Phase 1b/2 umbrella study of investigational immune and targeted combination therapies for patients with advanced clear cell renal cell carcinoma (ccRCC).
Bibliographic record
Abstract
TPS404 Background: New treatments for first and subsequent lines of therapy for ccRCC are needed. An adaptive, open-label, rolling-arm, multicenter, phase 1b/2 umbrella platform trial in advanced ccRCC is being conducted to evaluate the safety and efficacy of multiple combinations of investigational agents targeting CTLA-4 (quavonlimab [MK-1308]), hypoxia-inducible factor 2α (belzutifan [MK-6482]), lymphocyte-activation gene 3 (favezelimab [MK-4280]), immunoglobulinlike transcript 4 (MK-4830), PD-1 (pembrolizumab), and vascular endothelial growth factor–tyrosine kinase inhibitor (VEGF-TKI; lenvatinib) for advanced ccRCC. Substudy 03A (NCT04626479) will evaluate first-line therapy combinations, and substudy 03B (NCT04626518) will evaluate therapies in patients experiencing progression on PD-1/PD-L1 inhibitors and VEGF-TKIs in combination or in sequence. Methods: Adults with histologically confirmed ccRCC and KPS score ≥70% are eligible. Patients in substudy 03A cannot have previously received systemic therapy for advanced ccRCC. Patients in substudy 03B must have progression (per RECIST v1.1) on or after treatment with a PD-1/PD-L1 inhibitor and a VEGF-TKI for advanced ccRCC. Both substudies will have a safety lead-in phase for experimental combinations with investigational agents to establish a recommended phase 2 dose, followed by an efficacy phase. Experimental arms will enroll approximately 80 (03A) and 50 (03B) patients. Patients will be randomly assigned 2:1 (03A) or 1:1 (03B) to an experimental arm or a reference arm (pembrolizumab 400 mg IV every 6 weeks [Q6W] + lenvatinib 20 mg orally once daily [QD]). Experimental arms in 03A are MK-1308A (coformulation of quavonlimab 25 mg and pembrolizumab 400 mg IV Q6W) + lenvatinib (20 mg orally QD), MK-4280A (coformulation of favezelimab 800 mg and pembrolizumab 200 mg IV every 3 weeks [Q3W]) + lenvatinib (20 mg orally QD), and belzutifan (120 mg orally QD) + lenvatinib (20 mg orally QD) + pembrolizumab (400 mg Q6W IV). Experimental arms in 03B are MK-1308A, MK-4280A, pembrolizumab (400 mg Q6W IV) + belzutifan (120 mg orally QD), lenvatinib (20 mg orally QD) + belzutifan (120 mg orally QD), and pembrolizumab (200 mg IV Q3W) + MK-4830 (800 mg IV Q3W). Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Primary end points for the safety lead-in phase are safety and tolerability; coprimary end points for the efficacy phase are safety and objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points during the efficacy phase are duration of response, progression-free survival (RECIST v1.1 by BICR), clinical benefit rate, and overall survival. Both substudies are recruiting patients in Australia, Canada, France, Israel, South Korea, Spain, New Zealand, the United Kingdom, and the United States. Clinical trial information: NCT04626479; NCT04626518.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.010 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".