A Phase Ib Dose-Finding Study of Oral Panobinostat In Combination with Cytarabine (ara-C) and Mitoxantrone as Salvage Therapy for Refractory or Relapsed Acute Myeloid Leukemia (AML)

Panobinostat (PAN) is an oral pan-deacetylase inhibitor (pan-DACi) that increases acetylation of a series of proteins such as HSP90, p53, α-tubulin and HIF-1α which are involved in cell cycle regulation, gene transcription, angiogenesis, and tumor cell survival. Preclinical studies demonstrated that PAN potentiates the activity of cytarabine (ara-C) and fludarabine and has synergistic activity in combination with doxorubicin in AML cell lines and patient (pt) blast cells. Clinical activity of single-agent PAN has been demonstrated in a phase I trial, including complete responses in pts with AML. Acute myeloid leukemia (AML) is associated with a poor prognosis, particularly in pts with relapsed or refractory disease. The addition of PAN to a chemotherapeutic regimen that is active in pts with AML who have relapsed or are refractory to prior induction therapy has the potential to improve therapeutic outcomes in this setting.

This phase Ib, multicenter, open-label study is comprised of 3 parts: 1) dose-escalation to determine the maximum tolerated dose (MTD) of PAN in combination with ara-C and mitoxantrone, 2) dose-expansion to assess safety and preliminary activity at the MTD, and 3) optional dose extension to assess safety of single-agent PAN (60 mg thrice weekly) in pts who responded but are not eligible for other therapies. The primary objective is to determine the MTD of PAN in combination with a fixed dose of ara-C and mitoxantrone. The primary endpoint is incidence of dose-limiting toxicities (DLTs) within the first treatment cycle. Secondary and exploratory objectives include assessment of the safety profile of PAN and evaluation of anti-leukemic activity. Adult pts with AML (WHO criteria) who are relapsed or refractory to 1 prior treatment regimen with an ECOG PS ≤2 were eligible for enrollment on the study. PAN was orally administered (20 mg starting dose) thrice weekly on Days (D) 1, 3, 5, 8, 10, and 12, in combination with iv ara-C (1 g/m²) D1–6, and iv mitoxantrone (5 mg/m²) D1–5 of a 28-D cycle (C). Pts can receive a maximum of 3 cycles of combination therapy. Pts who are eligible for the optional dose extension part received single-agent PAN (60 mg thrice weekly).

As of July 29, 2010, 23 pts have been enrolled, 5 in cohort 1 (20 mg PAN), 8 in cohort 2 (30 mg PAN), and 10 in cohort 3 (40 mg PAN). Safety and efficacy analyses are based on 18 pts. The median age of the pts was 53.5 years (range 19–72). Prior to treatment, all had received ara-C. One DLT has been observed (sepsis and tachyarrhythmia) in the 40 mg cohort. Adverse events were observed with 16 pts (89%): hematologic adverse events (AEs) were observed in 12 pts (67%): including thrombocytopenia, febrile neutropenia, anemia, leukopenia and neutropenia. Non-hematologic AEs included: general disorders and administration site conditions (16 [89%]), gastrointestinal and metabolism/nutrition disorders (15 [83%] each), infections (12 [67%]), respiratory/thoracic disorders (11 [61%]), vascular and skin/subcutaneous tissue disorders (10 [56%] each) and cardiac disorders (8 [44%]). Most frequent Grade 3/4 adverse events (AEs) observed in all cohorts to date were hematologic, including febrile neutropenia and thrombocytopenia (8 [44%] each), leukopenia (5 [28%]), anemia and neutropenia (4 [22%] each). Grade 3/4 AEs suspected to be study treatment related were mostly related to thrombocytopenia (6 [33%]) and neutropenia (4 [22%]). Serious AEs were observed in all cohorts, with most related to infectious complications (8 [44%]), febrile neutropenia (6 [33%]) pneumonia and fungal pneumonia (2 [11%]). QTcF prolongation of ≥480 ms (but < 500 ms) was observed in 2 pts (11%), but no pt demonstrated QTcF prolongation of > 500 ms. Encouraging clinical efficacy was observed, especially with higher doses of PAN, with 8 responders (partial response [PR] or better) (44%): 3 complete remissions (CR), 2 complete remissions with incomplete blood count recovery (CRi) and 3 partial responses (PR).

The MTD of PAN in combination with ara-C and mitoxantrone has not been reached, and the study is ongoing. The current data show that the addition of PAN to ara-C and mitoxantrone is safe with no unexpected toxicities and showing promising activity in refractory or relapsed AML pts. Updated data, including safety and preliminary efficacy data will be presented at the meeting.

Krauter:Novartis: Research Funding. Off Label Use: Panobinostat is an investigational agent currently being evaluated for the treatment of hematologic and solid malignancies. Schlenk:Novartis: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Amgen: Research Funding; Cephalon: Research Funding. Winiger:Novartis Pharma AG: Employment. Squier:Novartis: Employment. Bengoudifa:Novartis Pharma AG: Employment. Ottmann:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.