Study of ACY-241 Alone and in Combination With Pomalidomide and Dexamethasone in Multiple Myeloma

Study Overview
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Brief Summary
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This is a phase 1a/1b, multicenter, single-arm, open-label, dose escalation study to determine the maximum tolerated dose (MTD) and evaluate the safety and preliminary antitumor activity of ACY-241 for oral administration as monotherapy and in combination therapy with orally administered pomalidomide and low-dose dexamethasone in eligible patients with relapsed or relapsed-and-refractory multiple myeloma (MM).

Detailed Description
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During phase 1a, patients will receive 1 cycle of ACY-241 monotherapy. Patients who complete the ACY-241 monotherapy cycle without a dose limiting toxicity (DLT) and are clinically stable may continue to phase 1b combination therapy, beginning with Cycle 2. During phase 1b, patients will receive ACY 241 in combination with pomalidomide and low dose dexamethasone at the currently approved pomalidomide dose and schedule. Each cohort of patients in phase 1a and phase 1b will consist of at least 3 patients. The first patient enrolled in each cohort of phase 1a will be observed for 1 week before enrollment of subsequent patients in the cohort. Patients who withdraw consent before entering phase 1b will be replaced. (Replacement patients must complete phase 1a prior to continuing to phase 1b.) Patients who experience a DLT or other unacceptable toxicity in Cycle 1 of phase 1a monotherapy or Cycle 2, the first cycle of phase 1b combination therapy, will be removed from study treatment. An assessment of the safety of treatment will be completed by the Safety Review Committee (SRC) prior to dose-escalation.

Official Title
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A Phase 1a/1b Multicenter, Single-Arm, Open-Label, Dose-Escalation Study to Determine the Maximum Tolerated Dose, Safety, and Preliminary Activity of Oral ACY-241 Alone and in Combination With Pomalidomide and Low-Dose Dexamethasone in Patients With Relapsed or Relapsed-and-Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: ACY-241
* Drug: Pomalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Must have a documented diagnosis of MM and have relapsed or relapsed-and-refractory disease. All patients must have relapsed after having achieved at least stable disease (SD) for at least 1 cycle of treatment to at least 1 prior regimen and then developed progressive disease (PD). Relapsed-and-refractory patients also have documented evidence of PD during or within 60 days of completing last treatment Must have undergone prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of proteasome inhibitor unless not a candidate. May have undergone prior treatment with pomalidomide if patient is not refractory to pomalidomide and has previously achieved a response of MR or better to pomalidomide. Must have measurable disease (serum M-protein or urine M-protein). Must have Eastern Cooperative Oncology Group (ECOG) Performance score of 0, 1, or 2. Must be able to take low-dose aspirin, low molecular weight heparin, or other equivalent antithrombotic or anticoagulant daily as prophylactic anticoagulation. Key Exclusion Criteria: Prior therapy with pomalidomide with best response of PD or SD. Prior therapy with histone deacetylase (HDAC) inhibitor. Any of the following laboratory abnormalities: Absolute neutrophil count(ANC) < 1,000/µL, Platelet count < 75,000/µL or < 50,000/µL for patients in whom ≥ 50% of bone marrow nucleated cells are plasma cells, Hemoglobin < 8 g/dL, Creatinine clearance < 45 mL/min according to Cockcroft-Gault formula. If creatinine clearance calculated from the 24 hour urine sample is ≥ 45 mL/min, patient will qualify for the trial, Aspartate transaminase (AST) or Alanine transaminase (ALT) > 3.0 × Upper Limited Normal (ULN), Serum total bilirubin > 2.0 mg/dL or > 3.0 × ULN for patients with hereditary benign hyperbilirubinaemia. Hematologic growth factors are not allowed at screening or during the first cycle of phase 1a or 1b. Nonsecretory myeloma or free light chain detected in serum only (ogliosecretory). Hypersensitivity to thalidomide, lenalidomide, pomalidomide, or dexamethasone Patients who received an allogeneic bone marrow or allogeneic peripheral blood stem cell transplant less than 12 months prior to initiation of study

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: ACY-241, Pomalidomide, and dexamethasone<br>Open label dosing cohorts will evaluate oral ACY-241 (dosing ranging from 180 mg to 480 mg days 1-21) in combination with oral pomalidomide (4 mg days 1-21), and oral dexamethasone (40 mg qd on days 1, 8, 15, 22). | Drug: ACY-241<br>* Dose escalation up to 480 mg administered orally on Days 1-21 of a 28 day cycle.<br>* Other names: Histone deacetylase inhibitor;Drug: Pomalidomide<br>* 4 mg qd dosed on days 1-21 of a 28 day cycle<br>* Other names: immunomodulatory agent;Drug: Dexamethasone<br>* 40 mg qd on days 1, 8, 15, 22<br>* Other names: corticosteriod;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of ACY-241 as monotherapy as assessed by dose limiting toxicities |  | Cycle 1 (28 days) | 
| Maximum tolerated dose of ACY-241 in combination with pomalidomide and low dose dexamethasone as assessed by dose limiting toxicities | First cycle of combination therapy | Cycle 2 (28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of AEs as measured by safety and tolerability |  | Cycle 1 (28 days) | 
| Single- and multiple-dose peak-plasma concentration |  | Cycle 1 days 1, 2, 15 and 16 | 
| Single- and multiple-dose area under the plasma concentration versus time curve |  | Cycle 1 days 1, 2, 15 and 16 | 
| Change in acetylation of histone and tubulin as a measure of pharmacodynamics |  | Cycles 1 days 1, 2, 15, 16 and 22 | 
| Change in fetal hemoglobin expression as a measure of pharmacodynamics |  | Cycles 1 days 1, 2, 15, 16 and 22 | 
| ACY-241 metabolite concentration in blood samples |  | Cycles 1 days 1, 2, 15, 16 and 22 | 
| Exposure response analyses of potential biomarkers of response. |  | Cycles 1 days 1, 2, 15, 16 and 22 | 
| Frequency and severity of AEs as measured by safety and tolerability in combination |  | Beginning at Cycle 2 (28 day cycle each) until end of treatment | 
| Change in fetal hemoglobin expression as a measure of pharmacodynamics |  | Cycle 2 days 1, 2, 15, 16 and 22 | 
| Change in acetylation of histone and tubulin as a measure of pharmacodynamics |  | Cycle 2 days 1, 2, 15, 16 and 22 | 
| Single- and multiple-dose area under the plasma concentration versus time curve |  | Cycle 2 days 1, 2, 15, and 16 | 
| Quantification of M-protein as a measure of anti-tumor activity |  | Day 1 of each cycle beginning at Cycle 2 |