Study of Initial Treatment With Elotuzumab, Carfilzomib, Lenalidomide and Dexamethasone in Multiple Myeloma

Study Overview
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Brief Summary
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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.

Detailed Description
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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 To evaluate the safety and tolerability of elotuzumab in combination with KRd, when administered to subjects with newly diagnosed multiple myeloma. 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. To estimate time to event, including duration of response (DOR), progression-free survival (PFS), time to progression (TTP), and overall survival (OS). Exploratory Objectives GEP, proteomics, and gene sequencing to evaluate the correlation between treatment outcome and pre-treatment subject profile. Immunologic correlative studies including FcγRIIIa V genotype.

Official Title
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Open-label, Single-arm, Phase 2 Study of Initial Treatment With Elotuzumab, Carfilzomib (Kyprolis), Lenalidomide (Revlimid) and Low Dose Dexamethasone (E-KRd) in Newly Diagnosed, Multiple Myeloma Requiring Systemic Chemotherapy

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Elotuzumab
* Drug: Carfilzomib
* Drug: Lenalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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 a. 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) Both transplant and non-transplant candidates are eligible. Diagnosis of symptomatic multiple myeloma as per current IMWG uniform criteria prior to initial treatment Monoclonal plasma cells in the BM 10% or presence of a biopsy-proven plasmacytoma Measurable disease, prior to initial treatment as indicated by one or more of the following: Serum M-protein ≥ 1 g/dL Urine M-protein ≥ 200 mg/24 hours If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable (≥ 1 g/dL) Involved serum free light chains ≥ 10 mg/dL provided that free light chain ratio is abnormal 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 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 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. Males and females ≥ 18 years of age ECOG performance status of 0-1 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). 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. 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. 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. 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. 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. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) Geriatric assessment score of ≥2 as defined by Palumbo et al. Known or suspected Amyloidosis Plasma cell leukemia Within 4 weeks since any plasmapheresis Within 3 weeks of any corticosteroids except per inclusion criteria #2 Waldenström's macroglobulinemia or IgM myeloma 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 Subjects not able to tolerate elotuzumab, lenalidomide, carfilzomib, or dexamethasone Peripheral neuropathy ≥ Grade 2 at screening Prior CVA with persistent neurological deficit Diarrhea > Grade 1 in the absence of antidiarrheals CNS involvement Corrected calcium ≥ 11.5 mg/dL within 2 weeks of randomization Pregnant or lactating females Radiotherapy within 14 days before randomization. Seven days may be considered if to single area Major surgery within 3 weeks prior to first dose Subject has clinically significant cardiac disease, including: 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 uncontrolled cardiac arrhythmia (NCI CTCAE Version 4 Grade 2:2) or clinically significant ECG abnormalities screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec Uncontrolled HTN 14 days prior to enrollment Prior or concurrent deep vein thrombosis or pulmonary embolism Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECG during screening 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 Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose Active infection 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. 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 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

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: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: All participants will receive E-KRd regimen (elotuzumab, carfilzomib, lenalidomide, and dexamethasone) for up to 12 Cycles. After Cycle 12, participants that are MRD negative will move to E-Rd (elotuzumab, carfilzomib, lenalidomide, and dexamethasone) maintenance regimen and continue until disease progression. Participants that are MRD positive will continue to receive E-KRd regimen for an additional 6 cycles followed by E-Rd maintenance regimen and continue until disease progression
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: E-KRd regimen<br>Participants will receive elotuzumab, carfilzomib, lenalidomide, and dexamethasone. | Drug: Elotuzumab<br>* Elotuzumab will be given on Cycles 1-2 on days 1, 8, 15, 22, Cycles 3 and Beyond on days 1 and 15<br>* Other names: Empliciti;Drug: Carfilzomib<br>* 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<br>* Other names: Kryprolis;Drug: Lenalidomide<br>* Lenalidomide will be given on days 1-21 for all cycles.<br>* Other names: Revlimid;Drug: Dexamethasone<br>* 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<br>|
| Experimental: E-Rd Regimen<br>Participants will receive elotuzumab, lenalidomide, and dexamethasone. | Drug: Elotuzumab<br>* Elotuzumab will be given on Cycles 1-2 on days 1, 8, 15, 22, Cycles 3 and Beyond on days 1 and 15<br>* Other names: Empliciti;Drug: Lenalidomide<br>* Lenalidomide will be given on days 1-21 for all cycles.<br>* Other names: Revlimid;Drug: Dexamethasone<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of sCR |  | At the end of eight months | 
| Rate of negative MRD |  | At the end of eight months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events of elotuzumab in combination with KRd | Adverse events will be monitored in real time and discussed at a weekly data and safety monitoring conference. | Through study completion an average of one year, adverse events will be monitored in real time | 
| Rate of MRD |  | At the end of four, eight, and twelve months for certain subjects. | 
| Duration of response | These events will be analyzed at differing points of time based on the individual subjects disease progression. | Through study completion an average of one year | 
| Progression free survival | These events will be analyzed at differing points of time based on the individual subjects disease progression. | Through study completion an average of one year | 
| Time to progression | These events will be analyzed at differing points of time based on the individual subjects disease progression. | Through study completion an average of one year | 
| Overall survival | These events will be analyzed at differing points of time based on the individual subjects disease progression. | Through study completion an average of one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Elotuzumab, Carfilzomib (Kyprolis), Lenalidomide (Revlimid), Dexamethasone (E-KRd)