Date: 2012-06-29
Type of information: Initiation of preclinical development
phase: 2
Announcement: results
Company: Topotarget (Denmark)
Product: belinostat
Action
mechanism: histone deacetylase inhibitor. Belinostat is a small molecule HDAC inhibitor being investigated for its role in the treatment of a wide range of solid tumors and hematologic malignancies either as a single agent, or in combination with other active anti-cancer agents, including carboplatin, paclitaxel, doxorubicin, idarubicin, cis-retinoic acid, azacytidine, 5-FU, etoposide and bortezomib for injection. HDAC inhibitors represent a new mechanistic class of anti-cancer therapeutics that target HDAC enzymes, and have been shown to: Arrest growth of cancer cells (including drug-resistant subtypes); induce apoptosis, or programmed cell death; promote differentiation; inhibit angiogenesis; and sensitize cancer cells to overcome drug resistance when used in combination with other anti-cancer agents.
Disease: carcinoma of unknown primary (CUP)
Therapeutic area: Cancer - Oncology
Country: Europe, USA
Trial
details: The CLN-17 study in CUP is a randomized, controlled, open-label, multinational, comparative efficacy and safety phase II trial of Topotarget’s compound belinostat (PXD101) in combination with carboplatin and paclitaxel (BelCaP), compared to carboplatin and paclitaxel (CaP), in patients with previously untreated CUP.
Patients from group A received belinostat (1000 mg/m2) IV infusion once daily on days 1, 2, and 3, followed by belinostat 2000 mg (flat dose) orally once daily on days 4 and 5, every 3 weeks, in combination with paclitaxel (175 mg/m2) administered IV, following the infusion of belinostat on cycle day 3, and carboplatin (AUC 6)
Patients from group B received paclitaxel (175 mg/m2) as an IV infusion directly followed bycarboplatin (AUC 6) on cycle day 1 of a 3-week cycle.
The objective of the trial is to provide an estimate of the hazard ratio of treatment effect of BelCaP compared to CaP, with the primary study endpoint being defined as a PFS improvement of at least 60%.
The secondary efficacy objective was to evaluate and compare further efficacy parameters (overall survival, objective response rate according to RECIST criteria, time to response, duration of response, and time to progression) in the randomized treatment groups.
Latest
news: * On July 23, 2014, BioAlliance Pharma and Topotarget announced that the cross-border merger between the two companies is legally effective as of 22 July 2014 to create Onxeo, dedicated to orphan oncology diseases. * On June 29, 2012, Topotarget has announced top-line results for its randomized phase II belinostat trial in patients with cancer of unknown primary (CUP). Data from the primary analysis of the on-going phase II trial in CUP showed that the difference in progression-free survival (PFS) did not meet the protocol-specified primary endpoint. However, the objective response rate (ORR), one of the secondary endpoints, showed statistically significant benefit for the BelCaP arm in the intent to treat (ITT) analysis.
A total of 89 patients have been recruited at 23 sites throughout Europe and the US. The patient population was well-balanced between the two arms.
Based on the ITT analysis, the primary PFS endpoint did not meet statistical significance. The analysis of secondary endpoints showed statistically significant difference in ORR (BelCaP 43.2% versus CaP 22.2%, p-value of 0.025). Responses occurred earlier in the BelCaP arm. The evaluation of overall survival (OS) indicates a separation of the survival curves after approximately eight months with a benefit for the BelCaP arm. The triple combination of belinostat and CaP was well-tolerated.
•The primary efficacy analysis of PFS for BelCaP versus CaP in ITT did not show statistical significance at the 10% level for the stratified, one-sided log-rank test. P-value is 0.5526 and median PFS is 5.4 versus 5.3 months
•The ORR in ITT, 43.2% versus 22.2%, is statistically significant, p = 0.0252
•The OS result is statistically not significant but indicates that the survival curves for OS separate after 8 months of treatment in favor of belinostat with p = 0.2906
•BelCaP compared to CaP during the first 6 cycles and during the maintenance where belinostat was given as mono treatment was generally well-tolerated.
“There are no approved drugs for the treatment of patients with CUP and there remains a high unmet medical need. Despite the fact that the study did not meet the primary efficacy endpoint of PFS we do see encouraging clinical signals for time to response and response rate, which may translate into an improvement in overall survival seen on this trial. Maintenance treatment with oral belinostat was generally well-tolerated allowing for prolonged treatment past 6 cycles of the BelCaP combination. Further analysis is on-going to evaluate subsets of patients that may benefit from belinostat treatment. We continue to believe in the potential of belinostat, used either as monotherapy or in combination with other treatments. We remain committed to the clinical development of belinostat in both solid tumors and hematologic malignancies”, says Francois Martelet, CEO of Topotarget.
