Phase I Study of CC-486 Alone and in Combination with Carboplatin or nab-Paclitaxel in Patients with Relapsed or Refractory Solid Tumors

Abstract

Purpose: This large two-part, three-arm phase I study examined the safety and tolerability of CC-486 (an oral formulation of azacitidine, a hypomethylating agent) alone or in combination with the cytotoxic agents, carboplatin or nab-paclitaxel, in patients with advanced unresectable solid tumors.Patients and Methods: Part 1 (n = 57) was a dose escalation of CC-486 alone (arm C) or with carboplatin (arm A) or nab-paclitaxel (arm B). The primary endpoint was safety, MTD, and recommended part 2 dose (RP2D) of CC-486. In part 2 (n = 112), the primary endpoint was the safety and tolerability of CC-486 administered at the RP2D for each treatment arm, in tumor-specific expansion cohorts. Secondary endpoints included pharmacokinetics, pharmacodynamics, and antitumor activity of CC-486.Results: At pharmacologically active doses CC-486 in combination with carboplatin or nab-paclitaxel had a tolerable safety profile and no drug-drug interactions. The CC-486 RP2D was determined as 300 mg (every day, days 1-14/21) in combination with carboplatin (arm A) or as monotherapy (arm C); and 200 mg in the same dosing regimen in combination with nab-paclitaxel (arm B). Albeit limited by the small sample size, CC-486 monotherapy resulted in partial responses (three/eight) and stable disease (four/eight) in patients with nasopharyngeal cancer. Three of the stable disease responses lasted more than 150 days.Conclusions: CC-486 is well tolerated alone or in combination with carboplatin or nab-paclitaxel. Exploratory analyses suggest clinical activity of CC-486 monotherapy in nasopharyngeal cancer and provided the basis for an ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT02269943). Clin Cancer Res; 24(17); 4072-80. ©2018 AACR.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

D.D. Von Hoff reports receiving commercial research grants from and is a consultant/advisory board member for Celgene. J.A. Lopez-Martin is a consultant/advisory board member for Celgene. M. Martin reports receiving commercial research grants from Novartis and Roche, and is a consultant/advisory board member for Novartis, Genentech, Lilly, and Pfizer. J. DiMartino holds ownership interest (including patents) in Celgene. E. Laille is an employee of and holds ownership interest (including patents) in Celgene. No potential conflicts of interest were disclosed by the other authors.

©2018 American Association for Cancer Research.

Figures

Figure 1.

Study design. The first part of the study consisted of three treatment arms, with CC-486 administered in combination with carboplatin (arm A), nab-paclitaxel (arm B), or as monotherapy (arm C). Patients were assigned to each arm based on investigator discretion. Patients continued treatment until either a DLT or progressive disease. In part 2, the treatment arms had the same drug combinations as in part 1, but patients were assigned to treatment arms based on tumor type. PD, pharmacodynamics.

Figure 2.

Mean (± SD) CC-486 plasma concentration versus time profiles following CC-486 administration alone (arm C) or in combination with carboplatin (arm A) or nab-paclitaxel (arm B).

Figure 3.

Preliminary efficacy evaluation of CC-486 in eight patients with NPC. A, Investigator-assessed best overall response and days on study for patients with NPC in arm C of study parts 1 and 2. B, Waterfall plot of best target lesion response for patients with NPC in arm C of study parts 1 and 2. Percent changes from baseline in the sum of the longest diameter of target lesions are derived by the study sponsor. Only patients with nonmissing values are included in the graph. CC-486 doses were 200 mg every day on days 1 to 21 of each 21-day cycle (DL1), 300 mg daily on days 1 to 21 of each 21-day cycle (DL2), or 300 mg daily on days 1 to 14 of each 21-day cycle (DL–1; determined to be RP2D in part 1). DL, dose level.