In:
Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3705-3705
Abstract:
Background: Approximately 3540 children are diagnosed with leukemia in the United States yearly (Bhatia and Robison, Oncology of Infancy and Childhood, 2008). Cooperative group trials have increased survival, particularly for acute lymphoblastic leukemia (ALL), but successful treatment of recurrent leukemia remains an unmet medical need. Resistance pathways and epigenetic alterations suggest a role for histone deacetylase (HDAC) inhibitors in children with leukemia (Burke and Bhatla, Frontiers in Pediatrics, 2014). Panobinostat is an orally administered pan-deacetylase inhibitor with activity against HDACs at concentrations in the nanomolar range (Atadja, Cancer Letters, 2009), and for which there is pre-clinical evidence of activity in pediatric leukemia (Stubbs, et al., ASH 2010). Panobinostat shows promise in a variety of adult hematologic malignancies (Khot et al., Expert Opinion on Investigational Drugs, 2013). We undertook a phase I trial of panobinostat in children with recurrent hematologic malignancies, and herein report the safety and pharmacokinetics (PK) from enrolled children with leukemia. Methods: T2009-012 is a first-in-child study coordinated by Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL). Children with relapsed or refractory leukemia between the ages of 1 and 21 years were enrolled to a multi-center, single agent trial of panobinostat dosed once per day three days per week for four successive weeks. Dose escalation was a standard 3+3 design with three dose levels planned. Subjects underwent lumbar puncture with prophylactic chemotherapy at treatment start and after a 28 day course. Blood was sampled pre-dose, at 0.5, 1, 6, 24 and 28-48 hours following the first dose. PK was obtained from blood on patients concurrently with optional specimens obtained from cerebrospinal fluid (CSF) on Day 29. Subjects who received fewer than 11 of the 12 planned doses and did not experience a dose limiting toxicity (DLT) were considered not evaluable for DLT, but were included in the summary of toxicities. Serial ECGs were monitored. Results: Seventeen subjects were enrolled with a diagnosis of acute leukemia, 10 with ALL and 7 with acute myelogenous leukemia (AML). Five were enrolled at dose level 1, 24 mg/m2/dose, 6 at dose level 2, 30 mg/m2/dose, and 6 at dose level 3, 34 mg/m2/dose. There have been no DLTs. Nine subjects are evaluable for DLT and 4 subjects were taken off study early due to increasing blast count. No subjects required removal from protocol therapy for QTc prolongation. One subject with infant ALL was removed early for progressive Aspergillus infection, 1 subject only received 10 doses owing to electrolyte abnormalities, and 2 subjects had nausea and vomiting after administration of 4 doses and did not continue. Grade 3/4 adverse events occurring in more than 20% of subjects included anemia in 82%, diarrhea in 24%, febrile neutropenia in 65%, hypokalemia in 41%, and hypophosphatemia in 24%. Concentration-time profiles were obtained from 9 subjects ages 16 months to 14 years in the 3 dose levels. Mean ± SE of PK for all subjects were Cmax 28.8 ± 6.1 ng/mL, Tmax 2.0 ± 0.8 hours, and T1/2 12.8 ± 3.0 hours. Two toddlers had the highest dose-normalized AUC0-inf and lowest oral clearance. Apparent oral clearance proportionally increased with increase in BSA. To date, 4 CSF specimens have been evaluated and found to have panobinostat below the lower limit of the quantification of 0.1 ng/mL, despite appreciable levels in the plasma. Two subjects on dose level two began a second cycle of therapy; one completed a second cycle for MLL rearranged leukemia and one discontinued study participation in the second cycle to undergo hematopoietic stem cell transplant for secondary AML after achieving a CRp in the first cycle. Conclusions: Panobinostat was tolerated these heavily pre-treated patients without unanticipated toxicities. PK in larger children and adults appears similar but PK in smaller children needs to be further explored. Penetration of panobinostat into the CSF was negligible. Two of 17 patients were able to receive a second cycle of therapy, but 4 had to be withdrawn early because of rapid increase in blast counts. Future trials will explore combination therapy in children with refractory hematologic malignancies, particularly those known to be driven by epigenetic mechanisms, in order to better control risk of rapid progression and improve efficacy through synergy. Disclosures Off Label Use: panobinostat for leukemia. Manley:Seattle Genetics, Inc.: Employment, Equity Ownership. Thomson:Epizyme, Inc: Employment.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V124.21.3705.3705
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2014
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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