Evaluation of Pembrolizumab Combined with XELOX and Bevacizumab in Microsatellite Stable Metastatic Colorectal Cancer with High Immune Infiltrate
- Trial ID
- 2024-515788-73-00
- Protocol
- FFCD1703
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of pembrolizumab in combination with XELOX and bevacizumab as a first-line treatment for patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) characterized by a high immune infiltrate. The efficacy will be assessed by analyzing the number of patients who are alive and without radiological and/or clinical progression at 10 months, based on RECIST 1.1 criteria evaluated by the investigator. This is clinically relevant as it aims to determine the potential of this combination therapy to improve outcomes in a specific subset of mCRC patients who typically have limited treatment options.
Secondary objectives include:
- Overall survival (median)
- Serious adverse events evaluated according to NCI-CTC v4.0
- Histological response in case of secondary resection (TRG criteria)
- Secondary resection rate (R0 and R1)
- Outcome of tumour markers (CEA and CA19.9)
- Percentage of patients alive and without progression at 10 months (centralised review) evaluated according to the investigator and centralised review (according to RECIST V1.1 criteria)
- Progression-free survival (median), evaluated according to the investigator and centralised review (according to RECIST V1.1 criteria)
- Time to progression, evaluated according to the investigator and centralised review (according to RECIST V1.1 criteria)
- Time to objective response, evaluated according to the investigator and centralised review (according to RECIST V1.1 criteria)
- Best response during treatment, evaluated according to the investigator and centralised review (according to RECIST V1.1 criteria)
- Depth of response, evaluated according to the investigator and centralised review (according to RECIST V1.1 criteria)
- Early tumour shrinkage at 9 weeks, evaluated according to the investigator and centralised review (according to RECIST V1.1 criteria)
- Percentage of patients alive and without progression at 10 months, evaluated according to centralised review according to iRECIST criteria
- Progression-free survival (median), evaluated according to centralised review according to iRECIST criteria
- Time to progression, evaluated according to centralised review according to iRECIST criteria
- Early tumour shrinkage at 9 weeks, evaluated according to centralised review according to iRECIST criteria
Participants
The clinical trial involves participants diagnosed with **microsatellite stable (MSS) metastatic colorectal cancer** with a high immune infiltrate. The study population includes both male and female subjects aged 18 years and older. Participants are required to have adequate liver and renal function, as well as a life expectancy greater than three months. The trial does not include a vulnerable population. The total number of participants is not provided by the sponsor. Participants were selected based on specific inclusion criteria, such as having unresectable cancer with at least one measurable metastatic target and a high immune response. Lifestyle factors such as diet and physical activity are not specified. The trial population was chosen to ensure adequate health status, including hematological function and absence of severe neuropathy. The study does not focus on any particular lifestyle considerations beyond the medical criteria outlined.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **pembrolizumab** in combination with XELOX and **bevacizumab** as a first-line treatment for patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) with a high immune infiltrate. This is a Phase II, non-randomized, multicenter study. The primary endpoint is the percentage of patients alive and without progression at 10 months, with progression defined by radiological criteria or death. The trial is expected to last until June 2026, with recruitment having started in April 2021.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, liver function, and cancer characteristics. Follow-up visits will occur regularly to monitor treatment response and adverse events, with assessments based on RECIST 1.1 criteria. The end-of-study visit will evaluate the overall survival and progression-free survival of participants. The expected length of participant involvement is up to 24 months, with conditions for early termination including severe adverse events or disease progression.
The trial involves the administration of **oxaliplatin** and **capecitabine** as part of the XELOX regimen, with **pembrolizumab** and **bevacizumab** administered via intravenous infusion. The study aims to provide insights into the potential benefits of combining chemotherapy with immunotherapy in this patient population. Participants will be closely monitored for safety and efficacy outcomes, with secondary endpoints including overall survival, adverse event rates, and tumor marker outcomes. The trial's design ensures rigorous assessment of treatment effects while maintaining participant safety.
Treatment
The clinical trial involves the administration of **pembrolizumab**, marketed as KEYTRUDA, which is provided as a 25 mg/mL concentrate for solution for infusion. This pharmaceutical form is intended for **intravenous infusion**. The maximum daily dose is 200 mg, with a total dose not exceeding 200 mg per administration. The treatment period is set for a maximum of 24 months. Pembrolizumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF02, and is produced by Merck Sharp & Dohme B.V.
