Camonsertib in DNA damage response-deficient advanced solid tumors: phase 1 trial results.
Nat Med
; 29(6): 1400-1411, 2023 Jun.
Article
de En
| MEDLINE
| ID: mdl-37277454
ABSTRACT
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-1) 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 .
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Tumeurs de l'ovaire
/
Ataxie-télangiectasie
Limites:
Female
/
Humans
Langue:
En
Journal:
Nat Med
Sujet du journal:
BIOLOGIA MOLECULAR
/
MEDICINA
Année:
2023
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique