Neoadjuvant Long-course Chemoradiation Plus PD-1 Blockade for Mid-low Locally Advanced Rectal Cancer (POLAR-STAR)

Efficacy and Safety of Neoadjuvant Long-course Chemoradiation Plus Tislelizumab in Mid-low Locally Advanced Rectal Cancer: a Phase II, Multi-center, Open-label, Randomized Controlled Trial (POLARSTAR Trial)

This is a phase II/III, multi-center, open-label, 3-arm, randomized controlled trial assessing the efficacy and safety of neoadjuvant long-course chemoradiation combined with Tislelizumab (PD-1 inhibitor) and subsequent TME surgery, by comparing assorted endpoints between two experiment groups (Experiment group 1: chemoradiation+concurrent PD-1 inhibitor; Experiment group 2: chemoradiation+sequential PD-1 inhibitor) with a control group (chemoradiation only).

Study Overview

• Status: Recruiting
• Conditions: Locally Advanced Rectal Cancer
• Intervention / Treatment: Combination product: Long-course chemoradiation, with or without Tislelizumab (PD-1 inhibitor)

Detailed Description

This phase II, multi-center, open-label, 3-arm, randomized trial aims to recruit patients aged 18-75 years, diagnosed histologically as rectal adenocarcinoma, without metastasis (by CT), staged II/III (by MRI, T4b excluded), with distal margin within 10cm to anal verge. All patients should have no history of immune diseases, nor history of immunotherapy or radiotherapy. Sample size was thoroughly calculated to be 186. Eligible participants will be randomly assigned to Experiment Arm 1 (50.4Gy radiation, capecitabine, and anti-PD1 starting at Day 8 of radiation), Experiment Arm 2 (50.4Gy radiation, capecitabine, and anti-PD1 starting 2 weeks after completion of radiation), and Control Arm (50.4Gy radiation, capecitabine) in a 1:1:1 ratio. Randomization is stratified by different centers, with a block size of 6. For both experiment arms, Tislelizumab (anti-PD1) is scheduled to be administered at 200mg each time for 3 times, with 3-week intervals. The primary endpoint is pCR rate, and secondary endpoints include sphincter-preserving rate, adverse event rates, and DFS and OS rate at 2, 3 and 5 years post-operation. Data will be analyzed with an intention-to-treat or modified intention-to-treat approach.

• Study Type: Interventional
• Enrollment (Estimated): 186
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Zhongtao Zhang, M.D.; Phone Number: +8613801060364; Email: zhangzht@ccmu.edu.cn

