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Study of ACY-1215 in Combination With Lenalidomide, and Dexamethasone in Multiple Myeloma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01583283
Recruitment Status : Active, not recruiting
First Posted : April 24, 2012
Last Update Posted : April 8, 2020
Information provided by (Responsible Party):

Brief Summary:
The purpose of this study is to determine the best dose of ACY-1215 in combination with lenalidomide and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma. Once determined, the purpose of this study will be to determine the efficacy of ACY-1215 in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma who have had 1-3 prior therapies and who are not lenalidomide-refractory.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: ACY-1215 Drug: lenalidomide Drug: Dexamethasone Phase 1 Phase 2

Detailed Description:

This is phase 1, single-arm, multicenter, open-label study in patients with relapsed or relapsed/refractory MM. The study employs a sequential group dose-escalation design to determine the DLT and MTD of ACY-1215 in combination with lenalidomide and dexamethasone, all administered orally (PO). The safety, tolerability, single- and multiple-dose PK, pharmacodynamics, and anti-tumor activity of ACY 1215 in combination with lenalidomide and dexamethasone also will be evaluated.

Each cohort will enroll 3 patients. Study drug doses will be escalated sequentially after the Safety Review Committee (SRC) reviews safety data collected in C1 (28 days) from patients enrolled at the current dose level as well as emerging data from ongoing studies of ACY-1215. If there are no DLTs (as defined in Section 5.2.6) during C1 or concerns based on data from other ongoing studies, the study will proceed with dose escalation to the next cohort following safety data review by the SRC. If 1 of 3 patients has a DLT, then up to 3 additional patients will be enrolled in that cohort; if none of the additional 3 patients experience a DLT during C1, escalation may then continue to the next cohort following SRC review. If 2 or more patients have DLTs during C1, the DLT dose level will have been reached.

The MTD is defined as the dose level immediately below the DLT dose level. A total of up to 6 additional patients may be enrolled at the MTD or other appropriate dose level to obtain additional AE, PK, pharmacodynamic, and anti-tumor activity data on ACY 1215 in combination with lenalidomide and dexamethasone.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 38 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2, Open-Label, Multicenter Study of ACY-1215 (Ricolinostat) in Combination With Lenalidomide and Dexamethasone for the Treatment of Relapsed or Relapsed/Refractory Multiple Myeloma
Actual Study Start Date : July 12, 2012
Estimated Primary Completion Date : November 2, 2020
Estimated Study Completion Date : December 31, 2020

Arm Intervention/treatment
Experimental: ACY-1215, Lenalidomide and Dexamethasone
Open label dosing cohorts will evaluate oral ACY-1215 (doses ranging from 40 - 480 mg days 1-5, 8-12, 15-19) in combination with oral Lenalidomide (doses ranging from 15 - 25 mg days 1-21) and oral Dexamethasone (40 mg once weekly).
Drug: ACY-1215
Dose escalation up to 480 mg administered orally on Days 1-5, 8-12 and 15-19 of a 28 day dosing schedule.
Other Name: Histone deacetylase inhibitor

Drug: lenalidomide
Dosed on Days 1-21 of a 28 day cycle.
Other Name: Revlimid

Drug: Dexamethasone
Dosed on Days 1, 8, 15 and 22 of a 28 day treatment cycle.
Other Name: steroid

Primary Outcome Measures :
  1. To determine DLT of ACY-1215 administered in combination with lenalidomide and dexamethasone in patient with relapsed/refractory MM [ Time Frame: up to 7 years ]
    Number of participants with Dose Limiting Toxicity (DLT)

  2. To determine MTD of ACY-1215 administered in combination with lenalidomide and dexamethasone in patient with relapsed/refractory MM [ Time Frame: up to 7 years ]
    Maximum Tolerated Dose is defined as the dose level immediately below the DLT dose level.

  3. Objective Response Rate of ACY-1215 [ Time Frame: up to 7 years ]
    The objective response rate is the proportion of subjects achieving an investigator conformed partial response (PR) or better, to treatment according to IMWG (International Myeloma Working Group).

Secondary Outcome Measures :
  1. Duration of Response [ Time Frame: Up to approximately 7 years ]
    The duration of response is defined as the time (in weeks) from the date of the first documentation of objective response to the first documentation of objective tumor progression or death on study due to any cause, whichever comes first.

  2. Adverse Events (AEs) [ Time Frame: From enrollment until at least 28 days after completion of study treatment ]
    Number of participants with adverse event

  3. Disease Control Rate [ Time Frame: Up to approximately 7 years ]
    Disease control rate is defined as the proportion of subjects with a response (Unconfirmed or Confirmed) of SD or better, more specifically sCR, CR, VGPR, PR, MR, or SD respectively.

  4. Progression-free Survival [ Time Frame: Up to approximately 7 years ]
    PFS is defined as the time (in weeks) from the date of first dose to the date of first documentation of disease progression or death on study due to any cause, whichever comes first.

  5. Evaluate the pharmacodynamics of ACY-1215 in combination with lenalidomide and dexamethasone in patients with relapsed or relapsed/refractory MM [ Time Frame: up to 28 days ]
    Exposure-response of ACY-1215 in combination with lenalidomide and dexamethasone, including biomarkers relating to intracellular protein acetylation, levels of proteins, messenger ribonucleic acid (mRNA) and microRNA expression profiles will be analyzed for potential relationships.

