Neoadjuvant Short-course Radiotherapy Followed by the Combination of Immunotherapy and Chemotherapy in Locally Advanced Rectal Cancer

The Combination of Neoadjuvant Short-course Radiotherapy and Immunotherapy in Locally Advanced Rectal Cancer：A Open-label Single-arm Phase II Trial.

This is a single arm, open-label, prospective phase II clinical trial to evaluate the combination of neoadjuvant short-course radiotherapy and immunotherapy (PD-1 antibody) for patients with locally advanced rectal cancer (LARC). A total of 40 patients will be enrolled in this trial to receive 5*5Gy short-course radiotherapy, followed by 4 cycles of CAPOX chemotherapy and PD-1 antibody. Then they will receive the TME surgery and another 4 cycles of CAPOX chemotherapy. There are two cohorts according to the microsatellite instability status: (1) the micro-satellite stable (MSS) cohort（n=32), (2) the MSI-high cohort (n=8). The primary end point is the rate of pathological complete response (pCR). The long-term prognosis and adverse effects will also be evaluated and analyzed.

Study Overview

• Status: Not yet recruiting
• Conditions: Locally Advanced Rectal Cancer
• Intervention / Treatment: Drug: PD-1 antibody; Drug: Capecitabine; Drug: Oxaliplatin

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yuping Zhu, MD; Phone Number: 86-0571-88128011; Email: drzyp@163.com
• Study Contact Backup: Name: Yibo Cai, MD; Phone Number: 86-0571-88128011; Email: caiyiyibo@zju.edu.cn

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 571
      • Zhejiang Cancer Hospital
      • Contact: Yuping Zhu, MD; Phone Number: 86-0571-88128011; Email: drzyp@163.com
      • Contact: Yibo Cai, MD; Phone Number: 86-0571-88128011; Email: caiyiyibo@zju.edu.cn
      • Sub-Investigator: Zhuo Liu, MD
      • Sub-Investigator: Yibo Cai, MD

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. Pathological confirmed rectal adenocarcinoma and the distance from anal verge less than 12 cm;

  2. Clinical stage T3-4 and/or N+ (AJCC 8th);

  3. No distant metastases;

  4. Age 18-70 years old, female and male;

  5. ECOG 0-1;

  6. No previous chemotherapy, radiotherapy, immunotherapy or other anti-tumor treatment;

  7. Adequate organ function defined at baseline as:

  1. ANC ≥1.5×109 /L，PLt ≥75×109 /L，Hb ≥90 g/L;
  2. TBIL ≤1.5×ULN, ALT ≤2.5ULN, AST ≤2.5ULN, BUN and Cr ≤1×ULN or Ccr ≥50ml/min (Cockcroft-Gault formula);
  3. INR ≤1.5×ULN or PT ≤1.5×ULN (If the patient is receiving anticoagulant therapy, PT should be within the intended use range of the anticoagulant drug);

  8. With good compliance and no serious comorbidity;

  9. Women of childbearing age must have taken reliable contraceptive measures or have a pregnancy test (serum or urine) within 7 days prior to enrollment and the results are negative;

  10. Subject volunteers to join the study, sign the informed consent.

Exclusion Criteria:

• 1. History of other uncured malignancies within 5 years. Cured tumor with good prognosis, such as skin basal cell carcinoma, cervical cancer and superficial bladder cancer, will be excluded;

  2. Have received surgery within 4 weeks before the enrollment;

  3. History of obstruction within 6 months before the enrollment;

  4. History of active autoimmune disease, interstitial lung disease, epilepsy and dysphrenia;

  5. With uncontrolled cardiovascular disease: active coronary heart disease; grade III-IV cardiac insufficiency according to the NYHA criteria; and myocardial infarction within 1 year;

  6. With active infection or fever of >38.5 ℃ with unknown cause (tumor-induced fever judged could be enrolled);

  7. DPD deficiency;

  8. Allergic to any component of chemotherapy or immunotherapy;

  9. With congenital or acquired immunodeficiency (such as those with HIV infection), active hepatitis B or hepatitis C;

  10. Usage of corticosteroids (prednison dose of > 10 mg/day) or other immunosuppressors for systemic treatment within the first 14 days of research;

  11. Receive attenuated live vaccine within 4 weeks before the research;

  12. Pregnant women or breast-feeding women;

  13. With other factors that would force to terminate the clinical trial ahead of time, such as the development of other severe comorbidity that required combined treatment, and family or social factors affecting the safety of patients or experimental data collection, as judged by the researchers.

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: Neoadjuvant short-course radiotherapy+immunotherapy+chemotherapy; A total of 40 patients receive 5*5Gy short-course radiotherapy, followed by 4 cycles of CAPOX chemotherapy and PD-1 antibody, finally receive the TME surgery and another 4 cycles of CAPOX chemotherapy. Interventions: Shor-course radiotherapy: 25Gy/5Fx; Induction immunotherapy: Sintilimab 200mg ivgtt d1 q3w x 4 cycles; Concurrent Chemotherapy: Oxaliplatin: 130mg/m2 d1 q3w + Capecitabine: 1000mg/m2 d1-14 q3w x 4 cycles;

Drug: PD-1 antibody; Sintilimab is a humanized IgG4 monoclonal antibody against the programmed death-1 (PD-1) receptor. Usage: 200mg ivgtt d1 q3w.; Other Names: Sintilimab; Drug: Capecitabine; Usage: 1000mg/m2 d1-14 q3w; Drug: Oxaliplatin; Usage: 130mg/m2 d1 q3w

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pCR rate	Pathologic complete response rate	The TME surgery will be recommended at 1 week after the neoadjuvant therapy. The pCR rate is evaluated after surgery. Assessed up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-year DFS	3-year disease free survival rate	Assessed up to 3 years
3-year local recurrence rate	3-year local recurrence rate	Assessed up to 3 years
3-year OS	3-year overall survival rate	Assessed up to 3 years
Grade 3-4 adverse effects rate	Radiotherapy, immunotherapy and chemotherapy related grade 3-4 adverse events rate	Assessed up to 3 years
Surgical complications	Type and Rate of surgical complications	Assessed up to 3 years from the TME surgery
Quality of Life Scale	The Quality of Life Scale (QoLS, range 0-60) will be used to evaluate the quality of life. Higher scores mean the better quality of life	Assessed up to 5 years

Collaborators and Investigators

• Sponsor: Zhejiang Cancer Hospital
• Investigators: Principal Investigator: Yuping Zhu, MD, Zhejiang Cancer Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2020
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: November 28, 2020
• First Submitted That Met QC Criteria: December 4, 2020
• First Posted (Actual): December 11, 2020

Study Record Updates

• Last Update Posted (Actual): December 11, 2020
• Last Update Submitted That Met QC Criteria: December 4, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Immunotherapy; Locally advanced rectal cancer; Pathological complete response; Neoadjuvant short-course radiotherapy
• 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; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Antibodies; Capecitabine; Oxaliplatin
• Other Study ID Numbers: IRB-2020-336

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