PD-1 Inhibitors Combined With VEGF Inhibitors for Locally Advanced dMMR/MSI-H Colorectal Cancer

PD-1 Inhibitors (Camrelizumab) Combined With VEGF Inhibitors (Apatinib) for Locally Advanced dMMR/MSI-H Colorectal Cancer: an Open-label, Multi-center, Phase II Clinical Trial

In this open-label phase II study, patients will be scheduled for neoadjuvant treatment with PD-1 inhibitors (Camrelizumab) plus VEGF inhibitor (Apatinib) for dMMR/MSI-H colorectal cancer staged as locally advanced (cT3-4N+/-M0 for rectal cancer, cT4 or cT3 with extramural extension ≥5mm for colon cancer). Radiological evaluation will be preformed after 4 cycles of treatment. Patients (either with colon or rectal cancer) who achieve complete clinical response will be offered the choice of Watch & Wait.

Study Overview

• Status: Active, not recruiting
• Conditions: Colorectal Cancer; Microsatellite Instability High
• Intervention / Treatment: Drug: PD-1 inhibitor plus VEGF inhibitors

Detailed Description

This is an open-label phase II study, with the aim of determining the efficacy of PD-1 inhibitors (Camrelizumab) plus VEGF inhibitor (Apatinib) as a neoadjuvant therapy for dMMR/MSI-H locally advanced colorectal cancer.

Patients will be evaluated for eligibility within 14 days prior to study initiation with CT (for colon cancer) and/or MRI (for rectal cancer).

Patients will be given four cycles of Camrelizumab (200mg iv every 3 weeks) plus Apatinib (250mg QD day1-14) before being evaluated for response. For patients with colon cancer, if a SD/PD is achieved and the tumor is deemed unresectable, they will be offered chemotherapy±radiotherapy, while if a CR or PR is achieved, they will be offered another four cycles of Camrelizumab + Apatinib. After completing 8 cycles of treatment, if a CR is achieved they will be offered the choice of Watch & Wait. For patients with rectal cancer who have a SD/PD (after 4 cycles), chemoradiotherapy will be offered, while for those with a CR/PR, another four cycles of the treatment will be given. After completing 8 cycles of treatment, if a CR is achieved patients will be offered the choice of Watch & Wait.

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • 651 Dongfeng Road East

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Locally confirmed dMMR or MSI-H colorectal carcinoma
• Tumor staging based on CT/MR or transrectal ultrasound imaging:
• Colon cancer: radiological high risk (rT4 or rT3 tumour with extramural extension ≥ 5mm with or without lymph node involvement)
• Rectal cancer: <12 cm from the anal verge and radiological high risk (rT3/4 with or without lymph node involvement)
• No sign of bowel obstruction, or bowel obstruction has been relieved by ostomy
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 10 days prior to study start
• Aged 18 or over
• Life expectancy of at least 2 years
• Measurable disease
• Female participants of childbearing potential must be willing to use adequate contraception for the course of the study starting with the first dose of study medication through 120 days after the last PD-1 antibody dose
• Male participants must agree to use adequate contraception for the course of the study starting with the first dose of study medication through 120 days after the last PD-1 antibody dose
• Adequate organ function

Exclusion Criteria:

• Active autoimmune disease that has required systemic treatment in past 2 years
• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 2 weeks prior to this study start
• Currently participating and receiving treatment in another study within 4 weeks of study start
• History of severe allergic reaction to monoclonal antibody
• Strong evidence of distant metastases or peritoneal nodules (M1)
• Colonic obstruction that has not been defunctioned
• Has received prior therapy with an immune checkpoint inhibitor (e.g., anti-programmed cell death [PD]-1, anti-PD ligand 1 [L1], anti-PD-L2 agent, or anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] agent, etc.) or anti-VEGF agents (e.g., Bevacizumab, Apatinib)
• Any other malignant disease within the preceding 5 years with the exception of non-melanomatous skin cancer, carcinoma in situ and early stage disease with a recurrence risk <5%
• Received a live vaccine within 30 days of planned start of study medication
• Known history of Human Immunodeficiency Virus (HIV), Hepatitis B or C
• Known history of, or any evidence of interstitial lung disease or active, non-infectious pneumonitis
• Known history of active tuberculosis (Bacillus tuberculosis [TB])
• Active infection requiring systemic therapy

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: PD-1 inhibitors plus VEGF inhibitors; Patients will be given 4 cycles of Camrelizumab (200mg iv every 3 weeks) plus Apatinib (250mg QD day1-14) before being evaluated for response.	Drug: PD-1 inhibitor plus VEGF inhibitors; Camrelizumab 200mg IV every 3 weeks; Apatinib 250mg QD day 1-14. Rescue chemotherapy: Oxaliplatin 130mg/m2 IV drip Q3W d1+Capecitabine 1000mg/m2 QD d1-d14 Rescue chemoradiotherapy: Long-course radiotherapy +Capecitabine 825mg/m2 QD d1-d14; Other Names: Camrelizumab plus Apatinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical complete response or pathological complete response	Clinical complete response or immunotherapy-related pathological complete response (cCR or immunotherapy-related pCR)	up to 2 year

Secondary Outcome Measures

Outcome Measure	Time Frame
Objective Response Rate (ORR, PR+CR)	up to 2 year
3-year relapse-free survival	up to 3 years
3-year overall survival	up to 3 years
Surgical complications	within 1 month after surgery
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	up to 2 year

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: Guangdong Provincial Hospital of Traditional Chinese Medicine; Guangdong Provincial People's Hospital
• Investigators: Principal Investigator: Pei-Rong Ding, M.D., Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2020
• Primary Completion (Anticipated): December 30, 2023
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: January 13, 2021
• First Submitted That Met QC Criteria: January 18, 2021
• First Posted (Actual): January 20, 2021

Study Record Updates

• Last Update Posted (Actual): January 31, 2023
• Last Update Submitted That Met QC Criteria: January 28, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Genomic Instability; Colorectal Neoplasms; Microsatellite Instability; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Apatinib; Immune Checkpoint Inhibitors
• Other Study ID Numbers: B2020-120-03

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