Efficacy and Safety of PF-08634404 and Combination Therapy Versus Bevacizumab and Combination Therapy in Treatment-Naïve Participants With Metastatic Colorectal Cancer

Trial ID: 2025-523521-18-00
Protocol: C6461003
Sponsor: Pfizer Inc.

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Diseases & Conditions

Colorectal cancer metastatic

Objectives

The primary objective of this study is to evaluate whether the combination of PF-08634404 and mFOLFOX6 is superior to bevacizumab plus mFOLFOX6 in terms of prolonging progression-free survival and overall survival in participants with metastatic colorectal cancer. The secondary objectives include:

Assessment of efficacy through objective response rate, duration of response, and secondary measures of progression-free survival.
Evaluation of safety and tolerability.
Investigation of the pharmacokinetics of PF-08634404 when administered with mFOLFOX6.
Analysis of the immunogenicity of PF-08634404 in combination with mFOLFOX6.
Evaluation of patient reported outcomes.

Participants

This study involves a total of 580 participants diagnosed with metastatic colorectal cancer. The study population includes both male and female patients within specific age ranges. Eligible participants must have histologically or cytologically confirmed colorectal adenocarcinoma with evidence of Stage IV disease. Inclusion requires a known RAS mutation status and an ECOG performance status of 0-1. Participants must present with at least one measurable lesion according to RECIST 1.1 and possess sufficient available tumor tissue. To be eligible, individuals must have had no prior systemic therapy for metastatic disease and must demonstrate adequate hematologic, hepatic, and renal function. Women of childbearing potential are required to have a negative serum pregnancy test prior to the administration of the first dose.

Plans and Procedures

This Phase 3, double-blind, randomized study is designed to evaluate the efficacy and safety of PF-08634404 in combination with mFOLFOX6 compared to bevacizumab in combination with mFOLFOX6 for the treatment of metastatic colorectal cancer. The trial aims to demonstrate superiority in terms of progression-free survival and overall survival. The study methodology involves the administration of the experimental or comparator regimen via intravenous infusion. The research period is estimated to occur between April 2026 and March 2030. Participants undergo a screening visit to confirm histological or cytological evidence of colorectal adenocarcinoma, Stage IV disease, RAS mutation status, and adequate hematologic, hepatic, and renal function. Eligibility also requires an ECOG performance status of 0-1 and at least one measurable lesion according to RECIST 1.1. The study includes assessments for adverse events, objective response rate, and duration of response. Specific monitoring is conducted for pharmacokinetics and the incidence of anti-drug antibodies, alongside patient-reported quality of life measures.

Treatment

The experimental treatment consists of PF-08634404, administered as a concentrate for solution for infusion via intravenous injection at a dosage of 000 mg/kg.

The chemotherapy regimen includes oxaliplatin, administered via intravenous route at a dosage of 000 mg/m2, calcium folinate at a dosage of 000 mg/m2, and fluorouracil at a dosage of 000 mg/m2.

The comparator treatment involves the administration of bevacizumab via intravenous route at a dosage of 000 mg/kg in combination with chemotherapy for metastatic colorectal cancer.

Efficacy

The efficacy of the study intervention in participants with metastatic colorectal cancer is evaluated using several predefined endpoints. The primary endpoints consist of progression-free survival (PFS) assessed by blinded independent central review (BICR) and overall survival (OS).

Secondary efficacy parameters include:

PFS as assessed by the investigator;
Objective response rate (ORR) determined by both BICR and the investigator;
Duration of response (DOR) determined by both BICR and the investigator;
PFS2, representing progression-free survival after next-line therapy, as assessed by the investigator;
Mean score changes from baseline in global health status (GHS), quality of life (QoL), physical function, and symptoms measured via the EORTC QLQ-C30;
Mean score changes from baseline in function and symptom scales measured via the EORTC QLQ-CR29;
Time to definitive deterioration in GHS, QoL, function, and symptoms as measured by the EORTC QLQ-C30;
Time to definitive deterioration in function and symptoms as measured by the EORTC QLQ-CR29.

