Final Results of a Phase I Trial of Oral Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Patients with Advanced Multiple Myeloma.
Authors: Richardson Paul G. , Mitsiades Constantine S. , Colson Kathleen , Reilly Eileen , McBride Laura , Chiao Judy , Sun Linda , Ricker Justin L. , Rizvi Syed , Oerth Carol , Atkins Barbara , Fearen Ivy , Anderson Kenneth C. , Siegel David S. 
Published: October 2019

Abstract
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.
Table 1. Clinical outcomes of patients per EBMT Criteria* 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 0 2.6 62 SD Cohort 2 (250 mg twice daily x 5 days/week)     1004 38 I 5 0 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 0 10.1 118 SD     1008 42 III 5 0 4.7 109 SD     1009 50 III 5 0 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