An Adaptive-design Prospective Cohort Study of Watch and Wait Strategy in Patients With Locally Advanced Rectal Cancer

Watch and Wait Strategy in Patients With Locally Advanced Rectal Cancer After Neoadjuvant Chemoradiotherapy: A Multi-centre, Adaptive-design, Phase II Prospective Cohort Study

The study is designed to test the hypothesis that the clinical complete response (CCR) rate of patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy will increase after an adaptive-design paradigm, as well as the rate of 2-year organ preservation, recurrence, quality of life, DFS and OS.

Study Overview

• Status: Not yet recruiting
• Conditions: Rectal Cancer
• Intervention / Treatment: Drug: Capecitabine (Xeloda) Pharmacogenetic Test Reagents; Drug: irinotecan; Radiation: IMRT; Drug: Oxaliplatin; Drug: 5Fluorouracil; Drug: Tislelizumab

Detailed Description

1. Primary objective:

   Evaluate the CCR rate of low rectal cancer using adaptive and optimized chemotherapy and radiotherapy strategies (all population and dMMR/MSI-H subgroup)

2. Secondary objectives:

   2.1 Evaluate the 2-year anal preservation rate, recurrence rate, quality of life, DFS and OS 2.2 Explore the subgroup of patients suitable for observation.

3. Outline:

Patients after long-course chemoradiation are grouped based on their MSI-H/dMMR status. For patients with MSI-H/dMMR, consolidation immunotherapy of Tislelizumab (BGB-A317) will be assigned. For patients with MSS/pMMR, consolidation chemotherapy will be given according to their tumor response. After completion of consolidation therapy, those who reach clinical complete response will receive organ preservation (watch and wait) strategy in place of radical surgery. During treatment, once local regrowth occurs or poor tumor response, total mesorectal excision (TME) surgery will be performed.

• Study Type: Interventional
• Enrollment (Anticipated): 222
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ji Zhu; Phone Number: 81607 +86-2164175590; Email: leo.zhu@126.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Fudan University Shanghai Cancer Cencer

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:

• pathological confirmed adenocarcinoma
• clinical stage T2-4 and/or N+, inappropriate for local excision
• the distance from anal verge less than 5 cm, or considered inappropriate for anal preservation by surgeons.
• Strong desire to preserve the anus, able to receive close surveillance for at least 2 years after chemoradiotherapy.
• without distance metastases
• aged between 18 to 75 years old.
• performance status score: 0~1
• UGT1A1*28 6/6 or 6/7
• sign the inform consent

Exclusion Criteria:

• pregnancy or breast-feeding women
• serious medical illness
• difficult to achieve complete response assessed by current evidence: the maximal diameter of tumor >10cm; the maximal diameter of lateral lymph node >2cm; baseline CEA>=100; biopsy pathology confirmed signet ring cell carcinoma components; digital rectal examination found that the tumor is peri-narrowed.
• baseline blood and biochemical indicators do not meet the following criteria: neutrophils≥1.5×10^9/L, Hb≥90g/L, PLT≥100×10^9/L, ALT/AST ≤2.5 ULN, Cr≤ 1 ULN
• DPD deficiency
• UGT1A1*28 7/7

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm 1; Arm 1 includes patients with MSS/pMMR. In this arm, patients receive consolidation chemotherapy after neoadjuvant chemoradiation (nCRT). The chemotherapy regimens either XELIRI or FOLFIRINOX, and the cycles of chemotherapy depend on patient tumor responses. For patients who reach cCR will enter the "W&W" cohort and omit radical surgery, while those without cCR will receive radical surgery.	Drug: Capecitabine (Xeloda) Pharmacogenetic Test Reagents; CRT: 625mg/m2 bid Monday-Friday per week XELIRI: 1000mg/m2 bid d1-14; Drug: irinotecan; CRT:80mg/m2 (UGT1A1*28 6/6) or 65mg/m2 (UGT1A1*28 6/7) XELIRI: 200mg/m2 bid d1 FOLFIRINOX: 150mg/m2 d1; Radiation: IMRT; Pelvic Radiation: 50Gy/25Fx; Drug: Oxaliplatin; FOLFIRINOX: 85mg/m2 d1; Drug: 5Fluorouracil; FOLFIRINOX: 400mg/m2 iv d1bolus, 2400mg/m2 ivgtt 46h
EXPERIMENTAL: Arm 2; Arm 2 includes patients with MSI-H/dMMR status. In this arm, patients receive consolidation immunotherapy of 3 cycles of tislelizumab after nCRT. For patients who reach cCR will enter the "W&W" cohort and omit radical surgery, while those without cCR will receive radical surgery.	Drug: Capecitabine (Xeloda) Pharmacogenetic Test Reagents; CRT: 625mg/m2 bid Monday-Friday per week XELIRI: 1000mg/m2 bid d1-14; Drug: irinotecan; CRT:80mg/m2 (UGT1A1*28 6/6) or 65mg/m2 (UGT1A1*28 6/7) XELIRI: 200mg/m2 bid d1 FOLFIRINOX: 150mg/m2 d1; Radiation: IMRT; Pelvic Radiation: 50Gy/25Fx; Drug: Tislelizumab; 200mg iv

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
clinical complete response rate	After nCRT, the lesions of rectal completely respond. Tumor residue cannot be found by digital rectal examination, endoscopic biopsy and radiology.	two weeks after completion of CRT or consolidation chemotherapy.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
2y-anal preservation rate	2-year anal preservation rate will be defined as the percentage of patients alive without receiving abdominoperineal resection at 2 years measured from the date of completion of CRT.	2 years
2y-local recurrence rate	2-year local recurrence rate will be defined as the percentage of patients alive developing local recurrence at 2 years measured from the date of completion of CRT.	2 years
Impact of participants' quality of life	quality of life is evaluated according to EORTC C-30 questionnare.	2 years
overall survival	3-year OS will be defined as the percentage of patients alive at 3 years measured from the date of completion of CRT.	3 years

Collaborators and Investigators

• Sponsor: Fudan University

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): June 22, 2020
• Primary Completion (ANTICIPATED): June 30, 2026
• Study Completion (ANTICIPATED): December 31, 2026

Study Registration Dates

• First Submitted: June 20, 2020
• First Submitted That Met QC Criteria: June 20, 2020
• First Posted (ACTUAL): June 23, 2020

Study Record Updates

• Last Update Posted (ACTUAL): June 30, 2020
• Last Update Submitted That Met QC Criteria: June 27, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: capecitabine; irinotecan; Chemoradiotherapy; Tislelizumab; organ preservation; watch and wait
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Fluorouracil; Capecitabine; Oxaliplatin; Irinotecan
• Other Study ID Numbers: CARTOnG-2001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No