Inclusion and Exclusion Criteria

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Inclusion Criteria

18 years of age or older (or the minimum age of consent in accordance with local regulations) at screening. Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female (Section 10.4.2) participants. Participants of childbearing potential (Section 10.4.3) must have a negative serum pregnancy test (minimum sensitivity 25 mIU/mL or equivalent quantitative assay) result within 72 hours prior to the first dose of study treatment. Participants with false positive results and documented verification that the participant is not pregnant are eligible for participation.
Histological or cytological confirmed colorectal adenocarcinoma.
Evidence of Stage IV metastatic disease.
Known RAS mutation status per local test (CCI). Participants with unknown RAS status despite attempt to test are eligible for participation.
No prior systemic therapy for metastatic disease. Note: Participants with early-stage disease who received prior systemic neoadjuvant or adjuvant chemotherapy and present with reoccurrence/metastatic disease within 6 months of stopping treatment will count as having prior therapy in the metastatic setting and are not eligible.
ECOG performance status 0-1.
At least one measurable lesion according to RECIST 1.1 per Investigator assessment. Participants with prior definitive radiotherapy must have measurable disease per RECIST 1.1 that is outside the radiation field or have unequivocal progression of previously irradiated lesions.
Have tumor tissue available, either paraffin block or slides from a core, or excisional biopsy (FNA cell blocks, cytology samples and biopsies containing bone are not adequate). a. See Central Laboratory Manual for tissue specifications, handling, and shipping instructions. b. If less than the required amount of slides as outlined in the laboratory manual are available, the sponsor must be contacted to determine if available slides are sufficient. c. If sufficient archival tissue is not available, a new baseline tumor biopsy with adequate tissue is required, unless medically infeasible and with prior agreement with the medical monitor and documentation submitted to the sponsor.
Adequate hematologic, hepatic, and renal function by meeting the following criteria a. Participants must meet the hematologic criteria below without the use of transfusions or growth factors (platelet or red blood cell transfusions, TPO, EPO, G-CSF, IL-11, etc.) within 7 days prior to screening laboratory tests.
The participant must provide informed consent.

