This phase I trial studies the best dose of ibrutinib when given together with pembrolizumab in treating patients with stage III-IV melanoma that cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and ibrutinib may work better in treating patients with melanoma.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose of ibrutinib in combination with pembrolizumab in patients with advanced melanoma. (Phase I) II. To estimate the overall response rate treated at the maximum tolerated dose of ibrutinib in combination with pembrolizumab in patients with advanced melanoma. (Dose expansion cohort) SECONDARY OBJECTIVES: I. To assess the safety and adverse-event profiles of combination of ibrutinib with pembrolizumab in patients with advanced melanoma. II. To evaluate the overall response rate (ORR) in patients advanced melanoma receiving ibrutinib and pembrolizumab. III. To evaluate the duration of response, progression-free survival (PFS), and overall survival (OS) in patients with advanced melanoma receiving ibrutinib and pembrolizumab. IV. To assess the effect of treatment with ibrutinib and pembrolizumab on Th1/Th2 immune polarity. EXPLORATORY OBJECTIVES: I. To assess the CD8 T cell response to multiple melanoma-associated antigens, and to correlate CD8 T cell responses with changes in Th1/Th2 immune polarity. II. To assess changes in plasma cytokines induced by treatment with ibrutinib and pembrolizumab. III. To assess the change in potential biomarkers, such as tumor-bound and soluble PD-L1 levels and tumor-infiltrating lymphocytes, that may correlate with treatment responses. OUTLINE: This is a dose-escalation study of ibrutinib. Patients receive ibrutinib orally (PO) daily on days 1-28 of cycle 1 and days 1-21 of cycle 2 and subsequent cycles. Patients also receive pembrolizumab intravenously (IV) over 30 minutes on day 8 of cycle 1 and day 1 of cycle 2 and subsequent cycles. Cycle 1 continues for 28 days and subsequent cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months for 5 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
20
Mayo Clinic in Rochester
Rochester, Minnesota, United States
Maximum tolerated dose (Phase I)
Will be defined as the highest dose level among those tested where at most one out of 6 patients develops a dose limiting toxicity prior to the start of their second course of treatment. The maximum grade of each type of toxicity will be recorded for each patient. For each toxicity reported by dose level, the percentage of patients developing any degree of that toxicity as well as the percentage of patients developing a severe degree (grade 3 or higher) will be determined.
Time frame: Up to start of second course of treatment
Tumor response (dose expansion cohort)
Estimates of tumor response and binomial confidence intervals will be reported.
Time frame: Up to 5 years
Tumor response evaluated according to Response Evaluation Criteria in Solid criteria (RECIST)
A patient whose tumor has met the RECIST criteria for complete response or partial response on two consecutive evaluations at least 8 weeks apart is considered to have had a tumor response.
Time frame: Up to 5 years
Progression-free survival
Will be examined in an exploratory and hypothesis-generating fashion.
Time frame: From study entry to the documentation of disease progression, assessed up to 5 years
Overall survival
Will be examined in an exploratory and hypothesis-generating fashion.
Time frame: From study entry to death due to any cause, assessed up to 5 years
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