Phase 3 Evaluation of MK-4280A (Favezelimab and Pembrolizumab) Versus Standard Care in Metastatic PD-L1 Positive Colorectal Cancer
- Trial ID
- 2024-511043-25-00
- Protocol
- MK-4280A-007
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3 study is to compare **MK-4280A** (a coformulation of favezelimab and pembrolizumab) to the standard of care, which includes regorafenib or TAS-102, in terms of overall survival in patients with previously treated metastatic PD-L1 positive **Colorectal Cancer**. This objective is clinically relevant as it aims to determine if MK-4280A can provide a survival benefit over existing treatments, potentially offering a new therapeutic option for this patient population.
Secondary objectives include:
- Comparing MK-4280A to standard of care with respect to progression-free survival and objective response rate, both assessed per RECIST 1.1 by blinded independent central review (BICR).
- Assessing the efficacy of MK-4280A and standard of care concerning the duration of response per RECIST 1.1 by BICR.
- Determining the safety and tolerability of MK-4280A and standard of care.
- Comparing the change from baseline and time to deterioration in global health status/quality of life (QoL), physical functioning, appetite loss, and bloating for MK-4280A versus standard of care.
Participants
The clinical trial involves a total of **587 participants** diagnosed with **colorectal cancer**, specifically those with histologically confirmed metastatic and unresectable colorectal adenocarcinoma. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on their previous treatment history and progression of the disease, as well as their ability to provide a tumor tissue sample. The trial does not include a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group Performance Score (ECOG PS) of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. They must also have a life expectancy of at least three months and adequate organ function. The ability to swallow and retain oral medication is necessary, and participants should not have significant gastrointestinal abnormalities that could affect drug absorption. The trial aims to compare the efficacy of MK-4280A to standard care treatments such as regorafenib or TAS-102 in terms of overall survival.
Plans and Procedures
The clinical trial is a **Phase III** study designed to evaluate the efficacy and safety of MK-4280A, a combination of **pembrolizumab** and **favezelimab**, compared to standard care treatments such as **regorafenib** or TAS-102 in patients with previously treated metastatic **colorectal cancer**. The trial employs a randomized, double-blind, controlled design to ensure unbiased results. The estimated duration of the trial is from October 2021 to November 2025, with a maximum treatment period of 105 days for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as having a histologically confirmed metastatic colorectal adenocarcinoma, measurable disease per RECIST 1.1, and adequate organ function. Following the screening, participants will be randomized to receive either the investigational product or standard care. The study includes regular follow-up visits to monitor safety, efficacy, and any adverse events. The end-of-study visit will assess the primary endpoint of overall survival and secondary endpoints such as progression-free survival, objective response rate, and quality of life changes.
The expected length of participant involvement is approximately 3.5 months, with conditions for early termination including significant adverse events or disease progression. Participants must have a life expectancy of at least three months and the ability to swallow oral medication. The trial aims to provide comprehensive data on the comparative effectiveness of MK-4280A in improving survival outcomes for patients with metastatic colorectal cancer.
Treatment
The clinical trial involves the administration of **MK-4280A**, a coformulated solution for infusion containing the active substances **pembrolizumab** and **favezelimab**. This investigational product is provided as a **solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose is 1000 mg, with a total maximum dose of 35,000 mg over a treatment period of 105 days. The formulation is not pediatric and is classified as a biological medicinal product. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.
In addition to the experimental treatment, the study includes a comparator treatment with **trifluridine, tipiracil**, marketed under the name **TAS-102**. This comparator is of chemical origin and is administered orally. The pharmaceutical form is denoted as PHF00082MIG, with a maximum daily dose of 70 mg/m² and a total maximum dose of 18,375 mg/m² over the same treatment period of 105 days. The dosing schedule is designed to align with standard-of-care practices for the treatment of metastatic PD-L1 positive colorectal cancer.
