Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours
Mené sur des patientes présentant des mutations constitutionnelles du gène BRCA1 ou BRCA2 et atteintes d'une tumeur de l'ovaire (28 patientes), du sein (13 patientes) ou d'une autre tumeur solide (3 patientes), cet essai de phase I évalue la dose maximale tolérée et l'activité antitumorale de l'olaparib, un inhibiteur de PARP par voie orale, en combinaison avec la doxorubicine liposomale
Background: Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours (NCT00819221). Methods: Patients received 28-day cycles of olaparib, continuously (days 1–28) or intermittently (days 1–7), plus PLD (40 mg m−2, day 1); seven olaparib dose cohorts (50–400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)). Results: Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade greater than or equal to3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation. Conclusions: Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m−2) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.