Neoplasms

Symptoms and General Pathology

All Conditions

Digestive System Diseases

Neoplasm Metastasis

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Bevacizumab

Pembrolizumab

Immunoglobulins

Immunoglobulin G

Mitogens

Immunoglobulins, Intravenous

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Immune Checkpoint Inhibitors

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.

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.

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.

An intravenous, potent and highly selective humanized monoclonal antibody of the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

The pharmacokinetics of bevacizumab are characterized by a slow CL, long half-life, and a volume of distribution consistent with limited extravascular distribution.

Binimetinib (MEK162/ARRY-438162) is an orally bioavailable, small molecule selective and potent mitogen-activated protein kinase (MEK) 1 and MEK 2 inhibitor.

Binimetinib

Christopher Lieu, MD

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.

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.

Study of Pembrolizumab, Binimetinib, and Bevacizumab in Patients With Refractory Colorectal Cancer

Phase II Study of Pembrolizumab in Combination With Binimetinib and Bevacizumab in Patients With Refractory Colorectal Cancer

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.

The median progression-free survival was calculated using the Kaplan-Meier product-limit method.

OS is defined as the time (measured in months) from each subject starting treatment until either death (from any cause) or being censored at their last contact.

Grade 1, 2, 3, 4, or 5 adverse events (AE) as defined by CTCAE v4 were summarized. All adverse events summarized were non-baseline AEs (i.e. each AE was not present at baseline). AEs were summarized by generating counts of AEs by AE description and severity, but no formal statistical test was performed on the AEs.

For the purpose of this section, the outcome measure will be defined as the number of subjects who had at least 1 AE.

University of Colorado, Denver

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.

Safety run-in

Cohort A

Cohort B

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Christopher Lieu

Phase 1: Triplet tx w/o run-in of binimetinib (see 'Arms and Interventions' description in Protocol Section)

Safety Run-In

Phase 2: Triplex tx with 7-day run-in of binimetinib (see 'Arms and Interventions' in Protocol Section)

Phase 2: Triplex tx w/o 7-day run-in of binimetinib (see 'Arms and Interventions' of Protocol Section)

Objective Response

Phase 1: Triplet tx w/o run=in of binimetinib (see 'Arms and Interventions' of Protocol Section)

Phase 2: Triplet tx w/ 7-day run-in of binimetinib (see 'Arms and Interventions' of Protocol Section)

Phase 2: Triplet tx w/o 7-day run-in of binimetinib (see 'Arms and Interventions' of Protocol Section)

All patients who had follow-up data. Among the 50 total subjects, subjects 11, 19, 32, 33, and 53 did not have follow-up data. This resulted in 45 subjects being included in the PFS analysis.

Progression-Free Survival (PFS)

Phase 1: Triplet tx w/o run-in of binimetinib (see 'Arms and Interventions' of Protocol Section)

Overall Survival (OS)

Phase 2: Triplet tx w 7-day run-in of binimetinib (see 'Arms and Interventions' of Protocol Section)

Phase 2: Triplet tx w/o 7-day run-in of binimetinib (see 'Arms and Interventions' of Protocol Section

Spots Global Cancer Trial Database for Study of Pembrolizumab, Binimetinib, and Bevacizumab in Patients With Refractory Colorectal Cancer

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

Useful links and downloads for this trial