title: Preclinical analyses and phase I evaluation of LY2603618 administered in combination with pemetrexed and cisplatin in patients with advanced cancer.
abstract: LY2603618 is an inhibitor of checkpoint kinase 1 (CHK1), an important regulator of the DNA damage checkpoints. Preclinical experiments analyzed NCI-H2122 and NCI-H441 NSCLC cell lines and in vitro/in vivo models treated with pemetrexed and LY2603618 to provide rationale for evaluating this combination in a clinical setting. Combination treatment of LY2603618 with pemetrexed arrested DNA synthesis following initiation of S-phase in cells. Experiments with tumor-bearing mice administered the combination of LY2603618 and pemetrexed demonstrated a significant increase of growth inhibition of NCI-H2122 (H2122) and NCI-H441 (H441) xenograft tumors. These data informed the clinical assessment of LY2603618 in a seamless phase I/II study, which administered pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) and escalating doses of LY2603618: 130-275 mg. Patients were assessed for safety, toxicity, and pharmacokinetics. In phase I, 14 patients were enrolled, and the most frequently reported adverse events included fatigue, nausea, pyrexia, neutropenia, and vomiting. No DLTs were reported at the tested doses. The systemic exposure of LY2603618 increased in a dose-dependent manner. Pharmacokinetic parameters that correlate with the maximal pharmacodynamic effect in nonclinical xenograft models were achieved at doses ≥240 mg. The pharmacokinetics of LY2603618, pemetrexed, and cisplatin were not altered when used in combination. Two patients achieved a confirmed partial response (both non-small cell lung cancer), and 8 patients had stable disease. LY2603618 administered in combination with pemetrexed and cisplatin demonstrated an acceptable safety profile. The recommended phase II dose of LY2603618 was 275 mg.
authors.affiliation: START Madrid, Clara Campal Comprehensive Cancer Center, Medical Oncology Division, Madrid Norte Sanchinarro University Hospital, Madrid, Spain, 28050, Emiliano.Calvo@start.stoh.com.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Chen
authors.forename: Mark
authors.initials: M
authors.lastname: Marshall
authors.forename: Ute
authors.initials: U
authors.lastname: Ohnmacht
authors.forename: Scott M
authors.initials: SM
authors.lastname: Hynes
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kumm
authors.forename: H Bruce
authors.initials: HB
authors.lastname: Diaz
authors.forename: Darlene
authors.initials: D
authors.lastname: Barnard
authors.forename: Farhana F
authors.initials: FF
authors.lastname: Merzoug
authors.forename: Lysiane
authors.initials: L
authors.lastname: Huber
authors.forename: Lisa
authors.initials: L
authors.lastname: Kays
authors.forename: Philip
authors.initials: P
authors.lastname: Iversen
authors.forename: Antonio
authors.initials: A
authors.lastname: Calles
authors.forename: Beatrice
authors.initials: B
authors.lastname: Voss
authors.forename: Aimee Bence
authors.initials: AB
authors.lastname: Lin
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dickgreber
authors.forename: Thomas
authors.initials: T
authors.lastname: Wehler
authors.forename: Martin
authors.initials: M
authors.lastname: Sebastian
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D004247:DNA / Q000378:metabolism; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000068437:Pemetrexed; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D005971:Glutamates; C582547:LY2603618; D010671:Phenylurea Compounds; D011719:Pyrazines; D000068437:Pemetrexed; D006147:Guanine; D004247:DNA; D002945:Cisplatin