Beleodaq (Belinostat) Receives FDA Approval for the Treatment of Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

Lisa A. Raedler, PhD, RPh

November 2014, Vol 4, No 7 - Drug Update


Peripheral T-cell lymphoma (PTCL) is a broad term that encompasses several rare and often aggressive types of non-­Hodgkin lymphoma.1 The Leukemia & Lymphoma Society estimates that between 10% and 15% of patients with non-­Hodgkin lymphoma have a T-cell lymphoma subtype.1 According to data from the Surveillance, Epidemiology, and End Results registry, the incidence of PTCL is less than 1 case per 100,000 individuals in the United States.2 PTCL is most often identified in patients aged ≥60 years.1

PTCL comprises multiple subtypes, each with unique clinical features.3 The most common PTCL subtypes include PTCL not otherwise specified (PTCL-NOS), anaplastic large-cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL); these subtypes account for approximately 70% of all PTCL cases in the United States.3

PTCL is typically characterized by enlarged lymph nodes in the neck, armpit, or groin.1 PTCL also affects the bone marrow, liver, spleen, stomach, and skin.1 Other symptoms of PTCL may include night sweats, fever, weight loss, and rash.1

Compared with patients with aggressive B-cell lymphomas, patients with PTCL have very poor outcomes.4 According to the International T-Cell Lymphoma Study, the overall survival at 10 to 15 years was 10% for patients with PTCL-NOS.5

Traditionally, treatment advances for patients with PTCL have been slower than treatment advances in other types of lymphoma.4 Patients with newly diagnosed PTCL are often treated with single-agent drugs and drug combinations that are used in B-cell lymphomas, including the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and the EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone) regimens.3,4 Because virtually all patients with PTCL will experience disease relapse, high-dose chemotherapy followed by autologous stem-cell transplantation is considered a treatment option for eligible patients.3

For relapsed or refractory PTCL, the relatively new treatment options include pralatrexate and romidepsin, both of which were approved by the US Food and Drug Administration (FDA) in 2009; older cytotoxic drugs and drug combinations include gemcita­bine-based combinations, DHAP (dexamethasone, cytarabine, and cisplatin), and ICE (ifosfamide, carboplatin, and etoposide).3

In 2011, the FDA approved brentuximab vedotin, an antibody-drug conjugate, for the treatment of patients with relapsed or refractory systemic ALCL.6 Clinical trials are under way to assess the activity of this monoclonal antibody in other subtypes of PTCL.3

The cost burden associated with PTCL is significant. A recent retrospective cost analysis evaluated claims data for commercially insured patients with Medicare supplemental benefits to identify patients with PTCL.7 A total of 1000 patients with PTCL were included in the analysis. Results showed that patients with PTCL were hospitalized more often and experienced longer lengths of hospital stays compared with the matched controls without PTCL.7 In addition, patients with PTCL utilized more physician office visits, pharmacy services, emergency department visits, and hospice care compared with the matched control group.7

The mean annual healthcare costs were $75,934 for patients with PTCL compared with $4661 for the matched controls.7 The medical costs for patients with PTCL were primarily driven by hospitalizations (ie, 32% of the overall costs) and pharmacy services (ie, 20% of the overall costs).7

Overall, 11% of patients with PTCL underwent stem-cell transplantation compared with none of the patients in the control group. The average cost of stem-cell transplantation exceeded $126,000 per patient.7

Belinostat: A New Treatment Option for PTCL

On July 3, 2014, the FDA approved belinostat (Beleodaq; Spectrum Pharmaceuticals) for the treatment of patients with relapsed or refractory PTCL.8 This approval was based on an open-label, single-arm, nonrandomized, international clinical trial conducted at 62 centers and included 129 patients with relapsed or refractory PTCL.8-10 The primary end point was overall response rate, including complete response and partial response, as assessed by an Independent Review Committee using the International Workshop Criteria.8-10

Belinostat, which is administered via intravenous infusion, was approved under the FDA’s accelerated approval program based on 2 surrogate end points—tumor response rate and duration of response.8,9 An improvement in survival or disease-­related symptoms has not yet been established.9

Mechanism of Action

Belinostat is a histone deacety­lase inhibitor.9 Histone deacety­lases are enzymes that facilitate the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins.9

In vitro, belinostat causes the accumulation of acetylated histones and other proteins, which results in cell apoptosis and/or cell-cycle arrest of some transformed cells. Belinostat demonstrates preferential cytotoxicity toward tumor cells relative to normal cells.9

Dosing and Administration

In patients with relapsed or refractory PTCL, the recommended dosage and schedule of belinostat is 1000 mg/m2 administered intravenously on day 1 to day 5 of a 21-day cycle. Treatment with belinostat should be repeated every 21 days until disease progression or until unacceptable toxicity.9

Belinostat should be infused over 30 minutes. The infusion time may be extended to 45 minutes if infusion-site pain or other symptoms attributable to the infusion occur.

