Table 2 Phase I Results of Vorinostat in Combination Therapy in Patients With Hematologic Malignanciesa
Tumor Type | No. Pts | Treatment | Summary of Results | Ref |
|---|---|---|---|---|
Relapsed multiple myeloma | 23 | Vorinostat + bortezomib | DLTs: prolonged QT interval (1), fatigue (1) MTD vorinostat 400 mg qd on Days 4–11 + bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11 every 21 days Response: 2 VGPR, 7 PR, 10 SD (21 evaluable patients) | [78] |
Relapsed, refractory or poor prognosis acute leukemia or refractory anemia with excess blasts-2 | 22 | Vorinostat + flavopiridol (bolus or 'hybrid' infusion schedules) | DLTs: infectious colitis with sepsis (1 [bolus]) and atrial fibrillation (1 ['hybrid']) MTD: not yet reached on vorinostat 200 mg tid given in a 'hybrid' schedule with flavopiridol at 30/30 mg/m2 (load/infusion) on Days 1 and 8 of a 21-day cycle, identification of the MTD and recommended phase II dose is ongoing Response: 10 patients experienced some clinical benefit (20 evaluable patients) | [81] |
Advanced acute leukemia | 20 | Vorinostat + idarubicin | DLTs: myelosuppression, encephalopathy, and dysphagia 2 CR and 2 complete marrow responses observed in patients who had failed previous anthracycline-based therapy Recruitment ongoing at vorinostat 400 mg tid for 3 days + idarubicin 12 mg/m2 for 3 days every 14 days | [82] |
Relapsed or newly-diagnosed acute myelogenous leukemia or myelodysplastic syndrome | 70 | Vorinostat + decitabine (concurrent or sequential regimens) | DLT: prolonged QT interval (1 [sequential]) Response: concurrent (n = 34), 7 CR, 2 PR, 2 HI, 12 SD; sequential (n = 36), 3 CR, 2 HI, 16 SD MTD not reached Last cohort: vorinostat 400 mg qd for 14 days (Days 1–14 concurrent or Days 6–19 sequential) + decitabine 20 mg/m2/day on Days 1–5 every 28 days | [83] |
Relapsed, refractory or poor prognosis leukemia | 31 | Vorinostat + decitabine | DLTs: pulmonary embolism and diarrhea (1) Response: 1 CR, 4 significant reduction in bone marrow blasts, 4 SD, 14 PD, 7 NE (30 evaluable patients) Last cohort: decitabine 25 mg/m2 daily for 5 days followed by vorinostat 200 mg tid for 14 days | [84] |
Relapsed or refractory multiple myeloma | 18 | Vorinostat + lenalidomide + dexamethasone | DLTs: none yet reported MTD: not yet reached, DLT evaluation ongoing in patients enrolled to vorinostat 400 mg qd for 14 days (Days 1–7 and 15–21), combined with lenalidomide 25 mg qd for 21 days, and dexamethasone 40 mg/day (Days 1, 8, 15, and 22) every 28 days Response: 1 CR, 4 PR, 1 MR, 5 SD (15 evaluable patients) | [87] |
Myelodysplastic syndrome and acute myeloid leukemia | 28 | Vorinostat + azacitidine | DLTs: not reported Response: 9 CR, 2 incomplete CR, 7 HI, 2 SD (21 evaluable patients) Last cohort: azacitidine 55 mg/m2/day on Days 1–7 + vorinostat 300 mg bid on Days 3–5 every 28 days | [85] |
Advanced multiple myeloma | 34 | Vorinostat + bortezomib | DLTs: transient AST elevation (1), thrombocytopenia (1) MTD not yet reached, the maximum administered dose was vorinostat 400 mg qd on Days 1–14 + bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11 every 21 days. Response: 12 PR, 6 MR, 13 SD (33 evaluable patients). In 17 evaluable patients who had received prior bortezomib therapy, 6 PR, 4 MR, 7 SD | [79] |
Acute myeloid leukemia | 27 | Vorinostat + decitabine | DLT: fatigue (1) Response: 1 incomplete CR, 1 morphologic leukemia-free (without neutrophil recovery), 3 PR (25 evaluable patients) MTD not reached: maximum dose vorinostat 200 mg bid on Days 1–21 + decitabine 20 mg/m2/day on Days 1–5 every 28 days | [86] |