Another comparator treatment used in the study is **regorafenib**, provided as a **film-coated tablet**. This chemical-origin medication is also administered orally, with a maximum daily dose of 160 mg and a total maximum dose of 88,200 mg over 105 days. The administration of regorafenib follows established guidelines for its use in the treatment of colorectal cancer, ensuring consistency with standard therapeutic protocols.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Overall Survival (OS)**, which will be compared between the treatment group receiving MK-4280A and the standard of care group. Secondary endpoints include **Progression-Free Survival (PFS)**, **Objective Response Rate (ORR)**, and **Duration of Response (DOR)**, all evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR). Additionally, the trial will monitor the number of participants experiencing at least one adverse event (AE) and those who discontinue treatment due to an AE.
Patient-reported outcomes will be measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the Colorectal Cancer-Specific 29 Items (QLQ-CR29). Changes from baseline in global health status, quality of life, physical functioning, appetite loss, and bloating scores will be evaluated. Time to deterioration (TTD) in these scores will also be assessed. These assessments will provide a comprehensive evaluation of the treatment's impact on patients' quality of life and symptom management.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Has a histologically confirmed colorectal adenocarcinoma that is metastatic and unresectable.
- Has measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by the local site investigator.
- Has been previously treated for the disease and radiographically progressed on or after or could not tolerate standard treatment.
- Submits an archival (≤ 5 years) or newly obtained tumor tissue sample or newly obtained tumor tissue sample that has not been previously irradiated.
- Has an Eastern Cooperative Oncology Group Performance Score (ECOG PS) of 0 to 1 within 10 days prior to first dose of study intervention.
- Has a life expectancy of at least 3 months, based on the investigator assessment.
- Has the ability to swallow and retain oral medication and not have any clinically significant gastrointestinal abnormalities that might alter absorption.
- Has adequate organ function.
Exclusion Criteria
- Has previously been found to have deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumor status.
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis or leptomeningeal disease.
- Has a history of acute or chronic pancreatitis.
- Has neuromuscular disorders associated with an elevated creatine kinase (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
- Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.
- Has urine protein greater than or equal to 1g/24h.
- A woman of childbearing potential who has a positive urine/serum pregnancy test within 24/72 hours prior to the first dose of study intervention.
- Has received prior therapy with an anti-programmed cell death 1 (PD-1), anti-programmed death ligand 1 (PD-L1), or anti-programmed cell death ligand 2 (PD-L2), anti-lymphocyte activation gene 3 (LAG-3) antibody, with a tyrosine kinase inhibitor (TKI; eg, lenvatinib) other than rapidly accelerated fibrosarcoma (RAF) inhibitors (binimetinib is permitted if combined with a RAF inhibitor), or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4, OX-40, cluster of differentiation [CD] 137).
- Has previously received regorafenib or TAS-102.
- Has received prior systemic anticancer therapy including investigational agents within 28 days before randomization.
- Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
- Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention.
- Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
- Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
- Has an active autoimmune disease that has required systemic treatment in past 2 years.
- Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
- Has an active infection requiring systemic therapy (eg, tuberculosis, known viral or bacterial infections, etc.).
- Has a known history of human immunodeficiency virus (HIV) infection.
- Has known history of Hepatitis B or known active Hepatitis C virus infection.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
- Has had an allogenic tissue/solid organ transplant.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 29 Oct 2021 | 35 |
 Italy | Not Recruiting | 29 Oct 2021 | 24 |
 Norway | Not Recruiting | 29 Oct 2021 | 19 |
 Spain | Not Recruiting | 29 Oct 2021 | 24 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
MK-4280A | Test | SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1000 | 105 | PRD9364228 |
TRIFLURIDINE, COMBINATIONS | Comparator | PHF00082MIG | ORAL USE | 70 | 105 | SCP12480833 |
REGORAFENIB | Comparator | — | ORAL USE | 160 | 105 | SUB73090 |