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

NCT04301557 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: B2019-177-01
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

DMMR Colorectal Cancer; MSI-H Colorectal Cancer; Locally Advanced Colorectal Cancer

Keywords

DMMR Colorectal Cancer; MSI-H Colorectal Cancer; Locally Advanced Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• Pathological Complete Response(pCR)

  According to pathological response to assess the efficiency of treatment

  1 week after surgery

Secondary Outcomes (7)

• Acute toxicities

  Up to 3 months after adjuvant treatment

• Tumor regression grade

  1 week after surgery

• R0 resection rate

  1 week after surgery

• Surgical Complication

  Surgery scheduled 6-8 weeks after the end of neoadjuvant treatment

• Local recurrence

  From date of randomization until the date of local recurrence, assessed up to 10 years

Study Arms (1)

PD1 Antibody and Chemoradiotherapy for dMMR/MSI-H LACRC

EXPERIMENTAL

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; Drug: Oxaliplatin; Drug: Capecitabine; Radiation: External beam radiotherapy; Procedure: Total mesorectal excision

Interventions

PD-1 Antibody DRUG

PD-1 antibody 240mg,I.V,D1,repeat every 3 weeks, Four cycles in the neoadjuvant treatment, and four cycles in the adjuvant treatment,

Also known as: Toripalimab

PD1 Antibody and Chemoradiotherapy for dMMR/MSI-H LACRC

Oxaliplatin DRUG

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

PD1 Antibody and Chemoradiotherapy for dMMR/MSI-H LACRC

Capecitabine DRUG

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

PD1 Antibody and Chemoradiotherapy for dMMR/MSI-H LACRC

External beam radiotherapy RADIATION

Neoadjuvant radiotherapy, 50Gy/25Fractions to the GTV, 45Gy/25Fractions to the CTV

PD1 Antibody and Chemoradiotherapy for dMMR/MSI-H LACRC

Total mesorectal excision PROCEDURE

Total mesorectal excision

PD1 Antibody and Chemoradiotherapy for dMMR/MSI-H LACRC

Eligibility Criteria

• Age: 18 Years - 72 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically proven diagnosis of colorectal adenocarcinoma;
• 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;
• 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;
• 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;
• No symptoms of ileus; or ileus is alleviated after proximal colostomy.
• Previous treatment:
• No surgery except preventative stoma;
• No chemotherapy or radiotherapy;
• 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;
• No limit to previous endocrine therapy.
• Patient characteristics:
• Age between 18 and 72 years;
• ECOG performance status of 0 or 1;
• Life expectancy: more than 2 years;
• Hematopoietic: WBC\>3×109/L;PLT\>80×109/L; Hb\>90g/L;

You may not qualify if:

• All patients enrolled cannot have any of the following situation:
• 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;
• Severe hypertension with poor drug control;
• A known history of testing positive for HIV or chronic hepatitis B or C (high copy virus DNA) at active stage;
• Patients with active tuberculosis (TB) are receiving anti-tuberculosis treatment or have received anti-tuberculosis treatment within 1 year before screening;
• Other active severe clinical infections (NCI-CTC5.0);
• Apparent distant metastasis away from the pelvic before surgery;
• Cachexia, organ function decompensation;
• Previous pelvic or abdominal radiotherapy;
• Multiple primary colorectal cancers;
• Epilepsy require medical treatment (such as steroid or antiepileptic therapy);
• 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;
• Drug abuse and medical, psychological or social factors that may interfere with patients' participation in the study or affect the evaluation of the study;
• 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.
• Received any anti-infection vaccine (e.g. influenza vaccine, chickenpox vaccine, etc.) within 4 weeks before enrollment;

Sponsors & Collaborators

• Sun Yat-sen University: lead

Study Sites (1)

Sun Yat-sen University Cancer Center

Guangzhou, Guangdong, 510060, China

Location

Related Publications (13)

• Corrigendum to "Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial". J Natl Cancer Inst. 2018 Jul 1;110(7):794. doi: 10.1093/jnci/djy096. No abstract available.

