- Recommended dose of panobinostat: 20 mg PO once every other day for 3 doses/week in Weeks 1 and 2 or on Days 1, 3, 5, 8, 10, and 12 of each 21-day cycle for up to 8 cycles
- Recommended dose of bortezomib (BTZ): 1.3 mg/m2 given as an injection
- Recommended dose of dexamethasone: 20 mg PO per scheduled day, on a full stomach
- Treatment can be continued for an additional 8 cycles for patients with clinical benefit who do not experience unresolved severe or medically significant toxicity. The total duration of treatment may be up to 16 cycles (48 weeks)
Recommended dosing schedule of panobinostat in combination with bortezomib and dexamethasone
Cycles 1-8 (each cycle of 3 weeks or 21 days)- Panobinostat:
- Days 1, 3, 5 and 8, 10, 12
- Rest Days: 2, 4, 6, 7 and 9, 11, 13, 14
- Week 3: Rest period
- Bortezomib:
- Days 1, 4 and 8, 11
- Rest Days: 2, 3, 5, 6, 7 and 9, 10, 12, 13, 14
- Week 3: Rest period
- Dexamethasone:
- Days 1, 2, 4, 5 and 8, 9, 11, 12
- Rest Days: 3, 6, 7 and 10, 13, 14
- Week 3: Rest period
- Panobinostat:
- Days 1, 3, 5 and 8, 10, 12
- Rest Days: 2, 4, 6, 7 and 9, 11, 13, 14
- Week 3: Rest period
- Bortezomib:
- Days 1 and 8
- Rest Days: 2, 3, 4, 5, 6, 7 and 9, 10, 11, 12, 13, 14
- Week 3: Rest period
- Dexamethasone:
- Days 1, 2 and 8, 9
- Rest Days: 3, 4, 5, 6, 7 and 10, 11, 12, 13, 14
- Week 3: Rest period
Note:
- Monitor complete blood count, ECG, and serum electrolytes prior to initiating panobinostat and during treatment
Dose modifications based on toxicity
- Thrombocytopenia
- Platelets < 50 x 109/L:
- Panobinostat: Maintain dose and monitor platelet counts at least weekly
- BTZ: Maintain dose
- Platelets < 50 x 109/L with bleeding and Platelets < 25 x 109/L:
- Panobinostat: Interrupt dose. Monitor platelet counts at least weekly until
50 x 109/L, then restart at reduced dose - BTZ: Interrupt dose until thrombocytopenia resolves to 75 x 109/L; if only 1 dose was omitted prior to correction to these levels, restart at same dose; if 2 or more doses were omitted consecutively or within the same cycle, restart at a reduced dose
- Neutropenia
- Absolute neutrophil count (ANC) 0.75-1 x 109/L:
- Panobinostat: Maintain dose
- BTZ: Maintain dose
- ANC 0.5-0.75 x 109/L (2 or more occurrences):
- Panobinostat: Interrupt dose until ANC 1 x 109/L, then restart at same dose
- BTZ: Maintain dose
- ANC < 1 x 109/L with febrile neutropenia:
- Panobinostat: Interrupt dose until febrile neutropenia resolves and ANC 1 x 109/L, then restart at reduced dose
- BTZ: Interrupt dose until febrile neutropenia resolves and ANC 1 x 109/L; if only 1 dose was omitted prior to correction to these levels, restart at the same dose; if 2 or more doses were omitted consecutively or within the same cycle, restart at a reduced dose
- ANC < 0.5 x 109/L:
- Panobinostat: Interrupt dose until ANC 1 x 109/L, then restart at reduced dose
- BTZ: Interrupt dose until ANC 1 x 109/L; if only 1 dose was omitted prior to correction to these levels, restart at the same dose; if 2 or more doses were omitted consecutively or within the same cycle, restart at a reduced dose
- Anemia
- Hb < 8 g/dL:
- Panobinostat: Interrupt dose until Hb 10 g/dL; restart at reduced dose
- Diarrhea
- Moderate diarrhea (4-6 stools/day):
- Panobinostat: Interrupt dose until resolved; restart at same dose
- BTZ: Interrupt dose until resolved; restart at same dose
- Severe diarrhea ( 7 stools/day, IV fluids/hospitalization required):
- Panobinostat: Interrupt dose until resolved; restart at reduced dose
- BTZ: Interrupt dose until resolved; restart at reduced dose
- Life-threatening diarrhea:
- Panobinostat: Discontinue permanently
- BTZ: Discontinue permanently
- Nausea or vomiting
- Severe nausea:
- Panobinostat: Interrupt dose until resolved; restart at reduced dose
- Severe/life-threatening vomiting:
- Panobinostat: Interrupt dose until resolved; restart at reduced dose
- Myelosuppression
- Thrombocytopenia:
- Panobinostat: Discontinue if thrombocytopenia does not improve despite the recommended dose modification or if repeated platelet transfusions are required
- Neutropenia (Grade 3 or 4):
- Reduce panobinostat dose and/or use growth factors (e.g., G-CSF). Discontinue panobinostat if neutropenia does not improve despite dose modifications, G-CSF, or in case of severe infection
- Adverse drug reactions
- Grade 2 toxicity recurrence and Grade 3/4 toxicity:
- Omit panobinostat dose until recovery to
Grade 1 toxicity and restart treatment at a reduced dose - Grade 3/4 toxicity recurrence:
- Reduce dose further once the adverse events have resolved to Grade 1 toxicity
- Coadministered with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir)
- Panobinostat: Reduce the starting dose to 10 mg
Note:
- The dose of panobinostat should be reduced in increments of 5 mg (i.e., from 20 mg to 15 mg, or from 15 mg to 10 mg). If the dosing is reduced below 10 mg given 3 times per week, discontinue treatment
- Refer package insert for administration and monitoring instructions
- Safety and efficacy in pediatric patients has not been established
