A Phase I/II Dose-Escalation Trial of Leflunomide in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma
Overview
- Phase
- Phase 1
- Intervention
- Laboratory Biomarker Analysis
- Conditions
- Recurrent Plasma Cell Myeloma
- Sponsor
- City of Hope Medical Center
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- 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
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
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.
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).
Investigators
Eligibility Criteria
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)
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:
Arms & Interventions
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.
Intervention: Laboratory Biomarker Analysis
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.
Intervention: Leflunomide
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.
Intervention: Pharmacological Study
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.
Intervention: Laboratory Biomarker Analysis
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.
Intervention: Leflunomide
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.
Intervention: Pharmacological Study
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.
Intervention: Laboratory Biomarker Analysis
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.
Intervention: Leflunomide
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.
Intervention: Pharmacological Study
Outcomes
Primary Outcomes
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
Time Frame: 28 days
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.
Best Overall Response Rate: Proportion of Patients Reaching CR by IMWG Criteria
Time Frame: From the start of treatment until disease progression/recurrence, assessed up to 48 months
Stringent complete response \[sCR\]/complete response \[CR\]/very good partial response \[VGPR\]/or partial response \[PR\]), assessed by International Myeloma Working Group (IMWG) criteria.
Secondary Outcomes
- Clinical Benefit Response Rate (sCR/CR/VGPR/Partial Response [PR]/Minimal Response [MR] or Stable Disease [SD]), Assessed by IMWG Criteria(From the start of treatment until disease progression/recurrence, assessed up to 48 months)
- Response Duration(Assessed at ninety days.)