Phase II Study of Pembrolizumab in Combination With Binimetinib and Bevacizumab in Patients With Refractory Colorectal Cancer
Overview
- Phase
- Phase 2
- Intervention
- Pembrolizumab
- Conditions
- Colorectal Cancer
- Sponsor
- University of Colorado, Denver
- Enrollment
- 53
- Locations
- 1
- Primary Endpoint
- Objective Response
- Status
- Active, not recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
This is an open-label, single-center, single-arm phase II clinical trial evaluating the combination of pembrolizumab, binimetinib, and bevacizumab in patients with metastatic colorectal adenocarcinoma who have not responded to prior therapy.
Detailed Description
This study will be done in two stages. In stage 1, ten patients will be treated with standard doses of pembrolizumab, binimetinib, and bevacizumab to ensure that the doses are safe and tolerable. In stage 2, patients will be enrolled into either cohort A, where they will be treated with a 7-day run-in of binimetinib, followed by pembrolizumab, bevacizumab, and binimetinib combination treatment in 21 day cycles, or they will be enrolled to cohort B, which does not include the 7-day run-in of binimetinib. Treatment in cohort B will include combination therapy of pembrolizumab, binimetinib, and bevacizumab from first day of treatment.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provision to sign and date the consent form.
- •Age ≥ 18 years.
- •Able to comply with the study protocol, in the investigator's judgment.
- •Patient must state willingness to undergo pre- and post-treatment biopsies. According to the investigator's judgement, the planned biopsies should not expose the patient to substantially increased risk of complications.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or one.
- •Histologically confirmed unresectable metastatic colorectal adenocarcinoma.
- •Progression on at least two prior lines of therapy for unresectable metastatic colorectal adenocarcinoma.
- •o Administration of bevacizumab previously does not impact study inclusion.
- •Measurable disease, according to RECIST v1.
- •Note that lesions intended to be biopsied should not be target lesions.
Exclusion Criteria
- •Cancer-related exclusion criteria:
- •Patients with known MSI-high status or unknown MSI status are not eligible for study entry.
- •Patients with BRAF V600E mutations are not eligible for the study.
- •Surgical procedure (surgical resection, wound revision or any other major surgery) or significant traumatic injury within 60 days prior to enrollment, or anticipation of need for major surgical procedure during the course of the study. Minor surgical procedure within 7 days (including placement of a vascular access device) of study Cycle 1 Day
- •Study-related biopsies are NOT considered surgical procedures under the exclusion criteria
- •Untreated CNS metastases. Treatment of brain metastases, either by surgical or radiation techniques, must have been completed at least 4 weeks prior to initiation of study treatment.
- •Treatment with any investigational agent or approved therapy within 21 days (Cycle 1 Day 1).
- •Malignancies other than CRC within 3 years prior to Cycle 1 Day 1 with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year overall survival \> 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent).
- •Prior radiation therapy within 14 days prior to study Cycle 1 Day 1 and/or persistence of radiation-related adverse effects. However, palliative radiation therapy (as long as it does not involve target lesions) is permitted on the study.
- •Prior allogeneic bone marrow transplantation or solid organ transplant for another malignancy in the past.
Arms & Interventions
Safety run-in
Ten patients will be accrued to stage 1 and treated with standard doses of pembrolizumab, binimetinib and bevacizumab. If the standard doses are not tolerable and 2 or more patients experience a DLT, then patients would be enrolled in dose level -1 which would comprise of standard doses of pembrolizumab and bevacizumab but binimetinib would be at a dose lower of 30 mg PO BID. If 2 or more patients experience a DLT at dose level -1, then patients will be enrolled in dose level -2 which will comprise of standard doses of pembrolizumab and bevacizumab but a lower dose of binimetinib at 15 mg BID. Upon determination of the safety and tolerability of the treatment regimen, the study will proceed to stage 2.
