Abstract A120: A Phase Ib study of CC-486 (Oral Azacitidine) as a priming agent for carboplatin or NAB-paclitaxel in subjects with relapsed and refractory solid tumors.
Authors: LoRusso Patricia , Rasco Drew , Bendell Johanna , Sachdev Jasgit , Ramanathan Ramesh , Weiss Glenn , Munster Pamela , Edenfield William J. , Liu Kejian , Blackwood-Chirchir Anne , DiMartino Jorge , DiMartino Jorge , Von Hoff Daniel D. 
Published: August 2014

Abstract
Background: CC-486, an oral formulation of 5-azacitidine, induces global genomic hypomethylation and clinical responses in MDS patients at doses of 200 mg and 300 mg/day for 14 or 21/28 days with acceptable safety. This non-randomized, multi-center Phase Ib study was designed to determine whether CC-486 can be delivered safely as priming for carboplatin or NAB-Paclitaxel (ABI-007) in patients with solid tumors.
Methods: In Part 1 of this study, patients with refractory solid tumors were assigned to Arm A: CC-486 days 1 - 14 with carboplatin AUC 4 on day 8 of a 21 day cycle (n = 13) or Arm B: CC-486 days 1 - 14 with ABI-007 100 mg/m2 given weekly starting on Day 8 of Cycle 1 (n = 24). 200 mg and 300 mg dose levels (DLs) of CC-486 were evaluated in cohorts of 6 to identify a recommended Part 2 dose (RP2D).
Results: On Arm A, 200 mg and 300 mg doses of CC-486 were tolerated. There was one DLT (Grade 3 pericardial effusion) at the 300 mg DL. Other related treatment-emergent adverse events (TEAEs) included anemia (53.8%) and neutropenia (46.3%). On Arm B, there were 2 DLTs of neutropenia at the 200 mg DL. The protocol was amended to give ABI-007 on days 8 and 15/21. No DLTs were encountered on 200 mg of CC-486 with intermittent ABI-007. At 300 mg, the MTD was exceeded with 2 DLTs of neutropenia (cholangiocarcinoma, pancreatic). Other common TEAEs in Arm B included nausea/vomiting (45.8%) and peripheral neuropathy (50%). Evidence of activity seen at both DLs included hypomethylation in PBMCs, 3 PRs in Arm B and 5 subjects with stable disease (&gt; 4 mos) in Arm A. CC-486 plasma exposure showed high interpatient variability but was higher at 300 mg than 200 mg. Incidence and severity of AEs did not differ significantly between the 2 DLs. 300 mg was selected as the RP2D in combination with carboplatin and 200 mg in combination with ABI-007.
Conclusion: CC-486 dosed 14/21 days is tolerated as a priming agent with carboplatin and ABI-007. Both combinations show evidence of clinical activity. Expansion cohorts at the RP2D of Arm A (relapsed/refractory bladder or ovarian carcinoma) and Arm B (relapsed/refractory NSCLC or pancreatic carcinoma) are enrolling to further characterize safety, PK/PD and anti-tumor activity.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A120.
Citation Format: Patricia LoRusso, Drew Rasco, Johanna Bendell, Jasgit Sachdev, Ramesh Ramanathan, Glenn Weiss, Pamela Munster, William J. Edenfield, Kejian Liu, Anne Blackwood-Chirchir, Jorge DiMartino, Jorge DiMartino, Daniel D. Von Hoff. A Phase Ib study of CC-486 (Oral Azacitidine) as a priming agent for carboplatin or NAB-paclitaxel in subjects with relapsed and refractory solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A120.