Abstract CC04-01: First-in-human biomarker-driven phase I TRESR trial of ataxia telangiectasia and Rad3-related inhibitor (ATRi) RP-3500 in patients (pts) with advanced solid tumors harboring synthetic lethal (SL) genomic alterations
Bibliographic record
Abstract
Abstract Background: RP-3500 is a novel potent and selective ATRi. A genome-wide CRISPR/Cas9-based screening platform (SNIPRx) was utilized to identify and validate synthetic lethal (SL) genomic alterations that predict sensitivity to RP-3500. This is the first presentation of data from the ongoing Phase I TRESR (Treatment Enabled by SNIPRx) study. METHODS: Pts with advanced solid tumors harboring RP-3500 sensitizing alterations were recruited. Pts received oral RP-3500 in 21-day cycles on different doses and schedules using a BOIN design. Pharmacokinetic (PK) and pharmacodynamic (PD) studies were conducted in serial tumor and/or blood samples. Biomarker tests included somatic and germline NGS, including zygosity studies, ATM and γH2AX IHC, and circulating tumor DNA (ctDNA). RESULTS: 62 pts (mean age 62 y, 42% males, 43% ≥5 prior lines of therapy) received RP-3500 (range: 1–8+ cycles). 44 pts remained on RP-3500 at the June 4, 2021, data cut-off. Tumors with ATM (n=26), BRCA1/2 (n=16), CDK12 (n=5) and other (n=20) molecular alterations were included. Germline (22 germline and 15 somatic, 25 pending) and zygosity status (10 bi-allelic and 5 mono-allelic, 46 pending) will be presented. Treatment-related adverse events (TRAEs) were mostly Grade (G)1 and transient. TRAEs occurring in >10% of pts were limited to anemia (all grades 37%, G3 26%, G4–5 0%) and fatigue (all grades 13%, G3 2%). Other ≥G3 TRAEs occurred in <5% of pts and included thrombocytopenia (4.8%) and neutropenia (1.6%). No pts discontinued RP-3500 due to TRAEs, 17/62 discontinued due to progressive disease or clinical progression and 1/62 due to withdrawal of consent. RP-3500 plasma exposures showed a dose-dependent increase with T1/2 of 6 hrs. Once-daily dosing was sufficient to meet RP-3500 exposure requirements set from pre-clinical studies. Tumor γH2AX induction (median increase =140%; p-value =0.02) was seen across doses and genotypes confirming target modulation. Declines in variant allele frequencies (>50%) in ctDNA were observed in 8/14 evaluable pts and correlated with antitumor activity (Pearson correlation coefficient =0.65; p-value =0.015). Of 31 pts evaluable for response, 14 (45%) had tumor regression on at least 1 radiologic evaluation. Objective responses were seen in 6 pts: 4 RECISTv1.1 partial responses in tumors with CDK12 and BRCA1 alterations (2 confirmed; 2 unconfirmed), and 2 PCWG3 in tumors with ATM loss. Six pts had stable disease ≥4 cycles. CONCLUSIONS: The TRESR study represents the largest biomarker-driven FIH trial for a single agent ATRi and validates prospective pt selection based on the presence of SL genomic alterations. RP-3500 shows a robust PK/PD profile, preliminary anti-tumor activity, and predictable and manageable on-target anemia (<30% G3, no G4/5) with low potential for off-target toxicity. Enrollment continues, including combinations with PARPi and other therapies. Clinical trial information: NCT04497116. Citation Format: Timothy Yap, Elizabeth Lee, David Spigel, Elisa Fontana, Martin Højgaard, Stephanie Lheureux, Niharika B. Mettu, Louise Carter, Ruth Plummer, Danielle Ulanet, Peter Manley, Ying Jiang, Ezra Rosen. First-in-human biomarker-driven phase I TRESR trial of ataxia telangiectasia and Rad3-related inhibitor (ATRi) RP-3500 in patients (pts) with advanced solid tumors harboring synthetic lethal (SL) genomic alterations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr CC04-01.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".