Abstract CT139: Phase I study of GDC-0425, a checkpoint kinase 1 inhibitor, in combination with gemcitabine in patients with refractory solid tumors
Authors: Infante Jeffrey R. , Hollebecque Antoine , Postel-Vinay Sophie , Bauer Todd , Blackwood Beth , Evangelista Marie , Mahrus Sami , Peale Frank , Lu Xuyang , Sahasranaman Srikumar , Zhu Rui , Chen Yuan , Ding Xiao , Murray Elaine , Schutzman Jennifer , Lauchle Jennifer , Soria Jean-Charles , LoRusso Patricia 
Published: August 2015

Background: Checkpoint kinase 1 (Chk1) acts at S and G2/M checkpoints to allow time for high-fidelity DNA replication and repair before cell cycle progression. Chk1 inhibition converts a transient genotoxic insult from chemotherapy into a cytotoxic event by overriding cell cycle arrest, allowing cells mitosis with DNA damage. GDC-0425 is an oral, selective Chk1 inhibitor. GDC-0425 enhances gemcitabine (gem) efficacy in tumor xenograft models. Greater chemopotentiation is observed in cancer cell lines lacking p53 activity.

Methods: A phase I dose-escalation trial (3+3+3 design) included patients (pts) with refractory solid tumors and ECOG performance status (PS) ≤ 1. Pts received a single dose of GDC-0425 on day -7 for PK evaluation followed by 21-day cycles of gem on Days 1 and 8 and GDC-0425 on Days 2 and 9 at gem (mg/m2) + GDC-0425 (mg) dose levels of 750 + 60, 1000 + 60, and 1000 + 80. p53 was evaluated in archival tumor tissue by gene sequencing, immunohistochemistry, and gene expression signature. Safety, pharmacokinetics (PK), pharmacodynamics, and tumor response were investigated.

Results: Of 40 pts treated, 55% were female, median age was 56 years (range 33-82), and 68% had ECOG PS 0. Most common tumor types were breast (n = 10), non-small cell lung (n = 5), and cancer of unknown primary (CUP, n = 4). Maximum concentrations of GDC-0425 were achieved within 4 hours of dosing and its half-life was approximately 16 hours. Target exposures associated with checkpoint abrogation and anti-tumor activity in preclinical models were exceeded at 60 mg. No PK interaction was observed with GDC-0425 and gem. Dose escalation was halted at GDC-0425 80 mg with gem 1000 mg/m2 as 3 of 6 pts experienced Grade 4 thrombocytopenia as a dose-limiting toxicity (DLT); 1 pt also had Grade 3 neutropenia that delayed Cycle 2 (DLT). Blood counts recovered with treatment interruption and supportive care. The maximum tolerated dose of GDC-0425 was 60 mg with gem 1000 mg/m2. The most frequent adverse events (AEs) (all grades) related to GDC-0425 and/or gem were nausea (48%); anemia, neutropenia, vomiting (45% each); fatigue (43%); pyrexia (40%); and thrombocytopenia (35%). Serious AEs related to GDC-0425 and/or gem occurred in 8 pts: neutropenia and thrombocytopenia (n = 2 each); leukopenia, ALT/AST/GGT increased, pyrexia, rash, dyspnea, gastric ulcer, and gastroenteritis (n = 1 each). Median number of administered cycles was 3.5 (range 1-14). There were 3 partial responses in pts with triple-negative breast cancer (TNBC, TP53 mutated), melanoma, and CUP (n = 1 each).

Conclusions: It is safe and feasible to administer GDC-0425 with a standard dose of gem. At the doses assessed, bone marrow suppression is common but manageable and exposures exceed those predicted by preclinical models to inhibit Chk1. Clinical activity was observed, including 1 patient with TP53 mutated TNBC.

Citation Format: Jeffrey R. Infante, Antoine Hollebecque, Sophie Postel-Vinay, Todd Bauer, Beth Blackwood, Marie Evangelista, Sami Mahrus, Frank Peale, Xuyang Lu, Srikumar Sahasranaman, Rui Zhu, Yuan Chen, Xiao Ding, Elaine Murray, Jennifer Schutzman, Jennifer Lauchle, Jean-Charles Soria, Patricia LoRusso. Phase I study of GDC-0425, a checkpoint kinase 1 inhibitor, in combination with gemcitabine in patients with refractory solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT139. doi:10.1158/1538-7445.AM2015-CT139