Daratumumab in Combination With Lenalidomide and Dexamethasone in Relapsed and Relapsed-refractory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to establish the safety profile of daratumumab when given in combination with Lenalidomide and dexamethasone in participants with relapsed or relapsed and refractory Multiple Myeloma (MM).

Detailed Description
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The study is conducted in two parts. The dose escalation portion of the trial (Part 1) participants are enrolled into cohorts at increasing dose levels of daratumumab in combination with Len/Dex in 28 day treatment cycles. Part 2, the cohort expansion part of the trial, will further explore the maximum tolerated dose (MTD) (or the maximum tested dose) of daratumumab as determined in Part 1.

Official Title
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An Open Label, International, Multicenter, Dose Escalating Phase I/II Trial Investigating the Safety of Daratumumab in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed or Relapsed and Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Part 1 (Dose Escalation): Daratumumab
* Drug: Part 2 (Dose Expansion): Daratumumab
* Drug: Lenalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (Part 1) Have relapsed multiple myeloma after receiving a minimum of 2 and a maximum of 4 prior lines of therapy and be eligible for treatment with lenalidomide and dexamethasone (Len/Dex) (Part 2) Have received at least 1 prior line of therapy for multiple myeloma Be older than or be 18 years of age Eastern Cooperative Oncology Group (ECOG) performance status (0-2) Provide signed informed consent after receipt of oral and written information about the study and before any study-related activity is performed Exclusion Criteria: Have previously received an allogenic stem cell transplant Have received autologous stem cell transplant within 12 weeks before the first infusion Have received antimyeloma treatment, radiotherapy, or any experimental drug or therapy within 2 weeks before the first infusion Have discontinued lenalidomide due to any treatment-related adverse event or be refractory to any dose of lenalidomide. Refractory to lenalidomide is defined as either, participants whose disease progresses within 60 days of lenalidomide, or participants whose disease is nonresponsive while on any dose of lenalidomide. Nonresponsive disease is defined as either failure to achieve at least an minimal response (MR) or development of progressive disease (PD) while on lenalidomide

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daratumumab<br>Participants will receive daratumumab along with Lenalidomide and dexamethasone. | Drug: Part 1 (Dose Escalation): Daratumumab<br>* Participants will receive intravenous (injection of a substance into a vein) infusion of daratumumab in an increased fashion from 2 milligram per kilogram (mg/kg) up to maximum dose of 16 mg/kg. Considering the safety and efficacy of dose in Part 1, recommended phase 2 dose (RP2D) for Part 2 of the study will be decided. A predose infusion of 10 percent (%) of the full dose of daratumumab will be administered a day before the first full infusion of the first cycle. Participants will receive 4 weekly infusions in the first 2 treatment cycles. From cycles 3 to 6 infusions will be administered every alternate week and monthly infusions will be administered from cycle 7 until disease progression.<br>Drug: Part 2 (Dose Expansion): Daratumumab<br>* Participants will receive RP2D as determined in Part 1 of the study. Participants will receive 4 weekly infusions of RP2D in the first 2 treatment cycles. From cycles 3 to 6 infusions will be administered every alternate week and monthly infusions will be administered from cycle 7 until disease progression.<br>Drug: Lenalidomide<br>* All participants (Part 1 and Part 2) will receive 25 mg lenalidomide orally (by mouth) from days 1 to 21 of each 28-day cycle until disease progression.<br>Drug: Dexamethasone<br>* All participants (Part 1 and Part 2) will receive 40 mg (20 mg intravenously [injection of a substance into a vein]) dexamethasone once weekly. Participants older than 75 years or underweight (body mass index [BMI] less than [<] 18.5), the dexamethasone dose will be administered at a dose of 20 mg once weekly until disease progression.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Percentage of Participants With Overall Response Rate (ORR) | ORR is defined as percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR). International Myeloma Working Group (IMWG) criteria- CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and less than (<) 5 percentage (%) plasma cells in bone marrow; sCR: CR+Normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry or immuno fluorescence; PR: greater than equal to (>=) 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >= 90 percentage (%) or to <200 mg/24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100 mg per 24 hour. | Up to 3 years | 
| Phase 2: Percentage of Participants With Overall Response Rate (ORR) | ORR is defined as percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR). IMWG criteria- CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and less than (<) 5 percentage (%) plasma cells in bone marrow; sCR: CR+Normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence; PR: greater than eqaul to (>=) 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >= 90 percentage (%) or to <200 mg/24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100 mg per 24 hour. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Time to Progression (TTP) | TTP was defined as the number of days from the date of first infusion (Day 1) to the date of first record of disease progression. Disease progression (IMWG criteria): increase of >=25 percent (%) from lowest response level in Serum M-component and/or (the absolute increase must be >=0.5 g/dL) Urine M-component and/or (the absolute increase must be >=200 mg/24 hour; only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase must be >10 mg/dL; Bone marrow plasma cell percentage: the absolute % must be >=10 %; Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder. Median TTP was estimated by using the Kaplan-Meier method. | Up to 3 years | 
| Phase 2: Duration of Response | Duration of response was calculated from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease, as defined in the International Myeloma Working Group (IMWG) criteria. | Up to 3 years | 
| Phase 2: Progression-Free Survival (PFS) | Progression free survival (PFS) was defined as the time between the date of first dose of daratumumab and either disease progression or death, whichever occurs first. | Up to 3 years | 
| Phase 1: Time to Response | Time to first response was defined as the time from the date of first dose of daratumumab to the date of initial documentation of a response (PR or better). Time to best response was defined as the time between the date of first dose of daratumumab and the date of the initial evaluation of the best response (PR or better) to treatment. | Up to 3 years | 
| Phase 2: Time to Response | Time to first response was defined as the time from the date of first dose of daratumumab to the date of initial documentation of a response (PR or better). Time to best response was defined as the time between the date of first dose of daratumumab and the date of the initial evaluation of the best response (PR or better) to treatment. | Up to 3 years | 
| Phase 2: Overall Survival (OS) | Overall Survival (OS) was defined as the number of days from administration of the first infusion (Day 1) to date of death. Median Overall Survival was estimated by using the Kaplan Meier method. | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Daratumumab, Lenalidomide, Dexamethasone, Dose-escalation, Relapsed multiple myeloma, Multiple Myeloma, Relapsed and refractory multiple myeloma