In patients known to be homozygous for the UGT1A1*28 allele, the dose of belinostat should be reduced to 750 mg/m2.9

Belinostat is primarily metabolized by the liver. The data are insufficient to recommend a specific dose of belino­stat in patients with moderate or severe hepatic impairment or in patients with creatinine clearance ?39 mL/min.9

BELIEF: A Pivotal Phase 2 Clinical Trial

The safety and efficacy of belin­ostat in patients with relapsed or refracto­ry PTCL were demonstrated in the BELIEF clinical trial, a single-arm, open-­label, nonrandomized, international study.10 In this clinical trial, 129 patients with relapsed or refractory PTCL received belinostat 1000 mg/m2 administered intravenously over 30 minutes once daily on days 1 to 5 of a 21-day cycle.10 Patients received belinostat every 3 weeks until disease progression or until unacceptable toxicity.9,10

The primary efficacy end point was overall response rate, including complete response and partial response. Responses were assessed by an Independent Review Committee using the Cheson 2007 International Workshop Criteria.9,10 The duration of response was a secondary end point. Response assessments were performed every 6 weeks for the first 12 months of the trial, followed by every 12 weeks until 2 years from the initiation of the study treatment.9

The duration of response was measured from the first day of the documented response until disease progression or death. Disease progression was evaluated by the Independent Review Committee.9 The median duration of treatment with belinostat was 2 cycles (range, 1-33 cycles).9,10

Patient population
The median age of the 120 patients evaluable for efficacy in the BELIEF trial was 64 years, with 62 patients (52%) aged ≥65 years.9,10 The majority (52%) of the patients enrolled were male; 88% were white, and 77% had an Eastern Cooperative Oncology Group performance status of 0 or 1.9,10

Furthermore, 64% of the patients had confirmed PTCL-NOS, 18% had AITL, and 11% had anaplastic lymphoma kinase-1 negative ALCL.9 Overall, 17% of the patients had platelet counts <100,000/µL.9,10

The median time from the initial PTCL diagnosis was 12 months (range, 2.6-266.4 months). The median number of previous systemic treatments for PTCL was 2 (range, 1-8).9,10

Efficacy
Among patients receiving belino­stat, the overall response rate was 25.8% (Table 1). The response rate was 23.4% among patients with PTCL-NOS and 45.5% for patients with AITL.9,10

Table 1

Among patients whose disease responded to belinostat, the median duration of response was 8.4 months (95% confidence interval, 4.5-29.4).9,10 The median time to response was 5.6 weeks (range, 4.3-50.4 weeks). 10 Overall, 9 of the 120 patients proceeded to stem-cell transplantation after receiving belinostat.9,10

Adverse Reactions

The safety of belinostat was assessed in 129 patients with relapsed or refractory PTCL in the BELIEF clinical trial. Adverse reactions of any severity level were observed in 97% of the patients.9,10

Table 2 summarizes the adverse reactions associated with belin­ostat in patients with relapsed or refractory PTCL, regardless of causality.9

Table 2

A total of 61 patients (47%) experienced serious adverse reactions while receiving belinostat or within 30 days after their last dose of belinostat. The most common (>2%) serious adverse reactions included pneumonia, pyrexia, infection, anemia, increased creatinine clearance, thrombocytopenia, and multiorgan failure.9

Overall, 25 (19%) patients discontinued belinostat treatment as a result of adverse reactions, which included anemia, febrile neutropenia, fatigue, and multiorgan failure. In addition, 12% of patients receiving belinostat had to have dosage adjustments because of adverse reactions.9,10

Overall, 1 treatment-related­ death from hepatic failure was reported in the BELIEF trial.9,10 In addition, 1 treatment-related death from ventricular fibrillation was reported in another clinical trial with belino­stat monotherapy. Echocardiogram ­analysis did not identify a QT interval prolongation.9

Warnings and Precautions

Hematologic toxicity. Belinostat can cause thrombocytopenia, neutropenia, lymphopenia, and/or anemia. During treatment with belinostat, blood counts should be monitored weekly, and dosage modifications should be made as needed for hematologic toxicity.9

Infections
Pneumonia, sepsis, and other serious infections, including fatalities, have occurred with belinostat. Belinostat should not be administered to patients with an active infection.9

