ALLIANCE A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal cancer

Background Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after neoadjuvant therapy may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes.

In this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N+) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Patients will be randomized to receive neoadjuvant long course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3-4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8-12 (+/- 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 296 evaluable patients (148 per arm) will provide statistical power of 90.5% to detect an 17% increase in cCR rate, at a one-sided alpha=0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse effects. Biospecimens including archival tumor tissue, plasma and buffy coat in EDTA tubes, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and has a current accrual of 312. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org.

Building off of data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed the current trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer. Trial Registration Clinicaltrials.gov ID: NCT05610163; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG) Competing Interest Statement JGA claims ownership/equity interests for Intuitive Surgical Inc. JGA serves as a consulting/advisory role for Medtronic, Intuitive Surgical, and Johnson & Johnson EO - Research Funding to institution: Genentech/Roche, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute, NIH/NCI, Digestive Care, Break Through Cancer Consulting/DSMB: Arcus, Alligator, Agenus, BioNTech, Ipsen, Merck, Moma Therapeutics, Novartis, Syros, Leap Therapeutics, Astellas, BMS, Fibrogen, Revolution Medicine, Merus Agios (spouse), Genentech-Roche (spouse), Eisai (spouse) Servier (Spouse) PBR is an EMD Serono consultant and reports support for travel from Elekta and Philips Healthcare and prior research funding from EMD Serono. PBR is supported by an NIH/NCI Cancer Center Support Grant (P30 CA008748) and an NIH/NCI early career development award (K08 CA255574) JJS received travel support for fellow education from Intuitive Surgical (2015). JJS served as a clinical advisor for Guardant Health (2019) JJS served as a clinical advisor for Foundation Medicine (2022) JJS served as a consultant and speaker for Johnson and Johnson (2022) JJS serves as a clinical advisor and consultant for GSK (2023) QS reports consulting/advisory role from Yiviva Inc, Boehringer Ingelheim Pharmaceuticals, Inc, Regeneron Pharmaceuticals, Inc., Hoosier Cancer Research Network, Kronos Bio, and Mirati Therapeutics Inc; Honorarium/speaker role from Chugai Pharmaceutical Co., Ltd (to myself), research funds from Celgene/BMS, Roche/Genentech, Janssen, Novartis (to institution) TJG reports consulting/advisory role from Pfizer/Array, Tempus Labs, and Billion To One and is supported by an NIH/NCI Cancer Center Support Grant (P30 CA247796) and an NIH/NCI NCI-sponsored Clinical Trial Research Specialist (R50 CA281930). HS research funding: AstraZeneca, Roche, Amgen, Bristol-Myers Squibb, Pfizer, BioMed Valley Discoveries, Rgenix, Exelixis Clinical Trial NCT05610163 Clinical Protocols https://clinicaltrials.gov/study/NCT05610163 Funding Statement Support includes U10CA180868 (NRG) and U10CA180888 (SWOG), NCI sponsored Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: As of March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional Review Board (NCI CIRB) in order to participate in CTEP and Division of Cancer Prevention studies open to the NCTN and NCI Community Oncology Research Program (NCORP) Research Bases. In addition, U.S.-based sites must accept the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB review will continue to be accepted for studies that are not reviewed by the CIRB, or if the study was previously open at the site under the local IRB. International sites should continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office following country-specific regulations. Refer to the protocol in supplementary material for additional information. The patient must be aware of the neoplastic nature of his/her disease and willingly consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current human protection committee approval of this protocol and a consent form is required prior to patient consent and registration. Patients with an impaired decision-making capacity may be enrolled in this study, where institutional policy and IRB of record allow. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Not applicable, All data produced in the present study are available upon reasonable request to the authors LIST OF ABBREVIATIONS - Abbreviations - Definition - cCR - Clinical complete response - CRT - Chemoradiation - ctDNA - Circulating tumor DNA - CTEP - Cancer Therapy Evaluation Program - DFS - Disease-free survival - DRE - Digital rectal examination - LARC - Locally advanced rectal cancer - EOT - Early off treatment - LCRT - Long course chemoradiation - NCI - National Cancer Institute - nCR - Near complete response - NCTN - National Clinical Trials Network - OPRA - Organ Preservation in Patients with Rectal Adenocarcinoma - OS - Overall survival - PFS - Progression-free survival - pCR - Pathologic complete response - TME - Total mesorectal excision - TNT - Total neoadjuvant therapy - WW - Watch and wait approach/Active surveillance