Phase I Study to Evaluate the Tolerability, Pharmacokinetics (PK) and Pharmacodynamic (PD) of PM01183 (Lurbinectedin) in Combination with Olaparib ( Lynparza. ®. ) in Patients with Advanced Solid Tumors.
Sub-category: Ovarian Cancer
Category: Gynecologic Cancer
Meeting: 2017 ASCO Annual Meeting
Abstract No: 5573 .
Author(s): Andres Poveda, Ana Oaknin, Ignacio Romero, Angel Guerrero, Lorena Fariñas-Madrid, Victor Rodriguez-Freixinos, Arturo Soto-Matos, Carlos Peris, Marisa Teruel, Raquel Lopez-Reig, Jose Antonio Lopez-Guerrero; Clinical Area of Gynecologic Oncology, Instituto Valenciano de Oncología (IVO), Valencia, Spain; Vall d’Hebron University Hospital Institute of Oncology (VHIO), Barcelona, Spain; Instituto Valenciano de Oncología, Valencia, Spain; Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain; PharmaMar, Madrid, Spain; FINCIVO, Valencia, Spain; Valencian Oncology Institute, Valencia, Spain; Laboratory Molecular Biology, Instituto Valenciano Oncologia, Valencia, Spain; Laboratory of Molecular Biology, Instituto Valenciano de Oncología (IVO), Valencia, Spain
Abstract Disclosures
Abstract:
Background:
PM01183 (Lurbinectedin) is a new anticancer drug that exerts antitumor activity through inhibition of trans-activated transcription and modulation of tumor microenvironment and is highly active in platinum resistant ovarian cancer. (Poveda A et al. ASCO 2014.abstr #5505). Olaparib (AZD2281, KU-0059436) is a polyadenosine 5’diphosphoribose (poly [ADP ribose]) polymerase (PARP) inhibitor of PARP-1,-2 and-3 with proven antitumoral activity in homologous recombination deficient tumors.
The combination of PM01183 and Olaparib has shown synergistic activity in cell-lines, independent of BRCA mutation status.
Methods:
This phase I study evaluates the safety, PK and PD of PM1183 in combination with short course of Olaparib tablet formulation [days (d) 1-5] a cycle of 21 d, through a 3+3 dose escalation design (NCT02684318) Patients with advanced or metastatic solid tumors without established standard therapeutic alternatives were selected. Primary endpoints: safety (MTD, DLT and RP2D).
Secondary endpoints: PK and PD (western blot analysis of RAD51 and p-gH2AX) profiles at 0h,4.5h, 6.5h and 24h at first cycle of treatment.
Results:
20 patients were enrolled from Nov 2015 to Sep 2016 (15 ovarian, 5 endometrial) to 5 dose levels. 19/20 were evaluable for toxicity. Two dose limiting toxicities (DLTs) (both grade 4 neutropenia ≥ 4 days) occurred at the highest dose level (PM01183 2 mg/m2 iv d1 + Olaparib 250 mg [BID] oral on d 1-5. Grade 3 toxicities occurred in 30% of patients, including grade 3 neutropenia (6%) and grade 3 asthenia (10%).
PK data are available from 19 patients. Median of PM01183 total clearance (11.0 L/h) is the same as when PM01183 is given as single agent. Clearance of Olaparib (7 L/h) is consistent with results reported elsewhere (5.1 – 8.6 L/h).
PD: An overall increase of RAD51 and p-gH2AX was observed, being particularly evident in 56% of patients.
Conclusions:
The Recommended Dose for Phase II (RP2D) was PM01183 1,5 mg/m2 iv d1 + Olaparib 250 mg BID on d 1-5. This combination is feasible and without evidence of drug-drug interactions. A phase-II study at RP2D is ongoing .