An Efficacy and Safety Study of Daratumumab in Patients With Multiple Myeloma Who Have Received at Least 3 Prior Lines of Therapy (Including a Proteasome Inhibitor [PI] and Immunomodulatory Drug [IMiD]) or Are Double Refractory to a PI and an IMiD

Phase 2

Completed

• Conditions: Multiple Myeloma
• Interventions: Drug: Daratumumab 16 mg/kg (Part 1); Drug: Daratumumab 8 mg/kg (Part 1); Drug: Methylprednisolone; Drug: Daratumumab (Part 2); Drug: Acetaminophen; Drug: Diphenhydramine

• Registration Number: NCT01985126
• Lead Sponsor: Janssen Research & Development, LLC

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of 2 daratumumab treatment regimens in participants with multiple myeloma who have received at least 3 prior lines of therapy (including a proteasome inhibitor \[PI\] and immunomodulatory drug \[IMiD\]) or are double refractory to a PI and an IMiD.

Detailed Description

This is an open-label (identity of assigned study drug will be known) study of daratumumab for the treatment of participants with multiple myeloma who have received at least 3 prior lines of therapy including a PI and an IMiD or whose disease is double refractory to both a PI and an IMiD. Up to approximately 150 participants are to be enrolled. The study includes screening, treatment, and follow-up phases. Participants will receive daratumumab by intravenous infusion (28-day cycles) until disease progression, unacceptable toxicity, or other protocol-defined reasons. For all study drug administrations, participants will receive pre- and post-infusion medications for the prevention of infusion related reactions. Follow-up will continue until death, loss to follow up, consent withdrawal for study participation, or study end, whichever occurs first. The study will consist of 2 sequential parts (Part 1 and Part 2). The purpose of Part 1 is to select a dose and schedule for Part 2 of the study. Assessment of tumor response and disease progression will be conducted according to IMWG response criteria. Serial pharmacokinetic blood samples and a pharmacogenomic blood sample will be collected. Safety will be monitored throughout the study. At the end of the study, participants who are benefiting from treatment with daratumumab will have the option to continue treatment.

Study Timeline

• Study First Submitted: 2013-07-22
• Study Start: 2013-09-27
• Study First Submitted QC: 2013-11-07
• Study First Posted: 2013-11-15
• Primary Completion: 2015-01-09
• Results First Submitted: 2016-09-30
• Results First Submitted QC: 2016-12-09
• Results First Posted: 2017-02-02
• Study Completion: 2017-05-30
• Status Verified: 2018-06
• Last Update Submitted: 2018-06-21
• Last Update Posted: 2018-06-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 124

Inclusion Criteria

• Documented multiple myeloma according to protocol-defined criteria
• Evidence of disease progression on the most recent prior treatment regimen based on International Myeloma Working Group criteria
• Eastern Cooperative Oncology Group performance status score of 0, 1, or 2
• Laboratory values and electrocardiogram within protocol-defined parameters at screening

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Exclusion Criteria

• Received daratumumab or other anti-CD38 therapies previously
• Nonsecretory multiple myeloma
• Previously received an allogenic stem cell transplant or has received an autologous stem cell transplantation within 12 weeks
• Exhibiting clinical signs of meningeal involvement of multiple myeloma
• Known chronic obstructive pulmonary disease, persistent asthma, or a history of asthma within 5 years
• Seropositive for human immunodeficiency virus, hepatitis B or antibodies to hepatitis B surface and core antigens, or hepatitis C
• Has plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or amyloidosis

