Syed Rizvi

Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma

A Phase I trial (NCT00109109) of oral vorinostat 200, 250 or 300 mg twice daily for 5 days/week/4-week cycle or 200, 300, or 400 mg twice daily for 14 days/3-week cycle until progressive disease or intolerable toxicity was conducted. Patients with measurable, relapsed/refractory multiple myeloma were eligible. The objectives were to determine maximum tolerated doses (MTDs) and assess activity and safety. Thirteen patients (median age, 63 years; median prior therapies, 3) were enrolled. MTDs were not determined due to early study termination by sponsor decision. One patient (250 mg twice daily 5 days/week) developed dose-limiting toxicity (DLT; grade 3 fatigue). There were no other DLTs and the maximum administered doses were 250 mg twice daily for 5 days/week/4-week cycle and 200 mg twice daily for 14 days/3-week cycle. Drug-related adverse experiences included fatigue, anorexia, dehydration, diarrhea, and nausea and were mostly grade ≤2. Of 10 evaluable patients, 1 had a minimal response and 9 had stable disease, demonstrating modest single-agent activity in relapsed/refractory multiple myeloma.

Vorinostat in solid and hematologic malignancies

Vorinostat (Zolinza®), a histone deacetylase inhibitor, was approved by the US Food and Drug Administration 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 two systemic therapies. This review summarizes evidence on the use of vorinostat in solid and hematologic malignancies and collated tolerability data from the vorinostat clinical trial program. Pooled vorinostat clinical trial data from 498 patients with solid or hematologic malignancies show that vorinostat was well tolerated as monotherapy or combination therapy. The most commonly reported drug-related adverse events (AEs) associated with monotherapy (n = 341) were fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%), and Grade 3/4 drug-related AEs included fatigue (12.0%), thrombocytopenia (10.6%), dehydration (7.3%), and decreased platelet count (5.3%). The most common drug-related AEs observed with vorinostat in combination therapy (n = 157, most of whom received vorinostat 400 mg qd for 14 days) were nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), vomiting (31.2%), and anorexia (20.4%), with the majority of AEs being Grade 2 or less. In Phase I trials, combinations with vorinostat were generally well tolerated and preliminary evidence of anticancer activity as monotherapy or in combination with other systemic therapies has been observed across a range of malignancies. Ongoing and planned studies will further evaluate the potential of vorinostat in combination therapy, including combinations with radiation, in patients with diverse malignancy types, including non-small-cell lung cancer, glioblastoma multiforme, multiple myeloma, and myelodysplastic syndrome.

Evaluation of the long-term tolerability and clinical benefit of vorinostat in patients with advanced cutaneous T-cell lymphoma.

INTRODUCTIONnVorinostat, an orally active histone deacetylase inhibitor, was approved in October 2006 by the US Food and Drug Administration for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease during or after treatment with 2 systemic therapies.nnnPATIENTS AND METHODSnA multicenter, open-label phase IIb trial evaluated the activity and safety of vorinostat 400 mg orally daily in patients with > or = stage IB, persistent, progressive, or treatment-refractory mycosis fungoides or Sézary syndrome CTCL subtypes. We report the safety and tolerability of long-term vorinostat therapy in patients who experienced clinical benefit in the previous phase IIb study.nnnRESULTSnAs of December 11, 2008, 6 of 74 patients enrolled in the original study had received vorinostat for > or = 2 years: median age, 65 years; median number of previous therapies, 2.5; median time from diagnosis to enrollment, 1.8 years. At enrollment into the continuation phase, 5 of the 6 patients had achieved an objective response, and 1 patient had prolonged stable disease. During the follow-up study, the most common drug-related grade 1-4 adverse events (AEs) were diarrhea, nausea, fatigue, and alopecia (6, 5, 4, and 3 patients, respectively). Incidence of grade 3/4 AEs was low: anorexia (n = 1), increased creatinine phosphokinase (n = 1), pulmonary embolism (n = 1), rash (n = 1), and thrombocytopenia (n = 1). Five patients have discontinued the study drug, and 1 patient is continuing therapy.nnnCONCLUSIONnThis post hoc subset analysis provides evidence for the long-term safety and clinical benefit of vorinostat in heavily pretreated patients with CTCL, regardless of previous treatment failures.

A242 Vorinostat and Bortezomib in Relapsed/Refractory MM

reported by 2 patients (22%), but were not considered drug-related. No DLT has been observed to date. Of 8 patients evaluable for efficacy, the best responses were: complete response (n = 1), partial response (n = 1), minimal response (n = 2), stable disease (n = 2), and progressive disease (n = 2). Conclusion: These preliminary data suggest that vorinostat plus lenalidomide and dexamethasone represents a novel oral combination therapy that is active and relatively well tolerated in the treatment of relapsed or refractory multiple myeloma. Enrollment is ongoing and study updates will be presented.

A248 Vorinostat plus Bortezomib in MM: A Phase I Study

myeloma (MM). We report safety and efficacy data from the phase I portion, to determine the maximum tolerated dose (MTD) of cyclophosphamide in the VDCR combination. Methods: Patients received bortezomib 1.3 mg/m2 (days 1, 4, 8, 11), dexamethasone 40 mg (days 1, 8, 15), lenalidomide 15 mg (days 1-14), plus cyclophosphamide 100, 200, 300, 400, or 500 mg/m2 (days 1, 8) for up to eight 21-day cycles, then bortezomib 1.3 mg/m2 (days 1, 8, 15, 22) for four 42-day maintenance cycles. Patients could discontinue therapy after cycle 4 to undergo stem cell transplantation. Patients received prophylactic antibiotics, acyclovir, transfusion support, and concomitant anticoagulants as required. Results: Twenty-five of 26 patients enrolled were treated (Table 1; median age 61 years; 52% ISS stage lI/III; 44% KPS 80%). At data cut-off, median treatment duration is 4 cycles (range, 2-11 cycles); 9 patients have undergone successful transplantation and 11 remain on treatment. Two patients experienced doselimiting toxicity (grade 4 neutropenia > 7 days, dose level 4; grade 3 herpes zoster, dose level 5); MTD was not reached. The recommended phase II cyclophosphamide dose is 500 mg/m2. The most common toxicities were constipation (64%), fatigue (60%), and nausea (52%). Hematologic toxicities were acceptable. Peripheral neuropathy (56%) included 8% grade 3 (no grade 4). No DVT/PE was reported. Preliminary response rates are: 100% PR, 68% VGPR, 32% CR/nCR, 28% CR/sCR, 20% sCR (Table 1). Conclusion: VDCR is feasible, well tolerated, and highly active in front-line MM. Phase I enrollment is complete; phase ll enrollment is ongoing.