599TiP - PRABITAS study: A pragmatic, randomized, phase III trial of biweekly vs. conventional use of trifluridine/tipiracil plus bevacizumab for refractory metastatic colorectal cancer

Background

The standard treatment for metastatic colorectal cancer (mCRC) includes trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV); however, this treatment is often associated with toxicity, particularly for diverse patients with compromised conditions. Thus, biweekly FTD/TPI + BEV is favored in clinical practice for these patients. However, the efficacy of this regimen compared with the standard remains unestablished, necessitating a randomized comparative trial. To assess real-world effectiveness, we have employed a pragmatic clinical trial design, aiming to replicate daily clinical scenarios, to support decision-making in daily practice.

Trial design

PRABITAS is a pragmatic, randomized, phase III noninferiority trial of biweekly vs. conventional use of FTD/TPI + BEV for treating refractory mCRC. In this trial, patients will be randomized 1:1 to arm A (conventional: FTD/TPI on days 1–5 and 8–12 and BEV on days 1 and 15 every 28 days) or arm B (biweekly: FTD/TPI on days 1–5 and BEV day 1 every 14 days). Randomization is stratified by facility, RAS status, and ECOG PS. The eligibility criteria are as follows: excluding items from historical lists to increase inclusion and generalizability; diagnosis of unresectable colorectal cancer; prior exposure to fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF agents, and anti-EGFR antibody (RAS wild-type only); and an ECOG PS of 0–2. The protocol allows the initiation of treatment, adjustments in dosage, and the timing of laboratory/imaging tests at the physician’s discretion. The primary endpoint is overall survival, while the secondary endpoints are progression-free survival, disease control rate, and incidence of adverse events. Based on a hypothesis of 43% 1-year survival rate in arm A, with a noninferiority margin of 1.25, one-sided α = 0.025 and β = 0.2, and a 1-year registration and follow-up period, the target is to enroll 890 patients. By reducing barriers to enrollment and burden of data collection, 243 participating facilities across Japan could expedite enrollment. Since the trial's launch in December 2023, 248 participants have enrolled within 4 months.

Clinical trial identification

jRCTs041230120; 21 December 2023.

Editorial acknowledgement

Legal entity responsible for the study

Aichi Cancer Center Hospital.

Funding

Has not received any funding.

Disclosure

T. Masuishi: Financial Interests, Personal, Invited Speaker: Takeda, Chugai, Merck Bio Pharma, Taiho, Bayer, Eli Lilly, Yakult Honsha, Sanofi, Daiichi Sankyo, Ono, Bristol Myers Squibb, MSD, Nippon Kayaku; Financial Interests, Institutional, Funding: Daiichi Sankyo, Ono, Novartis, Amgen, Syneos Healthe Clinical, Boehringer-Ingelheim, Pfizer, Cimic Shift Zero, Eli Lilly, MSD. S. Mitani: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co., Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Chugai Pharmaceutical Co.; Financial Interests, Personal, Research Grant: Caris Life Science. M. Asayama: Financial Interests, Personal, Speaker, Consultant, Advisor: Chugai, Takeda, Merck Biopharma, Ono, Taiho; Financial Interests, Personal, Funding: Isofol Medical AB, SYSMEX, Seagen. A. Makiyama: Financial Interests, Personal, Invited Speaker: Eli Lilly, Taiho, Ono, Daiichi-Sankyo, Bristol Myers Squibb. H. Takeda: Financial Interests, Personal, Invited Speaker: Taiho, MSD, BMS, Chugai. M. Tajika: Financial Interests, Personal, Invited Speaker: EA Pharma Co.,Ltd., Otsuka Pharmaceutical Factory. M. Ando: Financial Interests, Personal, Invited Speaker: Eisai Co., Ltd., Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd. K. Muro: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Ono, Chugai, Astellas; Financial Interests, Personal, Invited Speaker: Eli Lilly, Ono, Daiichi Sankyo, Taiho, Bristol-Myers Squibb, Takeda, MSD; Financial Interests, Institutional, Research Grant, Including local PI as role: Astellas, Amgen, Sanofi, Daiichi Sankyo, Taiho, MSD, Pfizer, Merck Biopharma, Eisai, Ono, Novartis, PRA Health Sciences Inc., Parexel International Inc.; Financial Interests, Personal, Steering Committee Member: Chugai, AstraZeneca, Amgen; Non-Financial Interests, Principal Investigator: Takeda. K. Murotani: Financial Interests, Personal, Other, Lecture fee: Chugai Pharmaceutical; Financial Interests, Personal, Other, Lecturer fee: AstraZeneca, Taiho pharmaceutical, MSD, Nihon Shinyaku; Financial Interests, Personal, Advisory Board: Pfizer. H. Taniguchi: Financial Interests, Personal, Invited Speaker: Ono, Takeda, Eli Lilly, Chugai, Taiho, Merck Biopharma, Amgen, MSD K.K, Bristol-Myers Squibb Japan, Roche Diagnostics; Financial Interests, Institutional, Coordinating PI: Takeda, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Ono. All other authors have declared no conflicts of interest.