Spectrum Pharmaceuticals, Inc. (NasdaqGM: SPPI), a commercial stage biotechnology company with a primary focus in hematology and oncology, today announced that clinical data on belinostat will be presented at the 2010 Annual Meeting of the American Society of Clinical Oncology (ASCO), to be held June 4-8, 2010 at the McCormick Place Convention Center in Chicago, Illinois.
Shown below are the summary abstracts that are now available for viewing on the ASCO.org website (www.asco.org). More detailed information will be provided when the posters are presented.
Monday, June 7, 2010 - 8:00 a.m. - 12:00 p.m.
Trials in Progress Poster Session - Special Session, Clinical trials - S Hall A2
Abstract #TPS185: An Open-Label Randomized Phase 2 Trial Of Belinostat (PXD101) In Combination With Carboplatin And Paclitaxel (BelCaP) Compared To Carboplatin And Paclitaxel In Patients With Previously Untreated Carcinoma Of Unknown Primary.
- Karim Fizazi - Institut de Cancerologie Gustave Roussy, Villejuif, France
- John Hainsworth - Tennessee Oncology Sarah Canon Research Institute, US
Treatment options for patients with cancer of unknown primary (CUP) are limited; carboplatin and paclitaxel combination being one of the options. Belinostat, is a hydroxamate, class I and II histone deacetylase inhibitor (HDACi) with a broad antineoplastic activity. Phase I and II trials are ongoing in multiple indications and in more than 500 patients the most common adverse events have been nausea, vomiting and fatigue. Preclinical data shows synergistic effect when combined with carboplatin and paclitaxel in vitro and in vivo. In a Phase I study for patients with pretreated advanced solid tumors, BelCaP was well-tolerated and active with objective responses seen in pancreatic and rectal cancer patients. A patient with CUP (3 prior chemotherapy regimens) had disease control during 29 months of treatment. Therefore, we are conducting a randomized Phase 2 study (N~88) of CaP with or without belinostat in CUP patients.
Randomized, global, multicenter Phase 2 trial in 19 centers. Inclusion criteria include: a confirmed diagnosis of CUP, no prior therapy, ECOG PS 0-2, age > 18 years. Eligible patients are randomized to receive either arm A or B.
- Arm A: BelCaP; belinostat as a 30-min i.v. infusion once daily (1000 mg/m2) on days 1-3, followed by belinostat 2000mg orally once daily on days 4-5, with paclitaxel (175 mg/m2) administered 2-3 hours following belinostat on day 3 and carboplatin (AUC6) following directly after paclitaxel, up to 6 cycles. From cycle 7: belinostat 750 mg is administered orally once daily x 14 days.
- Arm B: Paclitaxel (175 mg/m2) administered day 1 and carboplatin (AUC6) following directly after paclitaxel. Cycles repeated every 3 weeks.
Primary endpoint is progression free survival (PFS) and secondary endpoints assess additional efficacy parameters and safety. Response is evaluated according to RECIST criteria. 33 patients have been randomized as of 06-Jan-2009.
Monday, June 7, 2010 - 8:00 a.m. - 12:00 p.m.
General Poster Session - Developmental Therapeutics - S Hall A2
Abstract #2585 - Phase 1 Pharmacokinetics and Metabolic Pathway of Belinostat in Patients with Hepatocellular Carcinoma.
Metabolic inactivation of several hydroxamic acid-derived histone deacetylase inhibitors (HDACi) involves glucuronidation. Vorinostat, a pan-HDACi, undergoes glucuronidation by UGT2B17. We studied the pharmacokinetics and metabolic pathway of belinostat (PXD101).
In vitro glucuronidation of belinostat was investigated; plasma pharmacokinetics of belinostat was studied in a phase I study in patients with hepatocellular carcinoma. Seventeen patients were treated with belinostat at escalating doses of 600 (n = 3), 900 (n = 3), 1200 (n = 6), 1400 (n = 5) mg/m2 daily by intravenous infusion over 30 minutes for 5 days every 21 days; blood was drawn on day 1 before infusion, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 5 and 24 hours after the start of infusion, plasma was isolated for determination of belinostat and identification of its metabolites using LC-MS/MS. Pharmacokinetics of belinostat was studied using non-compartmental methods.
Using a panel of 12 UGT isoforms, UGT1A1 was found to be the predominant enzyme for glucuronidation of belinostat with one third of unmetabolized belinostat left after 1 h incubation at 37 ºC. Belinostat glucuronide had no activity against HONE1 cell line at 10 μM, compared to an IC50 of 1.59 ± 0.90 μM for belinostat. Belinostat AUC increased linearly with dose, with a mean clearance of 34.34 ± 10.56 L/h/m2 and terminal half-life of 2.94 ± 0.48 h. Five metabolites in human plasma were identified. Glucuronidation was the most significant pathway of belinostat metabolism; 2 alternate biotransformation pathways involved methylation to methylated belinostat and reduction of hydroxamic group to its corresponding belinostat amide. In addition, two minor metabolites were found to be belinostat N-glucoside and belinostat acid. Belinostat glucuronide increased in levels shortly after administration, reaching the maximum concentration at 1 h from start of infusion.
Phase II biotransformation played a key role on belinostat disposition, with UGT 1A1 likely involved in the major pathway. Further studies should explore the role of common polymorphisms of UGT1A1 on belinostat disposition and pharmacodynamics.
Saturday, June 5, 2010 - 8:00 a.m. - 12:00 p.m.
General Poster Session - Leukemia, Myelodysplasia, and Transplantation - S Hall A2
Abstract #6607 - Phase 2 Study of the Histone Deacetylase (HDAC) Inhibitor Belinostat for the Treatment of Myelodysplastic Syndrome (MDS)
- Amanda Cashen, MD, et al.
Inhibition of HDAC can induce differentiation, growth arrest, and apoptosis in cancer cells. Belinostat is a potent inhibitor of both class I and class II HDAC enzymes. This Phase II study was undertaken to estimate the efficacy of belinostat for the treatment of MDS.
Adults with MDS (any WHO classification, plus at least 1 significant cytopenia if <5% bone marrow blasts) were eligible if they had ≤ 2 prior therapies for MDS, adequate renal and hepatic function, and ECOG 0-2. The primary endpoint was proportion of confirmed responses (CR, PR, and hematologic improvement [HI]) during the first 12 weeks of treatment. Patients were treated with belinostat 1000 mg/m2 as a 30 min IV infusion on days 1-5 of a 21 day cycle for 4 cycles. Responding patients could receive additional cycles until disease progression or unacceptable toxicity. 21 patients were to be enrolled in the first stage, and if 3 or more responses were observed, an additional 29 would be enrolled in stage 2.
21 patients (median age, 67 years) were enrolled, and all are evaluable. Patients were a median 13.4 months from diagnosis (range, 0.3-210) and had bone marrow blasts of <5%>
Although well-tolerated, belinostat does not have sufficient efficacy to warrant further investigation as a single agent in MDS. Supported by NCI N01-CM62205
Spectrum Pharmaceuticals, Inc.