Leflunomide in Treating Patients With Relapsed or Refractory Multiple Myeloma

A Phase I/II Dose-Escalation Trial of Leflunomide in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma

This phase I/II trial studies the side effects and best dose of leflunomide in treating patients with multiple myeloma that has come back (relapsed) or has not responded to previous treatment (refractory). Leflunomide may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Study Overview

• Status: Completed
• Conditions: Refractory Plasma Cell Myeloma; Recurrent Plasma Cell Myeloma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Leflunomide

Detailed Description

PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of leflunomide, when given as a single agent. (Phase I) II. To assess the safety and tolerability of leflunomide at each dose level by evaluation of toxicities including: type, frequency, severity, attribution, time course and duration. (Phase I) III. To evaluate the anti-myeloma activity of leflunomide, when given as a single agent, as assessed by overall response rate (ORR). (Phase II)

SECONDARY OBJECTIVES: I. To obtain estimates of: response duration, clinical benefit response, overall survival, progression-free survival. (Phase II)

TERTIARY OBJECTIVES: I. To characterize the relationship between serum concentration of the active leflunomide metabolite, teriflunomide (A77 1726), and toxicity. (Phase I/II) II. To assess the relationship between serum concentration of the active leflunomide metabolite, teriflunomide (A77 1726), and disease response. (Phase I/II) III. To explore the relationship between polymorphisms in the CYP1A2, CYP2C19, or DHODH genes and toxicity/response. (Phase I/II) IV. To explore the ex vivo cytotoxicity of leflunomide toward primary multiple myeloma (MM) cells, in order to evaluate whether individual ex vivo leflunomide response might be a useful predictor of therapeutic response. (Phase I/II) V. To explore the potential additive or synergistic effects of combining leflunomide with other classes of Food and Drug Administration (FDA)-approved drugs. (Phase I/II) VI. To generate a preliminary ribonucleic acid (RNA)/microRNA (miRNA) and deoxyribonucleic acid (DNA) methylation signature associated with response of MM cells to leflunomide in vivo (mRNA/miRNA and DNA methylation, phase II only) and teriflunomide ex vivo (messenger RNA [mRNA]/miRNA). (Phase I/II)

OUTLINE: This is a dose-escalation study. Patients receive leflunomide orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 28 days until disease progression (active follow-up) or every 3 months (long term follow-up).

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• All subjects must have the ability to understand and the willingness to sign a written informed consent
• Patients must have a life expectancy of > 3 months
• Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Patients must have a diagnosis of multiple myeloma
• Serum M-protein >= 0.5 g/dL
• Urine M-protein >= 200 mg/24 hr
• Serum free light chain >=10 mg/dL provided the free light chain (FLC) ratio is abnormal
• 10% plasma cells in bone marrow
• Patients must be relapsed or are refractory to at least 3 prior lines of therapy, including both a proteasome inhibitor an immunomodulatory drug (IMiD), and for whom a transplant is not recommended (induction therapy and stem cell transplant +/- maintenance will be considered as one regimen)
• At least 2 weeks from prior therapy to time of start of treatment; prior therapy includes steroids (except prednisone or equivalent - up to 10 mg per day is allowed)
• Platelet count >= 50,000/uL; platelet transfusions are not allowed within 14 days of platelet assessment
• Absolute neutrophil count (ANC) >= 1000/mm^3; growth factor is not permitted within 14 days of neutrophil assessment
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.0 x upper limit of normal (ULN)
• Total Bilirubin < 1.5 x ULN
• Calculated creatinine clearance (CrCl) >= 30 mL/min per 24 hour urine collection or the Cockcroft-Gault formula
• Negative serum or urine beta-human chorionic gonadotropin (B-HCG) test (female patient of childbearing potential* only), to be performed locally within the screening period
• Negative for tuberculosis antigen (e.g. T-Spot test)
• Negative for hepatitis A, B, or C infection
• Adequate pulmonary function as defined by forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) >= 50% of predicted by pulmonary function testing
• Agreement by females of childbearing potential* and sexually active males to use an effective method of contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for three months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately * A female of childbearing potential is defined as 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

Exclusion Criteria:

• Prior treatment with leflunomide
• Current or planned use of other investigational agents, or concurrent biological, chemotherapy, or radiation therapy during the study treatment period
• Current or planned growth factor or transfusion support until after initiation of treatment; if growth factor or transfusion support is provided between screening and start of treatment, the participant will no longer be eligible
• Prior diagnosis of rheumatoid arthritis
• Prior allogenic transplant
• Acute active infection requiring systemic therapy within 2 weeks prior to enrollment
• Pre-existing liver disease
• Known human immunodeficiency virus (HIV) infection
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to leflunomide or cholestyramine

• Non-hematologic malignancy within the past 3 years aside from the following exceptions:

