The mechanism of action of quisinostat (Q) includes protein acetylation, leading to re-activation of tumor suppressor genes and restoration of tumor sensitivity to chemotherapy
The primary endpoint was to identify the maximum tolerated dose (MTD) of Q. Secondary endpoints included safety, overall response rate, and pharmacokinetics parameters. Q was administered orally at escalated doses (8, 10 and 12 mg); 3 week cycle on Days 1, 3, 5, 7, 9, 11. In the 1st arm NSCLC pts received Q with G (1000 mg/m2) on Day 7 and 14 and Cis (75 mg/m2) on Day 7 of each cycle, for 2nd line. If Q was deemed tolerable at 12 mg, another dosage cohort was to have been started: Q (12 mg) with G (1250 mg/m2) on Days 7 and 14 and Cis (75 mg/m2) on Day 7 of each cycle for 1st line NSCLC. In the 2nd arm pts received Q with P (175 mg/m2) and Carbo (AUC5) on Day 7 of each cycle, in 2nd or subsequent lines for pts with NSCLC or OC. Dose escalation was according to the “3 + 3” dose-limiting toxicity (DLT) algorithm. After definition of MTD, additional pts were to have been included
51 pts (QGCis – 28 pts, QPCarbo – 23 pts; NCSLC – 33 pts, OC – 18 pts) were enrolled: 49% male; median age = 59.6 (range 40-74) years. There were no DLTs. Q was tolerated to the maximum dose of 12 mg chosen for this study, and therefore there were MTD criteria never met; Q at 12 mg in combo was chosen and is dose recommended for Phase 2 development. The most common adverse events (AE) were neutropenia - 56% and 57%, thrombocytopenia - 39% and 75%, anemia - 35% and 64% for group of QPCarbo and QGCis, respectively. Any serious AE were revealed in 21.6% pts, Q related serious AE – in 13.7%, AE ¾ grades – in 64.7%, and 23.5% pts discontinued therapy due to AE. 46 pts were evaluable for response, with responses observed in 8 (17%): 8 PRs (NSCLC: 2/30 pts, 6.7%; OC: 6/16 pts, 37.5%). Most pts with OC with partial response had platinum resistance relapses
On successfully completing the trial, the recommended dose of Q for phase 2 study is 12 mg in combination with G 1250 mg/m2) and Cis (75 mg/m2) or P (175 mg/m2) and Carbo (AUC5). The combination QPCarbo showed activity in the treatment of pts with platinum resistant OC
Clinical trial identification
Legal entity responsible for the study
M. Fedyanin: consultant of NewVac. S. Orlov: Employment - BioEq, LLC. A. Cakana: Employment - Janssen Pharmaceutica N.V. V. Azarova, O. Karavaeva, N. Vostokova: Employment - IPHARMA, LLC S. Baranovskiy: Employment – NewVac. All other authors have declared no conflicts of interest.