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A Phase 3, Randomized, Open Label Trial of Lenalidomide/dexamethasone With or Without Elotuzumab in Subjects with Previously Untreated Multiple Myeloma
- Primary Objective
- To compare the PFS of lenalidomide/dexamethasone + elotuzumab (LdE) versus lenalidomide/dexamethasone (Ld) in subjects with newly diagnosed, previously untreated multiple myeloma (MM).
- Secondary Objectives
- To compare objective response rate between treatment arms;
- To compare overall survival between treatment arms.
- Exploratory Objectives
- To assess safety in each arm;
- For those subjects who achieve an objective response, to assess the time to tumor response and duration of response;
- To assess the time to subsequent therapy in each arm;
- To assess the Health-related Quality of Life (HRQOL) outcomes (EORTC QLQ-C30 and QLQ-MY20) and the Brief Pain Inventory- Short Form (BPI-SF);
- To measure the serum concentrations of elotuzumab in the presence of lenalidomide and dexamethasone;
- To evaluate the immunogenicity of elotuzumab.
- To explore the relationship between the effectiveness of elotuzumab and high risk cytogenetic factors and sMICA (soluble major histocompatibility complex classI-related chain A) levels.
- Signed Written Informed Consent
- Subject is, in the investigator�s opinion, willing and able to comply with the protocol requirements.
- Subject has given voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to their future medical care.
- Target Population
- Age ≥ 18 years or legal age of consent per local regulations.
- ECOG performance status ≤ 2.
- Life-expectancy > 3 months.
- Newly diagnosed, untreated, symptomatic, documented myeloma AND;
- Who are not candidates for high-dose therapy plus SCT because of age (≥ 65 years) or coexisting conditions. Refusal to undergo high dose therapy with SCT is NOT sufficient for entry onto CA204006 for a subject < 65 years old. There must be a comorbidity that prevents SCT for a subject < 65 years old, AND;
- Measureable disease (patient must meet one of these criteria)
- serum IgG M-protein ≥ 0.5 g/dL OR
- serum IgA M-protein ≥ 0.5 g/dL OR
- serum IgM M-protein ≥ 0.5 g/dL OR
- serum IgD M-protein ≥ 0.05 g/dL OR
- Urine M-protein ≥ 200 mg/24-hour
- Age and Reproductive Status
- Women of childbearing potential (WOCBP) and men must be using 2 acceptable methods of contraception to avoid pregnancy throughout the study for a period of at least 1 month (4 weeks) before and women for up to 8 weeks, men for up to 90 days after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. See Section 3.3.3 for the definition of WOCBP and also refer to the Revlimid risk management plan guidelines.
- WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG). The first should be performed within 10 - 14 days and the second within 24 hours prior to the start of the investigational product. A prescription for lenalidomide for a female of childbearing potential must not be issued by the prescriber until negative pregnancy tests have been verified by the prescriber.
- Women must not be breastfeeding.
- Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile; see Section 3.3.3 for the definition of WOCBP) and men.
- Sexually active fertile men must use effective birth control if their partners are WOCBP. Men must agree to use a latex condom and a second form of birth control during sexual contact with WOCBP, even if they have had a successful vasectomy, and must agree to not donate semen during study drug therapy and for 90 days after therapy.
- Subjects must be willing to refrain from blood donations during study drug therapy and for 8 weeks after therapy.
- Target Disease Exceptions
- Subjects with non-secretory or oligo-secretory or serum free light-chain only myeloma.
- Smoldering MM, defined as asymptomatic MM with absence of lytic bone lesions.
- Monoclonal Gammopathy of Undetermined Significance (MGUS) defined by all of the following: serum M protein < 3 g/dL, absence of lytic bone lesions, anemia, hypercalcemia and renal insufficiency related to monoclonal protein and (if determined) proportion of plasma cells in the bone marrow of 10% or less.
- Diagnosis of Waldenstrom's disease or other conditions in which IgM M protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
- Plasma cell leukemia (defined as either 20% of peripheral WBC comprised of plasma/CD138+ cells or an absolute count of 2 x 109/L).
