Phase I Study of the Checkpoint Kinase 1 Inhibitor GDC-0575 in Combination with Gemcitabine in Patients with Refractory Solid Tumors

Abstract

Background

Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. We evaluated the safety, tolerability, and pharmacokinetic (PK) properties of GDC-0575 alone and in combination with gemcitabine. Anti-tumor activity and Chk1 pathway modulation were assessed.

Patients and methods

In this Phase I open-label study, in the dose escalation stage, patients were enrolled in a GDC-0575 monotherapy Arm (1) or GDC-0575 combination with gemcitabine Arm (2) to determine the maximum tolerated dose (MTD). Patients in Arm 2 received either IV gemcitabine 1000 mg/m² (Arm 2a) or 500 mg/m² (Arm 2b), followed by GDC-0575 (45 or 80 mg, respectively as RP2D). Stage II enrolled disease-specific cohorts.

Results

Of 102 patients treated, 70% were female, the median age was 59 years (range 27-85), and 47% were ECOG PS 0. The most common tumor type was breast (37%). The most frequent adverse events (all grades) related to GDC-0575 and/or gemcitabine were neutropenia (68%), anemia (48%), nausea (43%), fatigue (42%), and thrombocytopenia (35%). Maximum concentrations of GDC-0575 were achieved within 2 hours of dosing, and half-life was ∼23 hours. No PK drug-drug interaction was observed between GDC-0575 and gemcitabine. Among patients treated with GDC-0575 and gemcitabine, there were 4 confirmed partial responses, 3 occurring in patients with tumors harboring TP53 mutation. Pharmacodynamic data were consistent with GDC-0575 inhibition of gemcitabine-induced expression of pCDK1/2.

Conclusion

GDC-0575 can be safely administered as a monotherapy and in combination with gemcitabine, however, overall tolerability with gemcitabine was modest. Hematological toxicities were frequent but manageable. Preliminary anti-tumor activity was observed, but limited to a small number of patients with a variety of refractory solid tumors treated with GDC-0575 and gemcitabine.

Clinical trial number

NCT01564251

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2EL2nQt