Final Results of a Phase I Trial of Oral Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Patients with Advanced Multiple Myeloma.

Background: The histone deacetylase inhibitor vorinostat was approved by the United States FDA in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following 2 systemic therapies. Vorinostat has also demonstrated promising preclinical activity in multiple myeloma. Patients and Methods: A Phase I trial of oral vorinostat 200, 250 or 300 mg bid for 5 days each week of a 4 week cycle or 200, 300, or 400 mg bid for 14 days/3 week cycle until progressive disease or intolerable toxicity was conducted. Patients with measurable, relapsed and/or refractory multiple myeloma with adequate hematologic, hepatic, and renal function were eligible. The objectives were to determine the maximum tolerated dose (MTD) on each of the schedules and assess activity and safety. Results: Thirteen patients (median age, 63 years; median 7 prior systemic therapies) were enrolled. The MTDs were not determined due to early termination of the study due to the decision of the sponsor. One patient (250 mg bid 5 days/week) developed dose-limiting toxicity (DLT) of grade 3 fatigue. There were no other DLTs and the maximum administered doses were 250 mg bid for 5 days each week of a 4-week cycle and 200 mg bid for 14 days/3-week cycle. Common drug-related adverse experiences included fatigue (69%), anorexia (62%), dehydration (46%), diarrhea (46%), and nausea (38%) and were mostly grade ≤ 2. Of 10 evaluable patients, 1 had a minimal response and 9 had stable disease (Table 1). Conclusions: Oral vorinostat was generally well tolerated at 250 mg bid for 5 days each week of a 4 week cycle or 200 mg bid for 14 days/3 week cycle in patients with advanced multiple myeloma. Modest activity was demonstrated in relapsed and/or refractory multiple myeloma and combination studies with other anti-myeloma agents are warranted. | Allocation Number | Age | Baseline Myeloma Stage | Prior Systemic Therapies | Prior Bone Marrow Transplant | Baseline β2-microglobulin | On-study Duration (days) | Best Response | |:-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------:| --- | ---------------------- | ------------------------ | ---------------------------- | ------------------------- | ------------------------ | ------------- | | EBMT = European Group for Blood and Marrow Transplantation; MR = Minimal Response; ND = Not Determined; NE = Not Evaluable; SD = Stable Disease. *Cohorts 3, 5, and 6 were not initiated. | | Cohort 1 (200 mg twice daily x 5 days/week) | | 1001 | 55 | III | 12 | 1 | ND | 41 | NE | | 1002 | 47 | II | 3 | 1 | 2.0 | 254 | SD | | 1003 | 64 | III | 4 | | 2.6 | 62 | SD | | Cohort 2 (250 mg twice daily x 5 days/week) | | 1004 | 38 | I | 5 | | 1.7 | 55 | SD | | 1005 | 74 | III | 7 | 1 | 6.7 | 240 | MR | | 1006 | 65 | ND | 7 | 2 | 3.3 | 74 | NE | | 1007 | 67 | ND | 1 | | 10.1 | 118 | SD | | 1008 | 42 | III | 5 | | 4.7 | 109 | SD | | 1009 | 50 | III | 5 | | 1.4 | 123 | SD | | Cohort 4 (200 mg twice daily x 14 days/3 weeks) | | 861 | 69 | IIIa | 16 | 1 | 4.6 | 56 | SD | | 862 | 63 | IIIa | 20 | 1 | 3.1 | 25 | NE | | 863 | 61 | IIIa | 10 | 1 | 2.7 | 62 | SD | | 864 | 71 | IIIa | 16 | 1 | 11.0 | 155 | SD | Table 1. Clinical outcomes of patients per EBMT Criteria*