This phase II trial tests how well nivolumab and ipilimumab immunotherapy with or without cabozantinib works in treating patients with nasopharyngeal cancer that has come back (after a period of improvement) (recurrent), has spread from where it first started (primary site) to other places in the body (metastatic), or for which no treatment is currently available (incurable). Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Giving immunotherapy with nivolumab and ipilimumab and targeted therapy with cabozantinib may help shrink and stabilize nasopharyngeal cancer.
PRIMARY OBJECTIVE: I. To determine if the progression-free survival (PFS) of the triplet combination (cabozantinib S-malate, nivolumab, and ipilimumab \[CaboNivoIpi\]) is more favorable than the doublet (nivolumab and ipilimumab \[NivoIpi\]). SECONDARY OBJECTIVES: I. To compare safety and tolerability between the two arms (Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\]5.0.). II. To compare overall response rate (ORR) between the two arms via both Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST) criteria. III. To compare overall survival (OS) between the two arms. IV. To assess response by primary or acquired PD-1/L1 inhibitor resistance in the prior line of therapy. EXPLORATORY OBJECTIVE: I. To evaluate molecular and immunologic predictors of response (Epstein-Barr virus \[EBV\] viral load; PD-L1 score) between arms. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) and collection of blood samples throughout the trial. ARM B: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1 and cabozantinib S-malate orally (PO) daily on days 1-28 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may continue with cabozantinib S-malate after 2 years per treating investigator. Patients undergo CT or MRI and collection of blood samples throughout the trial. After completion of study treatment, patients are followed up every 8-12 weeks until progression of disease occurs or a new non-protocol anti-cancer therapy is initiated and then every 6 months for up to 2 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Undergo collection of blood samples
Given PO
Undergo CT scan
Given IV
Undergo MRI
Given IV
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, United States
RECRUITINGKeck Medicine of USC Koreatown
Los Angeles, California, United States
SUSPENDEDLos Angeles General Medical Center
Los Angeles, California, United States
RECRUITINGUSC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
Progression-free survival (PFS)
PFS will be estimated using the Kaplan-Meier method, where the log-rank test will be used to compare the 2 treatment arms.
Time frame: From randomization to the first of either progression or death from any cause, or censored at last known tumor assessment date, assessed up to 2 years
Overall survival (OS)
OS will be estimated using the Kaplan-Meier method, where the log-rank test will be used to compare the 2 treatment arms.
Time frame: From randomization to death from any cause, or censored at last known follow-up, assessed up to 2 years
Incidence of adverse events
The maximum grade for each type of adverse event will be summarized using Common Terminology Criteria for Adverse Events version 5.0. The frequency and percentage of grade 3+ adverse events will be compared between the 2 treatment arms. Comparisons between arms will be made by using either the chi-square or Fisher's exact test.
Time frame: Up to 2 years
Response by subgroups of interest
Will also report and compare the overall response rate (ORR) between different subgroups of interest (primary or acquired PD-1/L1 inhibitor resistance in the prior line of therapy (further defined below), etc.). These comparisons will be done via chi-square or Fisher's exact tests. We'll also assess primary versus acquired resistance to prior PD-1 inhibition in each arm as well. While not a formal stratification, in the interim and final analysis we'll also descriptively assess these subgroups between arms as well.
Time frame: Up to 2 years
ORR
The response rate will be compared via chi-square or Fisher's exact tests between the 2 treatment arms using both the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and also separately for the immune-modified RECIST criteria.
Time frame: Up to 2 years
Predictors of response
Will correlate the baseline data (Epstein-Barr virus viral load, p16 immunohistochemistry status, smoking history, and PD-L1 score) with ORR data. For this analysis, logistic regression models will be assessed using the baseline data to predict binary response data. Odds ratios and 95% confidence intervals will be reported. Will also summarize the data using descriptive statistics and graphical methods.
Time frame: Up to 2 years
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USC Norris Oncology/Hematology-Newport Beach
Newport Beach, California, United States
RECRUITINGUC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, United States
RECRUITINGStanford Cancer Institute Palo Alto
Palo Alto, California, United States
RECRUITINGEmory University Hospital Midtown
Atlanta, Georgia, United States
RECRUITINGSaint Alphonsus Cancer Care Center-Boise
Boise, Idaho, United States
SUSPENDEDSaint Alphonsus Cancer Care Center-Caldwell
Caldwell, Idaho, United States
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