Hepatotoxicity
Fatal hepatotoxicity and liver function test abnormalities have occurred with belinostat. Liver function tests should be assessed before initiating treatment and before the start of each cycle. Dose interruptions or adjustments are recommended until recovery. Belinostat should be permanently discontinued if the hepatic toxicity is severe.9

Tumor lysis syndrome
Tumor lysis syndrome has been associated with belinostat in patients with relapsed or refractory PTCL. Patients with advanced-stage disease and/or high tumor burden should be monitored carefully for this syndrome.9

Gastrointestinal toxicity
Nausea, vomiting, and diarrhea have been observed with the use of belinostat. Antiemetic and antidiarrheal medications may be required.9

Embryofetal toxicity
Belinostat can cause fetal harm when administered to a pregnant woman; teratogenicity and/or embryofetal lethality can occur. If belinostat is used during pregnancy, or if the patient becomes pregnant while taking belinostat, she should be counseled about the potential hazard to the fetus.9

Use in Specific Populations

Pregnancy
Belinostat has been assigned pregnancy category D. Because it is a genotoxic drug and targets actively dividing cells, belin­o­stat may cause teratogenicity and/or embryofetal lethality. Women should avoid becoming pregnant while receiving belinostat.9

Nursing mothers
Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from belinostat, either nursing or belinostat should be discontinued based on the importance of the drug to the mother.9

Pediatric use
The safety of belino­stat in pediatric patients has not been established.9

Geriatric use
In the BELIEF clinical trial, approximately 50% of the patients were aged ≥65 years; these patients had a higher response rate to belinostat compared with patients aged <65 years (36% vs 16%, respectively). No meaningful differences in response rates were observed in patients aged ≥75 years compared with patients aged <75 years. No clinically meaningful differences in serious adverse reactions were observed based on patients’ age.9,10

Conclusion

Belinostat is an effective and safe treatment option for patients with relapsed or refractory PTCL. Belinostat joins pralatrexate and romidepsin as active single agents that are FDA approved for use in this rare and aggressive type of lymphoma. Similar to these previously approved agents, belinostat was approved under the FDA’s accelerated approval program based on surrogate end points. An improvement in survival or in disease-free survival has not yet been established for belinostat. Ongoing clinical trials may provide further survival outcomes.

The relatively low incidence of myelosuppression that was observed with belinostat in patients with relapsed or refractory PTCL warrants further investigation of this drug in combination with other therapies.

The safety and efficacy of be­lino­stat in combination with the CHOP regimen and with other agents are being explored for the treatment of patients with newly diagnosed PTCL and B-cell hematologic malignancies.11 The activity of belinostat is also being evaluated in solid tumors, including small-cell lung cancer.11




References

  1. The Leukemia & Lymphoma Society. Peripheral T-cell lymphoma facts. Revised July 2014. www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/lymphoma/pdf/
    peripheraltcelllymphomafacts.pdf
    . Accessed August 13, 2014.
  2. Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood. 2006;107:265-276.
  3. Lymphoma Research Foundation. Peripheral T-cell lymphoma (PTCL). 2012. www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6300159. Accessed August 13, 2014.
  4. Foss FM, Zinzani PL, Vose JM, et al. Peripheral T-cell lymphoma. Blood. 2011;117:6756-6767.
  5. Vose JM, Armitage J, Weisenburger D; for the International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26:4124-4130.
  6. US Food and Drug Administration. FDA approves Adcetris to treat two types of lymphoma. Press release. August 19, 2011. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm268781.htm. Accessed August 14, 2014.
  7. Potashman MH, Burudpakdee C, Wang W, et al. Clinical and economic burden of peripheral T-cell lymphoma in the United States. Blood. 2013;122. Abstract 2963.
  8. US Food and Drug Administration. FDA approves Beleodaq to treat rare, aggressive form of non-Hodg kin lymphoma. Press release. July 3, 2014. www.fda.gov/newsevents/newsroom/pressannouncements/ucm403929.htm. Accessed August 14, 2014.
  9. Beleodaq (belinostat) for injection [prescribing information]. Irvine, CA: Spectrum Pharmaceuticals, Inc; July 2014.
  10. O’Connor OA, Masszi T, Savage KJ, et al. Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL): results from the BELIEF trial. J Clin Oncol (Meeting Abstracts). 2013;31(15 suppl). Abstract 8507.
  11. ClinicalTrials.gov. Belinostat. Search results. http://clinicaltrials.gov/ct2/results?term=belinostat&Search=Search. Accessed August 15, 2014.