  • Adequately treated basal cell or squamous cell skin cancer
  • Carcinoma in situ of the cervix
  • Prostate cancer < Gleason grade 6 with a stable prostate specific antigen (PSA)
  • Successfully treated in situ carcinoma of the breast
• Clinically significant medical disease or condition that, in the investigator's opinion, may interfere with protocol adherence or the patient's ability to give informed consent
• Pregnant women and women who are lactating; breastfeeding should be discontinued if the mother is enrolled on this study
• Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc
• NONCOMPLIANCE: Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: 20 mg leflunomide; Patients receive 20 mg leflunomide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Leflunomide; Given PO; Other Names: Arava; SU101
Experimental: Arm 2: 40 mg leflunomide; Patients receive 40 mg leflunomide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Leflunomide; Given PO; Other Names: Arava; SU101
Experimental: Arm 3: 60 mg leflunomide; Patients receive 60 mg leflunomide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Leflunomide; Given PO; Other Names: Arava; SU101

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MTD, Defined as the Highest Dose in Which =< 1/6 Patients Experience a Dose-limiting Toxicity, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03	Observed toxicities will be summarized, for all dose levels, in terms of type (organ affected or laboratory determination), severity, time of onset, duration, serum concentration of the active leflunomide metabolite, probable association with the study treatment and reversibility or outcome.	28 days
Best Overall Response Rate: Proportion of Patients Reaching CR by IMWG Criteria	Stringent complete response [sCR]/complete response [CR]/very good partial response [VGPR]/or partial response [PR]), assessed by International Myeloma Working Group (IMWG) criteria.	From the start of treatment until disease progression/recurrence, assessed up to 48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Benefit Response Rate (sCR/CR/VGPR/Partial Response [PR]/Minimal Response [MR] or Stable Disease [SD]), Assessed by IMWG Criteria	Clinical benefit response rate (sCR/CR/VGPR/partial response [PR]/minimal response [MR] or stable disease [SD]), assessed by International Myeloma Working Group (IMWG) criteria	From the start of treatment until disease progression/recurrence, assessed up to 48 months
Response Duration	Median and range of nine patients with Complete Response (CR)	Assessed up to 48 months
Response Duration	Number of patients with Stable Disease greater than or equal to 90 days	Assessed at ninety days.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Combination index (CI) values	CI values will be calculated using the CalcuSyn software program to determine which of the compounds work synergistically.	Up to 48 months
DNA methylation		Up to 48 months
Germline polymorphisms	All models will be adjusted for risk factors known to be associated with outcomes studies. Multiple comparisons adjustment with false discovery rate (FDR) will be conducted, and variants with FDR =< 0.05 will be considered significant. Will specifically look at DHODH, CYP1A2 and CYP2C19 gene polymorphisms and haplotypes identified in the literature that are associated with leflunomide response-toxicity. Functional annotation of the variants will be performed using ANNOVAR.	Up to 48 months
Half maximal inhibitory concentration values for teriflunomide in MM cells	Will be calculated suing Prism software (GraphPad). These values will be used for correlation analysis to determine the strength and linearity of the relationship between the ex vivo response and the response characteristics in vivo. These results will also be compared to responses from cell lines.	Up to 48 months
miRNA/mRNA expression profile		Up to 48 months
Potential new pathways to complement leflunomide treatment	Will compare the miRNA/mRNA/methylation profiles between responders and non-responders. Differentially expressed genes will be used to identify pathways that are activated in non-responders, which will provide insights into possible complementary therapy. Gene ontology and KEGG pathways will be analyzed using DAVID and GSEA. Pathway and gene ontology that are activated in non-responders will be sorted by their multiple comparison adjusted p-value. Potential miRNA targets will be identified using TargetScan and the enrichment of gene ontology and pathways will be identified as well.	Up to 48 months
Total and free teriflunomide levels	Descriptive statistics will be used to characterize possible inter-patient variability and relationship to dose, toxicity and response for future studies. Additional testing and analysis will be done on collected samples to assess, in an exploratory manner, the potential association between germline polymorphisms in the DHODH gene and either toxicity or response.	At 2 and 4 weeks

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Michael Rosenzweig, City of Hope Medical Center

Publications and helpful links

General Publications

• Rosenzweig M, Palmer J, Tsai NC, Synold T, Wu X, Tao S, Hammond SN, Buettner R, Duarte L, Htut M, Karanes C, Nathwani N, Pichiorri F, Sahebi F, Sanchez JF, Chowdhury A, Krishnan A, Forman SJ, Rosen ST. Repurposing leflunomide for relapsed/refractory multiple myeloma: a phase 1 study. Leuk Lymphoma. 2020 Jul;61(7):1669-1677. doi: 10.1080/10428194.2020.1742900. Epub 2020 Apr 8.

Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2015
• Primary Completion (Actual): September 18, 2018
• Study Completion (Actual): June 9, 2022

Study Registration Dates

• First Submitted: July 23, 2015
• First Submitted That Met QC Criteria: July 23, 2015
• First Posted (Estimated): July 27, 2015

Study Record Updates

• Last Update Posted (Estimated): October 10, 2023
• Last Update Submitted That Met QC Criteria: September 15, 2023
• Last Verified: September 1, 2023

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; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Leflunomide
• Other Study ID Numbers: 15140 (City of Hope Medical Center); NCI-2015-01181 (Registry Identifier: CTRP (Clinical Trial Reporting Program))