A phase I dose-escalation study of SCH 900776, a selective inhibitor of checkpoint kinase 1 (CHK1), in combination with gemcitabine (Gem) in subjects with advanced solid tumors.

3064 Background: In cells undergoing DNA synthesis,antimetabolite-induced replication arrest results in the induction of CHK1, halting the progression of cells through G1/S to allow for DNA damage repair. Inhibition of CHK1 by SCH 900776 is hypothesized to synergize with Gem to promote replication fork collapse and apoptosis, even in the setting of anti-metabolite resistance. Methods: A dose escalation study of SCH 900776 alone and in combination with fixed doses of Gem was conducted in subjects with advanced solid tumors. Subjects were assessed for safety, tolerability, dose-limiting toxicity (DLT), and maximal administered dose (MAD). A recommended phase II dose (RP2D) was determined based on the safety profile at pharmacologically active exposures. Results: Twenty-six subjects have been enrolled and treated with 10 (n=3), 20 (n=3), 40 (n=7), 80 (n=6), and 112 mg/m2 (n=7) of SCH 900776 administered alone and following Gem (800 mg/m2) on days 1 and 8 every 21 days. No SAEs or DLTs have been observed during SCH 900776 monotherapy lead-in. Three reversible DLTs have been observed for the combination; supraventricular tachycardia with pneumonia/pneumonitis at 40 mg/m2 and atrial fibrillation and grade 4 thrombocytopenia at 112 mg/m2 (1 subject each) of SCH 900776. MAD is 112 mg/m2. Clinical activity has been noted in 4 subjects: PR in melanoma, prolonged SD in spindle cell sarcoma, and SD in pancreatic cancer and cholangiocarcinoma previously treated with Gem. Mean t1/2 is 6.29-9.38 hrs. Cmax and AUC(I) increase dose-proportionally across the dose range of SCH 900776. Similar PK exposures exist between SCH 900776 monotherapy and in combination with Gem. Exposure threshold for preclinical activity (>0.5uM Cmax) and PD evidence of target engagement were achieved in the first dose cohort (10 mg/m2). Conclusions: Pharmacologically active plasma concentrations of SCH 900776 associated with the modulation of the CHK1 mechanism have been safely achieved in combination with Gem with early evidence of clinical activity, including in tumors previously progressing on Gem. Dose-related biomarker correlation and RP2D will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Research Laboratories Merck Research Laboratories Merck Research Laboratories Merck Research Laboratories