title: A phase I safety and pharmacokinetic study of ABT-263 in combination with carboplatin/paclitaxel in the treatment of patients with solid tumors.
abstract: Bcl-2 family proteins are the key regulators of the intrinsic apoptotic pathway, controlling the point-of no-return and setting the threshold to engage the death machinery in response to chemical damage. Bcl-2 proteins have emerged as attractive targets for anti-cancer drug development. Navitoclax is a selective, potent, orally bioavailable, small molecule Bcl-2 inhibitor. Primary endpoints assessed the safety and pharmacokinetic (PK) interactions between navitoclax in combination with carboplatin/paclitaxel or paclitaxel alone in patients with solid tumors The study comprised two arms, one a combination of navitoclax with paclitaxel and carboplatin, the second with navitoclax and paclitaxel alone. Nineteen patients were enrolled in this study. The most frequently reported treatment-emergent AEs were alopecia (57.9 %), anemia (52.6 %), nausea (52.6 %), constipation (42.1 %), diarrhea (42.1 %), fatigue (42.1 %), neutropenia (36.8 %), thrombocytopenia (36.8 %), vomiting (31.6 %), decreased appetite (31.6 %), dehydration (26.3 %), and hypomagnesaemia (26.3 %). In the light of significant hematological and non-hematological toxicity the study was ended before de-escalation of navitoclax. Only one partial response was obtained at any dose tested, thus lowering doses could not have increased efficacy. It is the combination of toxicity with modest efficacy that led to discontinuation. No apparent PK interaction was observed between navitoclax and carboplatin or paclitaxel and the combination of navitoclax and paclitaxel had modest anti-tumor activity.
authors.affiliation: Duke University Medical Center, Rm. 047 Baker House, Trent Drive, DUMC 3624, Durham, NC, 27710, USA, vlaho001@mc.duke.edu.
authors.forename: Gordana
authors.initials: G
authors.lastname: Vlahovic
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Karantza
authors.forename: Ding
authors.initials: D
authors.lastname: Wang
authors.forename: David
authors.initials: D
authors.lastname: Cosgrove
authors.forename: Nikita
authors.initials: N
authors.lastname: Rudersdorf
authors.forename: Jianning
authors.initials: J
authors.lastname: Yang
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
authors.forename: Todd
authors.initials: T
authors.lastname: Busman
authors.forename: Mack
authors.initials: M
authors.lastname: Mabry
mesh_terms: D000328:Adult; D000368:Aged; D000814:Aniline Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000814:Aniline Compounds; D013449:Sulfonamides; D016190:Carboplatin; D017239:Paclitaxel; C528561:navitoclax