Study of Initial Treatment With Elotuzumab, Carfilzomib, Lenalidomide and Dexamethasone in Multiple Myeloma
Study Details
Study Description
Brief Summary
This study will be a multi-center, open-label, Phase 2 study where newly diagnosed Multiple Myeloma requiring systemic chemotherapy will be eligible for enrollment. A total of 55 subjects will be enrolled. Time to progression or death will be calculated from the date of first treatment on protocol until the date of disease progression or death from any cause. Patients can expect to participate between 12-24 cycles. The primary endpoint will be the rate of response by next generation gene sequencing at the end of 8 cycles among non-transplant candidates and transplant candidates who agreed to defer transplant.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
Primary Objective
• The primary efficacy endpoint will be the rate of sCR and/or the rate of negative MRD by next generation gene sequencing (NGS) by clonoSIGHT (Adaptive Biotechnologies) at the end of 8 cycles among non-transplant candidates and transplant candidates who agreed to defer transplant
Secondary Objectives
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To evaluate the safety and tolerability of elotuzumab in combination with KRd, when administered to subjects with newly diagnosed multiple myeloma.
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To determine the rate of MRD by next generation gene sequencing (NGS) by clonoSIGHT (Adaptive Biotechnologies) and by multi-color flow cytometry (MFC) at the end of Cycle 4, 8,and 12 for all subjects, and end of C18 (for subjects who are MRD+ at the end of C8 but MRD- at the end of C12 only), 24 months after C1D1, and yearly after that.
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To estimate time to event, including duration of response (DOR), progression-free survival (PFS), time to progression (TTP), and overall survival (OS).
Exploratory Objectives
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GEP, proteomics, and gene sequencing to evaluate the correlation between treatment outcome and pre-treatment subject profile.
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Immunologic correlative studies including FcγRIIIa V genotype.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: E-KRd regimen Participants will receive elotuzumab, carfilzomib, lenalidomide, and dexamethasone. |
Drug: Elotuzumab
Elotuzumab will be given on Cycles 1-2 on days 1, 8, 15, 22, Cycles 3 and Beyond on days 1 and 15
Other Names:
Drug: Carfilzomib
Carfilzomib will be given on Day 1 and 8 of Cycle 1, Days 1, 8, and 15 of Cycles 2-8, and Days 1 and 15 of Cycles 9 and beyond
Other Names:
Drug: Lenalidomide
Lenalidomide will be given on days 1-21 for all cycles.
Other Names:
Drug: Dexamethasone
Dexamethasone will be given as follows:
Cycle 1 and 2: Days 1, 2, 8, 9, 15, 16, and 22 Cycles 3 and Beyond: Days 1, 8, 15, and 22
|
| Experimental: E-Rd Regimen Participants will receive elotuzumab, lenalidomide, and dexamethasone. |
Drug: Elotuzumab
Elotuzumab will be given on Cycles 1-2 on days 1, 8, 15, 22, Cycles 3 and Beyond on days 1 and 15
Other Names:
Drug: Lenalidomide
Lenalidomide will be given on days 1-21 for all cycles.
Other Names:
Drug: Dexamethasone
Dexamethasone will be given as follows:
Cycle 1 and 2: Days 1, 2, 8, 9, 15, 16, and 22 Cycles 3 and Beyond: Days 1, 8, 15, and 22
|
Outcome Measures
Primary Outcome Measures
- Rate of sCR [At the end of eight months]
- Rate of negative MRD [At the end of eight months]
Secondary Outcome Measures
- Number of participants with adverse events of elotuzumab in combination with KRd [Through study completion an average of one year, adverse events will be monitored in real time]
Adverse events will be monitored in real time and discussed at a weekly data and safety monitoring conference.
- Rate of MRD [At the end of four, eight, and twelve months for certain subjects.]
- Duration of response [Through study completion an average of one year]
These events will be analyzed at differing points of time based on the individual subjects disease progression.
- Progression free survival [Through study completion an average of one year]
These events will be analyzed at differing points of time based on the individual subjects disease progression.
- Time to progression [Through study completion an average of one year]
These events will be analyzed at differing points of time based on the individual subjects disease progression.
- Overall survival [Through study completion an average of one year]
These events will be analyzed at differing points of time based on the individual subjects disease progression.
Other Outcome Measures
- Logisitc Regression for analyzing exploratory biomarkers [After study completion an average of one year]
Subjects will have the option to participate in additional genetic components of this trial if they provide their consent. Once a subject has completed participation in the trial, if they agree to participate in the optional components their disease will be analyzed in relation to people with similar genetic make up.
Eligibility Criteria
Criteria
Inclusion Criteria:
- Subjects must meet all of the following inclusion criteria to be eligible to enroll in this study. No enrollment waivers will be granted.
