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

February 7, 2022 updated by: Celgene

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

38

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Dana Farber Cancer Institute
      • Boston, Massachusetts, United States, 2114
        • Massachusetts General Hospital
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • University of North Carolina
    • Tennessee
      • Nashville, Tennessee, United States, 37203
        • Sarah Cannon Research Institute Drug Development Unit
    • Washington
      • Seattle, Washington, United States, 98109
        • Fred Hutchinson Cancer Research Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / 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 Names:
  • Histone deacetylase inhibitor
Drug: lenalidomide
Dosed on Days 1-21 of a 28 day cycle.
Other Names:
  • Revlimid
Drug: Dexamethasone
Dosed on Days 1, 8, 15 and 22 of a 28 day treatment cycle.
Other Names:
  • steroid

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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)
up to 7 years
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.
up to 7 years
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).
up to 7 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Adverse Events (AEs)
Time Frame: From enrollment until at least 28 days after completion of study treatment
Number of participants with adverse event
From enrollment until at least 28 days after completion of study treatment
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.
Up to approximately 7 years
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.
Up to approximately 7 years
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.
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
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.
up to 28 days
Pharmacokinetic- Cmax
Time Frame: up to 28 days
Maximum serum concentration
up to 28 days
Pharmacokinetic- Cmin
Time Frame: up to 28 days
Minimum observed concentration
up to 28 days
Pharmacokinetic- Tmax
Time Frame: up to 28 days
Time to maximum serum concentration
up to 28 days
Pharmacokinetic- AUC
Time Frame: up to 28 days
Area under the plasma concentration time curve
up to 28 days
Pharmacokinetic- t1/2
Time Frame: up to 28 days
Serum half-life
up to 28 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Celgene

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

July 12, 2012

Primary Completion (ACTUAL)

March 15, 2021

Study Completion (ACTUAL)

March 24, 2021

Study Registration Dates

First Submitted

April 11, 2012

First Submitted That Met QC Criteria

April 20, 2012

First Posted (ESTIMATE)

April 24, 2012

Study Record Updates

Last Update Posted (ACTUAL)

February 23, 2022

Last Update Submitted That Met QC Criteria

February 7, 2022

Last Verified

February 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ACE-MM-101

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Clinical Study Report

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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