A Phase 1b/2, Dose-Escalation Study of Elotuzumab (Humanized Anti-CS1 Monoclonal IgG1 Antibody) in Relapsed Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the combination of elotuzumab, lenalidomide, and dexamethasone in subjects with relapsed multiple myeloma.

Official Title
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A Phase 1b/2, Multicenter, Open-label, Dose-escalation Study of Elotuzumab (Humanized Anti-CS1 Monoclonal IgG1 Antibody) in Combination With Lenalidomide and Dexamethasone in Subjects With Relapsed Multiple Myeloma

Conditions
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Hematologic Cancer

Intervention / Treatment
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* Biological: elotuzumab
* Drug: lenalidomide
* Drug: dexamethasone oral
* Drug: dexamethasone injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older with a confirmed diagnosis of multiple myeloma (MM) and documentation of one to three prior therapies. Confirmed evidence of disease progression from immediately prior MM therapy or refractory to the immediately prior treatment. Measurable monoclonal (M-) protein component in serum (≥ 0.5 g/dL) and/or urine (if present), (≥ 0.2 g excreted in a 24 hour collection sample). Subjects with free light chain only disease are excluded. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2. Creatinine clearance ≥ 50 mL/min measured by Cockcroft-Gault method. Hematologic parameters defined by: Absolute neutrophil count >1000 cells/mm^3 without growth factors for 7 days. Platelets ≥ 75,000 cells/mm^3 (75 × 10^9/L), without platelet transfusion, within 72 hours of screening evaluation. Hemoglobin ≥ 8 g/dL without red blood cell transfusion within 72 hours of screening. Alanine aminotransferase (ALT) AND aspartate aminotransferase (AST) < 3 × upper limit of normal. Total bilirubin < 2 × upper limit of normal, direct bilirubin < 2.0 mg/dL. Negative urine pregnancy test in women of childbearing potential at screening and prior to prescribing lenalidomide. Females of childbearing potential (FCBP) must either commit to continued abstinence from heterosexual intercourse or begin acceptable methods of birth control for 28 days prior to prescribing lenalidomide. Men must agree to use a latex condom during sexual contact with FCBP even if they have had a successful vasectomy, and must agree not to donate semen during study drug therapy and for a period of time after therapy. Able to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject's privacy regulations). Able to take aspirin daily as prophylactic anticoagulation therapy (subjects intolerant to aspirin may use warfarin or low-molecular-weight heparin). Exclusion Criteria: Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, or other cancer from which the subject has been disease-free for at least 2 years. Active or prior plasma cell leukemia (defined as either 20% of peripheral WBC comprised of plasma/CD138+ cells or an absolute count of 2 x 10^9/L). Uncontrolled medical problems such as diabetes mellitus, coronary artery disease, hypertension, unstable angina, arrhythmias, pulmonary disease, and symptomatic heart failure. Solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia. Treatment with any investigational drug within 2 weeks or 3 half lives (whichever is longer) of the first dose of elotuzumab. Use of corticosteroids, thalidomide, bortezomib, or cytotoxic chemotherapy within 2 weeks of the first dose of elotuzumab except for steroids with little or no systemic absorption (ie, topical or inhaled steroids). Prior lenalidomide therapy. Prior peripheral stem-cell transplant within 12 weeks of the first dose of elotuzumab. Treatment with nitrosoureas, such as carmustine (BiCNU), nitrogen mustard agents, or melphalan, within 6 weeks of first dose of elotuzumab. Neuropathy ≥ Grade 3 or painful neuropathy ≥ Grade 2 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v3.0). Known active infections requiring IV antibiotic, antiviral, or antifungal therapy. Hypersensitivity to recombinant proteins or excipients in elotuzumab, lenalidomide, or dexamethasone. Female subjects who are pregnant or breastfeeding. Subjects with serum calcium (corrected for albumin) ≥ 12 mg/dL.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Elotuzumab 5 mg/kg + Lenalidomide and Dexamethasone (Phase 1)<br>Elotuzumab 5 mg/kg administered as an IV infusion in combination with lenalidomide 25 mg and dexamethasone 40 mg administered orally. | Biological: elotuzumab<br>* Humanized Anti-CS1 Monoclonal IgG1 Antibody (HuLuc63) administered as an intravenous infusion once a week during Cycles 1 and 2, and every other week beginning with Cycle 3.<br>* Other names: HuLuc63;Drug: lenalidomide<br>* Lenalidomide 25 mg administered orally once daily on Days 1 to 21 of each 28-day cycle<br>Drug: dexamethasone oral<br>* Dexamethasone 40 mg administered orally once weekly; during weeks when elotuzumab is also administered, dexamethasone was administered as a split dose (28 mg orally and 8 mg intravenously)<br>Drug: dexamethasone injection<br>* Dexamethasone 40 mg administered orally once weekly; during weeks when elotuzumab is also administered, dexamethasone was administered as a split dose (28 mg orally and 8 mg intravenously)<br>|
