FDA Grants Spectrum Pharmaceuticals Accelerated Approval of Beleodaq™ (belinostat) for Injection
Early Action before PDUFA date of
August 9, 2014follows Priority Review
- Beleodaq to be launched through Spectrum's existing sales force
- Beleodaq is expected to be available to patients in less than 3 weeks
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-center, 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, tumor 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 15% of all
"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
"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
"Interestingly, Beleodaq was shown to have an Overall Response Rate of 25.8% with a high response rate (45.5%) in patients with Angioimmunoblastic T-cell Lymphoma, one of the common PTCL subtypes. In addition, 17% of the patients enrolled in this trial had low Baseline platelet counts ( < 100,000/mm3) and tolerated therapy with some (15%) 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 characterize the efficacy and safety of the Beleodaq
combination versus CHOP alone, is required by
The BELIEF study was an open-label, single-arm, non-randomized, international trial conducted at 62 centers 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% (n = 31; 95% CI, 18.3 - 34.6); with rates of 23.4% for PTCL, NOS and 45.5% 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 (95% CI: 4.5 - 29.4).
Data from the BELIEF study demonstrated that the most common adverse events (AEs) reported with Beleodaq ( > 25%) were nausea (42%), fatigue (37%), pyrexia (35%), anemia (32%), and vomiting (29%). Myelosuppression was observed with an overall rate of anemia of 32%, thrombocytopenia of 16.3% and neutropenia of 9.3%; Grade 3/4 adverse reactions were reported in 10.9%, 7.0% and 6.2% of patients, respectively. Sixty-one patients (47.3%) experienced serious adverse reactions while taking Beleodaq or within 30 days after their last dose of Beleodaq. The most common serious adverse reactions ( > 2%) were pneumonia (7%), pyrexia (5%), infection (3%), anemia (2%), increased creatinine (2%), thrombocytopenia (2%), and multi-organ failure (2%).
Beleodaq is a histone deacetylase (HDAC) inhibitor. HDACs catalyze 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 tumor cells compared to normal cells. Belinostat inhibited the enzymatic activity of histone deacetylases at nanomolar concentrations ( < 250 nM).
Important Beleodaq Safety Information
Warnings and Precautions
- Beleodaq can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia; monitor blood counts weekly during treatment, and modify dosage as necessary.
- Serious and sometimes fatal infections, including pneumonia and sepsis, have occurred with Beleodaq. Do not administer Beleodaq to patients with an active infection. Patients with a history of extensive or intensive chemotherapy may be at higher risk of life threatening infections.
- Beleodaq can cause fatal hepatotoxicity and liver function test abnormalities. Monitor liver function tests before treatment and before the start of each cycle. Interrupt or adjust dosage until recovery, or permanently discontinue Beleodaq based on the severity of the hepatic toxicity.
- Tumor lysis syndrome has occurred in Beleodaq-treated patients in the clinical trial of patients with relapsed or refractory PTCL. Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions.
- Nausea, vomiting and diarrhea occur with Beleodaq and may require the use of antiemetic and antidiarrheal medications.
- Beleodaq can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid pregnancy while receiving Beleodaq. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazard to the fetus.
- The most common adverse reactions observed in the trial in patients with relapsed or refractory PTCL treated with Beleodaq were nausea (42%), fatigue (37%), pyrexia (35%), anemia (32%), and vomiting (29%).
- Beleodaq is primarily metabolized by UGT1A1. Avoid concomitant administration of Beleodaq with strong inhibitors of UGT1A1.
Use in Specific Populations
- It is not known whether Beleodaq is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Beleodaq, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother.
Please see Beleodaq Full Prescribing Information at www.beleodaq.com.
FOLOTYN, (pralatrexate injection), a folate analogue metabolic
inhibitor, was discovered by
Important FOLOTYN® Safety Information
Warnings and Precautions
FOLOTYN may suppress bone marrow function, manifested by thrombocytopenia, neutropenia, and anemia. Monitor blood counts and omit or modify dose for hematologic toxicities.
Mucositis may occur. If greater-than or equal to Grade 2 mucositis is observed, omit or modify dose. Patients should be instructed to take folic acid and receive vitamin B12 to potentially reduce treatment-related hematological toxicity and mucositis.
Fatal dermatologic reactions may occur. Dermatologic reactions may be progressive and increase in severity with further treatment. Patients with dermatologic reactions should be monitored closely, and if severe, FOLOTYN should be withheld or discontinued. Tumor lysis syndrome may occur. Monitor patients and treat if needed.
FOLOTYN can cause fetal harm. Women should avoid becoming pregnant while being treated with FOLOTYN and pregnant women should be informed of the potential harm to the fetus.
Use caution and monitor patients when administering FOLOTYN to patients with moderate to severe renal function impairment.
Elevated liver function test abnormalities may occur and require monitoring. If liver function test abnormalities are greater-than or equal to Grade 3, omit or modify dose.
The most common adverse reactions were mucositis (70%), thrombocytopenia (41%), nausea (40%), and fatigue (36%). The most common serious adverse events are pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia.
Use in Specific Patient Population
Nursing mothers should be advised to discontinue nursing or the drug, taking into consideration the importance of the drug to the mother.
Co-administration of drugs subject to renal clearance (e.g., probenecid, NSAIDs, and trimethoprim/sulfamethoxazole) may result in delayed renal clearance.
Please see FOLOTYN Full Prescribing Information at www.FOLOTYN.com.
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