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Yap, Timothy A; Fontana, Elisa; Lee, Elizabeth K; Spigel, David R; Højgaard, Martin; Lheureux, Stephanie; Mettu, Niharika B; Carneiro, Benedito A; Carter, Louise; Plummer, Ruth; Cote, Gregory M; Meric-Bernstam, Funda; O'Connell, Joseph; Schonhoft, Joseph D; Wainszelbaum, Marisa; Fretland, Adrian J; Manley, Peter; Xu, Yi; Ulanet, Danielle; Rimkunas, Victoria; Zinda, Mike; Koehler, Maria; Silverman, Ian M; Reis-Filho, Jorge S; Rosen, Ezra
Nature medicine, 06/2023, Letnik: 29, Številka: 6Journal Article
Predictive biomarkers of response are essential to effectively guide targeted cancer treatment. Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) have been shown to be synthetic lethal with loss of function (LOF) of ataxia telangiectasia-mutated (ATM) kinase, and preclinical studies have identified ATRi-sensitizing alterations in other DNA damage response (DDR) genes. Here we report the results from module 1 of an ongoing phase 1 trial of the ATRi camonsertib (RP-3500) in 120 patients with advanced solid tumors harboring LOF alterations in DDR genes, predicted by chemogenomic CRISPR screens to sensitize tumors to ATRi. Primary objectives were to determine safety and propose a recommended phase 2 dose (RP2D). Secondary objectives were to assess preliminary anti-tumor activity, to characterize camonsertib pharmacokinetics and relationship with pharmacodynamic biomarkers and to evaluate methods for detecting ATRi-sensitizing biomarkers. Camonsertib was well tolerated; anemia was the most common drug-related toxicity (32% grade 3). Preliminary RP2D was 160 mg weekly on days 1-3. Overall clinical response, clinical benefit and molecular response rates across tumor and molecular subtypes in patients who received biologically effective doses of camonsertib (>100 mg d ) were 13% (13/99), 43% (43/99) and 43% (27/63), respectively. Clinical benefit was highest in ovarian cancer, in tumors with biallelic LOF alterations and in patients with molecular responses. ClinicalTrials.gov registration: NCT04497116 .
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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