PD1 Antibody Toripalimab and Chemoradiotherapy for dMMR/MSI-H Locally Advanced Colorectal Cancer

April 22, 2024 updated by: Yuan-hong Gao, Sun Yat-sen University
PD1 antibody is now recommended for dMMR/MSI-H metastatic colorectal cancer patients as second line. Chemoradiotherapy is standand treatment for locally advanced rectal cancer and is also recommended as an alternative choice for unresectable locally advanced colon cancer. Thus, this study will investigate the efficacy and toxicity of combination strategy using PD1 antibody and chemoradiotherapy for dMMR/MSI-H locally advnaced colorectal cancer patients.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

PD1 antibody is recommended for dMMR/MSI-H metastatic colorectal cancer patients as second line. Chemoradiotherapy is standand treatment for locally advanced rectal cancer and is also recommended as an alternative choice for unresectable locally advanced colon cancer. Thus, this phase II, single arm study will investigate the efficacy and toxicity of combination strategy using PD1 antibody and chemoradiotherapy for dMMR/MSI-H locally advnaced colorectal cancer patients, which is expected to yield higher tumor regressiona with tolerable toxicity.

Study Type

Interventional

Enrollment (Estimated)

25

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Guangdong
      • Guangzhou, Guangdong, China, 510060
        • Sun Yat-sen University Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 68 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Histologically proven diagnosis of colorectal adenocarcinoma;
  2. Biopsy tissues with IHC indicates deficient mismatch repair(dMMR),that is,the loss of at least one of the four proteins ,MSH1,MSH2,MSH6,PMS2;or gene detection implies MSI-H;
  3. Clinical stage for rectal cancer patients is cT3-4N0M0 or cTxN+M0;clinical stage of colon cancer should meet the following criteria (any one is sufficient): a)Tumor penetrates the whole wall and adherents to other organs or structures around(T4b).Tumor cannot reach R0 resection by imaging assessment; b)The intestinal lymph nodes involved are closely adjacent to large abdominal vessels. Lymph nodes dissection is not feasible by imaging assessment; c)Surgeons assess it is hard to achieve R0 resection after surgical exploration; d)Surgeons assess tumor is extensive multiviseral resection is needed, which is expected to damage the organs and seriously affect the quality of life after operation;
  4. Preoperative staging methods: all patients need to accept digital rectal examination(DRE).Patients with rectal cancer undergo high-resolution MRI±ultrasound colonoscopy/transrectal ultrasound for preoperative staging. Perienteric lymph nodes with short diameter ≥10mm or the shape of lymph nodes and its MRI characteristics are consistent with typical lymph node metastasis. If endoscopic ultrasonography is used in combination, and there is a contradiction between staging methods, the data should be submitted to the evaluation team of our center for the accurate staging;
  5. No symptoms of ileus; or ileus is alleviated after proximal colostomy.

Previous treatment:

  1. No surgery except preventative stoma;
  2. No chemotherapy or radiotherapy;
  3. No biotherapy (e.g.monoclonal antibodies), immunotherapy (e.g.anti-PD-1 antibody,anti-PD-L1 antibody,anti-PD-L2 antibody or CTLA-4 antibody),or other clinical trials agents;
  4. No limit to previous endocrine therapy.

Patient characteristics:

  1. Age between 18 and 72 years;
  2. ECOG performance status of 0 or 1;
  3. Life expectancy: more than 2 years;
  4. Hematopoietic: WBC>3×109/L;PLT>80×109/L; Hb>90g/L;
  5. Hepatic: ALT and AST<2 times upper limit of normal (ULN); bilirubin<1.5 times ULN;
  6. Renal: creatinine <1.5 times ULN or creatinine clearance ≥ 60 mL/min.

Exclusion Criteria:

All patients enrolled cannot have any of the following situation:

  1. Arrhythmias require antiarrhythmic therapy (with the exception of β-blockers or digoxin), symptomatic coronary artery disease or local myocardial ischemia (myocardial infarction within the past 6 months) or congestive heart failure exceeding NYHA II;
  2. Severe hypertension with poor drug control;
  3. A known history of testing positive for HIV or chronic hepatitis B or C (high copy virus DNA) at active stage;
  4. Patients with active tuberculosis (TB) are receiving anti-tuberculosis treatment or have received anti-tuberculosis treatment within 1 year before screening;
  5. Other active severe clinical infections (NCI-CTC5.0);
  6. Apparent distant metastasis away from the pelvic before surgery;
  7. Cachexia, organ function decompensation;
  8. Previous pelvic or abdominal radiotherapy;
  9. Multiple primary colorectal cancers;
  10. Epilepsy require medical treatment (such as steroid or antiepileptic therapy);
  11. Other malignancy within the past 5 years with the exception of effectively treated carcinoma in situ of the cervix or basal cell carcinoma of the skin;
  12. Drug abuse and medical, psychological or social factors that may interfere with patients' participation in the study or affect the evaluation of the study;
  13. Patients have any active autoimmune diseases or a history of autoimmune diseases(including but not limited to: interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, nephritis, hyperthyroidism and decreased thyroid function; patients with vitiligo or with complete remission of asthma in childhood and without any intervention in adulthood may be included; patients with asthma requiring bronchodilators intervention are not included.
  14. Received any anti-infection vaccine (e.g. influenza vaccine, chickenpox vaccine, etc.) within 4 weeks before enrollment;
  15. Complications require long-term treatment with immunosuppressive drugs, or requiring systemic or local use of immunosuppressive corticosteroids(>10mg/day prednisone or other therapeutic hormones);
  16. Known or suspected allergy to the study drugs or to any drugs related to this trial;
  17. Any unstable condition or which endangers the patients' safety and compliance;
  18. Pregnant or breast-feeding women who are fertile without effective contraception;
  19. Refuse to sign the informed consent.