- Medical History and Concurrent Diseases
- POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
- Significant cardiac disease as determined by the investigator including:
- Known or suspected cardiac amyloidosis;
- Congestive heart failure of Class III or IV of the NYHA classification;
- Uncontrolled angina, hypertension or arrhythmia;
- Myocardial infarction in past 6 months;
- Any uncontrolled or severe cardiovascular disease.
- Prior cerebrovascular event with persistent neurologic deficit.
- Known HIV infection or active hepatitis A, B, or C.
- Any medical conditions that, in the investigator�s opinion, would impose excessive risk to the subject. Examples of such conditions include:
- Any uncontrolled disease, such as pulmonary disease, infection, seizure disorder;
- Active infection that requires parenteral anti-infective treatment;
- Any altered mental status or any psychiatric condition that would interfere with the understanding of the informed consent.
- Prior or concurrent malignancy, except for the following:
- Adequately treated basal cell or squamous cell skin cancer;
- Or any other cancer from which the subject has been disease-free for > 5 years.
- Uncontrolled diabetes (defined as Hgb A1C ≥ 8.0%).
- Unable to tolerate thromboembolic prophylaxis including, aspirin, Coumadin (warfarin) or low-molecular weight heparin as clinically indicated.
- Physical and Laboratory Test Findings
- Corrected serum calcium ≥ 11.5 mg/dl within 2 weeks of randomization (despite appropriate measure such a short course of steroids, bisphosphonates, hydration, calcitonin).
- Absolute neutrophil count < 1000 cells/mm3. No granulocyte colony stimulating factors (G-CSF or GM-CSF) allowed within 1 week of randomization. No pegylated granulocyte colony stimulating factors allowed within 3 weeks of randomization.
- Platelets < 75,000 cell/mm3 (75 x 109/L). Qualifying laboratory value must occur at most recent measurement prior to randomization and must be no more than 14 days prior to randomization. No transfusions are allowed within 72 hours prior to qualifying laboratory value.
- Hemoglobin < 8 g/dL. Qualifying laboratory value must occur at most recent measurement prior to randomization and must be no more than 14 days prior to randomization. No transfusions are allowed within 72 hours prior to qualifying laboratory value.
- Total bilirubin ≥ 2 x ULN or direct bilirubin ≥ 2.0 mg/dL.
- AST or ALT ≥ 3 x ULN.
- Creatinine clearance (CrCl) < 30 mL/min measured by 24-hour urine collection or estimated by the Cockcroft and Gault formula:
Prior Therapy or Surgery
- Female CrCl = [(140 - age in years) x weight in kg] / [72 x serum creatinine in mg/dl] x 0.85
- Male CrCl = [(140 - age in years) x weight in kg] / [72 x serum creatinine in mg/dl] x 1.00
Allergies and Adverse Drug Reaction
- Administration of systemic chemotherapy, biological, immunotherapy, clarithromycin or any investigational agent (therapeutic or diagnostic) for multiple myeloma except bisphosphonate therapy within 3 weeks prior to randomization.
- Treatment with plasmapheresis within 4 weeks prior to randomization.
- Steroids within 3 weeks of randomization, except:
- short course (of ≤ 4 days) of 40 mg dexamethasone or equivalent for emergency use (baseline M proteins must be drawn after this short course and prior to randomization);
- ≤ 10 mg prednisone or equivalent per day;
- Steroid with little to no systemic absorption (ie, topical or inhaled steroids).
- Major surgery within 4 weeks prior to randomization (kyphoplasty is not considered major surgery); subjects should have been fully recovered from any surgical related toxicities.
Sex and Reproductive Status
- Known hypersensitivity to lenalidomide, dexamethasone, any excipients in the elotuzumab formulation or recombinant protein.
Other Exclusion Criteria
- Sexually active fertile men not using 2 forms of effective birth control if their partners are WOCBP.
- Prisoners or subjects who are involuntarily incarcerated.
- Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and to ensure that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria.
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