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

NCT01583283 | Completed Phase 1

• 1 other identifier: ACE-MM-101
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 5

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.

Conditions

Multiple Myeloma

Keywords

Multiple Myeloma; Relapsed; Refractory; Histone deacetylase inhibitors; Lenalidomide; Revlimid; Dexamethasone

Outcome Measures

Primary Outcomes (3)

• To determine DLT of ACY-1215 administered in combination with lenalidomide and dexamethasone in patient with relapsed/refractory MM

  Number of participants with Dose Limiting Toxicity (DLT)

  up to 7 years

• To determine MTD of ACY-1215 administered in combination with lenalidomide and dexamethasone in patient with relapsed/refractory MM

  Maximum Tolerated Dose is defined as the dose level immediately below the DLT dose level.

  up to 7 years

• Objective Response Rate of ACY-1215

  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).

  up to 7 years

Secondary Outcomes (10)

• Duration of Response

  Up to approximately 7 years

• Adverse Events (AEs)

  From enrollment until at least 28 days after completion of study treatment

• Disease Control Rate

  Up to approximately 7 years

• Progression-free Survival

  Up to approximately 7 years

• Evaluate the pharmacodynamics of ACY-1215 in combination with lenalidomide and dexamethasone in patients with relapsed or relapsed/refractory MM

  up to 28 days

Study Arms (1)

ACY-1215, Lenalidomide and Dexamethasone

EXPERIMENTAL

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; Drug: lenalidomide; Drug: Dexamethasone

Interventions

ACY-1215 DRUG

Dose escalation up to 480 mg administered orally on Days 1-5, 8-12 and 15-19 of a 28 day dosing schedule.

Also known as: Histone deacetylase inhibitor

ACY-1215, Lenalidomide and Dexamethasone

lenalidomide DRUG

Dosed on Days 1-21 of a 28 day cycle.

Also known as: Revlimid

ACY-1215, Lenalidomide and Dexamethasone

Dexamethasone DRUG

Dosed on Days 1, 8, 15 and 22 of a 28 day treatment cycle.

Also known as: steroid

ACY-1215, Lenalidomide and Dexamethasone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Celgene: lead

Study Sites (5)

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 2114, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Sarah Cannon Research Institute Drug Development Unit

Nashville, Tennessee, 37203, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

Location

Related Publications (5)

• 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.

  BACKGROUND

• Yee AJ, Bensinger WI, Supko JG, Voorhees PM, Berdeja JG, Richardson PG, Libby EN, Wallace EE, Birrer NE, Burke JN, Tamang DL, Yang M, Jones SS, Wheeler CA, Markelewicz RJ, Raje NS. Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial. Lancet Oncol. 2016 Nov;17(11):1569-1578. doi: 10.1016/S1470-2045(16)30375-8. Epub 2016 Sep 17.

  PMID: 27646843 RESULT

• Yee, Andrew & Bensinger, William & Voorhees, Peter & Berdeja, Jesus & Richardson, Paul & Supko, Jeffrey & Tamang, David & Jones, Simon & Wheeler, Catherine & Markelewicz, Robert & Raje, Noopur. (2015). Ricolinostat (ACY-1215), the First Selective HDAC6 Inhibitor, in Combonation with Lenalidomide and Dexamethasone in Patients with Relapsed and Relapsed-and-Refractory Multiple Myeloma: Phase 1b Results (ACE-MM-101 Study). Blood 2015; 126(23): 3055-3055.doi: 10.1182/blood.v126.23.3055.3055.

  RESULT

• Yee, Andrew & Voorhees, Peter & Bensinger, William & Berdeja, Jesus & Supko, Jeffrey & Richardson, Paul & Tamang, David & Jones, Simon & Patrick, Gretchen & Wheeler, Catherine & Raje, Noopur. (2014). Ricolinostat (ACY-1215), a Selective HDAC6 Inhibitor, in Combination with Lenalidomide and Dexamethasone: Results of a Phase 1b Trial in Relapsed and Relapsed Refractory Multiple Myeloma. Blood 2014; 124 (21): 4772-4772. doi:10.1182/blood.v124.21.4772.4772.

  RESULT

• RICOLINOSTAT (ACY-1215), THE FIRST SELECTIVE HISTONE DEACETYLASE 6 INHIBITOR, IS ACTIVE AND WELL TOLDERATED IN COMBINATION WITH LENALIDOMIDE OR BORTEZOMIB IN PATIENTS WITH REFRACTORY MYELOMA Raje N. EHA ePoster Jun 13, 2014; 53804 P358 https://library.ehaweb.org/eha/2014/19th/53804/noopur.raje.ricolinostat.28acy-121529

  RESULT

MeSH Terms

Conditions

Multiple Myeloma; Recurrence

Interventions

ricolinostat; Histone Deacetylase Inhibitors; Lenalidomide; Dexamethasone; Steroids

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 11, 2012
• First Posted: April 24, 2012
• Study Start: July 12, 2012
• Primary Completion: March 15, 2021
• Study Completion: March 24, 2021
• Last Updated: February 23, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will share

Locations

US (5)