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

• Sponsor: Celgene
• Information provided by (Responsible Party): Celgene

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma	Drug: ACY-241; Drug: Pomalidomide; Drug: Dexamethasone	Phase 1

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	85 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Actual Study Start Date :	May 7, 2015
Estimated Primary Completion Date :	July 30, 2020
Estimated Study Completion Date :	July 30, 2020

Arms and Interventions

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 Name: Histone deacetylase inhibitor; Drug: Pomalidomide; 4 mg qd dosed on days 1-21 of a 28 day cycle; Other Name: immunomodulatory agent; Drug: Dexamethasone; 40 mg qd on days 1, 8, 15, 22; Other Name: corticosteriod

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Locations

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United States, Arizona
University of Arizona
Tucson, Arizona, United States, 85719
United States, Colorado
Colorado Blood Cancer Institute
Denver, Colorado, United States, 80218
United States, Florida
University of Miami Medical Center
Miami, Florida, United States, 33136-2107
Moffitt Cancer Center
Tampa, Florida, United States, 33612
United States, Georgia
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States, 30322
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, New York
Weill Cornell Medical College
New York, New York, United States, 10065
United States, Ohio
Gabrail Cancer Center Research
Canton, Ohio, United States, 44718
United States, Texas
CTRC at The UT Health Science Center at San Antonio
San Antonio, Texas, United States, 78229
United States, Washington
Swedish Cancer Institute
Seattle, Washington, United States, 98104
France
CHRU de Lille-Hopital Claude Huriez Service des Maladies du Sang
Lille, France, 59037
Hotel Dieu CHU Nantes
Nantes Cedex 01, France, 44093
Germany
Universitatsklinikum Heidelberg Medizinische Klinik Krehl-Klinik Haematologie, Onkologie, Rheumato
Heidelberg, Germany, 69120
Greece
Alexandra Hospital, University of Athens
Athens, Greece, 11528
Spain
Clinica Universitaria de Navarra
Pamplona, Spain, 31008
Hospital Universitario de Salamanca
Salamanca, Spain, 37007

Sponsors and Collaborators

Celgene

Investigators

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Principal Investigator:	Ruben Niesvizky, MD	Weill Medical College of Cornell University

More Information

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Responsible Party:	Celgene
ClinicalTrials.gov Identifier:	NCT02400242 History of Changes
Other Study ID Numbers:	ACE-MM-200
First Posted:	March 27, 2015
Last Update Posted:	April 23, 2019
Last Verified:	April 2019

Additional relevant MeSH terms:

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Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Dexamethasone	Dexamethasone acetate; Pomalidomide; Thalidomide; BB 1101; Histone Deacetylase Inhibitors; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal