ORLANDO, FLCC-486, an oral formulation of azacitidine in clinical development for hematologic malignancies, was “reasonably well tolerated” in extended dosing schedules of 14 or 21 days per 28-day cycle in patients with acute myeloid leukemia (AML), according to results presented at the 57th American Society of Hematology (ASH) Annual Meeting.1

Previously, “phase 1 dose-finding study showed CC-486 administered for 7 days/cycle was safe and clinically active in patients with AML,” reported Michael R. Savona, MD, of the Vanderbilt University Medical Center in Nashville, TN.

The investigators hypothesized that extending dosing for more than 7 days might increase the number of leukemic cells exposed to azacitidine over the course of the cycle to improve response.

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In this study, 23 patients with AML from two phase 1/2 studies were sequentially assigned to receive CC-486 in 1 of 4 extended dosing regimens: 300 mg once daily for 14 of 28 days (4 patients), 300 mg once daily for 21 of 28 days (12 patients), 200 mg twice daily for 14 of 28 days (4 patients), or 200 mg twice daily for 21 of 28 days (3 patients).

Median age was 68.0 years (range, 44-93 years), 48% were male, and 22% had an ECOG performance status score of 2. Median time from diagnosis was 1.1 months (range, -0.2 to 82.1 months).

Of the patients, 11 (48%) had prior MDS, and 13 (57%) had received prior treatment for either MDS (5 patients) or AML (8 patients); this included 5 (22%) who had received hypomethylating agents.

For all patients, the median number of CC-486 cycles was 4 (range, 1-9).

Overall response—defined as complete remission (CR), partial remission, CR with incomplete hematologic recovery, marrow CR, hematologic improvement, and transfusion independence—was observed in 11 patients (48%), “with response types/rates generally comparable across dosing regimens,” Dr. Savona said.

A total of 69% of patients who received 2 or more cycles of CC-486 had a response; this included 7 of 9 patients in the 300 mg once daily dosing group and 4 of 7 patients in the 200 mg twice daily dosing group.

Responses were observed in 4 of the 8 patients (50%) who were relapsed or refractory to prior treatment for AML. Two of 5 patients (40%) who had received prior treatment with hypomethylating agents responded, “1 of whom attained CR,” he said. Hematologic improvement was achieved by 7 of 22 patients (32%); in addition, 3 of 15 patients (20%) who were red blood cell transfusion-dependent attained transfusion independence.

Five of 11 patients with prior MDS responded, and 1 proceeded to transplant.

The most common grade 3 to 4 treatment-emergent adverse events were febrile neutropenia (30%) and anemia (22%), with incidences generally similar across the 4 dosing regimens.

“One-half of these older patients with AML had a hematologic response, including patients who had prior MDS, or AML that failed or lost response to prior treatment,” Dr. Savona noted. This included responses in patients who previously received treatment with injectable hypomethylating agents, which “may reflect sustained hypomethylation pattern obtained with prolonged oral administration.”

“Ease of administration of CC-486 provides an additional treatment option after failure of IV/SQ [intravenous/subcutaneous] hypomethylating agent therapy, and facilitates use in combination treatment regimens, which warrant investigation,” he said.

Currently, the phase 3 Quazar AML maintenance trial is evaluating CC-486 in patients with AML in first remission after induction therapy, Dr. Savona concluded.


1. Savona MR, Gore SD, Kolibaba KS, et al. CC-486 (oral azacitidine) monotherapy in patients with acute myeloid leukemia (AML). Oral presentation at: 57th American Society of Hematology (ASH) Annual Meeting; December 7, 2015, Orlando, FL.