  PMID: 29800481 BACKGROUND

• Croner RS, Merkel S, Papadopoulos T, Schellerer V, Hohenberger W, Goehl J. Multivisceral resection for colon carcinoma. Dis Colon Rectum. 2009 Aug;52(8):1381-6. doi: 10.1007/DCR.0b013e3181ab580b.

  PMID: 19617748 BACKGROUND

• Lehnert T, Methner M, Pollok A, Schaible A, Hinz U, Herfarth C. Multivisceral resection for locally advanced primary colon and rectal cancer: an analysis of prognostic factors in 201 patients. Ann Surg. 2002 Feb;235(2):217-25. doi: 10.1097/00000658-200202000-00009.

  PMID: 11807361 BACKGROUND

• Eldar S, Kemeny MM, Terz JJ. Extended resections for carcinoma of the colon and rectum. Surg Gynecol Obstet. 1985 Oct;161(4):319-22.

  PMID: 4049200 BACKGROUND

• Chang H, Yu X, Xiao WW, Wang QX, Zhou WH, Zeng ZF, Ding PR, Li LR, Gao YH. Neoadjuvant chemoradiotherapy followed by surgery in patients with unresectable locally advanced colon cancer: a prospective observational study. Onco Targets Ther. 2018 Jan 17;11:409-418. doi: 10.2147/OTT.S150367. eCollection 2018.

  PMID: 29398921 BACKGROUND

• Curley SA, Carlson GW, Shumate CR, Wishnow KI, Ames FC. Extended resection for locally advanced colorectal carcinoma. Am J Surg. 1992 Jun;163(6):553-9. doi: 10.1016/0002-9610(92)90554-5.

  PMID: 1595834 BACKGROUND

• Xin Yu, WeiWei Xiao, Rong Zhang, LuNing Zhang, Bo Qiu, ZhiFan Zeng, Pei-Rong Ding, Zhi-zhong Pan, Li-ren LI, Yuan-Hong Gao. A pilot study of neoadjuvant chemoradiotherapy for unresectable locally advanced adherent colon cancer: Assessing local tumor response. JCO. 2016; 34（4S）: 727.

  BACKGROUND

• Qiu B, Ding PR, Cai L, Xiao WW, Zeng ZF, Chen G, Lu ZH, Li LR, Wu XJ, Mirimanoff RO, Pan ZZ, Xu RH, Gao YH. Outcomes of preoperative chemoradiotherapy followed by surgery in patients with unresectable locally advanced sigmoid colon cancer. Chin J Cancer. 2016 Jul 7;35(1):65. doi: 10.1186/s40880-016-0126-y.

  PMID: 27389519 BACKGROUND

• Cukier M, Smith AJ, Milot L, Chu W, Chung H, Fenech D, Herschorn S, Ko Y, Rowsell C, Soliman H, Ung YC, Wong CS. Neoadjuvant chemoradiotherapy and multivisceral resection for primary locally advanced adherent colon cancer: a single institution experience. Eur J Surg Oncol. 2012 Aug;38(8):677-82. doi: 10.1016/j.ejso.2012.05.001. Epub 2012 May 24.

  PMID: 22632848 BACKGROUND

• Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC; EORTC Radiotherapy Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006 Sep 14;355(11):1114-23. doi: 10.1056/NEJMoa060829.

  PMID: 16971718 BACKGROUND

• Lemery S, Keegan P, Pazdur R. First FDA Approval Agnostic of Cancer Site - When a Biomarker Defines the Indication. N Engl J Med. 2017 Oct 12;377(15):1409-1412. doi: 10.1056/NEJMp1709968. No abstract available.

  PMID: 29020592 BACKGROUND

• Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20. doi: 10.1056/NEJMoa1500596. Epub 2015 May 30.

  PMID: 26028255 BACKGROUND

• Diaz LA Jr, Le DT. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Nov 12;373(20):1979. doi: 10.1056/NEJMc1510353. No abstract available.

  PMID: 26559582 BACKGROUND

MeSH Terms

Interventions

spartalizumab; toripalimab; Oxaliplatin; Capecitabine

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: February 23, 2020
• First Posted: March 10, 2020
• Study Start: July 31, 2020
• Primary Completion: April 22, 2024
• Study Completion: December 30, 2024
• Last Updated: April 23, 2024

Record last verified: 2024-04

Locations

CN (1)