Abstract CT063: Phase Ib trial of ATR inhibitor (ATRi) tuvusertib + ATM inhibitor (ATMi) lartesertib (M4076) in patients (pts) with advanced solid tumors
Bibliographic record
Abstract
Abstract Ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) protein kinases are critical in the DNA damage response. ATR and ATM genes have a synthetic lethal relationship in cancer and ATMi synergistically potentiates the efficacy of ATRi in vitro and in vivo. Here, we studied the combination potential of the highly potent, oral agents tuvusertib and lartesertib. The open-label, multicenter study DDRiver Solid Tumors 320 (NCT05396833) investigated safety, tolerability, PK and PD of tuvusertib + lartesertib in pts with advanced solid tumors refractory to standard therapy. PK samples were analyzed by a validated LC/MS method, and PD via γ-H2AX in ex vivo-stimulated CD45+ fraction by flow cytometry. As of 03.01.2024, 42 pts received ascending doses of tuvusertib + lartesertib. 5 pts experienced DLTs (Table 1). Frequent TEAEs (≥25 % of pts, any grade) were: anemia 62 %, nausea 45 %, fatigue and vomiting (43 % each). Grade ≥3 TEAEs occurred in 21 (50 %) pts; those in ≥3 pts were: anemia (n=9), decreased platelets (n=5), fatigue and decreased neutrophils (n=3 each). Preliminary steady-state PK showed rapid absorption: median Tmax of ~2-3 h (tuvusertib) and ~1-3.5 h (lartesertib); mean elimination half-life range of ~3.2-4.5 h (tuvusertib) and ~5.5-8.7 h (lartesertib); minimal accumulation. Exposure of the combination was consistent with respective monotherapies, indicating no clinically meaningful mutual drug-drug interactions. Preliminary PD showed complete or almost complete target inhibition 1-6 h after tuvusertib ≥130 mg and rebound above baseline after 24 h and target inhibition ~50 % across all time points at lartesertib ≥100 mg. 6 pts (2 ovarian, 2 uterine, 1 prostate cancer and 1 melanoma) had stable disease >16 weeks; 3 remain on treatment. Multiple tolerated combination doses were identified. Tuvusertib 180 mg QD + lartesertib 150 mg QD 2 w on/2 w off was selected for investigation in expansion cohorts in pts with prostate and endometrial cancer. Table 1. DLTs by ascending dose (DLT-evaluable patients) Dose (tuvusertib + lartesertib), mg N DLT DLT AE terms by cohort 2 w on/2 w off regimen 90 + 50 QD 3 No NA 130 + 50 QD 4 No NA 130 + 100 QD 3 No NA 180 + 100 QD 3 No NA 180 + 200 QD 4 Yes, in 2 pts One pt experienced febrile neutropenia Grade 3, neutrophil count decreased Grade 4, anemia Grade 3, platelet count decreased Grade 4, and candida infection Grade 2. The second pt had neutrophil count decreased Grade 4 180 + 150 QD 9 No NA 2 w on/1 w off regimen 180 + 150 QD 4 Yes, in 2 pts Both pts had platelet count decreased Grade 2 and Grade 3 180 + 100 QD 7 Yes, in 1 pt Neutrophil count decreased Grade 4 AE, adverse event; DLT, dose-limiting toxicities; N, DLT-evaluable patients; NA, not applicable; PD, pharmacodynamics; PCa, prostate cancer; PK, pharmacokinetics; pts, patients; QD, once daily, TEAE, treatment-emergent adverse event; w, week Citation Format: Lillian L. Siu, Elena Garralda Cabanas, Valentina Boni, Anthony W. Tolcher, Enrique Sanz Garcia, Jesús Fuentes-Antrás, Omar Saavedra, Deepthi S. Vagge, Giuseppe Locatelli, Burak Kürsad Günhan, Gregory Pennock, Jatinder Kaur Mukker, Ioannis Gounaris, Timothy A. Yap. Phase Ib trial of ATR inhibitor (ATRi) tuvusertib + ATM inhibitor (ATMi) lartesertib (M4076) in patients (pts) with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT063.
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.003 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 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".