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Dr. Noopur Raje - ACY-1215, a selective HDAC6 inhibitor: interim results of combination therapy with bortezomib in patients with MM

Noopur Raje, MD
Cancer Center, Massachusetts General Hospital
Boston, MA, USA


Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Advances in Multiple Myeloma and Plasma Cell Leukemia

Monday, December 9, 2013: 6:45 PM, 393-394 (Ernest N. Morial Convention Center)

Noopur Raje, MD1, Dan T. Vogl, MD, MSCE2, Parameswaran N. Hari, MD, MRCP, MS3, Sundar Jagannath, MD4, Simon S Jones, PhD5, Jeffrey G Supko, PhD6*, Gina Leone, RN7*, Catherine Wheeler, MD8*, Robert Z. Orlowski, M.D., Ph.D.9, Paul G. Richardson, MD10 and Sagar Lonial, M.D.11

1Cancer Center, Massachusetts General Hospital, Boston, MA
2Multiple Myeloma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
3Medical College of Wisconsin, Center for International Blood and Marrow Transplant Research, Milwaukee, WI
4Multiple Myeloma Program, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY
5Acetylon Pharmaceuticals, Inc., Boston, MA
6Massachusetts General Hospital Cancer Center, Harvard Medical School., Boston, MA
7Acetylon Pharmaceuticals, Inc, Boston, MA
8Acetylon Pharmaceuticals., Boston, MA
9Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
10Dana-Farber Cancer Institute, Boston, MA
11Winship Cancer Institute, Emory University, Atlanta, GA

Background: Although non-selective HDAC inhibitors are active in MM, combination therapy is limited by significant adverse effects (AEs) including severe fatigue, gastrointestinal toxicity, and myelosuppression. ACY-1215 is the first-in-class selective oral HDAC6 inhibitor that inhibits the aggresome/autophagy pathway, an alternate pathway to proteasome clearance of misfolded proteins. ACY-1215 has demonstrated potent synergy with bortezomib preclinically in cell and animal models of MM (Santo, Blood, 119(1):2527).

Methods: ACY-100 is a three part single arm, open label study with cohort dose escalation in a standard 3+3 design as monotherapy (1a) and in combination with bortezomib (1b) followed by a phase 2 extension. Eligible patients (pts) for the phase 1a and 1b portions had relapsed or relapsed and refractory MM, previously received at least two lines of therapy including a proteasome inhibitor and an immunomodulatory agent,  had either progressed after or were ineligible for autologous stem cell transplant, and had adequate bone marrow reserve, hepatic function and creatinine clearance of >30 mg/mL/min.  ACY-1215 was given orally days 1-5 and 8-12 of a 21 day cycle, and bortezomib days 1,4,8,11 and dexamethasone 20 mg days 1,2,4,5,8,9,11,12. Peripheral blood samples were obtained for pharmacokinetic (PK) and pharmacodynamics (PD), assessment of acetylated tubulin (HDAC6 inhibition) and acetylated histones (Class 1 HDAC inhibition). Toxicity was assessed using CTCv4.0 and responses were evaluated by modified EMBT and Uniform Criteria.

Results: The monotherapy portion of ACY-100 has been previously presented (Raje, Blood, V20(21):4061). Fifteen heavily pretreated pts received ACY-1215 monotherapy at doses of 40 mg to 360 mg.  Most AEs were low grade and not related to ACY-1215. Two pts had grade 3 AEs, anemia and neutropenia, considered possibly related to ACY-1215. No dose limiting toxicities (DLTs) were observed. Stable disease (SD) was the best response in 6 patients.

Sixteen patients as of June 28, 2013 have received ACY-1215 at doses of 40 mg to 160 mg in combination with bortezomib (1.0 mg/m2 first cohort and 1.3 mg/m2 thereafter) and dexamethasone.  Median age was 60, and 16 patients had previously received up to 11 lines of therapy. The first combination cohort was expanded due to a dose limiting toxicity (DLT) of asymptomatic increase in amylase.  No other DLTs have been observed. Treatment emergent adverse events were predominantly low grade. Those occurring in >25% of patients were elevated creatinine, thrombocytopenia, anemia, fatigue, elevated ALT, AST and amylase, hypokalemia, cough, decreased appetite, dyspnea, hypoalbuminemia and peripheral neuropathy; most were not considered related to ACY-1215. Grade 3-4 AEs possibly related to ACY-1215 included asymptomatic elevated amylase (2), thrombocytopenia (3), anemia (1), stomach cramps (1) and elevated creatinine (1). Of 16 patients evaluable for response,  VGPR (1), PR (2), MR (1) were seen, with 5 pts achieving SD.. Responding patients were on study from 2 to 17 cycles. Eleven pts were refractory to bortezomib prior to study entry.. Of those the best outcome was MR (1) and SD (4), with the remaining having either progressive disease (5) or not evaluable (1). PK and PD data is available from 16 patients including the 160 mg dose level. PK for ACY-1215 is similar to the same dose levels in phase 1a monotherapy suggesting coadministration of bortezomib does not impact the PK of ACY-1215. Maximal levels were ≥ 1µM at ≥ 80 mg correlating with measurable increases >2x in acetylated tubulin with a minimal increase in acetylated histones.

Conclusions: ACY-1215 was well-tolerated when administered in combination with bortezomib and encouraging  disease responses were observed in this heavily pretreated patient population.  Future cohorts in phase 1b will explore twice daily dosing prior to start of phase 2.

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