Toripalimab Plus Bevacizumab and Chemotherapy as Neoadjuvant Therapy in Advanced MSI-H or dMMR Colorectal Cancer

The Efficacy and Safety of Toripalimab Combined With Bevacizumab and Chemotherapy as Neoadjuvant Therapy in Patients With Advanced MSI-H or dMMR Colorectal Cancer: an Open-label, Multicenter, Single-arm, Phase Ib/II Study

This is a trial investigating the efficacy and safety of Toripalimab combined with bevacizumab and chemotherapy as neoadjuvant therapy in patients with advanced microsatellite instability-high (MSI-H) or DNA mismatch repair-deficient (dMMR) colorectal cancer.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Carcinoma
• Intervention / Treatment: Drug: Toripalimab; Drug: Bevacizumab; Drug: Irinotecan

• Study Type: Interventional
• Enrollment (Anticipated): 44
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Jian Li, Professor; Phone Number: 86-10-88196561; Email: oncogene@163.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100142
      • Recruiting
      • Peking University Cancer Hospital and Institute
      • Contact: Jian Li, Professor; Phone Number: 86-10-88196561; Email: oncogene@163.com

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:

1. Histologically confirmed colorectal adenocarcinoma meeting any of the following criterion: a) T3-4 resectable rectal cancer; b) T1-2 rectal cancer located within 12 cm from the anal verge and refusing direct surgery or radiation therapy; c) T4a-b resectable colon cancer.
2. Microsatellite instability-high (MSI-H) or DNA mismatch repair-deficient (dMMR).
3. Measurable disease according to the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria and haven't received any local treatment.
4. Eastern Cooperative Oncology Group (ECOG) 0-1.
5. Fully aware of this study and having signed informed consent.
6. Age 18 to 75 years old without gender limitation.
7. Good compliance.
8. Absolute neutrophil count ≥1500/mm3, platelet ≥100,000/mm3, Hb ≥10g/dl, serum creatinine ≤1.5 times ULN, creatinine clearance rate ≥50mL/min, ALT and AST ≤2.5 times ULN, INR or aPTT ≤1.5 times ULN (INR ≤2 times ULN and aPTT in normal range for patients who are on prophylactic anticoagulant therapy within 14 days before study treatment), total bilirubin level ≤2 times ULN (within 7 days before study treatment).
9. Women of childbearing age should confirm that serum pregnancy test is negative and agree to use effective contraceptive methods during study treatment and the following 60 days.

Exclusion Criteria:

1. Previously received anti-PD1 or anti-PDL1 or anti-PDL2 or anti-CTLA4.
2. Uncontrolled active bleeding from the primary tumor or intestinal obstruction.
3. Contraindications of bevacizumab or irinotecan.
4. Hypersensitivity to other monoclonal antibodies.
5. Any active, known or suspected autoimmune disease.
6. Uncontrolled pleural effusion, pericardial effusion, or ascites to a moderate or greater extent.
7. History of one of the following dieases: idiopathic pulmonary fibrosis, organized pneumonia (eg. bronchiolitis obliterans), drug-induced pneumonia, idiopathic pneumonia and interstitial pneumonia, or evidence of active pneumonia through enhanced chest CT screening.
8. Major surgery within 4 weeks before enrollment and haven't fully recovered from the previous surgery.
9. Active bleeding or abnormal coagulation (aPTT >43s or INR >1.5 times ULN), or having a tendency to bleed or receiving thrombolytic or anticoagulant therapy.
10. Previously received allogeneic stem cell or parenchymal organ transplantation.
11. Any significant clinical or laboratory abnormality that the investigator considers to influence the safety assessment, eg. uncontrolled active infection, uncontrolled diabetes, hypertension that cannot be reduced to normal range with monotherapy, grade II or above peripheral neuropathy, congestive heart failure, heart disease (class II or higher) as defined by the New York College of Cardiology, myocardial infarction within 3 months prior to enrollment, unstable arrhythmias, unstable angina pectinis, chronic kidney disease, abnormal thyroid function and previous or co-existing malignancies.
12. History of uncorrected serum electrolyte disturbances such as potassium, calcium and magnesium.
13. HIV infection.
14. Active hepatitis B or hepatitis C.
15. Pregnancy or lactation period, or unwilling to use contraception during the trial.
16. With other malignancy within 5 year, except cervical carcinoma in situ, basal or squamous skin cancer, local prostatic carcinoma and ductal carcinoma in situ.
17. Use corticosteroids (dose of prednisone or similar drugs> 10mg/day) or other immunosuppressive agents within 14 days before enrollment.
18. Patients with active tuberculosis (TB) who are receiving anti-TB treatment or have received anti-TB treatment within 1 year.
19. Active infection, or treatment with oral or intravenous antibiotics within the first 2 weeks prior to neoadjuvant therapy, except prophylactic administration.
20. Anti-infective vaccine (eg. influenza vaccine, varicella vaccine, etc.) injection within 4 weeks before neoadjuvant therapy.
21. Previous participation in other clinical trials within 4 weeks before neoadjuvant therapy.
22. Any other disease, metabolic disorder, abnormal physical examination or abnormal laboratory results that may contrainn the use of trial drug, or affect the reliability of study results, or lead to high risk of treatment complications, or affect patient compliance.

