HDAC Inhibitor AR-42 and Pomalidomide in Treating Patients With Relapsed Multiple Myeloma

A Phase 1b Trial of AR-42 With Pomalidomide in Relapsed Multiple Myeloma

This pilot phase I trial studies the side effects and best dose of histone deacetylase (HDAC) inhibitor AR-42 (AR-42) when given together with pomalidomide in treating patients with multiple myeloma that has returned after a period of improvement. HDAC inhibitor AR-42 may work to stop cancer growth by blocking an enzyme needed for cell growth. Pomalidomide is a drug used in chemotherapy that works to stop the growth of cancer cells by causing them to die. Giving HDAC inhibitor AR-42 together with pomalidomide may cause patients to respond better to treatment.

Study Overview

• Status: Completed
• Conditions: Recurrent Plasma Cell Myeloma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Dexamethasone; Drug: Pomalidomide; Drug: HDAC Inhibitor AR-42

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose, safety and efficacy of AR-42 in combination with pomalidomide in relapsed multiple myeloma (MM) patients.

SECONDARY OBJECTIVES:

I. To determine time to progression (TTP). II. To determine overall survival (OS).

OUTLINE: This is a dose-escalation study of HDAC inhibitor AR-42 and pomalidomide.

Patients receive pomalidomide orally (PO) daily on days 1-21, dexamethasone PO twice weekly (BIW) or thrice weekly (TIW) weeks 1-3, and HDAC inhibitor AR-42 PO BIW or TIW on weeks 1-3. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 30 days.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center

Participation Criteria

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:

• Patients with measurable disease as defined by any of the following:

  • Serum M-protein >= 0.5 g/dl (>= 500 mg/dL)
  • Urine monoclonal protein >= 200 mg/24h
  • Involved free light chain (FLC) level >= 10 mg/dl (>= 100 mg/l) and an abnormal serum free light chain ratio (< 0.26, or > 1.65)
• Patients must have previously received Lenalidomide and proteasome inhibitor.
• Patients must be lenalidomide failures: disease progression on a prior lenalidomide-based therapy or progression within 60 days of the last dose of a lenalidomide; patients should have received at least 2 cycles of a lenalidomide-based regimen at standard doses to be evaluable for refractoriness; prior intolerance to lenalidomide does not exclude participation in the study except in cases of severe allergic reaction
• Prior radiation is permitted; however, at least 2 weeks must have elapsed since the completion of therapy and patients must have recovered from all therapy-associated toxicities to no greater than grade 1 at the time of registration; patients with symptomatic disease may receive palliative corticosteroids up to 1 week before initiating therapy
• Patient must have received 2 or more prior lines of systemic therapy for myeloma; patients must be off last treatment for at least 2 weeks (wks) by the beginning of treatment on this protocol
• Patients must have a Karnofsky performance score of 50% or greater
• Patients must have absolute neutrophil count (ANC) > 1000/uL
• Platelets >= 75,000/uL
• Total bilirubin =< 1.5 mg/dL
• Alkaline phosphatase =< 4 x institutional upper limit of normal (IULN)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x IULN
• Patients must have a serum creatinine limit of ≤1.5 ULN or creatinine clearance of ≥60 ml/min measured within 14 days of registration.
• All study participants must be registered into the mandatory POMALYST (pomalidomide) Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of the POMALYST REMS program
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL prior to starting therapy and prior to beginning another cycle (if applicable); women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; a female of childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

• The patient must be willing to comply with fertility requirements as below:

  • Male patients must agree to use an adequate method of contraception for the duration of the study and for 28 days afterwards
  • Female patients must be either postmenopausal, free from menses >= 2 yrs, surgically sterilized, willing to use two adequate barrier methods of contraception to prevent pregnancy, or agree to abstain from heterosexual activity starting with screening (4 weeks prior to initiating treatment) and 28 days after treatment, per POMALYST REMS™ program
  • Patients must agree not to donate blood, sperm/ova during the course of taking protocol therapy and for at least 4 weeks after stopping treatment

Exclusion Criteria:

• History of severe allergic reaction, including erythema nodosum, to lenalidomide
• Patients unable to receive adequate thromboprophylaxis in combination with pomalidomide
• Patients who have received investigational agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is longer) and who have not recovered from side effects of those therapies
• Patients with a mean QT interval corrected by Bazett's formula (QTcB) > 450 msec in males and > 470 msec in females
• Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C
• Patients with active (untreated or relapsed) central nervous system (CNS) metastasis of the patient's myeloma
• Any other medical condition, including mental illness or substance abuse, deemed by the investigator(s) to likely interfere with the patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results

• Patients with a prior history of malignancies, other than multiple myeloma, are excluded unless the subject has been free of the disease for ≥ 5 years with the exception of the following non-invasive malignancies:

  • Basal cell carcinoma of the skin
  • Squamous cell carcinoma of the skin
  • Carcinoma in situ of the cervix
  • Carcinoma in situ of the breast
  • Incidental histological finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative.
• Patients with malabsorption or any other condition that in the opinion of the principal investigator could cause difficulty in absorption of drug
• Patients that have previously progressed on pomalidomide treatment.

