A Phase I/II Study of Pembrolizumab in Combination With Ibrutinib for Advanced, Refractory Colorectal Cancers
Overview
- Phase
- Phase 1
- Intervention
- Pembrolizumab
- Conditions
- Colon Cancer
- Sponsor
- H. Lee Moffitt Cancer Center and Research Institute
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- Phase I - Recommended Phase II Dose (RP2D)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
The purpose of this study is to determine the safety and tolerability, describe the dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) (or the highest protocol-defined dose level in the absence of establishing an MTD) of ibrutinib in combination with pembrolizumab in participants with advanced, refractory colorectal cancers.
Detailed Description
On this study, one treatment cycle equals 21 days. On the first day of each study treatment cycle, 200 milligrams of pembrolizumab will be given through an IV (intravenously) for about thirty minutes. In addition, participants will begin taking the ibrutinib capsules every day starting on cycle 1, day 1. Participants will have a follow-up visit every 3 weeks, on about the first day of each cycle with laboratories drawn to make sure that the study drugs are not causing any side effects. In addition, participants will have a computed tomography (CT) scan every 6 to 7 weeks to determine whether your cancer is getting better or worse.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed diagnosis of colorectal adenocarcinoma.
- •Measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.
- •Stage IV or recurrent disease is required.
- •Participants must have received and progressed through or become intolerant to fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab. If RAS wild type, participants should have received and progressed or become intolerant to the above as well as cetuximab or panitumumab containing therapies. Prior therapy with Regorafenib and/or TAS 102 is allowed.
- •Eastern Cooperative Oncology Group (ECOG) Performance Score 0 or
- •Estimated life expectancy \> 3 months.
- •Adequate bone marrow, liver and renal function as assessed by the following:
- •Hemoglobin \> 8.0 g/dl
- •Absolute neutrophil count (ANC) \> 1,000/mm\^3 independent of growth factor support
- •Platelet count \> 100,000/mm\^3
Exclusion Criteria
- •Active central nervous system (CNS) metastases. If CNS metastases are treated and patients are at neurologic baseline for at least 2 weeks prior to enrollment, they will be eligible but will need a Brain MRI prior to enrollment. Must be off corticosteroids or on a dose of less than 10mg per day.
- •Active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
- •A condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses \> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
- •Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways).
- •Prior therapy with ibrutinib or other BTK inhibitors.
- •Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors \[Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)\].
- •Known history of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
- •Serologic status reflecting active hepatitis B or C infection. Patients who are hepatitis B core antibody positive and who are antigen negative, will need to have a negative PCR result prior to enrollment. Those who are hepatitis B antigen positive or PCR positive, will be excluded.
- •Child Pugh B or C cirrhosis.
- •History of severe hypersensitivity reactions to other monoclonal antibodies.
Arms & Interventions
Pembrolizumab and Ibrutinib
Pembrolizumab intravenously (IV): 200 mg every 3 weeks (Q3W). Ibrutinib by mouth (PO): Phase I Dose Escalation at doses of 420 mg daily (cohort 0) and 560 mg daily (cohort 1);. Phase II treatment at Recommended Phase II dose.
Intervention: Pembrolizumab
Pembrolizumab and Ibrutinib
Pembrolizumab intravenously (IV): 200 mg every 3 weeks (Q3W). Ibrutinib by mouth (PO): Phase I Dose Escalation at doses of 420 mg daily (cohort 0) and 560 mg daily (cohort 1);. Phase II treatment at Recommended Phase II dose.
Intervention: Ibrutinib
Outcomes
Primary Outcomes
Phase I - Recommended Phase II Dose (RP2D)
Time Frame: 42 days post first dose
Standard 3+3 Design: The first cohort will enroll a minimum of 3 participants, according to a standard 3+3 design. If 0 out of the first 3 participants in the first cohort experience a dose-limiting toxicity (DLT), then dose escalation will continue as planned. If 1 out of the first 3 participants experience a DLT, then the cohort will be expanded to a total of 6 participants, and if no more than 1 out of 6 participants experiences a DLT in a given dose cohort, dose escalation will continue as planned. If ≥ 2 DLTs are observed in the first dose cohort, the principle investigator will discuss with Janssen on how to proceed. The DLT evaluation period will be defined as the time from the first dose of pembrolizumab and ibrutinib to 42 days after the first dose or if a participant experiences a DLT within this time period.
Phase II - Disease Control Rate at 4 Months
Time Frame: 4 months
Percentage of participants who achieved disease control at 4 months. Disease control rate = Complete Response (CR) + Partial Response (PR) + Stable Disease (SD). Tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and RECIST based immune-related response criteria (irRC).