Phase I Study of Pembrolizumab in Combination With Ibrutinib in the Treatment of Unresectable or Metastatic Melanoma
Overview
- Phase
- Phase 1
- Intervention
- Ibrutinib
- Conditions
- Not specified
- Sponsor
- Mayo Clinic
- Enrollment
- 20
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose (Phase I)
- Status
- Active, Not Recruiting
- Last Updated
- 3 months ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •PRE-REGISTRATION- INCLUSION CRITERIA
- •Diagnosis of unresectable stage III or metastatic melanoma (stage IV) not amenable to local therapy
- •At least one non-nodal lesion considered measurable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria (that is, a lesion whose longest diameter can be accurately measured as \>= 1.0 cm with computed tomography \[CT\] scan, CT component of a positron emission tomography \[PET\]/CT, or magnetic resonance imaging \[MRI\]) or at least one malignant lymph node is considered measurable by RECIST criteria (that is, its short axis is \>= 1.5 cm when assessed by CT scan)
- •NOTE: tumor lesions in a previously irradiated area are not considered measurable disease
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
- •Provide informed written consent
- •Patient is willing to undergo treatment and monitoring at the enrolling institution
- •Willing to provide tissue and blood samples for correlative research purposes
- •REGISTRATION- INCLUSION CRITERIA
- •Histologic or cytologic confirmation of unresectable stage III or metastatic melanoma (stage IV) not amenable to local therapy
Exclusion Criteria
- •PRE-REGISTRATION EXCLUSION CRITERIA
- •Any of the following:
- •Pregnant women
- •Nursing women
- •Men or women of childbearing potential who are unwilling to employ adequate contraception within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study medication; adequate contraception is defined as 2 methods of birth control (e.g., hormonal contraceptives, intrauterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, or female condom with spermicide) or prior surgical sterilization, or abstinence from heterosexual activity
- •Prior treatment with ibrutinib or prior exposure to BTK inhibitors
- •Uveal melanoma
- •Current use of warfarin or other vitamin K antagonists
- •Require continuous treatment with a strong CYP3A inhibitor
- •Currently participating or has participated in a study of an investigational cancer therapy agent or using an investigational device within 28 days prior to study registration
Arms & Interventions
Treatment (ibrutinib, pembrolizumab)
Patients receive ibrutinib PO daily on days 1-28 of cycle 1 and days 1-21 of cycle 2 and subsequent cycles. Patients also receive pembrolizumab 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.
Intervention: Ibrutinib
Treatment (ibrutinib, pembrolizumab)
Patients receive ibrutinib PO daily on days 1-28 of cycle 1 and days 1-21 of cycle 2 and subsequent cycles. Patients also receive pembrolizumab 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.
Intervention: Laboratory Biomarker Analysis
Treatment (ibrutinib, pembrolizumab)
Patients receive ibrutinib PO daily on days 1-28 of cycle 1 and days 1-21 of cycle 2 and subsequent cycles. Patients also receive pembrolizumab 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.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Maximum tolerated dose (Phase I)
Time Frame: Up to start of second course of treatment
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.
Tumor response (dose expansion cohort)
Time Frame: Up to 5 years
Estimates of tumor response and binomial confidence intervals will be reported.
Secondary Outcomes
- Tumor response evaluated according to Response Evaluation Criteria in Solid criteria (RECIST)(Up to 5 years)
- Progression-free survival(From study entry to the documentation of disease progression, assessed up to 5 years)
- Overall survival(From study entry to death due to any cause, assessed up to 5 years)