| Experimental: Elotuzumab 10 mg/kg + Lenalidomide and Dexamethasone (Phase 1)<br>Elotuzumab 10 mg/kg administered as an IV infusion in combination with lenalidomide 25 mg and dexamethasone 40 mg administered orally. | Biological: elotuzumab<br>* Humanized Anti-CS1 Monoclonal IgG1 Antibody (HuLuc63) administered as an intravenous infusion once a week during Cycles 1 and 2, and every other week beginning with Cycle 3.<br>* Other names: HuLuc63;Drug: lenalidomide<br>* Lenalidomide 25 mg administered orally once daily on Days 1 to 21 of each 28-day cycle<br>Drug: dexamethasone oral<br>* Dexamethasone 40 mg administered orally once weekly; during weeks when elotuzumab is also administered, dexamethasone was administered as a split dose (28 mg orally and 8 mg intravenously)<br>Drug: dexamethasone injection<br>* Dexamethasone 40 mg administered orally once weekly; during weeks when elotuzumab is also administered, dexamethasone was administered as a split dose (28 mg orally and 8 mg intravenously)<br>|
| Experimental: Elotuzumab 20 mg/kg + Lenalidomide and Dexamethasone (Phase 1)<br>Elotuzumab 20 mg/kg administered as an IV infusion in combination with lenalidomide 25 mg and dexamethasone 40 mg administered orally. | Biological: elotuzumab<br>* Humanized Anti-CS1 Monoclonal IgG1 Antibody (HuLuc63) administered as an intravenous infusion once a week during Cycles 1 and 2, and every other week beginning with Cycle 3.<br>* Other names: HuLuc63;Drug: lenalidomide<br>* Lenalidomide 25 mg administered orally once daily on Days 1 to 21 of each 28-day cycle<br>Drug: dexamethasone oral<br>* Dexamethasone 40 mg administered orally once weekly; during weeks when elotuzumab is also administered, dexamethasone was administered as a split dose (28 mg orally and 8 mg intravenously)<br>Drug: dexamethasone injection<br>* Dexamethasone 40 mg administered orally once weekly; during weeks when elotuzumab is also administered, dexamethasone was administered as a split dose (28 mg orally and 8 mg intravenously)<br>|
| Experimental: Elotuzumab 10 mg/kg + Lenalidomide and Dexamethasone (Phase 2)<br>Elotuzumab 10 mg/kg administered as an IV infusion in combination with lenalidomide 25 mg and dexamethasone 40 mg administered orally. | Biological: elotuzumab<br>* Humanized Anti-CS1 Monoclonal IgG1 Antibody (HuLuc63) administered as an intravenous infusion once a week during Cycles 1 and 2, and every other week beginning with Cycle 3.<br>* Other names: HuLuc63;Drug: lenalidomide<br>* Lenalidomide 25 mg administered orally once daily on Days 1 to 21 of each 28-day cycle<br>Drug: dexamethasone oral<br>* Dexamethasone 40 mg administered orally once weekly; during weeks when elotuzumab is also administered, dexamethasone was administered as a split dose (28 mg orally and 8 mg intravenously)<br>Drug: dexamethasone injection<br>* Dexamethasone 40 mg administered orally once weekly; during weeks when elotuzumab is also administered, dexamethasone was administered as a split dose (28 mg orally and 8 mg intravenously)<br>|
| Experimental: Elotuzumab 20 mg/kg + Lenalidomide and Dexamethasone (Phase 2)<br>Elotuzumab 20 mg/kg administered as an IV infusion in combination with lenalidomide 25 mg and dexamethasone 40 mg administered orally. | Biological: elotuzumab<br>* Humanized Anti-CS1 Monoclonal IgG1 Antibody (HuLuc63) administered as an intravenous infusion once a week during Cycles 1 and 2, and every other week beginning with Cycle 3.<br>* Other names: HuLuc63;Drug: lenalidomide<br>* Lenalidomide 25 mg administered orally once daily on Days 1 to 21 of each 28-day cycle<br>Drug: dexamethasone oral<br>* Dexamethasone 40 mg administered orally once weekly; during weeks when elotuzumab is also administered, dexamethasone was administered as a split dose (28 mg orally and 8 mg intravenously)<br>Drug: dexamethasone injection<br>* Dexamethasone 40 mg administered orally once weekly; during weeks when elotuzumab is also administered, dexamethasone was administered as a split dose (28 mg orally and 8 mg intravenously)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Elotuzumab in Combination With Lenalidomide and Dexamethasone (Phase 1) | MTD was determined by testing increasing doses up to 20 mg/kg once daily dose escalation cohorts 1 to 3 with 3 patients each. MTD reflects highest dose of drug that did not cause an unacceptable side effect (dose limiting toxicity [DLT]) in more than 30% of patients; e.g., hematologic toxicities like Common Toxicity Criteria for Adverse Events (CTCAE) Grade 4 neutropenia in specific conditions, platelets < 10,000 cells/mm^3 that do not recover to 25,000 cells/mm^3; and specific non-hematologic/biochemical toxicities CTCAE Grade 3 or 4 (except fatigue and Grade 3 infections); CTCAE version 3.0 were used. | 4 weeks | 
