Abstract B185: Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the poly(ADP-ribose) polymerase (PARP) inhibitor E7016 in combination with temozolomide (TMZ) in patients with advanced solid tumors.
Authors: Mita Alain C. , Mita Monica M. , Sarantopoulos John , Martin Julie C. , Kueber Janet D. , McGonigle Sharon , Matijevic Mark , Mistry Bipin , Ferrada Javier L. , Sachdev Pallavi , Stephenson Joe J. 
Published: June 2012

Abstract
Background: E7016 is an orally bioavailable, nicotinamide mimetic PARP1 and PARP2 inhibitor. E7016 was shown to enhance the cytotoxic effect of the alkylating agent temozolomide (TMZ) in vivo through inhibition of PARP-mediated DNA repair. This phase I study was conducted to determine the maximum tolerated dose (MTD), dose-limiting toxities (DLTs), pharmacokinetics (PK) and pharmacodynamics (PD) of E7016 in combination with TMZ in patients (pts) with advanced solid tumors.
Methods: Eligible pts had performance status 0–2; ≥ 18 yrs of age; adequate bone marrow, hepatic and renal function. Treatment cycles were 28 days. E7016 was administered orally once on Day −7 and then orally once daily on Days 1 through 7 of each 28-day cycle. TMZ was administered orally once daily at 150 mg/m2/d on Days 1 through 5 of the same 28-day cycle. Blood samples for PK assessment of E7016 and its two metabolites M1 and M2 were collected post-dose on Day −7 and then on Days 1, 5 and 7 of Cycle 1 and for PK assessment of TMZ on Days 1 and 5 of Cycle 1. Peripheral blood mononuclear cells (PBMCs) were collected for PD assessments including, PARP inhibition and DNA damage using COMET assay.
Results: 12 pts were enrolled with carcinomas arising in kidney (1), breast (5), lung (1), ovary (2), colon (1), uterus (1), nasopharynx (1); median age was 55 years (38–64); M:33%, F:67%; median ECOG PS was 1 (0–2). Three patients were treated at the starting dose of 8 mg/kg which was found to be intolerable due to DLTs comprising tachychardia (n=2), hypotension (n=1) and presyncope (n=2). The dose was subsequently reduced to 4 mg/kg and 9 pts were treated at this dose level with no DLTs were observed. The most frequent adverse events (AEs) (all grades) at this dose level were fatigue 55.6% (Gr3: 33%), nausea 44.4% (Gr3: 0%), vomiting 44.4% (Gr3: 0%), headache 33.3% (Gr3: 11.1%), decreased appetite 22.2% (Gr3: 0%), anaemia 22.2% (Gr3: 11.1%). There was one grade 4 event at 4 mg/kg with hyponatraemia. PARP inhibition and increased DNA damage were observed in PBMC up-to 10 h after treatment with E7016 alone or in combination with TMZ. E7016 mean Cmax and AUC demonstrated a non-linear increase with dose. E7016 exhibited terminal half-life (12–16 h) with a Tmax between 3–8 h. Metabolic ratio of M1 and M2 was &lt; 12%. TMZ PK was consistent with published data and its co-administration did not influence E7016 PK.
Conclusions: The combination of E7016 with TMZ was feasible with MTD established as 4 mg/kg of E7016 oral once daily given Days 1–7 and 150 mg/m2/d TMZ given Days 1–5 (28-day cycles). PD analysis demonstrated that E7016, administered alone or in combination with TMZ, inhibited PARP activity in PBMCs with a concomitant increase in DNA damage. Further evaluation of E7016 in combination with TMZ will continue in a planned Phase 2 Study of E7016 and TMZ in advanced melanoma patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B185.