A Phase II Trial of Panobinostat, an Orally Available Deacetylase Inhibitor (DACi), in Patients with Primary Myelofibrosis (PMF), Post Essential Thrombocythemia (ET), and Post Polycythemia Vera (PV) Myelofibrosis

Abstract

630 Introduction: Medical treatment options for myelofibrosis (MF) are palliative in nature. Short of allogeneic stem cell transplantation, no therapies are available that are curative or confer a survival benefit. Panobinostat (PAN; LBH589) is a potent pan-deacetylase inhibitor that belongs to a structurally novel cinnamic hydroxamic acid class of compounds. Preclinical studies demonstrated that treatment with PAN alone depletes the levels of JAK2V617F (JAK2) and signaling downstream through STAT3 and 5, AKT, and c-RAF/MAPK in human MPN progenitor cells, including those from patients (pts) with MF (Blood 2009; 114:5024). In a prior phase IA/II study of PAN in pts with advanced hematologic malignancies, among 12 pts with MF evaluable for response, 4 pts demonstrated durable clinical improvement. Methods: In this phase II trial, approximately 50 adult pts with primary MF, post essential thrombocythemia, or post polycythemia vera MF who have an International Prognostic Scoring System -MF score of 2 or 3 along with either symptomatic splenomegaly (>10 cm below the costal margin [BCM]) or anemia, enrolled. Initial PAN dose is 40 mg three times a week until disease progression or unacceptable toxicity with dose adjustments as required. Response is assessed using the International Working Group criteria. Peripheral blood samples are collected for correlative science studies at 7 time points during treatment; pre-dose on the first day of the study, 6 and 24 hours after the first dose, pre-dose on the first day of cycles 2, 4 and 6, and at the end of the study. The correlative studies include the determination of JAK2V617F allelic burden, immunoblot analyses of the protein expression of p-STAT3, p-STAT5, p-AKT, p-ERK1/2, p-PIM, as well as of their un-phosphorylated counterparts. Also, protein levels of HSP70 and acetylated (Ac)-α-tubulin, as well as the mRNA expression of JAK2 and PRV-1 genes were determined. Results: As of August 12, 2010, 31 pts (24 JAK2 mutated, 7 JAK2 wild type) have been enrolled in the trial. The majority of pts required dose reduction. Adverse events observed are consistent with the known safety profile of PAN. Correlative studies have been performed on MPN cells from19 patients. As compared to the pre-treatment levels, treatment with PAN (for 6 and/or 24 hours) resulted in varying levels of depletion of p-STAT3, p-STAT5, p-AKT, p-ERK1/2 and p-PIM protein. A decline in JAK2 and PRV1 mRNA levels (20 to 80%) was also observed. Conversely, PAN treatment induced Ac-α-tubulin and HSP70 levels, consistent with HDAC6 and HSP90 inhibition. This was associated with decline in the protein levels of AKT, PIM1 and STAT3. PAN treatment also reduced MCL-1 and Bcl-xL, while inducing BIML levels. Notably, of the 10 patients in whom it has been determined, PAN treatment depleted the allelic burden of JAK2V617F by an amount ranging between 10 to 90%. Conclusions: Consistent with its role as a pan-deacetylase inhibitor, PAN exerts in vivo anti-MPN cell activity, as was highlighted by the decrease in the allelic burden of JAK2V617F. Further patient enrollment is ensuing, and more mature clinical toxicity and efficacy data will be presented. Disclosures: DeAngelo: Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Panobinostat is an investigational agent currently being evaluated for the treatment of hematologic and solid malignancies. Paley:Novartis: Employment. Snyder:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees. Ondovik:Novartis: Employment. Rine:Novartis: Employment.

Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies

“…Although three of the patients demonstrating CI were treated with 60 mg of panobinostat, all of these patients had dose reductions, and preliminary reports from recent studies seem to suggest that a lower dose (o40 mg) may allow for longer therapy duration. 32,33 Clinical trial experience with panobinostat has demonstrated longterm tolerability (ongoing 42 years) and remarkable clinical benefit in patients who received panobinostat at 25-30 mg, three times per week, every other week (Kavita Natrajan, personal communication). Furthermore, a recent study with another pan-DACi, givinostat, demonstrated clinical responses in patients with JAK2V617F-positive myeloproliferative neoplasms, including MF.…”

“…Promising single-agent activity was noted in patients with relapsed and refractory HL, and MF, and led to the design of phase II trials in these indications. 23,33 Of note, although the MTD was identified, a majority of patients who received long-term panobinostat had at least one dose reduction. These data seem to suggest that doses lower than the MTD may have higher longterm tolerability.…”

Unraveling the genetic underpinnings of myeloproliferative neoplasms and understanding their effect on disease course and response to therapy: Proceedings from the 6th international post‐ASH symposium

“…Interestingly, several patients experienced near CR results with extended therapy. DeAngelo et al also presented findings demonstrating that treatment with LBH‐589 reduces JAK2V617F allele burden in vivo , JAK‐STAT signaling, and inflammatory cytokine levels in patients treated on a separate clinical trial of LBH‐589 [75]. Based on these trials, a Phase II trial of LBH589 is underway with 25 mg po TIW as the recommended dose.…”

A phase I study of panobinostat (LBH589) in patients with primary myelofibrosis (PMF) and post‐polycythaemia vera/essential thrombocythaemia myelofibrosis (post‐PV/ET MF)

“…Currently, the results of three other clinical trials of HDACi therapy in MF patients have been reported (De Angelo et al , ; Rambaldi et al , ; Quintas‐Cardama et al , ). Panobinostat, at starting doses of 40 mg three times weekly, was evaluated in a separate phase II study demonstrating clinical activity in some patients at the expense of increased toxicity (De Angelo et al , ). A phase II study of givinostat in JAK2 V617F‐positve MPN patients included three major responses in the 16 treated MF patients (Rambaldi et al , ).…”