In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms,
administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On July 3, 2014, belinostat (Beleodaq) was granted accelerated approval for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma.1,2 As a condition of accelerated approval, the U.S. Food and Drug Administration requires the sponsor to conduct a dose-finding trial of belinostat combined with CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) and a subsequent phase III trial comparing belinostat in combination with CHOP vs CHOP alone. Approval was based on tumor response rate and duration of response. Improvement in survival or disease-related symptoms has not been demonstrated.
Supporting Trial
Approval was based on the results of a multicenter, single-arm trial of 120 evaluable patients with peripheral T-cell lymphoma refractory to or relapsing after prior treatment. The study included patients with baseline platelet counts < 100,000/µL. They had a median age of 64 years (range, 29–81 years), 52% were male, 88% were white, 77% had Eastern Cooperative Oncology Group performance status of 0 or 1, 83% had a platelet count ≥ 100,000/µL, and peripheral T-cell lymphoma subtypes were unspecified in 64%, angioimmunoblastic T-cell lymphoma in 18%, ALK1-negative anaplastic large cell lymphoma in 11%, and other in 7%. The median time from peripheral T-cell lymphoma diagnosis was 12 months, and the median number of prior treatments was 2 (range, 1–8).
Belinostat was given via intravenous infusion at 1,000 mg/m2 once daily on days 1 to 5 of a 21-day cycle. The overall response rate on independent review was 25.8% (95% confidence interval [CI] = 18.3%–34.6%), with complete and partial response being observed in 10.8% and 15.0% of patients. Median response duration was 8.4 months (95% CI = 4.5–29.4 months). Patients aged ≥ 65 years had a higher response rate compared with those aged < 65 years (36% vs 16%), with no meaningful difference observed between patients aged ≥ 75 vs < 75 years.
How It Works
Belinostat is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins. Histones act to package DNA into nucleosomes in eukaryotic cell nuclei, with gene expression being dependent on cellular control of the coiling and uncoiling of DNA around the histones.
Studies in vitro show that belinostat causes the accumulation of acetylated histones and other proteins, affecting gene expression and inducing cell-cycle arrest or apoptosis of transformed cells. Belinostat shows preferential cytotoxicity for tumor cells vs normal cells. The drug inhibits HDAC activity at nanomolar concentrations (< 250 nM).
How It Is Given
The recommended dose of belinostat is 1,000 mg/m2 via intravenous infusion over 30 minutes once daily on days 1 to 5 of a 21-day cycle. Cycles can be repeated until disease progression or unacceptable toxicity.
Patients must have an absolute neutrophil count ≥ 1.0 × 109/L, a platelet count ≥ 50 × 109/L, and nonhematologic toxicity ≤ grade 2 before the start of each cycle and before resuming treatment following interruption for toxicity. The dose should be decreased by 25% to 750 mg/m2 for neutrophil count < 0.5 × 109/L, platelet count < 25 × 109/L, or grade 3 or 4 nonhematologic toxicity. Treatment should be discontinued for recurrence of these events after two dose reductions.
Belinostat is primarily metabolized by UGT1A1. Concomitant administration with strong inhibitors of UGT1A1 (ie, indinavir and atazanavir) should be avoided and the starting dose should be reduced to 750 mg/m2 in patients homozygous for the
UGT1A1*28 allele. Patients with moderate and severe hepatic impairment were excluded from clinical trials of belinostat, and there are insufficient data to recommend a belinostat dose in such patients. Approximately 40% of the belinostat dose is renally excreted; there are insufficient data to recommend a belinostat dose in patients with creatinine clearance ≤ 39 mL/min.
Safety Profile
In the trial supporting approval, the most common adverse events of any grade were nausea (42%), fatigue (37%), pyrexia (35%), anemia (32%), and vomiting (29%); thrombocytopenia occurred in 16%. Grade 3 or 4 adverse events occurred in 61% of patients, with the most common being anemia (11%), thrombocytopenia (7%), dyspnea (6%), and fatigue (5%).
Serious adverse events occurred in 47% of patients, with the most common (> 2%) being pneumonia, pyrexia, infection, anemia, increased creatinine, thrombocytopenia, and multiorgan failure. No clinically meaningful differences in serious adverse events were observed in patients aged < 65 vs ≥ 65 years or < 75 vs ≥ 75 years.
Adverse events led to dose reduction in 12% of patients and to discontinuation of treatment in 19%, with discontinuation most commonly due to anemia, febrile neutropenia, fatigue, and multiorgan failure. One treatment-related death due to hepatic failure was reported. One patient with baseline hyperuricemia and bulky disease had grade 4 tumor lysis syndrome during the first cycle of treatment and died due to multiorgan failure. A treatment-related death from ventricular fibrillation was reported in another monotherapy clinical trial.
Belinostat carries warnings/precautions for thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; serious and fatal infections (eg, pneumonia and sepsis); hepatotoxicity; tumor lysis syndrome; and embryo-fetal toxicity. Complete blood counts should be monitored at baseline and weekly and serum chemistry tests, including renal and hepatic function tests, should be performed prior to the start of each cycle.
Patients with advanced disease or high tumor burden should be monitored for tumor lysis syndrome, with appropriate precautions taken. Women should be advised of potential harm to the fetus and to avoid pregnancy during treatment. ■
References
1. U.S. Food and Drug Administration: Belinostat. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm403960.htm.
2. BELEODAQ® (belinostat) for injection prescribing information, Spectrum Pharmaceuticals, Inc, July 2014. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2014/206256lbl.pdf.
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).
