Spectrum Pharmaceuticals, a biotechnology company with fully integrated commercial and drug development operations with a primary focus in hematology and oncology, announced that the US Food and Drug Administration (US FDA) has granted Accelerated Approval of Beleodaq for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is approved under accelerated approval based on Tumour Response Rate and Duration of Response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

Beleodaq was approved by the FDA on July 3rd, nearly 5 weeks before the PDUFA date (August 9th). This indication was approved based on data from the multi-centre, single-arm BELIEF trial in 120 evaluable patients, refractory to or who had failed at least one prior systemic therapy. In this trial, Beleodaq was associated with hematologic toxicity, infections, hepatotoxicity, Tumour lysis syndrome, gastrointestinal toxicity, and embryo-fetal toxicity.

PTCL comprises a group of rare and aggressive non-Hodgkin's Lymphomas (NHL) that develop from mature T-cells and accounts for approximately 10 to 15per cent of all NHL cases in the United States. These patients generally have a poor prognosis with a low response rate (25-27per cent) to available treatment options, and commonly experience repeated treatment failures until drug resistance or death. Therefore, there has been an important unmet medical need for these patients with PTCL for additional new treatment options that are specifically effective for this disease.

"This FDA approval enables us to help address this unmet medical need, and provide a new treatment option for patients with this difficult-to-treat and ultimately fatal disease," said Rajesh C. Shrotriya, MD, chairman and chief executive officer of Spectrum Pharmaceuticals. "First with Folotyn (pralatrexate injection) and now with Beleodaq, we are very proud to be able to offer patients and clinicians two approved treatment options for R/R PTCL, and be a leader in the treatment of T-cell lymphomas. We will be able to effectively leverage our existing Hematology clinical and sales infrastructure to expedite the launch of Beleodaq. Now with a total of five approved hematology/oncology drugs and a strong and maturing development pipeline, Spectrum is well positioned for continued future growth."

"Peripheral T-cell lymphoma (PTCL) is a poor prognosis subtype of non-Hodgkin's lymphoma with no accepted standard of care," said Owen A. O'Connor, MD, PhD, Director of Lymphoid Malignancies, Professor of Medicine and Experimental Therapeutics at Columbia Medical Centre, New York Presbyterian Medical Center, one of the lead investigators in the BELIEF study. "Relapse is common after initial treatment, and there are limited options for patients in 2nd line and beyond. Histone deacetylase inhibitors have emerged as one promising class of drugs for patients faced with this disease. One interesting observation in the study was the tolerability of Beleodaq in these heavily treated patients. Beleodaq was associated with myelosuppression with an overall rate of anaemia of 32per cent, thrombocytopenia of 16.3per cent and neutropenia of 9.3per cent and Grade 3/4 adverse reactions were reported in 10.9per cent, 7.0per cent and 6.2per cent of patients, respectively. The associated severity of hematologic toxicities may prove to be useful in previously treated patients who have poor bone marrow reserve."

"Interestingly, Beleodaq was shown to have an Overall Response Rate of 25.8 per cent with a high response rate (45.5 per cent) in patients with Angioimmunoblastic T-cell Lymphoma, one of the common PTCL subtypes. In addition, 17per cent of the patients enrolled in this trial had low Baseline platelet counts ( < 100,000/mm3) and tolerated therapy with some (15per cent) attaining partial and complete responses. I believe Beleodaq will be a valuable new option for physicians who treat patients with relapsed or refractory PTCL. This safety profile makes it a potential candidate for the development of new combination treatment paradigms for patients with PTCL," added Dr. O'Connor.

A review of data from a planned confirmatory Phase III trial of Beleodaq in combination with CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone), to characterise the efficacy and safety of the Beleodaq combination versus CHOP alone, is required by FDA to convert this Accelerated Approval to a Full Approval.

The BELIEF study was an open-label, single-arm, non-randomised, international trial conducted at 62 centres that enrolled 129 patients with relapsed or refractory PTCL; 120 patients had histologically confirmed PTCL by central review and were evaluable for efficacy. Patients received treatment with Beleodaq (1,000 mg/m2), administered over 30 minutes via IV infusion, once daily on Days 1-5 of a 21-day cycle. Treatment cycles were repeated every three weeks until disease progression or unacceptable toxicity.

The primary efficacy endpoint of the BELIEF study was Overall Response Rate (complete and partial responses) as assessed by an Independent Review Committee (IRC) using the International Workshop Criteria (IWC) (Cheson, 2007). The key secondary efficacy endpoint was Duration of Response. In all evaluable patients (N = 120) treated with Beleodaq, the Overall Response Rate (CR + PR) per central review using IWC was 25.8 per cent (n = 31; 95per cent CI, 18.3 - 34.6); with rates of 23.4per cent for PTCL, NOS and 45.5per cent for AITL, the two largest subtypes enrolled. The median Duration of Response based on the first date of response to disease progression or death was 8.4 months (95per cent CI: 4.5 - 29.4).

Data from the BELIEF study demonstrated that the most common adverse events (AEs) reported with Beleodaq ( > 25per cent) were nausea (42per cent), fatigue (37per cent ), pyrexia (35per cent), anaemia (32per cent), and vomiting (29per cent ). Myelosuppression was observed with an overall rate of anaemia of 32per cent, thrombocytopenia of 16.3per cent and neutropenia of 9.3per cent; Grade 3/4 adverse reactions were reported in 10.9per cent, 7.0per cent and 6.2per cent of patients, respectively. Sixty-one patients (47.3per cent) experienced serious adverse reactions while taking Beleodaq or within 30 days after their last dose of Beleodaq. The most common serious adverse reactions ( > 2per cent) were pneumonia (7per cent), pyrexia (5per cent, infection (3 per cent, anaemia (2per cent), increased creatinine (2per cent ), thrombocytopenia (2per cent), and multi-organ failure (2per cent).

Beleodaq is a histone deacetylase (HDAC) inhibitor. HDACs catalyse the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. In vitro, belinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Belinostat shows preferential cytotoxicity towards Tumour cells compared to normal cells. Belinostat inhibited the enzymatic activity of histone deacetylases at nanomolar concentrations ( < 250 nM).