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

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

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).

Study Overview

• Status: Terminated
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: ACY-241; Drug: Pomalidomide; Drug: Dexamethasone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Lille, France, 59037
    • Local Institution - 340
  • Nantes Cedex 01, France, 44093
    • Local Institution - 341
• Germany
  • Heidelberg, Germany, 69120
    • Local Institution - 330
• Greece
  • Athens, Greece, 115 28
    • Local Institution - 320
• Spain
  • Pamplona, Spain, 31008
    • Local Institution - 301
  • Salamanca, Spain, 37007
    • Local Institution - 300
• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • Local Institution - 109
  • Colorado
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
  • Florida
    • Miami, Florida, United States, 33136-2107
      • University of Miami Medical Center
    • Tampa, Florida, United States, 33612
      • Local Institution - 108
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Local Institution - 103
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Local Institution - 104
    • Boston, Massachusetts, United States, 02215
      • Local Institution - 105
  • New York
    • New York, New York, United States, 10065
      • Local Institution - 101
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center Research
  • Texas
    • San Antonio, Texas, United States, 78229
      • CTRC at the UT Health Science Center at San Antonio
  • Washington
    • Seattle, Washington, United States, 98104
      • Local Institution - 111

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ACY-241, Pomalidomide, and dexamethasone; 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; Dose escalation up to 480 mg administered orally on Days 1-21 of a 28 day cycle.; Other Names: Histone deacetylase inhibitor; Drug: Pomalidomide; 4 mg qd dosed on days 1-21 of a 28 day cycle; Other Names: immunomodulatory agent; Drug: Dexamethasone; 40 mg qd on days 1, 8, 15, 22; Other Names: corticosteriod

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: Celgene
• Investigators: Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS Clinical Trial Information
• FDA Safety Alerts and Recalls

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2015
• Primary Completion (Actual): June 3, 2024
• Study Completion (Actual): June 3, 2024

Study Registration Dates

• First Submitted: March 3, 2015
• First Submitted That Met QC Criteria: March 23, 2015
• First Posted (Estimated): March 27, 2015

Study Record Updates

• Last Update Posted (Actual): July 9, 2024
• Last Update Submitted That Met QC Criteria: July 8, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dexamethasone; Pomalidomide; Histone Deacetylase Inhibitors; Immunomodulating Agents
• Other Study ID Numbers: ACE-MM-200