Study of ACY-1215 Alone and in Combination With Bortezomib and Dexamethasone in Multiple Myeloma

Study Overview
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Brief Summary
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Phase 1(a & b): To evaluate the side effects and determine the best dose of oral ACY-1215 as monotherapy, and also in combination with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma. Phase 2a: To determine the objective response rate of oral ACY-1215 in combination with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma.

Official Title
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A Phase 1/2, Open-Label, Multicenter Study of ACY-1215 Administered Orally as Monotherapy and in Combination With Bortezomib and Dexamethasone for the Treatment of Relapsed or Relapsed/Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: ACY-1215


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has relapsed or relapsed/refractory MM with measurable disease parameters according to the International Myeloma Working Group (IMWG) Criteria Refractory is defined as experiencing less than minimal response (MR) to or progressive disease (PD) within 60 days after completion of the most recent anti-MM regimen Relapsed is defined as experiencing PD that requires therapy but which is not refractory following the achievement of stable disease (SD) or better to the most recent anti-MM regimen. Patient received at least 2 prior regimens for MM. Patient received prior treatment for MM with a proteasome inhibitor and an immunomodulatory drug, unless not a candidate for a proteasome inhibitor or an immunomodulatory drug. Patient either is not a candidate for autologous stem cell transplant (ASCT), has declined the option of ASCT, or has relapsed after prior ASCT. Patient is ≥18 years of age. Patient has a Karnofsky Performance Status score of ≥70 Patient has adequate bone marrow reserve, as evidenced by: Absolute neutrophil count (ANC) of ≥1.0x109/L. Platelet count of ≥ 75x109/L in patients in whom <50% of bone marrow nucleated cells are plasma cells and ≥50x109/L in patients in whom more than 50% of bone marrow nucleated cells are plasma cells. Patient has adequate renal function (calculated creatinine clearance of ≥30 mL/min according to the Cockroft-Gault) Patient has adequate hepatic function (serum bilirubin values <2.0 mg/dL and ALT and/or AST values <3 × the upper limit of normal ULN). Patient has a corrected serum calcium ≤ULN. Exclusion Criteria Patient has received any of the following therapies: Radiotherapy or systemic therapy within 2 weeks of baseline Prior peripheral autologous stem cell transplant within 12 wks of Baseline. Prior allogeneic stem cell transplant. Prior treatment with an HDAC inhibitor. Patient has an active systemic infection requiring treatment. Patient has a history of other malignancies unless has undergone definitive treatment more than 5 yrs prior to study and without evidence of recurrent malignant disease (excluding basal cell carcinoma of the skin; superficial carcinoma of the bladder; carcinoma of the prostate with a current prostate-specific antigen <0.1 ng/mL; or cervical intraepithelial neoplasia). Patient has known or suspected HIV, positive for hepatitis B or is known or suspected to have active hepatitis C infection. Patient has a history of significant cardiovascular, neurological, endocrine, gastrointestinal, respiratory, or inflammatory illness including recent myocardial infarction (within 6 months)or stroke; hypertension requiring >2 medications for adequate control; diabetes mellitus with >2 episodes of ketoacidosis in the preceding 12 months; or chronic obstructive pulmonary disease (COPD) requiring >2 hospitalizations in the preceding 12 months. Patient has a QTcF value of >480 msec; family or personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy; previous history of drug-induced QTc prolongation Patient has > Grade 2 painful neuropathy or peripheral neuropathy Patient has a history of allergic reaction attributable to bortezomib or other compounds containing boron or mannitol (Phase 1b and 2a only)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treat Regimen<br>ACY-1215 Bortezomib Dexamethasone | Drug: ACY-1215<br>* Liquid oral dose on Days 1-5 and 8-12 of 21-day treatment cycle<br>* Other names: HDAC6 inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 (a & b): To determine the maximum tolerated dose of ACY-1215 as monotherapy or in combination with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma. |  | Upon completion of 21-day treatment cycle | 
| Phase 2a: To determine the objective response rate to ACY-1215 in combination with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma. |  | Assessed every other treatment cycle (cycles 2, 4 and 6) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize the safety of ACY-1215 alone or in combination with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma |  | Up to 24 weeks | 
| Determine the single- and multiple-dose PK of ACY-1215 alone and in combination with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma |  | Upon completion of 21 day treatment cycle | 
| Evaluate the pharmacodynamics of ACY-1215 alone or in combination with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma. |  | Up to 24 weeks. |