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Exclusion Criteria

Locally confirmed BRAF V600E mutation
Locally confirmed MSI-high or dMMR colorectal cancer
Participants with known active symptomatic CNS lesions, including leptomeningeal metastasis, brainstem, meningeal, or spinal cord metastases or compression Note: Participants with definitively treated brain metastases (surgery and/or radiotherapy) may be enrolled if all of the following are met: a. CNS metastases have been clinically stable with no evidence of clinical or radiographic disease progression for ≥14 days after completion of definitive radiotherapy and/or surgery and prior to study intervention. b. The participant has not required steroids for brain metastasis symptom management for 7 days prior to first dose of study intervention.
Known DPD deficiency (refer to the local 5-FU label or local clinical guidance for DPD status recommendation prior to starting treatment).
Clinically significant risk of hemorrhage or fistula including but not limited to the following: a. Significant tumor necrosis or cavitation b. The investigator deems that participation in the study poses a risk of hemorrhage; c. Tumor invasion or compression of surrounding critical organs (such as aorta, heart and pericardium, superior vena cava, trachea, and esophagus) or a risk of developing tracheoesophageal or pleuroesophageal fistula d. Mediastinal lymph node metastasis with invasion of the trachea or main bronchi. If centrally located mediastinal masses (<30 mm from the carina) identified by CT scan or chest x-ray, CT scan with intravenous contrast or MRI within 21 days prior to randomization must exclude major airway or blood vessel invasion by tumor.
Major surgery or severe trauma within 4 weeks prior to the first dose, or planned major surgery during the study; minor local surgery (excluding peripherally inserted central catheter placement and implantable central venous port placement) within 3 days prior to the first dose. Participants must have recovered adequately from the toxicity or complications from the surgery prior to starting study intervention.
History of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.
Any Grade ≥3 bleeding/hemorrhage events within 28 days of Cycle 1 Day 1, or prior history of clinically significant bleeding events, including unhealed wounds following surgical procedure.
Participants with acute, chronic or symptomatic infections including: a. Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted. b. Known seropositivity of HIV, except for participants with controlled HIV infection on a stable regimen of ART (CD4+ count >200/mm3 and viral load of <400 copies/mL). The investigator will ensure the ART does not result in substantial interactions with study or concomitant medications. c. Known active HBV infection by positive HBV surface antigen. d. Active HCV infection (positive HCV viral load by PCR). Participants who have been treated for HCV infection are eligible if they have documented sustained virologic response 12 weeks after completion of antiviral therapy. Note: Testing for HIV, HBV, or HCV is not required unless mandated by local health authorities. e. Participants with known active TB infection • Participants suspected to have active TB are required to undergo clinical evaluation to rule out the condition.
Clinically significant cardiovascular disease, or other comorbidities, within 6 months prior to first dose including but not limited to the following: a. Unstable angina b. Myocardial infarction c. Uncontrolled or significant arrhythmia (including sustained ventricular tachyarrhythmia and ventricular fibrillation), untreated serious conduction system abnormalities (eg, bifascicular block [defined as right bundle branch and left anterior or posterior hemiblock], 3rd degree AV block) d. Coronary/peripheral artery bypass graft e. Transient ischemic attack, cerebrovascular accident, cerebral infarction (excluding lacunar infarction), or cerebral hemorrhage f. Symptomatic congestive heart failure or symptoms consistent with NYHA Functional Class II or higher g. Baseline QTcF interval > 480 msec • If QTcF exceeds 480 msec, the ECG is to be repeated twice and the average of the 3 QTcF values should be used to determine the participant’s eligibility. Computer-interpreted ECGs with abnormal findings should be overread by an investigator physician experienced in reading ECGs before excluding participants. h. Decompensated liver cirrhosis i. Nephrotic syndrome j. Uncontrolled hypertension (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥100 mm Hg, or poor compliance with antihypertensive medications) k. Arterial thromboembolic event and venous thromboembolic event Grade ≥3 as specified in CTCAE 5.0 l. Hypertensive crisis m. Hypertensive encephalopathy
Participants with active autoimmune diseases requiring systemic treatment within the past 2 years (ie, with use of disease-modifying agents, corticosteroids or immunosuppressive drugs): a. Replacement therapy (eg, thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic disease modifying treatment and is allowed. b. Participants with vitiligo, psoriasis, type 1 diabetes mellitus (if not excluded per exclusion criterion 11), or resolved childhood asthma/atopy are allowed. c. Participants with Sjögren’s syndrome are allowed.
Evidence of non-infectious or drug-induced ILD pneumonitis that: • Was previously diagnosed and was managed with parenteral steroids for any duration or oral steroids for >6 weeks, or; • Had onset during or after treatment with immunotherapy, improved or resolved, then recurred after immunotherapy rechallenge, or; • Is currently diagnosed and managed with systemic therapy, or; • Is suspected on radiologic imaging at screening.
Unresolved toxicities from prior anti-tumor therapy, that did not recover to NCI CTCAE v5.0 Grade 0 or 1, or to levels specified in the inclusion/exclusion criteria, with the exception of alopecia. Participants who experience irreversible toxicity that is not expected to worsen with continued administration of the study intervention (eg, hearing loss) may be enrolled in the study after consultation with the medical monitor. Participants with long-term toxicity from radiotherapy that is deemed irreversible by the investigator may be enrolled in the study after consultation with the medical monitor.
Grade ≥3 baseline neuropathy, or ongoing residual Grade ≥2 neuropathy from prior oxaliplatin.
History of esophageal varices, severe ulcers, unhealed wounds, gastrointestinal perforation, abdominal fistula, gastrointestinal obstruction, intra-abdominal abscess, or acute gastrointestinal bleeding within 6 months prior to the first dose.
Participants with any history of another malignancy within 3 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (eg, 5-year OS ≥ 90%), such as adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer. Participants with a history of other curatively treated malignancies with low risk of recurrence not listed may also be considered eligible after consultation with sponsor or designee.
Known or suspected hypersensitivity to any component of study intervention or their excipients at the planned doses.
Other circumstances that may increase the study-related risks or interfere with interpretation of the study results, in the opinion of the investigator.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Recruiting	07 Apr 2026	15
Denmark	Not Yet Recruiting	07 Apr 2026	15
France	Recruiting	07 Apr 2026	30
Germany	Recruiting	07 Apr 2026	18
Italy	Recruiting	07 Apr 2026	54
The Netherlands	Not Yet Recruiting	07 Apr 2026	—
Poland	Recruiting	07 Apr 2026	20
Spain	Recruiting	07 Apr 2026	63
Netherlands	—	—	5

Sites & Investigators

Research sites

Istituto Oncologico Veneto Hospital Vall d’Hebron Pia Fondazione Di Culto E Religione Card G Panico Krankenhaus Nordwest GmbH

Investigators

Iñigo M. D.Stefan B.Emiliano T.Erika M.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Treatment Duration	EU MP Number
OXALIPLATIN	Test	—	INTRAVENOUS	33	SUB09490MIG
BEVACIZUMAB	Comparator	—	INTRAVENOUS	33	SUB16402MIG
PF-08634404	Test	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS	33	PRD12922792
FLUOROURACIL	Test	—	INTRAVENOUS	33	SUB07721MIG
CALCIUM FOLINATE	Test	—	INTRAVENOUS	33	SUB06052MIG