title: Phase I study of XL281 (BMS-908662), a potent oral RAF kinase inhibitor, in patients with advanced solid tumors.
abstract: Background XL281 is a potent and selective inhibitor of wild-type and mutant RAF kinases with anti-tumor activity in multiple xenograft models. Mutations in KRAS or BRAF can activate the RAF/MEK/ERK pathway in human tumors and may confer sensitivity to RAF kinase inhibitors. Methods We performed a phase I study of XL281 in patients with advanced solid tumors. Patients were enrolled in successive cohorts of XL281 orally once daily in 28-day cycles. Twice daily dosing, different formulations, and the effect of food and famotidine were also studied. At the MTD expanded cohorts with defined mutations were treated. Results In total, 160 patients were treated. The MTD on the QD schedule was 150 mg. The most common toxicities were diarrhea, nausea, and fatigue. Plasma Cmax and AUC increased with dose. Famotidine resulted in lower AUC while food had no effect. Two patients had partial responses by RECIST: One with papillary thyroid cancer with NRAS mutation and one with uveal melanoma. Another nine patients had tumor decrease of >10% but did not meet RECIST criteria for PR. Matched tumors pairs from 33 patients showed evidence of RAF inhibition with significant decreases in pERK, pMEK and pAKT. Conclusions XL281 was generally well tolerated and the MTD was established at 150 mg/day. Partial responses and clinical benefit were observed in several patients. Tumor biopsies demonstrated effective target inhibition.
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA, dicksonm@mskcc.org.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dickson
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.forename: Gerald
authors.initials: G
authors.lastname: Edelman
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.forename: Ragini R
authors.initials: RR
authors.lastname: Kudchadkar
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Johnston
authors.forename: Douglas O
authors.initials: DO
authors.lastname: Clary
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004336:Drug Antagonism; D015738:Famotidine / Q000494:pharmacology; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D048490:raf Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; C000593770:BMS 908662; D001562:Benzimidazoles; D002219:Carbamates; D015738:Famotidine; D048490:raf Kinases