A phase I safety and pharmacokinetic study of ABT-263 in combination with carboplatin/paclitaxel in the treatment of patients with solid tumors
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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.
KeywordsABT-263 Carboplatin Paclitaxel Phase I
Statistical analyses were performed by Min Tian and Joseph Beason and medical writing assistance was provided by Keith J. Gaddie, Ph.D.; all are AbbVie employees.
The design, study conduct, and analysis of the clinical trial were provided by AbbVie. AbbVie provided the financial support and participated in the interpretation of data, review, and approval of the manuscript.
Conflict of interest
Gordana Vlahovic is on the speaker bureau for Genentech and Pfizer. Vassiliki Karantza, Ding Wang, and David Cosgrove have no conflict of interests to declare. Nikita Rudersdorf, Jianning Yang, Hao Xiong, Todd Busman, and Mack Mabry are employees and stock owners of AbbVie.
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