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China
      • Recruiting
      • Peking University People's Hospital
      • Contact: Shuang Cao, M.D.; Email: 1610301226@pku.edu.cn
      • Principal Investigator: Yingjiang Ye, M.D.
      • Sub-Investigator: Zhidong Gao, M.D.
      • Sub-Investigator: Shuang Cao, M.D.
    • Beijing, Beijing, China, 100050
      • Recruiting
      • Beijing Friendship Hospital, Capital Medical University
      • Contact: Kai Pang, M.D.; Phone Number: 86 18811792819; Email: pk2wys@foxmail.com
      • Principal Investigator: Zhongtao Zhang, M.D.
      • Sub-Investigator: Yingchi Yang, M.D.
      • Sub-Investigator: Hongwei Yao, M.D.
      • Sub-Investigator: Kai Pang, M.D.
    • Beijing, Beijing, China
      • Recruiting
      • Peking Union Medical College Hospital
      • Contact: Danyang Zhu, M.D.; Phone Number: 86 13466711222; Email: 17710202092@163.com
      • Principal Investigator: Yi Xiao, M.D.
      • Principal Investigator: Guole Lin, M.D.
      • Sub-Investigator: Jiaolin Zhou, M.D.
      • Sub-Investigator: Danyang Zhu, M.D.
    • Beijing, Beijing, China
      • Recruiting
      • Peking University First Hospital
      • Contact: Yingchao Wu, M.D.; Phone Number: 86 13693214551; Email: wuyingchao112@163.com
      • Principal Investigator: Xin Wang, M.D.
      • Sub-Investigator: Yingchao Wu, M.D.
    • Beijing, Beijing, China
      • Completed
      • Beijing Cancer Hospital
    • Beijing, Beijing, China
      • Completed
      • Beijing Chaoyang Hospital, Capital Medical University
    • Beijing, Beijing, China
      • Completed
      • Beijing Hospital
    • Beijing, Beijing, China
      • Completed
      • Xuanwu Hospital, Capital Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• aged 18~75
• ECOG score 0~2
• biopsy diagnosed rectal adenocarcinoma, distal margin within 10cm to anal verge
• no distant metastasis, staged II/III (T4b excluded) by MRI
• maximum diameter of rectal cancer lesion≥10mm according to baseline CT or MRI (i.e. a "measurable lesion" as per RECIST 1.1 criteria)
• willing and able to comply with study protocol
• consent to the use of blood and tissue specimens for study
• no history of previous anti-tumor treatment (e.g. radiation, chemo, immuno, bio, herbal, etc.)
• no disorders/diseases of immune system (e.g. systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, hyperthyroidism/hypothyroidism, ulcerative colitis, autoimmune hemolytic anemia, HIV infection, etc.)
• no significant dysfunction of major viscera (e.g. heart, lung, liver, kidney, etc.)
• no jaundice or gastrointestinal obstruction
• no acute/ongoing infection
• no significant irregularities in blood routine test and biochemical test results, particular requirements include: neutrophils≥1.5×109/L, HGB≥80g/L, platelet≥100×109/L, serum creatinine≤1.5×ULN, total bilirubin≤1.5×ULN, ALT、AST≤2.5×ULN
• no social or mental disorder
• for women of child-bearing age, a negative result of serological pregnancy test is required, and effective contraception measures from inclusion till 60 days after the last dose of study drug is required

Exclusion Criteria:

• multiple cancers, or with concomitant malignant tumors besides rectal cancer
• having received any anti-cancer treatment (surgery, drugs, etc.) in the past 5 years
• history of recent major surgery
• with condition that affects the absorption of capecitabine via gastrointestinal tract (e.g. inability to swallow, nausea, vomiting, chronic diarrhea, etc.)
• with uncontrolled, severe, concomitant diseases of any sort
• allergic to any of the ingredients under study
• estimated survival ≤ 5 years due to any reason
• preparing for or having previously received organ or bone marrow transplant
• having received immunosuppressive or systemic hormone therapy for immunosuppressive purposes within 1 month prior to inclusion
• for patients with history of disorder of central nervous system, investigator discretion is required as to whether the clinical severity prevents the signing of informed consent or affects the patient's oral medication compliance
• with other conditions/issues that may affect the study results or cause the study treatment to be terminated halfway (e.g. alcoholism, drug abuse, etc.)
• pregnant or lactating women, or women intending on conception during treatment period

