Clinical trial NCT05245474: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Locally Advanced Rectal Cancer
Keywords: LARC
radiation
chemoradiation
PD-1
Tislelizumab
neoadjuvant
randomized
controlled
Lead sponsor: Beijing Friendship Hospital
Sponsor class: OTHER
Collaborators: name: Beijing Chao Yang Hospital
name: Xuanwu Hospital, Beijing
name: Beijing Hospital
name: Peking Union Medical College Hospital
name: Peking University First Hospital
name: Peking University People's Hospital
name: Peking University Cancer Hospital & Institute
name: BeiGene
First posted: 2022-02-18
Enrollment: 186
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

Primary outcomes:
measure: pCR rate
timeFrame: within 10 days after surgery
Secondary outcomes:
measure: NAR score
timeFrame: within 10 days after surgery
measure: 2-y OS rate
timeFrame: 2 year
measure: 2-y DFS rate
timeFrame: 2 year
measure: 3-y OS rate
timeFrame: 3 year
measure: 3-y DFS rate
timeFrame: 3 year
measure: 5-y OS rate
timeFrame: 5 year
measure: 5-y DFS rate
timeFrame: 5 year
measure: median OS time
timeFrame: 0~60 months
measure: median DFS time
timeFrame: 0~60 months
measure: R0 resection rate
timeFrame: within 10 days after surgery
measure: sphincter preserving rate
timeFrame: instantly after surgery
measure: nearly pCR rate
timeFrame: within 10 days after surgery
measure: ORR
timeFrame: before surgery
measure: immune-related adverse event rate
timeFrame: from commencing of PD-1 inhibition to the 30th day after surgery
measure: Grade 3+ immune-related adverse event rate
timeFrame: from commencing of PD-1 inhibition to the 30th day after surgery
measure: treatment-related adverse event rate
timeFrame: from commencing of treatment to the 30th day after surgery
measure: Grade 3+ treatment-related adverse event rate
timeFrame: from commencing of treatment to the 30th day after surgery
measure: cCR rate
timeFrame: before surgery
measure: incidence rate of surgical complications
timeFrame: within 30 days after surgery
measure: incidence rate of Grade 3+ surgical complications
timeFrame: within 30 days after surgery
measure: quality of life score
timeFrame: during the 5 years after surgery
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Friendship Hospital, Capital Medical University
state: Beijing
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Beijing
country: China
facility: Beijing Chaoyang Hospital, Capital Medical University
state: Beijing
city: Beijing
country: China
facility: Beijing Hospital
state: Beijing
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
city: Beijing
country: China
facility: Peking University First Hospital
state: Beijing
city: Beijing
country: China
facility: Peking University People's Hospital
state: Beijing
city: Beijing
country: China
facility: Xuanwu Hospital, Capital Medical University
state: Beijing
Study officials:
affiliation: Beijing Friendship Hospital
name: Zhongtao Zhang
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.