Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies

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.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Schema for the phase 0 clinical study. A tumor biopsy was obtained during the week before drug administration and then 3 to 6 hours after drug administration. Blood was collected at 0.5, 1, 1.5, 2, 3, 4, 7, 12, and 24 hours; urine in 8-hour periods for 24 hours. (*) Tumor biopsies were planned once there was either significant inhibition of poly (ADP-ribose) (PAR) in peripheral blood mononuclear cells from at least one of three participants at a given dose level, or a plasma Cmax of 0.21 μmol/L achieved in at least one participant. Patients were required to have a minimum baseline PAR level to allow post-drug biopsy. At the 50-mg dose level, three additional patients underwent a tumor biopsy 24 ± 3 hours post drug administration to evaluate the time to recovery of poly (ADP-ribose) polymerase activity.

Fig 2.

Average plasma concentrations (μM) of ABT-888 in patients before and after administration of a single 10-, 25-, or 50-mg dose of ABT-888 over 24 hours. Plasma Cmax levels exceeding the target threshold of 0.21 μmol/L were achieved in all patient cohorts. Vertical bars represent standard deviations (SD).

Fig 3.

PAR levels in (A) peripheral blood mononuclear cells (PBMCs) and (B, C) tumor samples after administration of a single dose of ABT-888. Results are presented relative to baseline (100%). (*) Indicates the percent reduction exceeded 99% for that time point. Note: patient 5 poly (ADP-ribose) (PAR) levels were below the defined minimum at baseline; thus, no post-drug PBMC sampling was performed. PAR levels in the baseline tumor biopsy for patient 8 were below the required minimum, so this patient did not undergo a postdrug biopsy.

Fig 4.

Timeline of the phase 0 trial of ABT-888 from clinical study concept approval by the National Cancer Institute (NCI) and Abbott Laboratories to completion. Time from accrual of the first patient on the phase 0 study to the initiation of phase I combination trials of DNA-damaging agents with ABT-888 was approximately 13 months. Note: over the past decade, for all anticancer agents for which the NCI held the Investigational New Drug Application, the median time from entry of the first patient on a first-in-human clinical trial to the initiation of phase I combination trials was approximately 30 months (N = 90 investigational agents).