| Objective Response Rate (ORR) According to the International Myeloma Working Group Uniform Response Criteria (Phase 2) | ORR: Percentage of participants with confirmed complete response (CR; negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and ≤5% plasma cells in bone marrow), partial response (PR; ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to ≤200 mg per 24 hour; if serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved free light chain (FLC] levels is required in place of the M-protein criteria; if serum and urine M-protein are unmeasurable, and serum FLC is also unmeasurable, a ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%; and, if present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas), very good PR (VGPR; normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence), or stringent CR (sCR; CR plus VGPR). | From date of randomization until 60 days following the last infusion (or before initiation of new therapy), up to 101 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) According to the International Myeloma Working Group Uniform Response Criteria (Phase 1) | ORR: Percentage of participants with confirmed complete response (CR; negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and ≤5% plasma cells in bone marrow), partial response (PR; ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to ≤200 mg per 24 hour; if serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved free light chain (FLC] levels is required in place of the M-protein criteria; if serum and urine M-protein are unmeasurable, and serum FLC is also unmeasurable, a ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%; and, if present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas), very good PR (VGPR; normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence), or stringent CR (sCR; CR plus VGPR). | From first dose of elotuzumab until 60 days following the last infusion (or before initiation of new therapy), up to 100.5 months | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either definitely related, probably related, possibly related or unrelated. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent events (TEAEs/TESAEs) are defined as any event that began or worsened in severity after the first dose of study drug. For more details on adverse events please see the Adverse Event section. | Treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) were collected from first dose of study drug until 60 days after the last dose of study drug (up to 95 months) | 
| Number of Participants With Infusion Reactions | During Phase 1, a list of 118 pre-defined MedDRA preferred terms that had been adjudicated to be clinically relevant to infusion reactions by a safety committee was used to search for TEAEs that could potentially be associated with an infusion reaction following elotuzumab administration. Examples of these terms included angioedema, bronchospasm, chills, flushing, pyrexia, rash and urticaria. During Phase 2, the method for capturing TEAEs associated with an infusion reaction was modified to include investigators' designation of AEs judged as clinically relevant infusion reactions. The number of participants infusion reactions are provided overall and by highest toxicity grade (CTCAE v 3.0). | Cycles 1 and 2: Days 1, 8, 15, and 22 (day of infusion of elotuzumab) and Days 2, 9, 16, and 23 (day following infusion); and Cycles 3 and greater: Days 1 and 15 (day of infusion) and Days 2 and 16 (day after infusion) (up to 95 months) | 
| Mean Serum Concentrations of Elotuzumab During Cycle 1 | Blood samples were collected during Phase 1, Cycle 1, prior to elotuzumab infusion (time 0 hours) and 30 minutes (0.5 hours) and 4 hours post-infusion (Day 1), 30 minutes (0.5 hours) post-infusion (Day 8 and Day 15), or 30 minutes (0.5 hours), 2 hours, and 4 hours post-infusion (Day 15). Blood samples were collected during Phase 2, Cycle 1, prior to elotuzumab infusion (time 0 hours) and 30 minutes (0.5 hours), 2 hours, and 4 hours post-infusion (Day 1), 30 minutes (0.5 hours) and 2 hours post-infusion (Day 8 and Day 15), or 30 minutes (0.5 hours), 2 hours, and 4 hours post-infusion (Day 15). The samples were analyzed for the concentration of elotuzumab using validated analytical methods. Mean serum concentrations on Cycle 1, Days 1, 8, 15, and 22 (measured in μg/mL) are reported overall (across Phase 1 and Phase 2) by dose. | Cycle 1: Days 1 (pre-infusion and 0.5, 2 and 4 hours post-infusion), 8 (pre-infusion and 0.5 and 2 hours post-infusion), 15 (pre-infusion and 0.5 hours and 2 hours post-infusion), and 22 (pre-infusion and 0.5, 2, and 4 hours post-infusion) | 
| Maximum Serum Concentration (Cmax) of Elotuzumab | The maximum plasma concentration (Cmax; measured in ng/mL) is the highest concentration that a drug achieves in the blood after administration in a dosing interval. The Cmax of elotuzumab was to be estimated using non-compartmental methods and data reported as the mean ± standard deviation. No noncompartmental pharmacokinetic parameters (e.g., AUC, CL, V, t 1/2) were estimated due to sparse serum concentration collections. | Cycle 1: Days 1, 8, and 15; Cycle 2: Days 1 and 22; Cycle 3 and beyond: Day 1 | 