- Newly diagnosed, previously untreated myeloma requiring systemic chemotherapy
- Prior treatment of hypercalcemia or spinal cord compression or active and/or aggressively progressing myeloma with corticosteroids and/or lenalidomide and/or bortezomib/PI-based regimens does not disqualify the subject (the corticosteroid treatment dose should not exceed the equivalent of 160 mg of dexamethasone in a 4 week period or not more than 1 cycle of lenalidomide and/or PI-based therapy)
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Both transplant and non-transplant candidates are eligible.
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Diagnosis of symptomatic multiple myeloma as per current IMWG uniform criteria prior to initial treatment
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Monoclonal plasma cells in the BM 10% or presence of a biopsy-proven plasmacytoma
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Measurable disease, prior to initial treatment as indicated by one or more of the following:
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Serum M-protein ≥ 1 g/dL
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Urine M-protein ≥ 200 mg/24 hours
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If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable (≥ 1 g/dL)
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Involved serum free light chains ≥ 10 mg/dL provided that free light chain ratio is abnormal
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Screening laboratory values must meet the following criteria and should be obtained within 21 days prior to enrollment WBC ≥ 2000/µL Platelets ≥ 75 x103/µL ANC >1000/µL Hemoglobin > 8.0 g/dL Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 50 mL/min
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Use the Cockcroft-Gault formula below):
o Female CrCl = (140 - age in years) x weight in kg x 0.85
- 72 x serum creatinine in mg/dL
o Male CrCl = (140 - age in years) x weight in kg x 1.00
- 72 x serum creatinine in mg/dL
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Alternatively to Cockcroft-Gault formula of CrCl, 24hr urine CrCl can be used AST/ALT ≤ 3 x ULN Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) or ≤ 2 x ULN if lenalidomide is being prescribed.
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Males and females ≥ 18 years of age
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ECOG performance status of 0-1
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Females of childbearing potential (FCBP) must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to initiating lenalidomide. The first pregnancy test must be performed within 10-14 days before and the second pregnancy test must be performed within 24 hours before lenalidomide is prescribed for Cycle 1 (prescriptions must be filled within 7 days).
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FCBP must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study.
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Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy.
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All study participants in the US must be consented to and registered into the mandatory Revlimid REMS program and be willing and able to comply with the requirements of Revlimid REMS.
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Voluntary written informed consent
Exclusion Criteria:
- Subjects meeting any of the following exclusion criteria are not eligible to enroll in this study. No enrollment waivers will be granted.
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Non-secretory or hyposecretory multiple myeloma, prior to initial treatment defined as <1.0 g/dL M-protein in serum, <200 mg/24 hr urine M-protein, and no measurable disease as per IMWG by Freelite.
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POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
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Geriatric assessment score of ≥2 as defined by Palumbo et al.
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Known or suspected Amyloidosis
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Plasma cell leukemia
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Within 4 weeks since any plasmapheresis
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Within 3 weeks of any corticosteroids except per inclusion criteria #2
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Waldenström's macroglobulinemia or IgM myeloma
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Participation in an investigational therapeutic study within 3 weeks or within 5 drug half-lives (t1/2) prior to first dose, whichever time is greater
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Subjects not able to tolerate elotuzumab, lenalidomide, carfilzomib, or dexamethasone
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Peripheral neuropathy ≥ Grade 2 at screening
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Prior CVA with persistent neurological deficit
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Diarrhea > Grade 1 in the absence of antidiarrheals
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CNS involvement
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Corrected calcium ≥ 11.5 mg/dL within 2 weeks of randomization
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Pregnant or lactating females
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Radiotherapy within 14 days before randomization. Seven days may be considered if to single area
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Major surgery within 3 weeks prior to first dose
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Subject has clinically significant cardiac disease, including:
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myocardial infarction within 1 year before Cycle 1 Day 1, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV
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uncontrolled cardiac arrhythmia (NCI CTCAE Version 4 Grade 2:2) or clinically significant ECG abnormalities
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screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec
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Uncontrolled HTN 14 days prior to enrollment
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Prior or concurrent deep vein thrombosis or pulmonary embolism
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Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECG during screening
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Uncontrolled hypertension (defined as average systolic blood pressure ≥140 or average diastolic blood pressure ≥90, with blood pressure measured ≥3 times in the two weeks prior to enrollment ) or diabetes
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Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
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Active infection
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Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Subjects who are seropositive because of hepatitis B virus vaccine are eligible.
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Non-hematologic malignancy or non-myeloma 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
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Any clinically significant medical disease or condition that, in the Treating Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Chicago | Chicago | Illinois | United States | 60637 |
| 2 | NorthShore University Health System | Evanston | Illinois | United States | 60201 |
| 3 | University of Michigan Comprehensive Cancer Center | Ann Arbor | Michigan | United States | 48109 |
Sponsors and Collaborators
- University of Chicago
- Bristol-Myers Squibb
- Amgen
- Multiple Myeloma Research Foundation
Investigators
- Principal Investigator: Andrzej Jakubowiak, MD, University of Chicago
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IRB16-1138