evaluate the immune modifications mediated by the combination of cabozantinib, nivolumab and ipilimumab in patients with advanced nccRCC, using fresh tumor tissue and blood samples before and on therapy.
III. To evaluate the immunologic and molecular correlates of response and survival in patients with advanced nccRCC treated with cabozantinib, nivolumab and ipilimumab, from fresh tumor tissue and blood samples collected before therapy.
IV. To identify the immune and molecular mechanisms of resistance to cabozantinib, nivolumab and ipilimumab in patients with advanced nccRCC, using fresh tumor tissue collected at the time of radiographic progression, and blood samples collected before and on therapy.
OUTLINE:
Patients receive cabozantinib orally (PO), nivolumab intravenously (IV), and ipilimumab IV on study.
After completion of study, patients are followed up for 90 days, and then every 6 months for 2 years.
Eligibility
- Histologically or cytologically confirmed unresectable advanced or metastatic nccRCC, including but not limited to:
* Papillary renal cell carcinoma (RCC), any type
* Unclassified RCC
* Translocation RCC
* Chromophobe RCC
* Collecting duct RCC
* Renal cell carcinoma with 80% or more sarcomatoid features on primary nephrectomy specimen or a biopsy
* Other nccRCC histologies in discussion with principal investigator
- Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
- Participants must undergo fresh tumor biopsy after registration but prior to the start of treatment unless medically unsafe or not feasible. For the lesion that is biopsied, if it is a target lesion per RECIST 1.1, then the lesion should be moved to non-target. If the patient has only one target lesion per RECIST 1.1 at baseline, and this is the only lesion amenable to biopsy, then it can be biopsied and followed as a target lesion without excluding the patient from the trial. If a fresh tumor biopsy is not medically safe or not feasible, confirmation of the availability of archival tumor tissue is required. For archival tissue, a recommended minimum of 20 unstained slides should be obtained
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Hemoglobin >= 9 g/dL (transfusions allowed)
- Total bilirubin =< 2.0 x institutional upper limit of normal with the following exception: patients with known Gilbert disease should have a serum bilirubin =< 3 x upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional upper limit of normal with the following exception: patients with known liver metastases should have AST and ALT =< 5 x ULN
- Creatinine clearance >= 30 mL/min/1.73 m^2 according to the Cockcroft-Gault equation
- International normalized ratio (INR) =< 1.5
- Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 5 months after the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 7 months after completion of cabozantinib, nivolumab or ipilimumab administration
- Ability to understand and willingness to sign a written informed consent document
**Clinical trials are research studies that involve people. These studies test new ways to prevent, detect, diagnose, or treat diseases. People who take part in cancer clinical trials have an opportunity to contribute to scientists’ knowledge about cancer and to help in the development of improved cancer treatments. They also receive state-of-the-art care from cancer experts...
Click here to learn more about clinical trials.