Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies
- 1 June 2009
- journal article
- clinical trial
- Published by American Society of Clinical Oncology (ASCO) in Journal of Clinical Oncology
- Vol. 27 (16), 2705-2711
- https://doi.org/10.1200/jco.2008.19.7681
Abstract
Purpose: We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies. Patients and Methods: ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size. Results: Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels. Conclusion: Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology.Keywords
This publication has 24 references indexed in Scilit:
- Liquid Chromatographic Determination of NSC 737664 (ABT-888: An Inhibitor of Poly(ADP-ribose) Polymerase (PARP)) in Plasma and Urine in a Phase 0 Clinical TrialJournal of Liquid Chromatography & Related Technologies, 2008
- Preclinical Modeling of a Phase 0 Clinical Trial: Qualification of a Pharmacodynamic Assay of Poly (ADP-Ribose) Polymerase in Tumor Biopsies of Mouse XenograftsClinical Cancer Research, 2008
- Patient Perspectives on Phase 0 Clinical TrialsClinical Cancer Research, 2008
- Designing Phase 0 Cancer Clinical TrialsClinical Cancer Research, 2008
- Phase 0 Clinical Trials in Cancer Drug Development: From FDA Guidance to Clinical PracticeMolecular Interventions, 2007
- Compressing drug development timelines in oncology using phase '0' trialsNature Reviews Cancer, 2007
- Are We Taking Without Giving in Return? The Ethics of Research-Related Biopsies and the Benefits of Clinical Trial ParticipationJournal of Clinical Oncology, 2006
- Can the pharmaceutical industry reduce attrition rates?Nature Reviews Drug Discovery, 2004
- The PARP superfamilyBioEssays, 2004
- NEW TARGETS FOR CANCER CHEMOTHERAPY – POLY(ADPRIBOSYLATION) PROCESSING AND POLYISOPRENE METABOLISMBiological Reviews, 1990