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

NCT03475004 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 17-0466.cc
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

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.

Conditions

Colorectal Cancer; Metastatic Cancer

Keywords

Pembrolizumab; Binimetinib; Bevacizumab; Combination Therapy

Outcome Measures

Primary Outcomes (1)

• Objective Response

  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.

  Study beginning to study end; 12 months

Secondary Outcomes (3)

• Progression-Free Survival (PFS)

  Study start date to first sign of disease progression or death, whichever comes first.

• 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.

• Adverse Events

  Study beginning to study end, 12 months

Study Arms (3)

Safety run-in

OTHER

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.

Drug: Pembrolizumab; Drug: Bevacizumab; Drug: Binimetinib

Cohort A

EXPERIMENTAL

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.

Drug: Pembrolizumab; Drug: Bevacizumab; Drug: Binimetinib

Cohort B

EXPERIMENTAL

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.

Drug: Pembrolizumab; Drug: Bevacizumab; Drug: Binimetinib

Interventions

Pembrolizumab DRUG

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.

Also known as: Keytruda

Cohort A; Cohort B; Safety run-in

Bevacizumab DRUG

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

Also known as: Avastin

Cohort A; Cohort B; Safety run-in

Binimetinib DRUG

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

Cohort A; Cohort B; Safety run-in

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Measurable disease, according to RECIST v1.1. Note that lesions intended to be biopsied should not be target lesions.
• Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to first dose of study drug treatment:
• WBC ≥ 2.5 and ≤ 15.0 × 109/L
• ANC ≥ 1.5 × 109/L
• Platelet count ≥ 100 × 109/L
• Hemoglobin ≥ 9 g/dL without transfusion in the previous week
• Albumin ≥ 2.5 g/dL
• Serum bilirubin ≤ 1.5 x the upper limit of normal (ULN); patients with known Gilbert's disease may have a bilirubin ≤ 3.0 ×ULN

You may not qualify if:

• 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 1.
• 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.
• Spinal cord compression not definitively treated with surgery and/or radiation.
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.
• Uncontrolled tumor related pain. Patients who require narcotic pain medication during screening should be on a stable dose regimen prior to Cycle 1 Day 1.
• Current or recent (within 10 days of study enrollment) use of acetylsalicylic acid (\> 325 mg/day), clopidogrel (\> 75 mg/day) or current or recent (within 10 days of first dose of bevacizumab) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purpose. Note: The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least 2 weeks at the time of Cycle 1 Day 1. Prophylactic use of anticoagulants is allowed.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells, any components of Binimetinib, Pembrolizumab, or bevacizumab formulations or any premedications.
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-PD-1, anti-PD L1, anti-PD-L2 or MAPK pathway inhibitors (eg; BRAF, MEK, ERK inhibitors).

Sponsors & Collaborators

• University of Colorado, Denver: lead

Study Sites (1)

Universtiy of Colorado

Aurora, Colorado, 80045, United States

Location

MeSH Terms

Conditions

Colorectal Neoplasms; Neoplasm Metastasis

Interventions

pembrolizumab; Bevacizumab; binimetinib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Dr. Christopher Lieu
• Organization: University of Colorado

christopher.lieu@cuanschutz.edu

303-724-6390

Study Officials

• Christopher Lieu, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 14, 2018
• First Posted: March 23, 2018
• Study Start: September 17, 2018
• Primary Completion: April 14, 2022
• Study Completion: February 12, 2024
• Last Updated: September 19, 2024
• Results First Posted: December 23, 2022

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)