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 February 23, 2015, panobinostat (Farydak) was granted accelerated approval for use in combination with bortezomib (Velcade) and dexamethasone in the treatment of patients with multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent.1,2 As a condition of accelerated approval, the sponsor is required to conduct a trial to verify and describe the clinical benefit of panobinostat in patients with multiple myeloma.
Supporting Study
Approval was based on outcomes in a double-blind phase III trial in which 758 patients with relapsed multiple myeloma received oral panobinostat or placebo in combination with bortezomib and dexamethasone.2,3 Data supporting efficacy in the current indication were from a prespecified subgroup analysis of progression-free survival involving 193 patients (94 in the panobinostat group and 99 in the control group) who had received prior treatment with both bortezomib and an immunomodulatory agent and a median of two prior therapies. In this subgroup, the median age was 60 years (range, 28–79 years), and 76% had received at least two previous lines of treatment.
In the subgroup analysis, median progression-free survival was 10.6 months (95% confidence interval [CI] = 7.6–13.8 months) in the panobinostat group vs 5.8 months (95% CI = 4.4–7.1 months) in the control group (hazard ratio = 0.52, 95% CI = 0.36–0.76). Objective response rates were 58.5% vs 41.4%, including complete response in 8.5% vs 2.0% and near-complete response in 13.8% vs 7.1%.
How It Works
Panobinostat is a histone deacetylase (HDAC) inhibitor. These enzymes catalyze the removal of acetyl groups from lysine residues of histones and some nonhistone proteins. Inhibition of HDAC enzymatic activity results in increased acetylation of histone proteins, an epigenetic alteration that results in relaxing of chromatin and leads to transcriptional activation. In in vitro studies, panobinostat resulted in accumulation of acetylated histones and other proteins and induced cell-cycle arrest or apoptosis of some transformed cells. Panobinostat treatment resulted in increased levels of acetylated histones in mouse xenografts and exhibited greater cytotoxicity in tumor cells vs normal cells.
How It Is Given
The recommended starting dose of panobinostat is 20 mg once every other day for three doses per week in weeks 1 and 2 of each 21-day cycle for up to 8 cycles. In patients with clinical benefit who do not have unresolved severe or medically significant toxicity, continuation of treatment for an additional 8 cycles should be considered (total duration of 16 cycles over 48 weeks). The recommended dose of bortezomib is 1.3 mg/m2, and the recommended dose of dexamethasone is 20 mg. In cycles 1 through 8, the 21-day cycle consists of panobinostat on days 1, 3, and 5; bortezomib on days 1 and 4; and dexamethasone on days 1, 2, 4, and 5 of weeks 1 and 2, with no treatment during week 3. In cycles 9 through 16, the 21-day cycle consists of panobinostat on days 1, 3, and 5; bortezomib on day 1; and dexamethasone on days 1 and 2 of weeks 1 and 2, with no treatment during week 3.
Dose reduction of panobinostat for toxicity should occur in 5-mg increments; if a reduction to less than 10 mg three times per week is required, panobinostat should be discontinued. Panobinostat labeling provides specific instructions for dose modification for panobinostat and bortezomib for thrombocytopenia, neutropenia, and diarrhea and for panobinostat for anemia and nausea/vomiting.
The starting dose of panobinostat should be reduced to 15 mg in patients with mild hepatic impairment and to 10 mg in those with moderate hepatic impairment; panobinostat should be avoided in patients with severe hepatic impairment. The starting dose of panobinostat should be reduced to 10 mg when it is coadministered with strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, and lopinavir-ritonavir).
Safety Profile
In the total population of the phase III trial, the most common adverse events of any grade occurring at an incidence of at least 5% higher in the panobinostat vs control groups were diarrhea (68% vs 42%), fatigue (60% vs 42%), and nausea (36% vs 21%), and the most common grade 3 or 4 adverse events were diarrhea (25% vs 8%), fatigue (25% vs 12%), vomiting (7% vs 1%), and nausea (6% vs 1%). The most common grade 3 or 4 laboratory abnormalities were thrombocytopenia (67% vs 31%), lymphopenia (53% vs 40%), neutropenia (34% vs 11%), leukopenia (23% vs 8%), hypophosphatemia (20% vs 12%), anemia (18% vs 19%), hypokalemia (18% vs 7%), and hyponatremia (13% vs 7%).
Serious adverse events occurred in 60% vs 42%, with the most frequent in the panobinostat group being pneumonia (18%), diarrhea (11%), thrombocytopenia (7%), fatigue (6%), and sepsis (6%). Adverse events led to discontinuation of panobinostat in 36% of patients, with the most common causes being diarrhea, fatigue, and pneumonia. Electrocardiographic changes, including new T-wave changes and ST-segment depression, occurred in 64% vs 42% of patients, with arrhythmia occurring in 12% vs 5%. The incidence of death not due to progressive disease was 7% vs 3.2%.
Panobinostat carries boxed warnings for severe diarrhea and severe and fatal cardiac ischemic events, severe arrhythmia, and electrocardiographic changes. It also carries warnings/precautions for hemorrhage, including fatal and serious gastrointestinal and pulmonary hemorrhage, hepatotoxicity, and embryo-fetal toxicity.
Monitoring should include complete blood cell count; electrocardiography; measurement of serum electrolytes, including potassium and magnesium; and liver function tests prior to and during therapy. Prior to treatment, the platelet count should be ≥ 100 × 109/L, and the neutrophil count should be ≥ 1.5 × 109/L. Patients should receive transfusion for low platelet counts as needed.
Complete blood cell count should be monitored weekly or more often as clinically indicated. QT correction formula Fridericia (QTcF) should be < 450 msec prior to initiation of treatment; treatment should be interrupted for QTcF increases to ≥ 480 msec, with electrolyte abnormalities being corrected. Treatment should be permanently discontinued if QT prolongation does not resolve.
In the phase III trial, electrocardiography was performed at baseline and prior to initiation of each cycle for the first 8 cycles. Abnormal electrolyte values should be corrected before treatment. In the phase III trial, electrolyte monitoring was performed prior to the start of each cycle, at day 11 of cycles 1 through 8, and at the start of each cycle for cycles 9 through 16. The panobinostat dose should be adjusted if abnormal liver function tests are observed.
Women should be advised of potential hazard to the fetus and to avoid pregnancy while taking panobinostat. ■
References
1. U.S. Food and Drug Administration: Approved drugs. Panobinostat. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm435339.htm. Accessed March 4, 2015.
2. Farydak (panobinostat) capsules prescribing information, Novartis Pharmaceuticals, February 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205353s000lbl.pdf. Accessed March 4, 2015.
3. San-Miguel JF, Hungria VT, Yoon SS, et al: Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. Lancet Oncol 15:1195-1206, 2014.