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 1	Daratumumab 16 mg/kg (Part 1)	During Stage 1 of Part 1, participants will be randomized to receive daratumumab treatment regimens in Group A and Group B. If in Stage 1, 1 or both of the treatment groups is considered to be ineffective and/or not well tolerated, then that treatment group will be terminated. Participants in Group B will be given the option to cross over to Group A if the investigator deems it in the best interest of the participants.
Part 2	Daratumumab (Part 2)	Based on the Part 1 response rate, Group A or B daratumumab treatment will be selected as the treatment regimen for participants enrolled in Part 2.
Part 1	Daratumumab 8 mg/kg (Part 1)	During Stage 1 of Part 1, participants will be randomized to receive daratumumab treatment regimens in Group A and Group B. If in Stage 1, 1 or both of the treatment groups is considered to be ineffective and/or not well tolerated, then that treatment group will be terminated. Participants in Group B will be given the option to cross over to Group A if the investigator deems it in the best interest of the participants.
Part 1	Acetaminophen	During Stage 1 of Part 1, participants will be randomized to receive daratumumab treatment regimens in Group A and Group B. If in Stage 1, 1 or both of the treatment groups is considered to be ineffective and/or not well tolerated, then that treatment group will be terminated. Participants in Group B will be given the option to cross over to Group A if the investigator deems it in the best interest of the participants.
Part 1	Diphenhydramine	During Stage 1 of Part 1, participants will be randomized to receive daratumumab treatment regimens in Group A and Group B. If in Stage 1, 1 or both of the treatment groups is considered to be ineffective and/or not well tolerated, then that treatment group will be terminated. Participants in Group B will be given the option to cross over to Group A if the investigator deems it in the best interest of the participants.
Part 2	Acetaminophen	Based on the Part 1 response rate, Group A or B daratumumab treatment will be selected as the treatment regimen for participants enrolled in Part 2.
Part 2	Diphenhydramine	Based on the Part 1 response rate, Group A or B daratumumab treatment will be selected as the treatment regimen for participants enrolled in Part 2.
Part 1	Methylprednisolone	During Stage 1 of Part 1, participants will be randomized to receive daratumumab treatment regimens in Group A and Group B. If in Stage 1, 1 or both of the treatment groups is considered to be ineffective and/or not well tolerated, then that treatment group will be terminated. Participants in Group B will be given the option to cross over to Group A if the investigator deems it in the best interest of the participants.
Part 2	Methylprednisolone	Based on the Part 1 response rate, Group A or B daratumumab treatment will be selected as the treatment regimen for participants enrolled in Part 2.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Overall Response	Up to 14.4 Months	Overall response defined as percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR). Per IMWG criteria, sCR: is defined as normal free light chain (FLC) ratio, and absence of clonal plasma cells (PCs) by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5 % plasma cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or \>= 90% reduction in serum M-protein plus urine M-protein level \< 100mg/24 hours; PR: \>= 50 % reduction of serum M-protein and reduction in 24 hour urinary M-protein by \>= 90% or to \<200 mg/24 hours; if the serum and urine M-protein are not measurable, a decrease of \>=50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria.

Secondary Outcome Measures

Name	Time	Method
Time to Disease Progression	Up to 14.4 Months	Time to progression was defined as the number of days from the date of first dose of daratumumab to the date of first record of disease progression.
Time to Response	Up to 14.4 Months	Time to 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).
Overall Survival	Approximately up to 3 years	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.
Progression Free Survival	Up to 14.4 Months	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.
Duration of Response	Up to 14.4 Months	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 IMWG criteria. Disease progression (IMWG criteria): increase of 25 percent (%) from lowest response level in Serum M-component (the absolute increase must be \>=0.5 g/dL) and/or; urine M-component (the absolute increase must be \>=200 mg/24 hours) and/or; only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels (absolute increase must be \>10 milligram per deciliter (mg/dL); Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL or 2.65 millimole per liter \[mmol/L\]) that can be attributed solely to the plasma cell proliferative disorder.
Percentage of Participants With Clinical Benefit	Up to 14.4 Months	Clinical benefit rate defined as percentage of participants who achieved minimal response (MR) or better. MR: \>=25% but \<= 49% reduction of serum M-protein and reduction in urine M-protein by 50%-89%. If present at baseline 25% to 49% reduction in size of soft tissue plasmacytomas.