**Bevacizumab**, marketed as Avastin, is another experimental medication used in this trial. It is available as a 25 mg/mL concentrate for solution for infusion, also administered via **intravenous infusion**. The dosing regimen allows for a maximum daily dose of 7.5 mg/kg, with the same amount as the total dose per administration. The treatment duration is capped at 24 months. Bevacizumab is a protein-based therapeutic agent, classified under the ATC code L01FG01, and is manufactured by Roche Registration GmbH.
**Oxaliplatin**, marketed as OXALIPLATINE HOSPIRA, is provided as a 5 mg/mL solution for infusion. This chemical-based medication is administered through **intravenous infusion**. The dosing schedule permits a maximum daily dose of 130 mg/m², with the same total dose per administration. The treatment period is limited to 24 months. Oxaliplatin is classified under the ATC code L01XA03 and is produced by Pfizer Holding France.
**Capecitabine**, marketed as CAPECITABINE BIOGARAN, is available in the form of 500 mg film-coated tablets. This chemical-based medication is administered **orally**. The dosing regimen allows for a maximum daily dose of 2000 mg/m², with a total dose not exceeding 28000 mg over the treatment period. The treatment duration is set for a maximum of 24 months. Capecitabine is classified under the ATC code L01BC06 and is manufactured by Biogaran.
In this clinical trial, the combination of pembrolizumab, bevacizumab, oxaliplatin, and capecitabine is being evaluated for efficacy in patients with microsatellite stable metastatic colorectal cancer with a high immune infiltrate. The study aims to assess the number of patients alive and without radiological and/or clinical progression at 10 months, based on RECIST 1.1 criteria evaluated by the investigator. Participant compliance with the dosing schedule and administration routes will be monitored throughout the trial period.
Efficacy
Efficacy in this clinical trial will be assessed by evaluating the primary endpoint, which is the percentage of patients alive and without progression at 10 months. Progression is defined by radiological progression evaluated by the investigator according to RECIST v1.1 criteria or death from any cause. Secondary endpoints include overall survival, grades 3-4 adverse events, secondary resection rate, histological response in case of secondary resection, outcome of tumor markers (CEA and CA19.9), progression-free survival, time to progression, time to an objective response, best response during treatment, depth of response, and early tumor shrinkage at 9 weeks. These endpoints will be measured using various criteria, including RECIST and iRECIST, and will involve both investigator assessments and centralized reviews.
The primary endpoint will be measured at the 10-month mark, while secondary endpoints will be evaluated throughout the trial duration, which is estimated to end on June 20, 2026. The trial will utilize tools such as imaging studies to assess radiological progression and response, and laboratory tests to monitor tumor markers. The analysis will be conducted according to standardized criteria, ensuring consistency and reliability in the evaluation of the trial's efficacy outcomes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- ≥ 18 years
- Both MSS and pMMR metastatic colorectal adenocarcinoma (metachronous or synchronous metastases), histologically proven
- Patients who have had adjuvant/post-operative chemotherapy and/or post-operative radiotherapy for the treatment of their primary tumor or R0 resected metastatic lesions can be included if they have a recurrence more than 6 months after the end of this treatment
- High immune response defined as the immune infiltration score obtained on the primary tumour (resection of primary tumour containing at least 2 mm of tumour-free margin between the tumour and nontumour area)
- Unresectable cancer with at least one measurable metastatic target according to RECIST v1.1 criteria
- WHO PS ≤ 1
- Absence severe neuropathy (≥ grade 2) (chemo-induced or not)
- Life expectancy > 3 months
- Adequate haematological function: neutrophils > 1,500 /mm3, platelets > 100,000/mm3, Hb > 9 g/dL
- Adequate liver function: AST/ALT ≤ 5xULN, total bilirubin ≤ 2xULN, Alkaline phosphatase ≤ 5xULN
- Creatinine clearance > 50 mL/min according to the CKD-EPI formula
- Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour
- Patient who is a beneficiary of the social security system
- Information provided to patient and signature of the informed consent form