  6. Pharmacokinetic- Cmax [ Time Frame: up to 28 days ]
    Maximum serum concentration

  7. Pharmacokinetic- Cmin [ Time Frame: up to 28 days ]
    Minimum observed concentration

  8. Pharmacokinetic- Tmax [ Time Frame: up to 28 days ]
    Time to maximum serum concentration

  9. Pharmacokinetic- AUC [ Time Frame: up to 28 days ]
    Area under the plasma concentration time curve

  10. Pharmacokinetic- t1/2 [ Time Frame: up to 28 days ]
    Serum half-life

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

Inclusion Criteria:

  • Relapsed or Relapsed/Refractory MM with progressive disease (PD) according to IMWG.
  • Received at least 1 prior line of therapy for MM (Phase 1)
  • Secretory MM for which the patient previously received 1-3 prior lines of therapy (Phase 2).
  • Able to provide written consent
  • Not a candidate for autologous stem cell transplant (ASCT) or declined option.
  • ≥18 years of age
  • Karnofsky Performance Status score ≥ 70
  • Adequate bone marrow reserve as evidenced by ANC > 1.0x10^9/L;Platelet > 50x10^9/L
  • Creatinine Clearance of ≥ 50 mL/min
  • Adequate hepatic function as evidenced by serum bilirubin values < 2.0 mg/dL; ALT and/or AST < 3xULN.
  • Corrected serum calcium ≤ ULN
  • Recovered from the effects of any prior systemic therapy or radiotherapy for Multiple Myeloma
  • Able to take acetylsalicylic acid (ASA) (81 or 325 mg) daily as prophylactic anticoagulation. Patients intolerant to ASA may use low molecular weight heparin. Lovenox is recommended. Coumadin will be allowed provided the patient is fully anticoagulated, with an INR of 2 or 3.
  • Agreement to participate in RevAssist® Program
  • Female of childbearing potential must have a negative serum or urinary pregnancy test with a sensitivity of at least 50 mIU/mL 10-14 days prior to and again within 24 hours of prescribing lenalidomide for Cycle 1 and must either commit to continued abstinence or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method at the same time, at least 28 days prior to taking lenalidomide. Also agree to ongoing pregnancy testing.
  • If male, including those who have had a vasectomy, must agree to use a latex condom during any sexual contact with a female of childbearing potential.

Exclusion Criteria:

  • Received any of the following antitumor therapies

    • Radiotherapy or systemic therapy within 2 weeks of Cycle 1 Day 1 (C1D1)
    • Investigational or biologic therapies within 3 weeks of C1D1
    • Prior peripheral ASCT within 12 weeks of C1D1
    • Prior allogeneic stem cell transplant
    • Prior treatment with a histone deacetylase (HDAC) inhibitor
  • Presence of an active systemic infection requiring treatment.
  • History of other malignancies unless a.) the patient has undergone definitive treatment more than 5 years prior and is without evidence of recurrent malignant disease or b.) had basal or squamous cell carcinoma of the skin; superficial carcinoma of the bladder; carcinoma of the prostate with current prostat specific antigen < 0.1 ng/mL; ductal carcinoma in situ; or cervical intraepithelial neoplasia.
  • Known or suspected human immunodeficiency virus (HIV), hepatitis B surface antigen-positive status or known or suspected active hepatitis C infection.
  • If female, is lactating.
  • History of significant cardiovascular, neurological, endocrine, gastrointestinal, respiratory, or inflammatory illness that could preclude study participation, pose an undue medical hazard, or interfere with the interpretation of the study results, including but not limited to congestive heart failure (NYHA Class 3 or 4), unstable angina; cardiac arrhythmia, recent (within past 6 months) myocardial infarction or stroke; uncontrolled hypertension; diabetes mellitus with >2 episodes of ketoacidosis in the preceding 12 months, COPD requiring >2 hospitalizations in preceding 12 months
  • QTcF > 480 msec, family or personal history of long QTc syndrome or ventricular bigeminy; previous history of drug-induced QTc prolongation or the need for medications known or suspected of producing prolonged QTc intervals on ECG
  • Current enrollment in another clinical trial involving treatment and/or is receiving an investigational agent for any reason
  • Documented plasma cell leukemia or known amyloidosis. (Plasma cell leukemia is defined as the presence of >20% plasma cells in the peripheral blood and an absolute plasma cell count of ≥2000 muL
  • Known hypersensitivity to thalidomide or lenalidomide.
  • History of erythema nodosum characterized by desquamating rash while taking thalidomide or similar drugs.
  • Non-secretory or oligo-secretory Multiple Myeloma (Phase II only; such disease is permissible in Phase I).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01583283

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United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
Massachusetts General Hospital
Boston, Massachusetts, United States, 2114
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27599
United States, Tennessee
Sarah Cannon Research Institute Drug Development Unit
Nashville, Tennessee, United States, 37203
United States, Washington
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States, 98109
Sponsors and Collaborators
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Study Director: Mary Garelik, MD Celgene
Tamang D, et al. Tubulin Hyper-Acetylation In Blood Lymphocytes: Pharmacodynamic (PD) Biomarker For The Selective Histone Deacetylase (HDAC) 6 Inhibitor ACY-1215 In Multiple Myeloma (MM) Patients. Presented at American Society of Hematology 2013, December 7-10, 2013, New Orleans, LA. Abstract No. 3219.

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Celgene Identifier: NCT01583283    
Other Study ID Numbers: ACE-MM-101
First Posted: April 24, 2012    Key Record Dates
Last Update Posted: April 8, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Clinical Study Report
Keywords provided by Celgene:
Multiple Myeloma
Histone deacetylase inhibitors
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Histone Deacetylase Inhibitors
Anti-Inflammatory Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Immunologic Factors