Phase 2 Trial of Leflunomide in Patients With High-Risk Smoldering Multiple Myeloma
Phase 2 Trial of Leflunomide in Patients With High-Risk Smoldering Multiple Myeloma
This phase II trial studies how well leflunomide works in treating patients with high-risk smoldering multiple myeloma. Leflunomide may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES:
I. To evaluate the anti-myeloma activity of leflunomide, when given as a single agent, as assessed by freedom from progression at 2-years.
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) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 28 days.
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:
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
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.0 x upper limits 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 (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 diffusion 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. 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
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 < 40 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, computer tomography (CT), or positron emission tomography (PET)-CT
Any one or more of the following biomarkers of malignancy:
Participants with increased calcium level, renal dysfunction, anemia, and destructive 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:
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)