Exclusion Criteria
- Active infection requiring intravenous antibiotics at day 1 of cycle 1
- All uncontrolled progressive disorders during the last 6 months: hepatic insufficiency, renal insufficiency, respiratory insufficiency, arterial hypertension
- History of an inflammatory digestive disease, obstruction or subobstruction not resolved with symptomatic treatment
- Active or untreated central nervous system metastases
- Peptic ulcer disease not healed before the treatment
- Patient already enrolled in another therapeutic trial with an ongoing investigational drug or whose treatment ended less than 4 weeks before inclusion
- Absence of effective contraception in patients (male and/or female patients) of childbearing potential, a pregnant or breastfeeding woman, women of childbearing potential and who have not had a pregnancy test
- Impossibility to submit to medical follow-up of the trial due to geographic, social or psychological reasons
- Patients who have had neo-adjuvant treatment (chemotherapy or radiotherapy) for the treatment of primary tumor can not be included
- Another concomitant cancer or history of cancer during the last 5 years, except for carcinoma in situ of the uterine cervix or a basal cell or squamous cell skin carcinoma or any other carcinoma in situ considered as cured
- Previous bone marrow allogenic stem cell transplantation or previous organ transplantation
- Previous treatment with anti-PD1 or anti-PDL1 or another immunotherapy
- History of idiopathic pulmonary fibrosis, medicinal product-related pneumonia or proof of active pneumonia or pneumonitis on a chest CTscan prior to therapy
- HIV infection, active hepatitis B or C infection, active tuberculosis
- Colorectal cancer with microsatellite instability (dMMR and/or MSI)
- Patient eligible for curative treatment (resection and/or thermal ablation according to the opinion of the local multidisciplinary tumour meeting board) and patient with RAS wild-type tumour for whom a tumour shrinkage with an anti-EGFR is necessary to perhaps obtain a XML File Identifier: IjpoCuOJiXEw1TRpi8rHlb0n7yE= Page 27/63 downstaging for a secondary surgery (according to the opinion of the local multidisciplinary tumour meeting board and/or at investigator's discretion)
- Patient with only primary tumour biopsies available or only a sample of a metastasis (no surgical resection of the primary tumour)
- An auto-immune disease which may worsen during treatment with an immune-stimulating agent (patients with type I diabetes, vitiligo, psoriasis, hypo or hyperthyroidism not requiring immunosuppressant therapy are eligible)
- Long-term immunosuppressant therapy (patients requiring corticosteroid therapy are eligible if administration at a dose ≤ 10 mg prednisone equivalent dose per day, administration of steroids by a route of administration resulting in minimal systemic exposure (cutaneous, rectal, ocular or inhalation) is authorised)
- Known severe hypersensitivity to monoclonal antibodies, to one of the medicinal products used or to one of the excipients in the products used or a history of anaphylactic shock or of uncontrolled asthma
- Vaccinations (live vaccine) within 30 days prior to start of treatment
- Dihydropyrimidine Dehydrogenase (DPD) deficiency defined by uracilemy level ≥ 16 ng/mL
- QT/QTc interval > 450 msec in men and > 470 msec in women
- One of the following disorders during the 6 months prior to inclusion: myocardial infarction, unstable/severe angina pectoris, coronary artery bypass grafting, NYHA class II, III or IV congestive heart failure, stroke or transient ischaemic attack
- Concomitant treatment with brivudine or brivudine within 4 weeks before capecitabine or 5FU initiation
- Poor nutritional status
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 20 Apr 2021 | 55 |
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 |
|---|---|---|---|---|---|---|
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 400 | 24 | PRD4323105 |
Avastin 25 mg/ml concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 7.5 | 24 | PRD2153901 |
FLUOROURACIL | Test | — | INTRAVENOUS BOLUS INJECTION/IV INFUSION | 400 | 24 | SUB07721MIG |
CAPECITABINE BIOGARAN 500 mg, comprimé pelliculé | Test | COMPRIMÉ PELLICULÉ | ORAL | 2000 | 24 | PRD3811799 |
Avastin 25 mg/ml concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 7.5 | 24 | PRD2153902 |
OXALIPLATINE HOSPIRA 5 mg/ml, solution à diluer pour perfusion | Test | SOLUTION À DILUER POUR PERFUSION | INTRAVENIOUS INFUSION | 130 | 24 | PRD1169373 |