S1211, A Randomized Phase I/II Study of Optimal Induction Therapy of Bortezomib, Dexamethasone and Lenalidomide With or Without Elotuzumab (NSC-764479) for Newly Diagnosed High Risk Multiple Myeloma (HRMM)

Location:

Jacksonville, Fla.

Trial status:

Open for Enrollment

Why is this study being done?

OBJECTIVES: - To determine the appropriate Phase II dose of elotuzumab to use in combination with lenalidomide, bortezomib, and dexamethasone for patients with multiple myeloma. (Phase I) - To assess whether incorporation of the novel agent elotuzumab into the treatment algorithm of high-risk multiple myeloma (HRMM) will improve progression-free survival (PFS). (Phase II) - To estimate the frequency and severity of toxicities of this treatment strategy in this patient population. OUTLINE: This is a multicenter, phase I, dose-escalation study of elotuzumab, followed by a phase II, randomized study. Patients are stratified according to primary plasma cell leukemia and/or high lactic dehydrogenase (LDH) vs everyone else. Phase I: - Induction: Patients receive bortezomib subcutaneously (SC) or IV on days 1, 4, 8, and 11; lenalidomide orally (PO) once daily on days 1-14; and dexamethasone PO or IV on days 1, 2, 4, 5, 8, 9, 11, and 12. Patients also receive elotuzumab IV on days 1, 8, and 15 of courses 1 and 2 and on days 1 and 11 of courses 3-8. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. - Maintenance: Patients receive bortezomib SC or IV on days 1, 8, and 15; lenalidomide PO once daily on days 1-21; dexamethasone PO on days 1, 8, and 15; and elotuzumab IV on days 1 and 15. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Phase II: Patients are randomized to 1 of 2 treatment arms. - Arm I: - Induction: Patients receive bortezomib SC or IV on days 1, 4, 8, and 11; lenalidomide PO once daily on days 1-14; and dexamethasone PO or IV on days 1, 2, 4, 5, 8, 9, 11, and 12. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity (patients who received a course of chemotherapy prior to registration will begin protocol treatment with course 2 and receive a total of 7 courses of protocol therapy). - Maintenance: Patients receive bortezomib SC or IV on days 1, 8, and 15; lenalidomide PO once daily on days 1-21; and dexamethasone PO on days 1, 8, and 15. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. - Arm II: - Induction: Patients receive bortezomib, lenalidomide, and dexamethasone as in arm I. Patients also receive elotuzumab IV on days 1, 8, and 15 of courses 1 and 2 and on days 1 and 11 of courses 3-8. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. - Maintenance: Patients receive bortezomib, lenalidomide, and dexamethasone as in arm I. Patients also receive elotuzumab IV on days 1 and 15. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed every 3 months for up to 6 years.

Who is eligible to participate?

DISEASE CHARACTERISTICS: - Patients must have newly diagnosed active multiple myeloma (MM) - Patients with non-secretory MM or known amyloidosis are not eligible - For the Phase II portion only, patients must have high-risk MM based on one or more of the following criteria at the time of initial diagnosis (prior to any chemotherapy): - Poor-risk genomic signature according to the University of Arkansas 70-gene model (available clinically as MyPRS score, Signal Genetics, Inc.) - Translocation (14;16), and/or translocation (14;20), and/or deletion (17p) by florescence in-situ hybridization (FISH) or cytogenetics - Primary plasma cell leukemia (defined by either ≥ 2,000 plasma cells/mL of peripheral blood, or 20% on a manual differential count - Serum lactate dehydrogenase (LDH) ≥ 2 times institutional upper limit of normal (IULN) - Patients must have measurable disease within 28 days prior to registration (or prior to initiation of first induction course for patients with prior therapy) - Patients on the Phase I portion may not have received ANY prior chemotherapy - Patients on the Phase II portion may have received one prior cycle of any noninvestigational chemotherapy - Patients must not have active involvement of the central nervous system (CNS) with MM (by clinical evaluation) - Patients with documentation of or clinical signs or symptoms consistent with CNS involvement by MM must have a lumbar puncture that is negative for CNS involvement - Patients with no previous history of documented CNS involvement and with no clinical signs or symptoms consistent with CNS involvement are not required to have completed a lumbar puncture prior to registration PATIENT CHARACTERISTICS: - Zubrod performance status ≤ 2 - Absolute neutrophil count (ANC) ≥ 1,000 cells/mm³ without growth factor support - Platelet count ≥ 70,000 cells/mm³ for patients who have bone marrow plasmacytosis < 50% OR ≥ 50,000 cells/mm³ for patients who have bone marrow plasmacytosis of ≥ 50% - Total bilirubin ≤ 1.5 times institutional upper limit of normal (IULN) - Serum glutamic oxalo-acetic transaminase (SGOT)/aspartate aminotransferase (AST) and serum glutamic pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) ≤ 2.5 times IULN - Creatinine clearance (CrCL) ≥ 30 mL/min - Patients who are known to be human immunodeficiency virus (HIV)-positive are eligible providing they meet all of the following additional criteria within 28 days prior to registration: - CD4 cells ≥ 500/mm³ - Viral load of < 50 copies HIV mRNA/mm³ if on antiretroviral therapy (ART) or < 25,000 copies HIV mRNA if not on ART - No zidovudine or stavudine as part of ART - Patients must have baseline skeletal survey to document lytic lesions, osteopenia, or compression fracture - Patients with known hepatitis B or hepatitis C infection may be eligible providing they have viral load < 800,000 IU/L within 28 days prior to registration - Patients must not have POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) - Patients must not have clinically significant illness including any of the following: - Uncontrolled, active infection requiring intravenous antibiotics - New York Heart Association (NYHA) Class III or Class IV heart failure - Unstable angina pectoris - Myocardial infarction within the past 6 months - ≥ Grade 3 cardiac arrhythmias per Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 - Patients must have undergone an electrocardiogram (EKG) within 28 days prior to registration - Uncontrolled blood pressure (BP) or hypertension - Defined as systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg within 14 days prior to registration - An exception can be made by a healthcare provider for a patient with a single BP elevation who, upon rechecking, has a normal BP - Patients are permitted to be receiving multiple antihypertensive medications (unless otherwise indicated in the study) - Uncontrolled diabetes mellitus (defined as a glycosylated hemoglobin A1C (Hg A1C) > 7% within 14 days prior to registration) - The same criterion will be used in patients with confirmed diagnosis of diabetes mellitus who have been on a stable dietary or therapeutic regimen for this condition in the last three months - Patients must not have any psychiatric illness that could potentially interfere with the completion of treatment according to this protocol - Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to registration - FCBP must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before starting lenalidomide and continuing for at least 4 months after completion of study therapy - Men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy - Not pregnant or breastfeeding - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years PRIOR CONCURRENT THERAPY: - See Disease Characteristics - Prior chemotherapy must have been completed within 56 days prior to registration and all toxicities must have resolved to ≤ Grade 1 - Patients may have received prior radiotherapy for symptomatic localized bone lesions or impending spinal cord compression only - Radiotherapy must be completed at least 14 days prior to registration and all toxicities must have resolved to ≤ Grade 1

Last updated:

6/12/2014

NCT ID:

NCT01668719

IRB Number:

13-009137