Carfilzomib and Lenalidomide With Dexamethasone Combination in Newly Diagnosed, Previously Untreated Multiple Myeloma

Study Overview
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Brief Summary
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This study is designed to evaluate the safety and to determine the maximum tolerated dose of carfilzomib + lenalidomide in combination with dexamethasone in newly diagnosed Multiple Myeloma patients who have not received treatment.

Detailed Description
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During the Phase I portion of this clinical trial, the dose of Revlimid® and carfilzomib will be increased until the best and safest amount (or dose) is identified in combination with standard doses of Revlimid® and dexamethasone. Investigational means that the drug combination is still being studied and that research doctors are trying to find out more about it such as the safest dose to use, the side effects it may cause and how effective the Revlimid® and carfilzomib and dexamethasone investigational combination is for treating newly diagnosed multiple myeloma. In this clinical trial we are looking for the highest dose of the combination that can be given safely and see how well it works as a combination in newly diagnosed patients. The drug, carfilzomib, has not yet been approved by the FDA (U.S. Food and Drug Administration). Revlimid® and Dexamethasone have been approved by the FDA. The drugs have not been approved in this combination for use for your type of cancer or any other type of cancer. Carfilzomib is being researched to treat multiple myeloma. Dexamethasone is commonly used, either alone, or in combination with other drugs, to treat multiple myeloma. Revlimid® is currently approved by the US FDA in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. After the Phase I clinical trial defines the safest doses of Revlimid® and carfilzomib and dexamethasone that can be taken together, the research study will move on to its second portion, a Phase II clinical trial. The Phase II portion of the clinical trial will test the clinical effectiveness of the best dose combination of the three drugs.

Official Title
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Multicenter, Open-label, Single-arm, Phase 1b/2 Study of the Safety and Efficacy of Combination Treatment w/ Carfilzomib, Lenalidomide (Revlimid®) and Dexamethasone (CRD) in Subjects w/ Newly Diagnosed, Previously Untreated Multiple Myeloma Requiring Systemic Chemotherapy

