Date: 2015-06-23
Type of information: Presentation of results at a congress
phase: 2
Announcement: publication of results in the Journal of Clinical Oncology (JCO)
Company: Onxeo (France) Spectrum Pharmaceuticals (USA)
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.
Belinostat is also currently being evaluated in multiple clinical trials using IV and oral formulation as a potential treatment for cancer of unknown primary (CUP), a randomized, controlled Ph II trial, ovarian cancer, small cell lung cancer, thymoma, liver, soft tissue sarcoma, lymphoma, AML, and Myelodysplastic Syndrome (MDS), either alone or in combination with other anti-cancer therapies. Continuous intravenous administration (CIV) is being evaluated in clinical trials in solid tumours as well as in AML. Topotarget has a Clinical Trial Agreement (CTA) with the NCI to clinical studies on belinostat in order to better understand its anti-tumor activity.
Disease: peripheral T-cell lymphoma (PTCL)
Therapeutic area: Cancer - Oncology
Country: Europe, USA, Israel and South Africa
Trial
details: BELIEF is a registrational trial, pivotal trial, under a SPA. Belinostat is evaluated as monotherapy for relapsed and refractory peripheral T-cell lymphoma, an indication which has been granted Orphan Drug and Fast Track Designation by the FDA. The registrational trial is an open-label, multicenter, single arm efficacy and safety trial in patients with relapsed or refractory PTCL, who have failed at least one prior systemic therapy. The primary endpoint is centrally reviewed objective overall response rate (ORR). The trial was initiated in December 2008 and recruitment was completed with 129 patients in September 2011. In total, the study included approximately 100 clinical centers globally. (NCT00865969)
Latest
news: * On June 23, 2015, Onxeo announced the publication of results from the pivotal BELIEF (PXD101-CLN-19) study which was selected as a Rapid Communication in the Journal of Clinical Oncology (JCO), the journal of the American Society of Clinical Oncology. The study, led by Dr. Owen O’Connor from the Center for Lymphoid Malignancies, Department of Medicine, Columbia University Medical Center, New York, USA, showed that monotherapy with Beleodaq® (belinostat) produced complete and durable responses with manageable toxicity in patients with relapsed or refractory peripheral T-cell lymphoma (R/R PTCL) across the major subtypes, irrespective of the number or type of prior therapies. * 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 March 5, 2013, Topotarget has announced final top-line data of the BELIEF trial. These data confirm that the primary endpoint was met for the belinostat pivotal trial for patients with relapsed or refractory peripheral T-cell lymphoma with an encouraging objective response rate. Top-line data show an objective response rate (ORR) in the efficacy analysis set which is above the protocol criterion for a positive outcome of the trial. Belinostat thus has an ORR that is on par with the accelerated approved drugs Folotyn™ and Istodax®. A Special Protocol Assessment agreement with the FDA required the CLN-19 BELIEF trial to reach an ORR of at least 20%. Final data have been submitted for presentation to the 2013 ASCO annual meeting.
The BELIEF study evaluated the efficacy and tolerability of Beleodaq® as a single agent in R/R PTCL. This study was an open-label, single-arm, non-randomized, international trial conducted at 62 centers that enrolled 129 patients with R/R PTCL, who had progressed following ?1 prior therapy with a median number of prior therapies of two (1-8). These patients received Beleodaq® (1,000 mg/m2) as daily 30-minute infusions on Days 1-5 every 21 days until disease progression or unacceptable toxicity. The primary endpoint of the BELIEF study was objective response rate (ORR) as assessed centrally by an Independent Review Committee using the International Working Group (IWG) criteria.
The ORR in the 120 evaluable patients was 25.8% (31 patients) (95% CI 18.3 - 34.6), including 13 Complete Responses (10.8%) (95% CI 5.9 - 17.8), and 18 Partial Responses (15%) (95% CI 9.1 - 22.7). Single-agent belinostat was shown to induce complete and partial responses even in poor prognosis R/R PTCL subtypes, e.g. angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large-cell lymphoma (ALK). Secondary endpoints included a median duration of response of 13.6 months by IWG criteria and 8.4 months to disease progression or death, with the longest ongoing patient at ?36 months.
The most common Grade 3/4 adverse events were anemia (10.8%), thrombocytopenia (7%), dyspnea (6.2%), and neutropenia. In this pivotal study, monotherapy with Beleodaq® produced complete and durable responses with manageable toxicity in patients with R/R PTCL across the major disease subtypes, irrespective of the number or type of prior therapies and with a low incidence of Grade 3/4 thrombocytopenia.
Belinostat is currently being developed jointly by Topotarget and Spectrum Pharmaceuticals. Spectrum possesses the commercial rights to market belinostat in North America and India.
A New Drug Application (NDA) for belinostat in PTCL is expected to be filed with the FDA by Spectrum in mid-2013.
* On January 24, 2013, Topotarget announced that preliminary safety data from the BELIEF trial in PTCL, presented at the T-Cell Lymphoma Forum 2013 in San Francisco, USA, showed that belinostat has a favorable safety profile and that the compound has the potential to become a well-tolerated alternative for the treatment of PTCL. The favorable safety outcome from this trial, as well as experience from earlier belinostat trials, shows that full doses of belinostat can be combined with other cytotoxic regimens making combination therapy for cancer patients feasible. The low incidence of myelosuppression is of special notice as this offers the opportunity to combine belinostat with other cytostatic agents for the treatment of patients with PTCL.
Total of 129 patients, 53% men, median age 63 yr (range 29–81 yr) were treated. The median number of cycles was 2 (range 1–31). One dose reduction occurred in 11% of patients and 1% had two dose reductions. AEs resulted in dose delays in 21% of patients, and 18% discontinued for AEs, including death. Grade 3/4 non hematologic AEs observed in >3% of patients included asthenia/fatigue 9%, pneumonia 7%, dyspnea 6%, infection 4%, febrile neutropenia 4%, pruritus 3%, deep vein thrombosis 3%, and hypotension 3%. Grade 3 QTc prolongation was reported in 2% of patients. Grade 3/4 hematologic toxicities were: thrombocytopenia 6% in patients with platelet counts of ?100,000, anemia, leukopenia and neutropenia each 13%. A total of 23 patients (18%) died on treatment or within 30 days of last dose, predominantly due to PTCL progression. No death was attributed to belinostat.
* On September 26, 2011, Topotarget and Spectrum Pharmaceuticals have announced that they have now completed the enrollment of a minimum of 100 evaluable relapsed or refractory peripheral T-cell lymphoma (PTCL) patients in the PTCL registration trial. Belinostat, a novel HDAC inhibitor, is being evaluated, under a Special Protocol Assessment (SPA), as monotherapy treatment for relapsed or refractory PTCL, an indication for which it has been granted Orphan Drug and Fast Track Designation by the FDA. Central review of pathology for all patients entered into the trial is currently ongoing. Spectrum Pharmaceuticals plans to file a New Drug Application in 2012.
* On March 28, 2011, Topotarget has announced independent Data Monitoring Committee (DMC)recommends continuation of the belinostat pivotal BELIEF study in PTCL patients.The interim safety assessment and futility analysis were performed after the first 45 patients have entered the study and have received at least one dose of belinostat. The PTCL diagnosis had to be confirmed by an independent international pathology review committee for treated patients to be evaluable. No safety concerns were raised. The DMC recommends that the study continues according to the protocol until 100 evaluable patients are enrolled.