Exit Criteria:

  1. Patients withdraw the informed consent and ask for quit;
  2. Poor compliance;
  3. Disease progression during treatment;
  4. Serious adverse events or serious adverse reactions (SAE) occurred during the study;
  5. Any delay of treatment for more than two weeks (including two weeks) (referring to the delay of all drugs in the medication plan) shall be discussed by the researchers whether to quit.

Cessation Criteria:

Study suspension refers to the cessation of the whole study before the end of the program. The main purpose of this action is to protect the rights and interests of the subjects, ensure the quality of the study, and avoid unnecessary economic losses. The whole study will be stopped for the following reasons:

  1. Researchers find serious safety issues;
  2. Efficacy is poor that there is no need to continue the study;
  3. Severe mistakes in the scheme design or important deviations in the implementation process;
  4. Funds or management problems;
  5. The administrative department decide to cancel the study. A complete suspension of research is either temporary or permanent. When discontinued, all study records shall be retained for future reference.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: PD1 Antibody and Chemoradiotherapy for dMMR/MSI-H LACRC
Induction regimen: Capeox+PD1 antibody for 1 cycle, Concurrent chemoradiotherapy regimen: Capeox+PD1 antibody for 2 cycles and concurrent , Interval regimen: Capeox+PD1 antibody for 1 cycle, TME surgery or watch and wait for cCR patients Adjuvant regimen: Capeox+PD1 antibody for 2 cycles, Capecitabine+PD1 antibody for 2 cycles
Drug: PD-1 Antibody
PD-1 antibody 240mg,I.V,D1,repeat every 3 weeks, Four cycles in the neoadjuvant treatment, and four cycles in the adjuvant treatment,
Other Names:
  • Toripalimab
Drug: Oxaliplatin
Oxiliplatin 130mg/m^2 (100mg/m^2 during radiotherapy),I.V,D1,repeat every 3 weeks, Four cycles in the neoadjuvant treatment in Capeox regimen, and two cycles in the adjuvant treatment in Capeox regimen
Drug: Capecitabine
Capecitabine 1000mg/m^2,Bid,P.O,D1-D14,repeat every 3 weeks, Four cycles in the neoadjuvant treatment in Capeox regimen, and two cycles in the adjuvant treatment in Capeox regimen, and two cycles in adjuvant treatment in Capecitabine regimen
Radiation: External beam radiotherapy
Neoadjuvant radiotherapy, 50Gy/25Fractions to the GTV, 45Gy/25Fractions to the CTV
Procedure: Total mesorectal excision
Total mesorectal excision

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pathological Complete Response(pCR)
Time Frame: 1 week after surgery
According to pathological response to assess the efficiency of treatment
1 week after surgery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Acute toxicities
Time Frame: Up to 3 months after adjuvant treatment
Acute toxicities according to CTCAE5.0
Up to 3 months after adjuvant treatment
Tumor regression grade
Time Frame: 1 week after surgery
Tumor regression grade
1 week after surgery
R0 resection rate
Time Frame: 1 week after surgery
R0 resection rate
1 week after surgery
Surgical Complication
Time Frame: Surgery scheduled 6-8 weeks after the end of neoadjuvant treatment
Surgical Complication
Surgery scheduled 6-8 weeks after the end of neoadjuvant treatment
Local recurrence
Time Frame: From date of randomization until the date of local recurrence, assessed up to 10 years
Local recurrence
From date of randomization until the date of local recurrence, assessed up to 10 years
Distant metastasis
Time Frame: From date of randomization until the date of death of distant metastasis, assessed up to 10 years
Distant metastasis
From date of randomization until the date of death of distant metastasis, assessed up to 10 years
3 year disease free survival
Time Frame: From date of randomization until the date of disease recurrence, assessed up to 3 years
3 year disease free survival
From date of randomization until the date of disease recurrence, assessed up to 3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sun Yat-sen University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 31, 2020

Primary Completion (Estimated)

April 22, 2024

Study Completion (Estimated)

December 30, 2024

Study Registration Dates

First Submitted

February 23, 2020

First Submitted That Met QC Criteria

March 9, 2020

First Posted (Actual)

March 10, 2020

Study Record Updates

Last Update Posted (Actual)

April 23, 2024

Last Update Submitted That Met QC Criteria

April 22, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • B2019-177-01

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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