Determination of a Phase II Dose of Panobinostat in Combination with 5-Azacitidine in Patients with Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia

5-Azacitidine (AZA), a demethylating agent, is approved for treatment of myelodysplastic syndromes (MDS) and provides complete remission (CR) in 17% of patients (pts) and a median overall survival of 24.5 months, thus highlighting an unmet need in this population. Panobinostat, a potent pan-deacetylase inhibitor (pan-DACi), has demonstrated anti-tumor activity in pts with MDS and acute myeloid leukemia (AML). Preclinical studies suggest a combination of AZA and a pan-DACi may, in part through synergistic gene reactivation and apoptosis induction, improve outcomes in pts with MDS, AML, and chronic myelomonocytic leukemia (CMML) and appears to be a promising new approach in this population.

The primary objective of this phase I, open-label, multicenter, dose-escalation study is to determine maximum tolerated dose (MTD) of panobinostat with a fixed dose of AZA. Secondary objectives are to characterize safety and tolerability, with an exploratory objective to evaluate preliminary anti-leukemic activity of panobinostat in combination with AZA.

Adult pts (ECOG ≤ 2) with IPSS intermediate-2 or high-risk MDS, CMML, or AML with multi-lineage dysplasia and 20%–30% marrow blasts, not initially eligible for hematopoietic stem-cell transplantation, were treated with oral panobinostat (20 mg/day starting dose and 10-mg dose increments) during a 28-day cycle on days 3, 5, 8, 10, 12, and 15 in combination with a fixed dose of AZA (75 mg/m² sc) on days 1–7 of each cycle. On the basis of the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle and an overall assessment of safety and tolerability data from all cycles, a phase II dose was recommended. Safety and tolerability were described as type, duration, frequency, relatedness, and severity of adverse events (AEs) according to CTCAE, v3.0. The adaptive Bayesian logistic regression model was used to guide panobinostat dose escalation with overdose control at all dose levels. Cycle extension, up to day 42, is allowed in cases of toxicity. The minimum exposure criterion for determining MTD was 6 scheduled doses of panobinostat and 7 scheduled doses of AZA during cycle 1.

A total of 31 pts, with a median age of 70 years (range 34–81), in 3 cohorts were enrolled. Of these pts, 6 were treated at a dose level of 20 mg, 18 at 30 mg, and 7 at 40 mg of panobinostat; 28 pts were evaluable for MTD. Safety and efficacy data are based on 29 and 16 pts, respectively. One DLT (febrile neutropenia) was observed at 20 mg, 3 DLTs (dehydration/fatigue, colitis, a 1-day echocardiogram T-wave inversion, and an atrial fibrillation/syncope) were seen at 30 mg, and 2 DLTs (hyperbilirubinemia and nausea/vomiting) were reported in the 40-mg cohort. On the basis of the occurrence of DLTs and overall safety and tolerability data in cycle 1, dose levels at and above 40 mg were not further evaluated. Additional pts were enrolled at 30 mg. The most frequent AEs suspected to be related to the study treatment were gastrointestinal issues and fatigue. Grade 3/4 treatment-related AEs included thrombocytopenia (8 [28%]), neutropenia (5 [17%]), and febrile neutropenia (6 [21%]). Other frequent AEs of all grades, regardless of study drug relationship, included nausea (19 [67%]), fatigue (18 [62%]), diarrhea (16 [55%]), vomiting (15 [52%]), thrombocytopenia (13 [45%]), and decreased appetite (12 [41%]). The most common serious AEs (SAEs), regardless of study drug relationship, were febrile neutropenia (8 [28%]) and asthenia (5 [17%]). Based on the DLTs observed in cycle 1 and overall assessment of safety and tolerability, a phase II dose of 30 mg was recommended. Preliminary efficacy data for 8 pts with AML and 8 with MDS/CMML show 4 pts (2 at 30 mg, 2 at 40 mg) achieving CR or morphological CR (CRi) and 6 pts (4 at 30 mg, 2 at 40 mg) showing stable disease (SD). Hematologic improvement was seen in 4 pts, 2 of whom relapsed.

Current data show that oral panobinostat at 30 mg/day on days 1, 3, 5, 8, 10, and 12 of a 28-day cycle can be safely combined with AZA at the registered label dose in pts with intermediate-2 or high-risk MDS, CMML, or AML. Additional pts will be evaluated in an expansion phase to further characterize the safety profile and activity at the 30-mg dose level. To date, preliminary efficacy shows that CR/CRi was achieved in 4 pts, SD was achieved in 6 pts, and HI was observed in 4 pts.

Ottmann:Novartis Corporation: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. DeAngelo:Novartis Corporation: Membership on an entity's Board of Directors or advisory committees. Sekeres:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Zahlten:Novartis AG: Employee of Novartis, Employment. Squier:Novartis Corporation: Employment. Acharyya:Novartis Corporation: Employment. Winiger:Novartis AG: Employment, Equity Ownership, Honoraria. Fenaux:Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria; Roche: Research Funding; Janssen Cilag: Research Funding.