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: carfilzomib, lenalidomide plus dexamethasone
* Drug: carfilzomib, lenalidomide plus dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Newly diagnosed, histologically confirmed, previously untreated Stage I, II, or III multiple myeloma requiring systemic chemotherapy Diagnosis of symptomatic multiple myeloma per IMWG uniform criteria within the past 90 days Measurable disease, per IMWG (International Myeloma Working Group) criteria (>= one of the following) within the past 4 weeks: Monoclonal protein >= 0.5 g/dL by serum protein electrophoresis Monoclonal light chain >= 200 mg by 24-hour urine protein electrophoresis If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable Life expectancy > 3 months Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Adequate hepatic function, with bilirubin < 1.5 x the ULN, and AST (Aspartate Aminotransferase) and ALT (Alanine Transaminase) < 2.5 x ULN Absolute neutrophil count (ANC) >=1.0 x 109/L, hemoglobin >= 8 g/dL, platelet count >= 75 x 109/L Calculated creatinine clearance (by Cockroft-Gault) >= 60 ml/min Written informed consent in accordance with federal, local, and institutional guidelines. Subjects must agree to adhere to all study requirements, including birth control measures and pregnancy testing, visit schedule, outpatient treatment, required concomitant medications, and laboratory monitoring. Must be able to take either 81 mg or 325 mg aspirin daily as prophylactic anticoagulation. Exclusion Criteria Non-secretory or hyposecretory multiple myeloma, defined as <0.5 g/dL M-protein in serum, <200 mg/24 hr urine M-protein, or disease only measured by serum free light chain POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes) syndrome Plasma cell leukemia Waldenström's macroglobulinemia or IgM myeloma Radiotherapy to multiple sites or immunotherapy within 2 weeks before start of protocol treatment (localized radiotherapy to a single site at least 1 week before start is permissible) Patient must not have been previously treated with any prior systemic therapy for the treatment of multiple myeloma Prior treatment of hypercalcemia or spinal cord compression or aggressively progressing myeloma with corticosteroids does not disqualify the patient (the dose should not exceed the equivalent of 160 mg of dexamethasone in a 2 week period) Bisphosphonates are permitted Participation in an investigational therapeutic study within 3 weeks or within 5 drug halflives (t1/2) prior to first dose, whichever time is greater Pregnant or lactating females History of allergy to mannitol Major surgery within 3 weeks prior to first dose Myocardial infarction within 3 months prior to enrollment, NYHA (New York Heart Association) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities Uncontrolled hypertension or diabetes Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose Known or suspected HIV infection, known HIV seropositivity Active hepatitis infection Non-hematologic malignancy within the past 3 years except a) adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix, or prostate cancer < Gleason Grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone Any clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent Significant neuropathy (Grade >2) at the time of the first dose and/or within 14 days before enrollment Contraindication to any of the required concomitant drugs Subjects in whom the required program of PO and IV fluid hydration is contraindicated Subjects with known or suspected amyloidosis of any organ Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: carfilzomib, lenalidomide w/dexamethasone<br>Phase I: carfilzomib will be taken with a combination of lenalidomide plus dexamethasone in a series of escalating dosages to determine the maximum tolerated dose level Phase II: carfilzomib will be given at the MTD established in the Phase I portion of the study | Drug: carfilzomib, lenalidomide plus dexamethasone<br>* Phase I: Carfilzomib will be administered at the dosage assigned for the subject's cohort as an IV infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for Cycles 1 - 8 (induction) and on Days 1, 2, 15, and 16 of a 28-day cycle for Cycles 9+ (maintenance). Lenalidomide will be administered PO daily at 25 mg on Days 1- 21 of the 28-day cycle for Cycles 1 - 8+. Dexamethasone 40 mg will be administered PO or IV between 30 minutes and 4 hours preceding the carfilzomib push.<br>Drug: carfilzomib, lenalidomide plus dexamethasone<br>* Phase II: Carfilzomib will be administered at the Maximum Tolerated Dose (MTD) established in Phase I as an IV infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for Cycles 1 - 8 (induction) and on Days 1, 2, 15, and 16 of a 28-day cycle for Cycles 9+ (maintenance). Lenalidomide will be administered PO daily at 25 mg on Days 1- 21 of the 28-day cycle for Cycles 1 - 8+. Dexamethasone will be administered PO or IV between 30 minutes and 4 hours preceding the carfilzomib push on Days 1, 8, 15, and 22 as follows: Cycles 1-4: 40 mg; Cycles 5-8: 20 mg; and Cycles 9 and higher: 10 mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Maximum Tolerated Dose (MTD) of Carfilzomib | Determine the MTD of Carfilzomib when combined with Lenalidomide and Dexamethasone. The estimated time to determine the MTD is 6 months. | 6 Months | 
| The Percentage of Patients That Achieve a Response to Treatment | The percentage of patients that achieve at least a sCR (Stringent Complete Response), at least a VGPR (Very Good Partial Response) and at least a PR (Partial Response) will be determined. sCR is defined as: Negative immunofixation on the serum and urine and Disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow and Normal SFLC ratio and Absence of clonal cells in bone marrow VGPR is defined as: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-component with urine M-component < 100 mg per 24 hours PR is defined as: ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg per 24 hours If present at baseline, a ≥ 50% reduction in the size of soft tissue plasmacytomas is also required | 4 Months After Treatment Start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Patients Alive Without Progression | The Progression Free Survival (PFS) rate will be determined at 12 and 24 months post treatment. Progressive Disease (PD) is defined as an increase of greater than or equal to 25% from lowest response level in serum M-component and/ or urine M-component and/ or the difference between involved or uninvolved SFLC levels and/ or bone marrow % plasma cells. PD may also be the development of new bone lesions or soft tissue plasmacytomas or the increase in size of existing lesions. PD may also be the development of hypercalcemia. | 12 Months and 24 Months Post Treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma