Alvarez 2024 - JANUS Trial Protocol

Full citation: Alvarez JA, Shi Q, Dasari A, Garcia-Aguilar J, Sanoff H, George T, Hong T, Yothers G, Philip P, Nelson G, et al. 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. BMC Cancer. 2024;24:901. ClinicalTrials.gov NCT05610163.

Raw PDF: raw/Alvarez 2024 - JANUS Trial Protocol.pdf

Study type / design

This is a study protocol paper, not a results paper — no efficacy outcomes are reported; the trial had accrued 330 of a planned 760 patients as of May 2024. NCI-sponsored, national (NCTN), randomized, seamless phase II/III trial, run through the Alliance for Clinical Trials in Oncology with NRG Oncology, SWOG, and ECOG collaboration. Patients with locally advanced rectal cancer (stage II/III, T4N0 or any T with node-positive disease, or T3N0 requiring APR or a low coloanal anastomosis; MMR-proficient) are randomized 1:1 to, after identical induction long-course chemoradiation (LCRT: 45 Gy + 9 Gy boost with concurrent capecitabine):

• Experimental (Arm A): 8 cycles of consolidation mFOLFIRINOX (triplet chemotherapy).
• Control (Arm B): 8 cycles of consolidation mFOLFOX6 or CAPOX (doublet chemotherapy) — current standard.

Response assessed 8-12 weeks post-TNT via the MSK Regression Schema (endoscopy + DRE + MRI). Complete responders may pursue watch-and-wait (W&W); incomplete responders proceed to TME. Primary endpoints: clinical complete response (cCR) rate for the phase II portion (power to detect a 17% absolute increase over a 50% assumed control-arm rate); disease-free survival (DFS) for the phase III portion (power to detect HR 0.70).

Rationale (per the protocol’s own framing)

Builds directly on the OPRA trial’s finding that a consolidation-chemotherapy approach (LCRT → chemo, rather than chemo → LCRT) yields higher organ-preservation rates and lower regrowth rates at 5 years. JANUS asks whether triplet (FOLFIRINOX) consolidation chemotherapy — already the regimen tested as induction therapy in Conroy 2024 - PRODIGE 23 Long-Term Results and in Brouquet 2020 - GRECCAR16 Trial Protocol — improves cCR and DFS further when used specifically as consolidation (post-LCRT) rather than induction (pre-LCRT) chemotherapy. The protocol’s background section cites a related trial, the German CAO/ARO/AIO-12 study, reporting improved complete-response rates with a consolidation approach (25% vs 17% pCR) — CAO/ARO/AIO-12 itself is not independently ingested in this wiki, only referenced secondhand via this protocol’s background.

Status as of this ingest

No results available — protocol/design paper only (2024), trial still accruing (330/760 as of May 2024). This is a different trial from Brouquet 2020 - GRECCAR16 Trial Protocol’s FOLFIRINOX regimen despite the shared drug combination — GRECCAR16 tests FOLFIRINOX replacing radiotherapy entirely, while JANUS tests FOLFIRINOX after radiotherapy as consolidation, alongside doublet chemotherapy in both cases.

Limitations

• Protocol paper only — no outcomes to assess yet.
• MMRd/MSI-high tumors are explicitly excluded (this trial only enrolls MMR-proficient disease) — consistent with this wiki’s existing note that MMRd/MSI rectal cancer follows a different (immunotherapy-based) pathway, see Total Neoadjuvant Therapy (TNT)‘s indications table.
• The phase II cCR endpoint uses a fairly aggressive assumed effect size (17% absolute improvement) — worth reassessing once real interim/final data are available.

Relevance

Updates this wiki’s prior secondhand “JANUS trial (FOLFOXIRI vs. FOLFOX/CAPOX within TNT) … ongoing per the Boublikova review” note on Total Neoadjuvant Therapy (TNT) with the actual protocol — clarifying that “JANUS” specifically tests triplet-vs-doublet consolidation chemotherapy for cCR/organ preservation, not a head-to-head of TNT sequencing strategies generally. Results remain a genuine open item.