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CRT+concurrent PD-1 inhibition (Experiment Arm 1); Long-course chemoradiation plus PD-1 inhibition (Tislelizumab 200mg, 3 times, 3-week interval) starting on Day 8 of radiation therapy. TME surgery is scheduled in 8~12 weeks after completion of radiation.	Combination product: Long-course chemoradiation, with or without Tislelizumab (PD-1 inhibitor); Tislelizumab is added to long-course chemoradiation (CRT) of LARC patients, with CRT+concurrent Tislelizumab for Arm 1, CRT+sequential Tislelizumab for Arm 2, and CRT only for Arm 3
Experimental: CRT+sequential PD-1 inhibition (Experiment Arm 2); Long-course chemoradiation plus PD-1 inhibition (Tislelizumab 200mg, 3 times, 3-week interval) starting on Day 15 after completion of radiation therapy. TME surgery is scheduled in 8~12 weeks after completion of radiation.	Combination product: Long-course chemoradiation, with or without Tislelizumab (PD-1 inhibitor); Tislelizumab is added to long-course chemoradiation (CRT) of LARC patients, with CRT+concurrent Tislelizumab for Arm 1, CRT+sequential Tislelizumab for Arm 2, and CRT only for Arm 3
Active Comparator: CRT without PD-1 inhibition (Control Arm); Long-course chemoradiation plus PD-1 inhibition with no PD-1 inhibition. TME surgery is scheduled in 6~12 weeks after completion of radiation.	Combination product: Long-course chemoradiation, with or without Tislelizumab (PD-1 inhibitor); Tislelizumab is added to long-course chemoradiation (CRT) of LARC patients, with CRT+concurrent Tislelizumab for Arm 1, CRT+sequential Tislelizumab for Arm 2, and CRT only for Arm 3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pCR rate	pathological complete response rate	within 10 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NAR score	neoadjuvant rectal score	within 10 days after surgery
2-y OS rate	2-year overall survival rate	2 year
2-y DFS rate	2-year disease free survival rate	2 year
3-y OS rate	3-year overall survival rate	3 year
3-y DFS rate	3-year disease free survival rate	3 year
5-y OS rate	5-year overall survival rate	5 year
5-y DFS rate	5-year disease free survival rate	5 year
median OS time	median length (in months) of overall survival period	0~60 months
median DFS time	median length (in months) of disease free survival period	0~60 months
R0 resection rate	rate of R0 resection	within 10 days after surgery
sphincter preserving rate	proportion of patients with preserved anal sphincter	instantly after surgery
nearly pCR rate	nearly pathological complete response rate	within 10 days after surgery
immune-related adverse event rate	adverse event rate that is deemed to be associated with PD-1 inhibition	from commencing of PD-1 inhibition to the 30th day after surgery
Grade 3+ immune-related adverse event rate	adverse event (above Grade 3) rate that is deemed to be associated with PD-1 inhibition	from commencing of PD-1 inhibition to the 30th day after surgery
treatment-related adverse event rate	adverse event rate that is deemed to be associated with all treatments	from commencing of treatment to the 30th day after surgery
Grade 3+ treatment-related adverse event rate	adverse event (above Grade 3) rate that is deemed to be associated with all treatments	from commencing of treatment to the 30th day after surgery
cCR rate	clinical complete response rate	before surgery
ORR	objective response rate	before surgery
incidence rate of surgical complications	incidence rate of surgical complications within 30 days after surgery	within 30 days after surgery
incidence rate of Grade 3+ surgical complications	incidence rate of Grade 3+ surgical complications within 30 days after surgery	within 30 days after surgery
quality of life score	quality of life score during the 5 years after surgery, multiple timepoint assessment	during the 5 years after surgery

Collaborators and Investigators

• Sponsor: Beijing Friendship Hospital
• Collaborators: Peking University First Hospital; Peking University People's Hospital; Peking Union Medical College Hospital; Peking University Cancer Hospital & Institute; Xuanwu Hospital, Beijing; Beijing Chao Yang Hospital; Beijing Hospital; BeiGene
• Investigators: Principal Investigator: Zhongtao Zhang, Beijing Friendship Hospital

Publications and helpful links

General Publications

• Pang K, Yang Y, Zhao P, Wu G, Li J, Gao J, Yao H, Yang Y, Zhang Z. Adding immune checkpoint blockade to neoadjuvant chemoradiation in locally advanced rectal cancer. Br J Surg. 2022 Oct 14;109(11):1178-1179. doi: 10.1093/bjs/znac298. No abstract available.

Helpful Links

• Study protocol was published as an abstract on 2022 ESMO Congress

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2022
• Primary Completion (Estimated): March 1, 2024
• Study Completion (Estimated): September 1, 2029

Study Registration Dates

• First Submitted: February 6, 2022
• First Submitted That Met QC Criteria: February 6, 2022
• First Posted (Actual): February 18, 2022

Study Record Updates

• Last Update Posted (Actual): January 10, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: neoadjuvant; radiation; PD-1; chemoradiation; randomized; Tislelizumab; LARC; controlled
• 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; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Tislelizumab
• Other Study ID Numbers: BFH-POLARSTAR

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Export of individual patient data is a sensitive issue according to current Chinese laws

Drug and device information, study documents

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