Intervention: Pembrolizumab
Safety run-in
Ten patients will be accrued to stage 1 and treated with standard doses of pembrolizumab, binimetinib and bevacizumab. If the standard doses are not tolerable and 2 or more patients experience a DLT, then patients would be enrolled in dose level -1 which would comprise of standard doses of pembrolizumab and bevacizumab but binimetinib would be at a dose lower of 30 mg PO BID. If 2 or more patients experience a DLT at dose level -1, then patients will be enrolled in dose level -2 which will comprise of standard doses of pembrolizumab and bevacizumab but a lower dose of binimetinib at 15 mg BID. Upon determination of the safety and tolerability of the treatment regimen, the study will proceed to stage 2.
Intervention: Bevacizumab
Safety run-in
Ten patients will be accrued to stage 1 and treated with standard doses of pembrolizumab, binimetinib and bevacizumab. If the standard doses are not tolerable and 2 or more patients experience a DLT, then patients would be enrolled in dose level -1 which would comprise of standard doses of pembrolizumab and bevacizumab but binimetinib would be at a dose lower of 30 mg PO BID. If 2 or more patients experience a DLT at dose level -1, then patients will be enrolled in dose level -2 which will comprise of standard doses of pembrolizumab and bevacizumab but a lower dose of binimetinib at 15 mg BID. Upon determination of the safety and tolerability of the treatment regimen, the study will proceed to stage 2.
Intervention: Binimetinib
Cohort A
Patients will start with 7-day run-in of binimetinib on day -7 of cycle 1 only. Pembrolizumab and bevacizumab will then be added to binimetinib on cycle 1 day +1. Cycle 1 will end on day 21. Patients will start treatment with pembrolizumab, binimetinib, and bevacizumab on day 1 of all subsequent cycles.
Intervention: Pembrolizumab
Cohort A
Patients will start with 7-day run-in of binimetinib on day -7 of cycle 1 only. Pembrolizumab and bevacizumab will then be added to binimetinib on cycle 1 day +1. Cycle 1 will end on day 21. Patients will start treatment with pembrolizumab, binimetinib, and bevacizumab on day 1 of all subsequent cycles.
Intervention: Bevacizumab
Cohort A
Patients will start with 7-day run-in of binimetinib on day -7 of cycle 1 only. Pembrolizumab and bevacizumab will then be added to binimetinib on cycle 1 day +1. Cycle 1 will end on day 21. Patients will start treatment with pembrolizumab, binimetinib, and bevacizumab on day 1 of all subsequent cycles.
Intervention: Binimetinib
Cohort B
Patients will be treated with pembrolizumab, bevacizumab, and binimetinib together on day 1 of all cycles including cycle 1. Patients will start treatment with pembrolizumab, binimetinib, and bevacizumab on day 1 of all subsequent cycles.
Intervention: Pembrolizumab
Cohort B
Patients will be treated with pembrolizumab, bevacizumab, and binimetinib together on day 1 of all cycles including cycle 1. Patients will start treatment with pembrolizumab, binimetinib, and bevacizumab on day 1 of all subsequent cycles.
Intervention: Bevacizumab
Cohort B
Patients will be treated with pembrolizumab, bevacizumab, and binimetinib together on day 1 of all cycles including cycle 1. Patients will start treatment with pembrolizumab, binimetinib, and bevacizumab on day 1 of all subsequent cycles.
Intervention: Binimetinib
Outcomes
Primary Outcomes
Objective Response
Time Frame: Study beginning to study end; 12 months
Each study subject will be considered as a responder if their best CT imaging result is either CR (complete response) or PR (partial response) based on the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) evaluation criteria.
Secondary Outcomes
- Progression-Free Survival (PFS)(Study start date to first sign of disease progression or death, whichever comes first.)
- Adverse Events(Study beginning to study end, 12 months)
- Overall Survival (OS)(Time (measured in months) from each subject starting treatment until either death (from any cause) or being censored at their last contact.)