Panobinostat (Farydak)

Approved in combination with bortezomib (Velcade) and dexamethasone for patients with previously treated multiple myeloma.

Works by inhibiting the activity of enzymes, known as histone deacetylases (HDACs).

Inhibition of HDAC enzyme acivity increases acetylation of histone proteins resulting in epigenetic alteration of chromatin and transcriptional activation.

Use results in accumulation of acetylated histones and other proteins inducing cell-cycle arrest aor apoptosis of transfromed cells.

The first HDAC inhibitor approved to treat multiple myeloma.

It is intended for patients who have received at least two prior standard therapies, including bortezomib and an immunomodulatory agent.

It is to be used in combination with bortezomib, and dexamethasone.

Shown to slow the progression of multiple myeloma.

The approval was based on a prespecified subgroup analysis from the PANORAMA-1 trial for patients who received prior treatment with bortezomib and an immunomodulatory (IMiD) agent.

Phase III trial included 193 patients who were pretreated with bortezomib and an IMiD the median progression-free survival (PFS) with panobinostat was 10.6 months versus 5.8 months with placebo.

Approved along with a Risk Evaluation and Mitigation Strategy (REMS) for severe diarrhea, and severe and fatal cardiac events, arrhythmias and electrocardiogram (ECG) changes.

The PANORAMA-1 study randomized 768 patients at a median age of 63 with relapsed multiple myeloma to receive bortezomib and dexamethasone with panobinostat (n = 387) or placebo.

In phase 1, panobinostat was administered orally at 20 mg 3 times a week for two weeks in a 3-week cycle. Bortezomib was administered intravenously at 1.3 mg/m2 twice weekly for 2 weeks along with 20-mg dexamethasone.

In this study patients who responded to therapy or had stable disease without grade 2 or higher adverse events in phase 1 continued to phase 2, where the bortezomib schedule was reduced to 2 doses every 3 weeks. (44% of patients in the panobinostat arm continued to phase 2 of treatment compared with 50% with placebo ).

Treatment with the 3-drug panobinostat regimen improved the primary endpoint of PDS by 3.9 months compared with bortezomib and dexamethasone alone.

The median PFS was 12 months in the panobinostat arm compared with 8.1 months with placebo, and the median PFS was 9.9 months with panobinostat versus 7.7 months with placebo.

The overall response rate was 61% with panobinostat versus 55% in the placebo arm, and the median duration of response with panobinostat was 13.1 versus 10.9 months with placebo.

The complete response rate was 12% versus 7% and the duration of response was 11.8 versus 9.7 months, for panobinostat and placebo, respectively.

Among patients who completed treatment phase 1 only, the median PFS was 14.7 months in the panobinostat arm compared with 12.1 months in the control group. ORR was 85.2% versus 80.2%, respectively, with near complete response (nCR)/CR rates of 46.2% versus 25.0%. In phase 2, the median PFS was 17.6 months in the panobinostat arm compared with 15.6 months in the control group. The ORR was 88.2% versus 91.2%, respectively, with nCR/CR rates of 52.9% versus 38.2%.

Improves progression-free survival in relapsed multiple myeloma patients who have received at least two prior regimens, including bortezomib and an IMiD.

The most frequently reported grade 3/4 AEs in the panobinostat versus the placebo arm were thrombocytopenia (67.4% vs 31.4%), lymphopenia (53.2% vs 39.8%), neutropenia (34.5% vs 11.4%), and diarrhea (25.5% vs 8%).

Additionally, 59 percent of panobinostat-treated participants saw their cancer shrink or disappear after treatment, versus 41 percent in those receiving bortezomib and dexamethasone.

Starting dose is 20mg once every other day for 3 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 significant toxicity, an additional 8 cycles should be considered for a total of 16 cycles over 48 weeks.

Dose reduction of Panobinostat for toxicity should be in 5 mg increments and if her reduction to less than 10 mg 3 times a week is required the drug should be discontinued.

The starting drug dose should be reduced 10- 15 mg in patients with hepatic impairment, and should be reducedto 10 mg 1: Administered with strong CYP3A inhibitorssuch as clarithromycin, boceprevir, Kew, ketoconazole, itraconazole, and lopinavir-rotonavir.

Panobinostat may cause severe diarrhea, cardiac events, arrhythmias and electrocardiogram (ECG) changes.

Approved with a Risk Evaluation and Mitigation Strategy (REMS).

Most common side effects are diarrhea, tiredness, nausea, swelling in the arms or legs, decreased appetite, weight loss, fever, vomiting and weakness.

The most common laboratory abnormalities are hypophosphatemia, hypokalemia, hyponatremia, increased creatinine, thrombocytopenia, leukopenia and anemia.

Associated with risk of bleeding in the gastrointestinal tract and the lungs, and hepatotoxicity.

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