Safety and Efficacy of Pembrolizumab in Combination with Bevacizumab + CapeOX in the Neoadjuvant Treatment of RAS-mutated, BRAF Wild-type, Microsatellite-stabilized, Locally Advanced Colorectal Cancer

To explore the efficacy and safety of pembrolizumab in combination with bevacizumab and CapeOX neoadjuvant therapy for the treatment of RAS-mutated, BRAF wild-type, microsatellite-stabilized, locally advanced colorectal cancer.

Methods and analysis: A prospective, open-label, single-arm, phase 2 clinical study protocol will enroll a total of 20 patients. The study is designed as a Simon II Optimal study involving 20 locally advanced rectal cancer (LACRC) patients. Initially, 9 patients will be recruited in the Simon I phase, and if more than 1 patient achieves a pathological complete response (pCR), the study will proceed to the II phase. Recruit up to 20 patients in Phase II, and if more than 4 patients achieve pCR, the trial will be considered successful. All enrolled patients will receive 2-4 cycles of neoadjuvant therapy with pembrolizumab + bevacizumab and CapeOX (bevacizumab + oxaliplatin + capecitabine). The primary efficacy endpoint is the pathological complete response (pCR) of the cancer following neoadjuvant therapy. Secondary efficacy endpoints include major pathological response (MPR), objective response rate (ORR), and assessment of adverse events (AEs).

Ethics: Ethics approval has been obtained from the Ethics Committee at the First Affliated Hospital (Xijing Hospital)(KY20232402-F-1)

Study Overview

• Status: Recruiting
• Conditions: Locally Advanced Colorectal Cancer
• Intervention / Treatment: Drug: Pabolizumab+ bevacizumab and CapeOX (bevacizumab + oxaliplatin + capecitabine)

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jianjun Yang, Professor; Phone Number: 86-02984771531; Email: yangjj@fmmu.edu.cn
• Study Contact Backup: Name: Shu Wang; Email: ws0286@163.com

Study Locations

• China
  • Shaanxi
    • Xi'an, Shaanxi, China, 710032
      • Recruiting
      • the First Affliated Hospital (Xijing Hospital),the First Affiliated Hospital of Air Force Military Medical University
      • Contact: Jianjun Yang; Email: yangjj@fmmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age: ≥18 years;
• Confirmed RAS mutation and BRAF wild-type in LACRC by pathological histology or genetic sequencing.;
• ECOG Performance Status (PS) score of 0 or 1;
• Previously untreated;
• Microsatellite-stable status;
• Hematological parameters within normal limits: White blood cell count ≥4×10^9/L; Absolute neutrophil count ≥1.5×10^9/L; Platelets ≥100×10^9/L. Hemoglobin ≥90g/L;
• Normal renal function: Serum creatinine ≤1.5× upper limit of normal (ULN) or creatinine clearance (CrCl) >60 mL/min (calculated using Cockcroft-Gault formula): Female CrCl = (140 - age) × weight (kg) × 0.85 / (72 × Scr mg/dl)；Male CrCl = (140 - age) × weight (kg) × 1.00 / (72 × Scr mg/dl);
• Normal liver function: Serum total bilirubin ≤1.5× ULN; Aspartate aminotransferase (AST) ≤2.5× ULN; Alanine aminotransferase (ALT) ≤2.5× ULN;
• Female patients must have a negative pregnancy test before the study initiation (not applicable to bilateral oophorectomy and/or hysterectomy patients or postmenopausal patients);
• Signed written informed consent form.