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: Treatment (pomalidomide, dexamethasone, HDAC inhibitor AR-42); Patients receive pomalidomide PO daily on days 1-21, dexamethasone PO BIW or TIW weeks 1-3, and HDAC inhibitor AR-42 PO BIW or TIW for weeks 1-3. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Dexamethasone; Given PO; Other Names: Decadron; Aacidexam; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Amplidermis; Anemul mono; Auricularum; Auxiloson; Baycuten; Baycuten N; Cortidexason; Cortisumman; Decacort; Decadrol; Decalix; Decameth; Decasone R.p.; Dectancyl; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Fluorodelta; Fortecortin; Gammacorten; Hexadecadrol; Hexadrol; Lokalison-F; Loverine; Methylfluorprednisolone; Millicorten; Mymethasone; Orgadrone; Spersadex; Visumetazone; Drug: Pomalidomide; Given PO; Other Names: Pomalyst; 4-Aminothalidomide; Actimid; CC-4047; Drug: HDAC Inhibitor AR-42; Given PO; Other Names: OSU-HDAC42; AR-42; HDAC-42

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD) of HDAC inhibitor AR-42 in combination with pomalidomide, defined as the highest dose level at which less than 20% of patients experience a dose-limiting toxicity	In the scenario where the MTD does not follow the assumption of non-decreasing toxicity of dose in both directions of the agent dose combinations, the MTD will be estimated by a bivariate isotonic estimator.	21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in biomarker levels	Summary statistics will be computed for baseline biomarkers. The absolute and percent change from baseline will be calculated for each subsequent measurement. Summary statistics will be computed for each collection time point.	Baseline to up to 30 days after completion of study treatment
Clinical benefit, defined as the proportion of patients experiencing complete response, very good partial response, or partial response		Up to 30 days after completion of study treatment
Duration of response	Evaluated using the methods of Kaplan and Meier, with a focus on graphical evaluation as well as early timepoint and median estimates of survival distributions.	From first observation of partial response to the time of disease progression (taking as a reference for progressive disease the smallest measurements recorded since treatment started), assessed up to 30 days after completion of study treatment
Incidence of toxicity, evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4 standard toxicity grading	Frequency distributions and other descriptive measures will form the basis of analysis of toxicity number and severity. Adverse events will be summarized by CTCAE v.4 category and perceived causal relationship to the study therapy. Tolerability will also be determined through assessing the number of patients who required dose modifications and/or dose delays in subsequent cycles. In addition, the proportion of patients who go off treatment due to adverse reactions or those who refuse further treatment for lesser toxicities that inhibit their willingness to continue on trial will be captured.	Up to 30 days after completion of study treatment
Number of patients experiencing objective response, based on criteria adapted from the International Myeloma working Group Uniform Response Criteria	The number and percentage of patients experiencing objective response will be descriptively summarized overall and by dose level. The objective response rate will be analyzed by using a 95% confidence interval for the proportion responding at trial closure in the treated population.	Up to 30 days after completion of study treatment
Progression-free survival	Evaluated using the methods of Kaplan and Meier, with a focus on graphical evaluation as well as early timepoint and median estimates of survival distributions.	From start of treatment to disease progression or death, regardless of cause of death, whichever comes first, assessed up to 30 days after completion of study treatment
Time to progression	Evaluated using the methods of Kaplan and Meier, with a focus on graphical evaluation as well as early timepoint and median estimates of survival distributions.	From the start of the treatment until the criteria for disease progression are met, assessed up to 30 days after completion of study treatment

Collaborators and Investigators

• Sponsor: Ohio State University Comprehensive Cancer Center
• Collaborators: Celgene

Publications and helpful links

General Publications

• Cheng H, Xie Z, Jones WP, Wei XT, Liu Z, Wang D, Kulp SK, Wang J, Coss CC, Chen CS, Marcucci G, Garzon R, Covey JM, Phelps MA, Chan KK. Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents. AAPS J. 2016 May;18(3):737-45. doi: 10.1208/s12248-016-9876-3. Epub 2016 Mar 4.

Helpful Links

• The Jamesline

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2016
• Primary Completion (Actual): November 14, 2020
• Study Completion (Actual): March 10, 2021

Study Registration Dates

• First Submitted: October 3, 2015
• First Submitted That Met QC Criteria: October 3, 2015
• First Posted (Estimate): October 6, 2015

Study Record Updates

• Last Update Posted (Actual): June 15, 2021
• Last Update Submitted That Met QC Criteria: June 10, 2021
• Last Verified: June 1, 2021

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; Protease Inhibitors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dermatologic Agents; Dexamethasone; Dexamethasone acetate; BB 1101; Pomalidomide; Histone Deacetylase Inhibitors; Ichthammol
• Other Study ID Numbers: OSU-15004; NCI-2015-01557 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); PO-CL-MM-PI-003687

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No