Abstract
Introduction: Histone deacetylases (HDACs) affect cell growth at the transcriptional level by regulating the acetylation status of nucleosomal histones, and HDAC inhibition induces differentiation and/or apoptosis in transformed cells. We have recently shown that HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), induce apoptosis of human multiple myeloma (MM) cells via a constellation of antiproliferative and/or proapoptotic molecular events, including decreased expression of multiple signaling molecules and oncogenes implicated in MM pathophysiology. Based on these promising pre-clinical data, we embarked on a phase I clinical trial of oral SAHA in patients with advanced MM.
Methods: An open-label phase I dose-escalation of oral SAHA (200, 250 and 300 mg po bid for 5 consecutive days followed by 2 days of rest) was administered in 4-week cycles in pts with relapsed/refractory MM. The primary objective was to determine the maximum tolerated dose (MTD), and secondary objectives included evaluation of tumor response, as well as assessment of markers of biologic activity in peripheral blood mononuclear cells and bone marrow plasma cells. Dose limiting toxicity (DLT) was defined as grade 4 or greater hematologic toxicity and/or grade 3 or greater non-hematologic toxicity within the first 28 days of treatment.
Results: To date, 8 pts with advanced MM (5 relapsed and 3 with relapsed, refractory MM) have been enrolled at the first 2 dose levels, receiving a median of 3 cycles (range 2–9) of therapy. In 7 evaluable pts, one pt at the 2nd dose level (250 mg po bid) developed DLT with grade 3 fatigue, prompting dose reduction with the next cycle. Other side effects have included grade 2 fatigue (3 pts), grade 2 diarrhea (2 pts), grade 2 indigestion (2 pts) and grade 2 dehydration (2 pts), which have been manageable with appropriate supportive care. In one patient, during cycle 4 at dose level 2, grade 3 dehydration occurred with associated metabolic abnormalities that readily resolved with electrolyte supplementation and rehydration. The patient has continued on therapy at reduced dose (250 mg po bid, 4 days on, 3 days off) without recurrence of this toxicity. Importantly, no significant myelosuppression, neuropathy or sedation, which are associated with other anti-MM agents, has been seen. In 7 evaluable pts: minor responses (MR) were documented in 2 patients (25–50% reduction in serum paraprotein levels); stable disease (SD: less than 25% reduction in paraprotein levels) was observed in 2 pts; and progressive disease (PD) was documented in 3 pts.
Conclusion: SAHA is an orally administered HDAC inhibitor with manageable toxicity and preliminary evidence of antitumor activity in advanced MM. Clinical evaluation of this agent continues, with enrolment at 250 mg b.i.d. ongoing, to further define the safety and tolerability at this dose level and provide insight into the future uses of SAHA, either alone or in combination with other agents, to treat pts with advanced MM.
Histone Deacetylase Inhibitors: Synthesis of Tetrapeptide Analogue SAHA/TPX
