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Encouraging Data from a Novel Deacetylase Inhibitor in Hematologic Malignancies
December 8, 2009—During the 51st ASH Annual Meeting and Exposition in New Orleans, data were presented demonstrating the efficacy and safety of panobinostat in Hodgkin lymphoma (HL), myelofibrosis (MF), and multiple myeloma (MM).
Inhibition of histone deacetylases has been shown to result in decreased growth factor signaling and tumor cell proliferation, decreased angiogenesis, and increased apoptosis in vitro. Panobinostat, a highly potent and novel pan-deacetylase inhibitor (pan-DACi), exhibits antiproliferative activity in a variety of tumor cell lines accompanied by an increase in histone acetylation. Dose escalation phase I studies of panobinostat in a wide range of hematologic malignancies have yielded promising results.
Relapsed/refractory Hodgkin lymphoma
Data recently reported from a phase I clinical trial demonstrated that treatment with oral panobinostat in patients with relapsed/refractory HL resulted in an overall response rate (ORR) of approximately 40% (DeAngelo DJ, et al. Haematologica. 2009;94(2): Abstract 0505). Anas Younes, MD (M. D. Anderson Cancer Center, Houston, Texas), presented data from a phase II trial evaluating the efficacy of panobinostat in heavily pretreated patients (≤5 prior systemic lines of treatment) with relapsed or refractory HL after high-dose chemotherapy with autologous stem cell transplant.
The following results were obtained from this study:
- Overall disease control achieved in 88% of patients
- 69% of patients experienced a decrease in tumor size
- 2 patients had a complete response (complete normalization)
- 14 patients had a partial response (≥50% tumor reduction)
- 35 patients had a minor response (<50% tumor reduction)
- Median time to response was 6 weeks
- Median duration of response was >22 weeks
The most common adverse event was reversible thrombocytopenia, and there were no reports of significant QTcF interval changes (>500 msec). Interestingly, patients with significant tumor reduction were more likely to experience grade 4 thrombocytopenia. These data suggest that panobinostat is well-tolerated and exerts antitumor activity in this population of heavily pretreated patients with relapsed/refractory HL. A phase III trial evaluating the use of panobinostat for maintenance of response in the post-transplant setting is currently being planned.
Blood. 2009;114(22): Abstract 923.
Myelofibrosis
John Mascarenhas, MD (Tisch Cancer Institute, New York, New York), presented data from a phase I study evaluating the use of panobinostat in patients with primary myelofibrosis (PMF) and postpolycythemia/essential thrombocythemia myelofibrosis (PostPV/ET MF). The primary objectives of this trial were to assess the safety and tolerability, define dose-limiting toxicity (DLT), determine the maximum tolerated dose (MTD), and establish a recommended phase II dose (RPTD) for panobinostat in this patient population. The starting dose was panobinostat 20 mg PO tiw.
The following results were obtained from this study:
- 4 patients demonstrated clinical improvement by IWG criteria
- Resolution of palpable spleen
- 2 g/dL increase in hemoglobin
- 5 patients had stable disease by IWG criteria
- 1 patient had progressive disease by IWG criteria
Grade 1 fatigue and nausea were the most common nonhematologic adverse events, and thrombocytopenia was the DLT in the panobinostat 20 mg and 30 mg cohorts. One patient experienced grade 2 renal dysfunction, and no patients experienced a prolongation of QTcF. Data from this early phase study demonstrated that treatment of MF with panobinostat was associated with acceptable toxicity and could result in clinical improvement in patients with advanced disease. The authors conclude that panobinostat appears to be a promising new agent for the treatment of patients with MF.
Blood. 2009;114(22): Abstract 308.
Relapsed/refractory multiple myeloma
Encouraging preclinical data on the effects of panobinostat and bortezomib on myeloma cells has been previously reported. Jesús F. San Miguel, MD, PhD (Hospital Universitario de Salamanca, Salamanca, Spain), presented data from a phase Ib dose-escalation trial of panobinostat and bortezomib in patients with relapsed MM. The design of this study required a minimum of 6 evaluable patients per cohort for decision to dose escalate, and a minimum of 12 evaluable patients were required to declare the MTD, followed by expansion to 22 patients to assess safety and tolerability at the declared MTD.
The following results were obtained from this study:
- 26 responses were observed in 38 evaluable patients:
- 4 complete responses
- 2 very good partial responses
- 16 partial responses
- 4 minor responses
- For 38 patients enrolled in 5 cohorts, DLTs were:
- Absent in Cohort 1 (panobinostat 10 mg + bortezomib1.0 mg/m2) and Cohort 3 (panobinostat 20 mg + bortezomib 1.3 mg/m2)
- Single occurrences in Cohort 2 (panobinostat 20 mg + bortezomib 1.0 mg/m2) and Cohort 5 (panobinostat 25 mg + bortezomib 1.3 mg/m2)
- Excessive in Cohort 4 (panobinostat 30 mg + bortezomib 1.3 mg/m2), observed in 4 of 7 evaluable patients, including two DLTs of thrombocytopenia requiring transfusions
Data from this ongoing trial suggest that oral panobinostat can be combined with intravenous bortezomib with a predictable and manageable safety profile. The combination of panobinostat and bortezomib shows promising activity in patients with MM who have received up to 7 prior lines of therapy, including patients who do respond to or who are insensitive to bortezomib.
Blood. 2009;114(22): Abstract 3852.
James R. Berenson, MD (Institute for Myeloma & Bone Cancer Research, West Hollywood, California), reported data from a phase I/II study evaluating the efficacy and safety of oral melphalan plus panobinostat for patients with relapsed or refractory MM. A total of 19 patients have been enrolled in the trial.
The following results were obtained from this study:
- 68% of patients demonstrated disease control
- 11% of patients demonstrated a complete response
- 11% of patients demonstrated a partial response
- 47% of patients demonstrated stable disease
- 21% of patients demonstrated an objective response
- 32% of patients experienced progressive disease
Fatigue was the most common adverse event, and 2 patients experienced reversible thrombocytopenia. There was no incidence of QTcF prolongation >500 msec. Based on an encouraging response rate, an expanded phase II trial of panobinostat and melphalan in relapsed/refractory MM will be conducted once the MTD has been determined and the dosing schedule optimized.
Blood. 2009;114(22): Abstract 1855.
Taken together, data from these studies demonstrate a potential role for the use of pan-deacetylase inhibitors, specifically panobinostat, in a wide range of disease states. Several clinical trials are underway to further evaluate the clinical use of panobinostat in hematologic malignancies.
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