Exclusion criteria:

• Receiving anti-tumor therapy prior to enrollment, including but not limited to PD-1 inhibitors, CTLA-4 antibodies, EGFR monoclonal antibodies, EGFR-TKI, and anti-angiogenic drugs;
• History of autoimmune diseases, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome-associated vascular thrombosis, Wegener's granulomatosis, desiccation syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. (Note: Vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune disease, psoriasis not requiring systemic therapy, or patients not expected to have a relapse without external triggers may be allowed to enroll);
• Enrolled in another interventional clinical trial within 30 days prior to screening;
• History of other malignancies (except cured basal cell carcinoma of the skin);
• Presence of severe, poorly controlled co-morbidities such as heart failure, diabetes mellitus, hypertension, hepatic failure, renal failure, thyroid disease, psychiatric disorders, etc;
• Known HIV infection or active viral hepatitis or tuberculosis;
• Major surgery or planned surgery within 30 days prior to the first dose of the investigational drug;
• Hypersensitivity to the drugs used in the trial or their components;
• Pregnancy (confirmed by blood or urine HCG test) or breastfeeding women, or subjects of childbearing potential unwilling or unable to use effective contraception until at least 6 months after the last trial treatment;
• Deemed inappropriate for participation in the study by the investigator.
• Unwilling or unable to participate in the study or sign the informed consent form.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: pembrolizumab + bevacizumab and CapeOX (bevacizumab + oxaliplatin + capecitabine); all enrolled patients received a combination of chemotherapy and immunotherapy, as outlined below: Pembrolizumab: Day 1：Pembrolizumab injection 200mg was administered once and repeated every 21 days, expected to last 2-4 cycles. Two vials (200 mg) of pembrolizumab injection should be diluted into 100-200 mL of saline, and the infusion time should be more than 30 minutes. Chemotherapy (CapeOX regimen): Day 2: Bevacizumab (7.5 mg/kg) + Oxaliplatin (135 mg/m2) + Capecitabine (1 g/m2, did, d1-d14). Treatment repeated every 3 weeks (q3w) until disease progression or intolerable toxicity.

Drug: Pabolizumab+ bevacizumab and CapeOX (bevacizumab + oxaliplatin + capecitabine); Pabolizumab is an lgG4 subclass monoclonal antibody humanized against PD-l molecules thatblocks the immune escape mechanism of cancer cells by inhibiting the PD-l receptor oflymphocytes, thereby allowing the immune system to destroy them. In the single-arm study, all enrolled patients received a combination of chemotherapy and immunotherapy, as outlined below: Pembrolizumab: Day 1：Pembrolizumab injection 200mg was administered once and repeated every 21 days, expected to last 2-4 cycles. Two vials (200 mg) of pembrolizumab injection should be diluted into 100-200 mL of saline, and the infusion time should be more than 30 minutes. Chemotherapy (CapeOX regimen): Day 2: Bevacizumab (7.5 mg/kg) + Oxaliplatin (135 mg/m2) + Capecitabine (1 g/m2, did, d1-d14). Treatment repeated every 3 weeks (q3w) until disease progression or intolerable toxicity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response rate (pCR)	Pathological complete reand the postoperative pathological findings were statistically completse rate (pCR rate): The pathological status of the primary site was determined in the surgical patient Proportion of patients with complete response:	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR) in the neoadjuvant phase	Obiective response rate (ORR) at the neadjuvant stage: proportion of subjects who achieved partiaand complete response on radiographic assessment (RECIST v1.l) after the end of neoadjuvanttherapy;	36 months
Major pathological response rate (MPR)	Major pathological response rate (MPR rate): The pathological status of the primary site wadetermined in the patients undergoing surgery, and the proportion of patients with residuatumor cells <10% by pathological detection in postoperative specimens was counted	36 months
Adverse event rate (AE)	Safety: all adverse events, serious adverse events;	36 months

Collaborators and Investigators

• Sponsor: yangjianjun

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2024
• Primary Completion (Estimated): January 15, 2025
• Study Completion (Estimated): January 15, 2026

Study Registration Dates

• First Submitted: August 2, 2024
• First Submitted That Met QC Criteria: August 10, 2024
• First Posted (Actual): August 13, 2024

Study Record Updates

• Last Update Posted (Estimated): November 12, 2024
• Last Update Submitted That Met QC Criteria: November 9, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: pembrolizumab; Locally advanced colorectal cancer (LACRC); microsatellite-stabilized; CapeOX neoadjuvant
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Antineoplastic Agents, Immunological; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Capecitabine; Oxaliplatin; Bevacizumab
• Other Study ID Numbers: KY20232402

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No