This phase II trial studies the efficacy (the effect on the tumor) and the safety (the effect on the body) of the study drugs when given as a combination in participants with this type of cancer. Another purpose of the study is to see which tumor markers (proteins in the blood that the body produces in response to the cancer) lead to better results in participants treated with the study drugs. Nivolumab and ipilimumab are antibodies, which are human proteins that recognize and attach to a part of the tumor and/or body's immune cells. They work in slightly different ways to activate the immune system and help the body's immune system to work against tumor cells. Nivolumab and ipilimumab are investigational because they are not approved by the FDA to be used for the type of cancer being studied.
PRIMARY OBJECTIVES: I. To assess median progression-free survival rate (PFSR) as well as PFSR at 6 and 12 months in patients with recurrent or metastatic adenoid cystic carcinoma (ACC) treated with a combination of nivolumab and ipilimumab. SECONDARY OBJECTIVES: I. To assess the efficacy of nivolumab and ipilimumab according to response rate (RR), disease control rate (DCR; complete response \[CR\], partial response \[PR\], and stable disease \[SD\] at 6 and 12 months), overall survival (OS) and progression free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) criteria in patients with recurrent or metastatic ACC. II. To assess the efficacy of nivolumab and ipilimumab according to overall response rate (ORR), DCR, progression free survival (PFS), and OS in patients with recurrent or metastatic ACC using immune-related response criteria (irRC) criteria. III. To assess the safety and tolerability profile of nivolumab and ipilimumab therapy in patients with recurrent or metastatic ACC using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. TERTIARY OBJECTIVES: I. Assess safety, tolerability and activity of Nivolumab and Ipilimumab in non-ACC malignant salivary gland tumors (MSGT's) using clinical benefit rate (CBR), ORR, PFS, OS. II. To assess the predictive value of genomic aberrations observed upon comprehensive genomic profiling of the tumor deoxyribonucleic acid (DNA) derived from archival tumor tissue, if available, or blood from patients with recurrent or metastatic ACC and non-ACC MSGTs. III. Circulating cell free DNA genomic profiling will also be performed at baseline and during treatment with each imaging to explore the genomic landscape of clonal evolution that may elucidate mechanisms behind response or resistance with immunotherapy in adenoid cystic carcinoma and non-ACC MSGTs. IV. Correlation between expression of PD-L1 and response to treatment will be explored in all patients enrolled in the study. V. Correlations between other markers of inflammatory/immune signature will be performed that may include but not be limited to PD-1, OX40, CD73, CD39, T cell immunoglobulin and mucin domain containing protein 3 (TIM3), GITRL, CTLA-4, CD3, CD4, CD8, protein tyrosine phosphatase receptor type C (CD45RO), forkhead box P3 (FOXP3), and granzyme by immunohistochemistry analysis and/or flow cytometry. OUTLINE: Patients receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, 29, 43, 57, and 71 of course 1 and on days 1 and 15 of course 2, over 60 minutes on days 29 and 57 of course 2 and on days 1, 29, and 57 of subsequent courses. Patients also receive ipilimumab over 90 minutes on days 1 and 43. Courses repeat every 84 days in the absence of disease progression, unexpected toxicity, or withdrawal of consent. After completion of study treatment, patients are followed up for 30 days, every 4 weeks for 12 weeks, and then every 12 weeks for up to 2 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
25
Northwestern University
Chicago, Illinois, United States
Progression-Free Survival
Progression-Free Survival assessed per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria at time of first study treatment. PFS defined as absence of death and of progressive disease. Progressive disease per RECIST v. 1.1 defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm). The appearance of one or more new lesions is also considered progression. Response rates and 95% confidence intervals will be calculated using exact binomial probability distributions for discrete outcomes. Efficacy will be evaluated in all patients who receive at least one dose of study treatment and have had their disease re-evaluated.
Time frame: From the start of treatment and every 12 weeks during treatment, for up to two years, where 1 cycle =12 weeks/84 days, and range of cycles attempted was 1-11.
Median Progression-free Survival
Progression-Free Survival assessed per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria at time of first study treatment. PFS defined as absence of death and of progressive disease. Progressive disease per RECIST v. 1.1 defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm). The appearance of one or more new lesions is also considered progression. Response rates and 95% confidence intervals will be calculated using exact binomial probability distributions for discrete outcomes. Efficacy will be evaluated in all patients who receive at least one dose of study treatment and have had their disease re-evaluated.
Time frame: From the start of treatment and every 12 weeks during treatment, for up to two years, where 1 cycle =12 weeks/84 days, and range of cycles attempted was 1-11.
Response Rate (RR)
Response rate (RR) is percentage of patients whose cancer shrinks or disappears after treatment. Patients with adenoid cystic carcinoma who have a complete response (CR) or partial response (PR) per RECIST criteria v. 1.1 will be included in the results. Per RECIST v. 1.1, CR is defined as "disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm." A PR is defined as "At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters."
Time frame: On Cycle 2 Day 1, and every cycle thereafter (1 cycle = 12 weeks), about 27 months
Clinical Benefit Rate (CBR)
Clinical Benefit Rate (CBR) is defined as the percentage of patients with Complete Response (CR), Partial Response (PR), and Stable Disease (SD) and will be assessed by RECIST 1.1 in patients with adenoid cystic carcinoma (ACC). Per RECIST v. 1.1, CR is defined as, "Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm." PR is defined as, "At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters." SD is defined as, "Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study."
Time frame: On Cycle 2 Day 1, and every cycle thereafter (1 cycle = 12 weeks), about 27 months
Overall Survival (OS)
Overall survival (OS) is defined as time in months from the date of first study treatment to the date of death or withdrawal from study, whichever comes first. The percentage of patients alive at 6 months, 12 months, and 24 months will be reported. All patients who receive at least one dose of nivolumab will be included in the secondary analyses of OS.
Time frame: Up to 2 years from start of treatment
Number of Adverse Events Possibly Related to Study Drugs Graded 3, 4, and 5
Toxicity, both frequency and severity, will continue to be measured by monitoring the occurrence of adverse events. Adverse events will be defined as those included in CTCAE v 4.03. AEs that were determined to be at least possibly related to study drug and graded 3, 4, 5 are included here. Grade 1 (mild): the event causes discomfort without disruption of normal daily activities. Grade 2 (moderate): the event causes discomfort that affects normal daily activities. Grade 3 (severe): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Grade 4 (Life-threatening): the patient was at risk of death at the time of the event. Grade 5 (fatal): the event caused death.
Time frame: Up to 30 days after discontinuation, where range of cycles attempted was 1-11, where 1 Cycle = 84 days/12 weeks
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