Clinical Trials /

Leflunomide for the Treatment of High-Risk Smoldering Multiple Myeloma

NCT04370483

Description:

This pilot trial studies how well leflunomide works for the treatment of patients with high-risk smoldering plasma cell myeloma, for the delay of disease progression. Anti-inflammatory drugs, such as leflunomide lower the body's immune response and are used with other drugs in the treatment of some types of cancer. The information learned from this study will help researchers to learn more about the anti-myeloma activity of leflunomide, and whether it may delay the onset of symptomatic multiple myeloma in patients with high-risk smoldering multiple myeloma.

Related Conditions:
  • Smoldering Plasma Cell Myeloma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Leflunomide for the Treatment of High-Risk Smoldering Multiple Myeloma
  • Official Title: Pilot Trial of Leflunomide in Patients With High-Risk Smoldering Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: 19456
  • SECONDARY ID: NCI-2020-01505
  • SECONDARY ID: 19456
  • NCT ID: NCT04370483

Conditions

  • Smoldering Plasma Cell Myeloma

Interventions

DrugSynonymsArms
LeflunomideArava, SU101Treatment (leflunomide)

Purpose

This pilot trial studies how well leflunomide works for the treatment of patients with high-risk smoldering plasma cell myeloma, for the delay of disease progression. Anti-inflammatory drugs, such as leflunomide lower the body's immune response and are used with other drugs in the treatment of some types of cancer. The information learned from this study will help researchers to learn more about the anti-myeloma activity of leflunomide, and whether it may delay the onset of symptomatic multiple myeloma in patients with high-risk smoldering multiple myeloma.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To estimate the anti-myeloma activity of leflunomide, when given as a single agent, as
      assessed by 6-month progression-free response rate based on International Myeloma Working
      Group (IMWG) criteria.

      SECONDARY OBJECTIVES:

      I. To evaluate the safety and tolerability of single agent leflunomide. II. To summarize and
      assess toxicities by type, frequency, severity, attribution, time course and duration.

      III. To estimate overall and progression-free survival probabilities. IV. To estimate
      response rate and duration of response. V. To describe the impact of treatment on quality of
      life, as assessed by the European Organization for Research and Treatment of Cancer Quality
      of Life Questionnaire (EORTC QLQ‐C30) Score version (v)3.0.

      EXPLORATORY OBJECTIVES:

      I. To characterize the molecular evolution of the tumor cells. II. To evaluate whether
      specific genetic subtypes respond differently to leflunomide.

      III. To evaluate the role of immune cells in the progression of smoldering multiple myeloma
      (SMM).

      IV. To evaluate the role of leflunomide in modulating the immune system. V. To examine the
      relationship between immunological changes and disease progression.

      OUTLINE:

      Patients receive leflunomide orally (PO) once daily (QD). Cycles repeat every 28 days in the
      absence of disease progression or unacceptable toxicity.

      After the completion of study treatment, patients are followed up at 30 days, every 28 days
      until an alternative myeloma therapy has commenced or until disease progression, and then up
      to 6 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (leflunomide)ExperimentalPatients receive leflunomide PO QD. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Leflunomide

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 high risk smoldering multiple myeloma, as defined
             below:

               -  The presence of >= 2 of the following risk factors:

                    -  Bone marrow plasma cell percentage (BMPC%) > 20%

                    -  Serum M-protein > 2 g/dL

                    -  Free light chain ratio (FLCr) > 20

          -  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)

          -  Within 5 years of a diagnosis of high-risk smoldering multiple myeloma (MM)

          -  Platelet count >= 50,000/uL. Platelet transfusions are not allowed within 14 days of
             platelet assessment

          -  Absolute neutrophil count (ANC) >= 1000/mm^3

          -  Aspartate transaminase (AST) and alanine transferase (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.

               -  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. The effects of study treatment on a developing fetus have
                  the potential for teratogenic or abortifacient effects. 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:

                    -  Has not undergone a hysterectomy or bilateral oophorectomy;

                    -  Has not been naturally postmenopausal for at least 24 consecutive months

          -  Negative for tuberculosis antigen (e.g. T-Spot test)

          -  Negative for hepatitis A, B, or C infection

        Exclusion Criteria:

          -  Prior treatment with leflunomide

          -  Prior treatment for smoldering multiple myeloma

          -  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

          -  Evidence of end organ damage that can be attributed to the underlying plasma cell
             proliferative disorder, specifically:

               -  Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upper
                  limit of normal or > 2.75 mmol/L (> 11 mg/dL)

               -  Renal insufficiency: creatinine clearance < 30 mL per min or serum creatinine >
                  177 umol/L (> 2 mg/dL)

               -  Anemia: hemoglobin value of > 20 g/L below the lower limit of normal, or a
                  hemoglobin value < 10 g/dL

               -  Bone lesions: one or more osteolytic lesions on skeletal radiography, computed
                  tomography (CT), or positron emission tomography (PET)-CT

          -  Any one or more of the following biomarkers of malignancy:

               -  Clonal bone marrow plasma cell percentage >= 60%

               -  Involved:uninvolved serum free light chain ratio >= 100 (Involved free light
                  chain must be >= 100 mg/L) > 1 focal lesions on magnetic resonance imaging (MRI)
                  studies (>= 5 mm in size each)

                    -  Participants with calcium (elevated), renal failure, anemia, and bone
                       lesions (CRAB) criteria that are attributable to conditions other than the
                       disease under study may be eligible

          -  Prior diagnosis of rheumatoid arthritis

          -  Prior allogeneic 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 and 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. Leflunomide has potential for teratogenic
             or abortifacient effects. Because there is a potential risk for adverse events in
             nursing infants secondary to treatment of the mother with these agents, 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

          -  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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progressive disease
Time Frame:Up to 48 months
Safety Issue:
Description:Will be defined by International Myeloma Working Group (IMWG) criteria. Progression to overt multiple myeloma is always considered progressive disease.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 30 days after end of treatment
Safety Issue:
Description:Will be defined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5 to grade toxicities. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.
Measure:Incidence of toxicities
Time Frame:Up to 30 days after the end of treatment
Safety Issue:
Description:Will be defined using the NCI CTCAE version 5 to grade toxicities. Will assess toxicities by type, frequency, severity, attribution, time course and duration. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.
Measure:Overall response rate
Time Frame:From the date of first documented response (confirmed complete response [CR], very good partial response [VGPR], partial response [PR] or minor response [MR]) to documented disease relapse, progression or death, assessed up to 48 months
Safety Issue:
Description:The overall response rate and 95% Clopper Pearson binomial confidence interval (CI) will be calculated. Response rates will also be explored based on number/type of prior therapy(ies). Response rate (CR, VGPR, PR, or MR), based on the IMWG 2016 criteria will be calculated as the percent of evaluable patients that have confirmed CR/VGPR/PR or MR.
Measure:Overall survival
Time Frame:From start date of therapy to date of death from any cause, assessed up to 48 months
Safety Issue:
Description:Overall survival will be estimated using the product-limit method of Kaplan and Meier.
Measure:Quality of life Questionnaire
Time Frame:At baseline and every 6 cycles thereafter up to 36 cycles (end of treatment), length of one complete cycle is 28 days
Safety Issue:
Description:The Quality of Life Questionnaire Core 30 (QLQ-C30) scales (five functional scales, three symptom scales, a global health status / quality of life (QoL) scale, and six single items) will be summarized using descriptive statistics. Changes in reported QOL over time from baseline will also be summarized.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated

April 28, 2020