Phase I trial of a first-in-class ATR inhibitor VX-970 as monotherapy (mono) or in combination (combo) with carboplatin (CP) incorporating pharmacodynamics (PD) studies.

Abstract

2504 Background: ATR is a regulator of cellular responses to replication stress, where it signals DNA damage repair by homologous recombination. Many cells depend on ATR to survive DNA damage. VX-970 is a potent, selective ATR inhibitor with marked preclinical antitumor activity in combo with chemotherapy. Methods: Patients (pts) with advanced cancers were enrolled in 2 parts. Part A: N=1 pt cohorts received VX-970 QW; 3 + 3 cohorts were commenced if ³ G2 drug-related toxicities occurred. Part B: 3 + 3 pt cohorts received CP on d1 + VX-970 on d2 and 9 in 21-day cycles. Timed pre- and post-VX-970 tumor biopsies were assessed for pS345 CHK1 levels by IHC in part B. Hematologic toxicities were modeled for pts in part B. Results: 26 pts were treated; M/F 10/16, ECOG PS 0/1: 9/17. Median age: 66 yrs (range 49-76 years). VX-970 was generally well tolerated as mono or CP combo with mainly G1-2 toxicities. CP dose delays and reductions occurred in 3/3 pts (B1); 2/2 pts (B2); 0/3 pts (B3); 1/6 pts (B4) due to neutropenia and/or thrombocytopenia. Clinical data were consistent with toxicity modeling that predicted probabilities of ≤5% G4 neutropenia and <1% thrombocytopenia at B4. Recommended phase 2 doses (RP2D) were DL A3 (mono) and B4 (CP combo). VX-970 PK was dose proportional with no CP interaction. VX-970 PK exposures at combo RP2D led to tumor regression in mouse models. Tumor biopsy studies showed decreased pCHK1 by 73-90% after VX-970. In part A, a pt with ATM loss colorectal cancer had RECIST complete response (19 mths+) and 4 pts had RECIST stable disease (SD). In part B: a pt with germline BRCA1 mutant and platinum-refractory, PARP inhibitor-resistant ovarian cancer with a somatic Y220C TP53 mutation had RECIST partial response for 6 mths and 8 pts had RECIST SD. Conclusions: VX-970 is generally well tolerated as mono and in CP combo with early evidence of PD and antitumor activity. VX-970 is now being tested in phase 2 combo trials and as mono in pts with DNA repair defects. Clinical trial information: 2013. Clinical trial information: #8209;005100. Clinical trial information: #8209;34.Dose Level (DL) VX-970 dose (mg/m2) CP dose (AUC) # pts Dose limiting toxicities A1 60 - 1 - A2 120 - 2 - A3 240 - 1 - A4 480 - 7 - B1 240 5 3 Febrile neutropenia B2 120 5 3 Hypersensitivity B3 120 4 3 - B4 90 5 6 Febrile neutropenia