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

MSI-H Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04301557
• Other study ID #: B2019-177-01
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: July 31, 2020
• Est. completion date: December 30, 2024

Study information

• Verified date: April 2024
• Source: Sun Yat-sen University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 25
• Est. completion date: December 30, 2024
• Est. primary completion date: April 22, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 72 Years

Eligibility

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 ß-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.

Related Conditions & MeSH terms

• Colorectal Neoplasms
• DMMR Colorectal Cancer
• Locally Advanced Colorectal Cancer
• MSI-H Colorectal Cancer

Intervention

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,
• 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
• 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

Locations

Country	Name	City	State
China	Sun Yat-sen University Cancer Center	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Sun Yat-sen University

Country where clinical trial is conducted

China, 

References & Publications (13)

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. Erratum In: N Engl J Med. 2007 Aug 16;357(7):728. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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.

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pathological Complete Response(pCR)	According to pathological response to assess the efficiency of treatment	1 week after surgery
Secondary	Acute toxicities	Acute toxicities according to CTCAE5.0	Up to 3 months after adjuvant treatment
Secondary	Tumor regression grade	Tumor regression grade	1 week after surgery
Secondary	R0 resection rate	R0 resection rate	1 week after surgery
Secondary	Surgical Complication	Surgical Complication	Surgery scheduled 6-8 weeks after the end of neoadjuvant treatment
Secondary	Local recurrence	Local recurrence	From date of randomization until the date of local recurrence, assessed up to 10 years
Secondary	Distant metastasis	Distant metastasis	From date of randomization until the date of death of distant metastasis, assessed up to 10 years
Secondary	3 year disease free survival	3 year disease free survival	From date of randomization until the date of disease recurrence, assessed up to 3 years