Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors.
OBJECTIVE
LY2603618, a selective inhibitor of checkpoint kinase 1 (CHK1) and key regulator of the DNA damage checkpoint, may enhance the effects of antimetabolites. This phase I study defined the recommended phase II dose of LY2603618 combined with gemcitabine.


METHODS
Patients with advanced/metastatic disease were administered doses of LY2603618 (70-250 mg/m2 or flat-fixed doses of 200 or 230 mg) after gemcitabine (1,000 mg/m2). Safety and pharmacokinetics (PK) were assessed.


RESULTS
Among the 50 patients enrolled, frequent adverse events possibly related to study drug treatment included fatigue (44%), decreased platelets (42%), decreased neutrophils (32%), nausea (26%), and decreased hemoglobin (20%). Systemic exposure of LY2603618 increased dose dependently, while clearance was relatively dose independent. The mean LY2603618 half-life varied; however, the durations were still suitable for maintaining human exposures while minimizing accumulation. LY2603618 PK were not altered by gemcitabine administration. Plasma exposures that correlate with the maximal pharmacodynamic effect in nonclinical models were achieved for all doses. One patient with non-small cell lung cancer carcinoma achieved a partial response; 22 patients had stable disease.


CONCLUSIONS
The maximum tolerated dose of LY2603618 combined with gemcitabine was 200 mg/m2, but a fixed LY2603618 dose of 230 mg combined with gemcitabine was selected as the recommended phase II dose.
START Madrid, Centro Integral Oncológico Clara Campal, Madrid Norte Sanchinarro University Hospital, Madrid, Spain.
Emiliano
E
Calvo
Fadi
F
Braiteh
Daniel
D
Von Hoff
Robert
R
McWilliams
Carlos
C
Becerra
Matthew D
MD
Galsky
Gayle
G
Jameson
Ji
J
Lin
Scott
S
McKane
Enaksha R
ER
Wickremsinhe
Scott M
SM
Hynes
Aimee
A
Bence Lin
Karla
K
Hurt
Donald
D
Richards
D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013921:Thrombocytopenia / Q000139:chemically induced; D055815:Young Adult; D000093542:Gemcitabine
C582547:LY2603618; D010671:Phenylurea Compounds; D011719:Pyrazines; D003841:Deoxycytidine; D000071877:Checkpoint Kinase 1; D000093542:Gemcitabine