Abstract A94: Dose determination of LY2603618, a Chk1 inhibitor, administered in combination with gemcitabine in patients with advanced cancer.
Authors: Calvo Emiliano , Richards Donald , Braiteh Fadi , Von Hoff Daniel , McWilliams Robert , Becerra Carlos , Galsky Matthew , Jameson Gayle , Hurt Karla C. , Hynes Scott , Garcia-Ribas Ignacio , Bence Aimee , Westin Eric 
Published: June 2012

Background: LY2603618 is a selective inhibitor of Chk1, a protein kinase that plays a key role in the DNA damage checkpoint. Inhibition of Chk1 is predicted to enhance the effects of antimetabolites, such as gemcitabine.

Methods: This study is a Phase 1–2 study in patients with solid tumors (Phase 1) and advanced pancreatic adenocarcinoma (Phase 2). In Phase 1, gemcitabine (1000 mg/m2) was administered on Days 1, 8, and 15 of a 28-day cycle. LY2603618 was administered on Days 2, 9, and 16. Patients were assessed for safety, tolerability, and dose-limiting toxicity (DLT). A recommended Phase 2 dose (RP2D) was determined based on safety, dose intensity, and pharmacokinetics (PK).

Results: A total of 50 patients were enrolled. Patients were treated at 70 (n =3), 105 (n=3), 150 (n=7), 200 (n=11), 250 (n=6) mg/m2and at 2 additional flat-fixed dose cohorts of 200 (n=10) and 230 (n=10) mg. The most frequent AEs reported included fatigue, thrombocytopenia, anemia, nausea, neutropenia, and constipation, which are consistent with those reported with gemcitabine monotherapy. During escalation, DLTs included neutropenia, infusion-related reaction and thrombocytopenia, with thrombocytopenia being dose limiting. The maximum tolerated dose (MTD) was determined to be 200 mg/m2. The systemic exposure of LY2603618 increased in a dose-dependent manner and the LY2603618 systemic clearance was dose-independent across all doses on average. The mean LY2603618 half-life varied across doses but was consistent with a half-life (i.e., &gt;10 hr and &lt;24 hr) suitable for maintaining required human exposures while minimizing intra and intercycle accumulation. The administration of gemcitabine approximately 24 hours before LY2603618 administration did not alter LY2603618 PK. Following dose escalation, identification of the MTD and results from a population PK analysis, 2 additional flat-fixed dose cohorts of 200 and 230 mg (n=10 in each cohort) were added in an effort to minimize dose reduction/omissions of gemcitabine and reduce PK variability. At a dose of 230 mg, the plasma exposures that correlate with the maximal pharmacodynamic (PD) effect in nonclinical models (i.e., AUC(0−∞) &gt;21,000 ng hr/mL and Cmax &gt; 2000 ng/mL) were achieved by all but one patient. Based on safety/tolerability, the ability to maintain dose intensity, and PK, a RP2D of 230 mg was selected. A total of 17 of 30 patients received more than 2 cycles of therapy.

Conclusions: LY2603618 administered in combination with gemcitabine demonstrated an acceptable safety profile; the MTD for this regimen was defined at 200 mg/m2 in the originally designed study. However at a fixed dose of 230 mg, LY2603618 in combination with gemcitabine had an acceptable safety profile and the observed exposures exceed those required for biological effect in nonclinical models. This dose is being evaluated in the Phase 2 component of the study.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A94.