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

Official title

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)

Overview

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).

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.

Interventions

• 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

Primary outcome measures

• pCR rate [Time frame: within 10 days after surgery]

Secondary outcome measures (12)

• NAR score [Time frame: within 10 days after surgery]
• 2-y OS rate [Time frame: 2 year]
• 2-y DFS rate [Time frame: 2 year]
• 3-y OS rate [Time frame: 3 year]
• 3-y DFS rate [Time frame: 3 year]
• 5-y OS rate [Time frame: 5 year]
• 5-y DFS rate [Time frame: 5 year]
• median OS time [Time frame: 0~60 months]
• median DFS time [Time frame: 0~60 months]
• R0 resection rate [Time frame: within 10 days after surgery]
• sphincter preserving rate [Time frame: instantly after surgery]
• nearly pCR rate [Time frame: within 10 days after surgery]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 8 centers

• Beijing Friendship Hospital, Capital Medical University — Beijing
• Beijing Cancer Hospital — Beijing
• Beijing Chaoyang Hospital, Capital Medical University — Beijing
• Beijing Hospital — Beijing
• Peking Union Medical College Hospital — Beijing
• Peking University First Hospital — Beijing
• Peking University People's Hospital — Beijing
• Xuanwu Hospital, Capital Medical University — Beijing

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. PMID 36001602
• Pang K, Sun P, Liu X, Yang D, Zhao P, Huang Y, Cao S, Gao Y, Chen G, Yu H, Duan L, Yang Y, Zhang Z. Development of the rationale of a personalized cancer vaccine based on the in situ vaccine effect of radiotherapy: a mechanistic study of the POLARSTAR trial. Cancer Immunol Immunother. 2025 Nov 12;74(12):369. doi: 10.1007/s00262-025-04229-3. PMID 41222702
• Yang Y, Pang K, Lin G, Liu X, Gao J, Zhou J, Xu L, Gao Z, Wu Y, Li A, Han J, Wu G, Wang X, Li F, Ye Y, Zhang J, Chen G, Wang H, Kong Y, Wu A, Xiao Y, Yao H, Zhang Z. Neoadjuvant chemoradiation with or without PD-1 blockade in locally advanced rectal cancer: a randomized phase 2 trial. Nat Med. 2025 Feb;31(2):449-456. doi: 10.1038/s41591-024-03360-5. Epub 2025 Jan 6. PMID 39762418
• Pang K, Yang Y, Tian D, Zeng N, Cao S, Ling S, Gao J, Zhao P, Wang H, Kong Y, Zhang J, Chen G, Deng W, Bai Z, Jin L, Wu G, Zhu D, Wang Y, Zhou J, Wu B, Lin G, Xiao Y, Gao Z, Ye Y, Wang X, Li A, Han J, Yao H, Yang Y, Zhang Z. Long-course chemoradiation plus concurrent/sequential PD-1 blockade as neoadjuvant treatment for MMR-status-unscreened locally advanced rectal cancer: protocol of a multicentr PMID 37699634

Identifiers

NCT: NCT05245474 · BFH-POLARSTAR

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