Bench to Bedside: From the Bench to the Pharmacy
OSU-15004: A Phase 1b Trial of AR-42 With Pomalidomide in Relapsed Multiple Myeloma
Hypothesis: AR-42, a histone deacetylase inhibitor (HDACi), in combination with an immunomodulator will increase response to therapy in patients with refractory multiple myeloma. Research has shown that AR-42, a drug designed at The Ohio State University, improves uptake of immune modulatory agents by downregulating CD44. Immune modulators then exert an anti-myeloma effect by downregulating the IKZF1-IRF4-c-Myc pathway. OSU-15004 tests this hypothesis through the combination of AR-42 and the immunomodulator pomalidomide in relapsed multiple myeloma patients. The trial will identify the maximum tolerated dose and the dose-limiting toxicities of this regimen. Because most myeloma patients are already exposed to immune modulator lenalidomide, a frontline therapy, this trial focuses on pomalidomide and uses therapeutic concentrations of both pomalidomide and AR-42, even at the starting dose level.
Rationale: Multiple myeloma (MM) is the second most common hematologic malignancy, with approximately 22,000 new cases diagnosed annually in the United States. There is no cure for the disease, and many patients will relapse and become refractory to the first-line therapies, lenalidomide and bortezomib. Prior to the availability of carfilzomib and pomalidomide, MM patients refractory to both lenalidomide and bortezomib had an event-free survival of approximately 5 months and an estimated median overall survival of 9 months. The median overall survival has been extended with the use of pomalidomide and carfilzomib to over 15 months. Unfortunately, patients eventually become resistant to these drugs, so new agents with novel mechanisms of action are needed.
More recently, the HDACi vorinostat (SAHA) has been tested in phase II and III trials and has been shown to improve progression-free survival and overall survival in multiple myeloma, but patients have experienced serious side effects.
AR-42 demonstrated a 20,000-fold improvement in deacetylase inhibitory potency relative to its parent molecule, and it has shown greater antiproliferative effects than vorinostat in vitro and in vivo. It promotes both histone H3 and H4 lysine acetylation and tubulin acetylation. Our preliminary data also show that AR-42 has a specific, dose-dependent, antimyeloma activity compared to vorinostat and other pan-HDACi.
At a Glance
Trial no.: OSU-15004 (NCT02569320)
Eligibility: Patients must be 18 years of age or older with measurable disease; patients must have previously received lenalidomide and a proteasome inhibitor and must have failed lenalidomide; patients must have received two or more prior lines of systemic therapy for myeloma and have a Karnofsky performance score of 50 percent or greater; females of childbearing potential must have two negative serum or urine pregnancy tests; males and females must comply with fertility requirements.