Metastatic Melanoma, Stage IIIA Cutaneous Melanoma AJCC v7, Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7, Stage III Cutaneous Melanoma AJCC v7, Stage IV Cutaneous Melanoma AJCC v6 and v7, Unresectable Melanoma
Conditions
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.
Interventions
DRUGIbrutinib
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
BIOLOGICALPembrolizumab
Given IV
Sponsors
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 * Only if patient has had previous exposure to anti-PD-1 or anti-PD-L1 therapy: * Patient had disease progression on or within 6 months after anti-PD-1/anti-PD-L1 therapy in the metastatic setting OR * Patient had disease progression within 6 months after the last dose of adjuvant/neoadjuvant anti-PD-1/anti-PD-L1 treatment * Absolute neutrophil count (ANC) \>= 1000/mm\^3 (obtained =\< 14 days prior to registration) * Platelet count \>= 75,000/mm\^3 (obtained =\< 14 days prior to registration) * Criteria must be met without a transfusion =\< four weeks prior to registration * Hemoglobin \>= 9.0 g/dL (obtained =\< 14 days prior to registration) * Total bilirubin =\< 1.5 X upper limit of normal (ULN); if total bilirubin \> 1.5 X ULN then direct bilirubin =\< ULN (obtained =\< 14 days prior to registration) * Aspartate aminotransferase (aspartate transaminase \[AST\]) and alanine aminotransferase (alanine transaminase \[ALT\]) =\< 2.5 x ULN OR =\< 5 X ULN for patients with liver metastases (obtained =\< 14 days prior to registration) * Creatinine =\< 1.5 X ULN and creatinine clearance (CrCL) \>= 30 ml/min per Cockcroft Gault formula (obtained =\< 14 days prior to registration) * Patients of childbearing potential only, negative urine pregnancy test done =\< 7 days prior to study registration
Exclusion criteria
* PRE-REGISTRATION
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum tolerated dose (Phase I) | 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) | Up to 5 years | Estimates of tumor response and binomial confidence intervals will be reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor response evaluated according to Response Evaluation Criteria in Solid criteria (RECIST) | Up to 5 years | 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. |
| Progression-free survival | From study entry to the documentation of disease progression, assessed up to 5 years | Will be examined in an exploratory and hypothesis-generating fashion. |
| Overall survival | From study entry to death due to any cause, assessed up to 5 years | Will be examined in an exploratory and hypothesis-generating fashion. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMatthew S. Block, M.D., Ph.D.
Mayo Clinic in Rochester
Outcome results
None listed