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: Toripalimab combined with bevacizumab and chemotherapy

Drug: Toripalimab; Neoadjuvant therapy: Toripalimab is given by intravenous infusion at 3mg/kg d1 every 2 weeks for 3 cycles. Adjuvant therapy: Toripalimab is given by intravenous infusion at a dose of 240mg every 3 weeks for up to 9 cycles.; Drug: Bevacizumab; Neoadjuvant therapy: Bevacizumab is given by intravenous infusion at 5mg/kg d1 every 2 weeks for 3 cycles.; Drug: Irinotecan; Neoadjuvant therapy: Irinotecan is given by intravenous infusion at 180mg/m2 d1 every 2 weeks for 2 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response rate based on blinded, independent, central review	Percentage of patients who achieve pathological complete response (pCR) based on blinded, independent, central review (BICR).	10 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
R0 recession rate	Percentage of patients who achieve R0 recession.	10 weeks
Time to surgery	Measure of time from study treatment to surgery.	10 weeks
Pathological complete response rate assessed by local investigator	Percentage of patients who achieve pathological complete response (pCR) based on assessment of local investigator.	10 weeks
Pathological complete response rate based on blinded, independent, central review (BICR) and the assessment of local investigator	Percentage of patients who achieve pathological complete response (pCR) based on both blinded, independent, central review (BICR) and assessment of local investigator.	10 weeks
Tumor regression grade (TRG)		10 weeks
Objective response rate	Percentage of patients who achieve partial response (PR) or complete response (CR) based on Response Evaluation Criteria In Solid Tumors (RECIST).	Up to 3 years
Event free survival	Measure of time from study treatment to disease progression or death.	Up to 3 years
Disease-free survival	Measure of time from the date of surgery to disease relapse or death.	Up to 3 years
One-year or two-year disease-free survival rate	Percentage of patients who achieve disease-free survival lasting for more than one and two years respectively from the date of surgery.	Up to 2 years
One-year or two-year overall survival rate	Percentage of patients who achieve survival for more than one and two years respectively from date of first dose.	Up to 2 years
Score of life quality	Accessment of life quality based on EORTC QLQ-C30 and EORTC QLQ-CR29 scale.	Until 30 days after the last treatment
Incidence of Treatment-Related Adverse Events	Number of adverse events.	Until 30 days after the last treatment

Collaborators and Investigators

• Sponsor: Peking University

Study record dates

Study Major Dates

• Study Start (Actual): December 24, 2020
• Primary Completion (Anticipated): June 24, 2023
• Study Completion (Anticipated): December 24, 2023

Study Registration Dates

• First Submitted: July 31, 2021
• First Submitted That Met QC Criteria: July 31, 2021
• First Posted (Actual): August 3, 2021

Study Record Updates

• Last Update Posted (Actual): August 3, 2021
• Last Update Submitted That Met QC Criteria: July 31, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Topoisomerase I Inhibitors; Bevacizumab; Irinotecan
• Other Study ID Numbers: JS001-ISS-115

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