| Area Under the Concentration-time Curve From 0 to Infinity (AUC0-inf) of Elotuzumab | The area under the plasma concentration-time curve (AUC; measured in ng*hr/mL) is a method of measurement to determine the total exposure of a drug in blood plasma. The AUC24 of elotuzumab was to be estimated using non-compartmental methods and data reported as the mean ± standard deviation. No noncompartmental pharmacokinetic parameters (e.g., AUC, CL, V, t 1/2) were estimated due to sparse serum concentration collections. | Cycle 1: Days 1, 8, and 15; Cycle 2: Days 1 and 22; Cycle 3 and beyond: Day 1 | 
| Systemic Clearance (CL) of Elotuzumab | Systemic clearance (CL, measured in mL/kg/hr) is a measure of the efficiency with which a drug is irreversibly removed from the body. The CL of elotuzumab was to be estimated using non-compartmental methods and data reported as the mean ± standard deviation. No noncompartmental pharmacokinetic parameters (e.g., AUC, CL, V, t 1/2) were estimated due to sparse serum concentration collections. | Cycle 1: Days 1, 8, and 15; Cycle 2: Days 1 and 22; Cycle 3 and beyond: Day 1 | 
| Volume of Distribution (V) of Elotuzumab | Volume of distribution (V, measured in L/kg) is the hypothetical volume of body fluid that would be required to dissolve the amount of drug needed to achieve the same concentration in the blood. The V of elotuzumab was to be estimated using non-compartmental methods and data reported as the mean ± standard deviation. No noncompartmental pharmacokinetic parameters (e.g., AUC, CL, V, t 1/2) were estimated due to sparse serum concentration collections. | Cycle 1: Days 1, 8, and 15; Cycle 2: Days 1 and 22; Cycle 3 and beyond: Day 1 | 
| Serum Half-life (t1/2) of Elotuzumab | The serum half-life of a drug (t1/2, measured in hours) is the time necessary to reduce the plasma concentration by half. The t1/2 of elotuzumab was to be estimated using non-compartmental methods and data reported as the mean ± standard deviation. No noncompartmental pharmacokinetic parameters (e.g., AUC, CL, V, t 1/2) were estimated due to sparse serum concentration collections. | Cycle 1: Days 1, 8, and 15; Cycle 2: Days 1 and 22; Cycle 3 and beyond: Day 1 | 
| Duration of Response | Duration of response is defined as the time from the initial objective response to disease progression or death, whichever occurs first. The distribution of duration of response was estimated for each treatment group using Kaplan-Meier methodology. Point estimates and 95% CIs for the median for the duration of response distribution are provided. | From first dose of elotuzumab (phase 1) or randomization (phase 2) until 60 days following the last infusion (or before initiation of new therapy), up to 101 months | 
| Time to Progression (TTP) | TTP is defined as the time from first dose (phase 1) or time from randomization (phase 2) to disease progression. The distribution of TTP was estimated for each treatment group using Kaplan-Meier methodology. Point estimates and 95% CIs for the median for the TTP distribution are provided. | From first dose of elotuzumab (phase 1) or randomization (phase 2) until 60 days following the last infusion (or before initiation of new therapy), up to 101 months | 
| Progression-free Survival (PFS) | PFS is defined as the time from first dose (phase 1) or time from randomization (phase 2) to disease progression or death. The distribution of PFS was estimated for each treatment group using Kaplan-Meier methodology. Point estimates and 95% CIs for the median for the PFS distribution are provided. | From first dose of elotuzumab (phase 1) or randomization (phase 2) until 60 days following the last infusion (or before initiation of new therapy), up to 101 months | 
| Percentage of Participants With Treatment-emergent Anti-elotuzumab Antibody (ADA) | Treatment-emergent (post-dose) positive elotuzumab-specific ADA is differentiated from pre-existing (positive at the predose time point) positive elotuzumab-specific ADA. The percentage of participants with confirmed treatment-emergent ADA overall by dose is provided. | From screening through 60-day follow up period (up to 101 months) | 
| Plasma Cell Myeloma Cytogenetic Subtype | Plasma cell myeloma cytogenetic subtype was assessed at the screening visit using standard karyotyping and/or fluorescence in situ hybridization. The number of participants in each cytogenetic risk category are provided: High Risk (International Staging System [ISS] stage II or III and t(4;14) or del(17p) abnormality); Standard Risk (not high or low risk); and Low Risk (ISS stage I or II and absence of t(4;14), del(17p) and 1q21 abnormalities AND age < 55). | Screening (up to 14 days prior to dosing) | 

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