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

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.

Time frame: 4 weeks

Population: All participants in the safety population (all randomized participants who received at least 1 dose of study drug) in the escalation cohorts (Elotuzumab 5 mg/kg + Lenalidomide and Dexamethasone \[Phase 1\]; Elotuzumab 10 mg/kg + Lenalidomide and Dexamethasone \[Phase 1\]; and Elotuzumab 20 mg/kg + Lenalidomide and Dexamethasone \[Phase 1\]).

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).

Time frame: From date of randomization until 60 days following the last infusion (or before initiation of new therapy), up to 101 months

Population: Safety population: All randomized participants who received at least 1 dose of study drug

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.

Time frame: Cycle 1: Days 1, 8, and 15; Cycle 2: Days 1 and 22; Cycle 3 and beyond: Day 1

Population: No noncompartmental pharmacokinetic parameters (e.g., AUC, CL, V, t 1/2) were estimated (collected data not reliable due to assay limitations caused by sparse serum concentrations).

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.

Time frame: 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

Population: Safety population: All randomized participants who received at least 1 dose of study drug

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.

Time frame: Cycle 1: Days 1, 8, and 15; Cycle 2: Days 1 and 22; Cycle 3 and beyond: Day 1

Population: No noncompartmental pharmacokinetic parameters (e.g., AUC, CL, V, t 1/2) were estimated (collected data not reliable due to assay limitations caused by sparse serum concentrations).

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.

Time frame: 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)

Population: Safety population: All randomized participants who received at least 1 dose of study drug, with evaluable data at given time point.

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).

Time frame: 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)

Population: Safety population: All randomized participants who received at least 1 dose of study drug

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.

Time frame: 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)

Population: Safety population: All randomized participants who received at least 1 dose of study drug

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).

Time frame: From first dose of elotuzumab until 60 days following the last infusion (or before initiation of new therapy), up to 100.5 months

Population: Safety population: All randomized participants who received at least 1 dose of study drug

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.

Time frame: From screening through 60-day follow up period (up to 101 months)

Population: All participants who received at least one dose of study drug and with at least one evaluable post-dose sample.

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).

Time frame: Screening (up to 14 days prior to dosing)

Population: Safety population: All randomized participants who received at least 1 dose of study drug

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.

Time frame: 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

Population: Safety population: All randomized participants who received at least 1 dose of study drug

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.

Time frame: Cycle 1: Days 1, 8, and 15; Cycle 2: Days 1 and 22; Cycle 3 and beyond: Day 1

Population: No noncompartmental pharmacokinetic parameters (e.g., AUC, CL, V, t 1/2) were estimated (collected data not reliable due to assay limitations caused by sparse serum concentrations).

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.

Time frame: Cycle 1: Days 1, 8, and 15; Cycle 2: Days 1 and 22; Cycle 3 and beyond: Day 1

Population: No noncompartmental pharmacokinetic parameters (e.g., AUC, CL, V, t 1/2) were estimated (collected data not reliable due to assay limitations caused by sparse serum concentrations).

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.

Time frame: 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

Population: Safety population: All randomized participants who received at least 1 dose of study drug

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.

Time frame: Cycle 1: Days 1, 8, and 15; Cycle 2: Days 1 and 22; Cycle 3 and beyond: Day 1

Population: No noncompartmental pharmacokinetic parameters (e.g., AUC, CL, V, t 1/2) were estimated (collected data not reliable due to assay limitations caused by sparse serum concentrations).