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A Study to Evaluate Subcutaneous Daratumumab in Combination With Standard Multiple Myeloma Treatment Regimens

NCT03412565

Description:

The purpose of this study is to evaluate the clinical benefit of subcutaneous (SC) daratumumab administered in combination with standard multiple myeloma (MM) regimens in participants with MM as measured by overall response rate (ORR) or very good partial response (VGPR) or better rate.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate Subcutaneous Daratumumab in Combination With Standard Multiple Myeloma Treatment Regimens
  • Official Title: A Multicenter Phase 2 Study to Evaluate Subcutaneous Daratumumab in Combination With Standard Multiple Myeloma Treatment Regimens

Clinical Trial IDs

  • ORG STUDY ID: CR108435
  • SECONDARY ID: 2017-004203-41
  • SECONDARY ID: 54767414MMY2040
  • NCT ID: NCT03412565

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
DaratumumabD + Bortezomib + Melphalan + Prednisone (D-VMP)
BortezomibD + Bortezomib + Melphalan + Prednisone (D-VMP)
LenalidomideDaratumumab + Lenalidomide + Dexamethasone (D-Rd)
DexamethasoneDaratumumab + Carfilzomib + Dexamethasone (D-Kd)
MelphalanD + Bortezomib + Melphalan + Prednisone (D-VMP)
PrednisoneD + Bortezomib + Melphalan + Prednisone (D-VMP)
CarfilzomibDaratumumab + Carfilzomib + Dexamethasone (D-Kd)

Purpose

The purpose of this study is to evaluate the clinical benefit of subcutaneous (SC) daratumumab administered in combination with standard multiple myeloma (MM) regimens in participants with MM as measured by overall response rate (ORR) or very good partial response (VGPR) or better rate.

Detailed Description

      The hypothesis is that the addition of daratumumab administered SC to standard MM regimens
      will improve responses compared to response data observed in completed phase 3 studies
      without daratumumab. Disease evaluations will include measurements of myeloma proteins, bone
      marrow examinations, skeletal surveys, assessment of extramedullary plasmacytomas, and
      measurements of serum calcium corrected for albumin. Safety will be measured by adverse
      events, laboratory test results, electrocardiogram (ECGs), vital sign measurements, physical
      examination findings, SC injection-site assessments, and assessment of Eastern Cooperative
      Oncology Group (ECOG) performance status score. Study will consist of 3 phases (screening,
      treatment and follow-up) and duration of study is approximately 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Daratumumab(D)+Bortezomib+Lenalidomide+Dexamethasone (D-VRd)ExperimentalParticipants will receive daratumumab 1800 milligram (mg) by subcutaneous (SC) injection on Days 1, 8 and 15 of Cycles 1 to 3 (each cycle of 21 days) and on Day 1 of Cycle 4; bortezomib 1.3 milligram per square meter (mg/m^2) SC injection on Days 1, 4, 8 and 11 of Cycles 1 to 4; lenalidomide 25 mg orally on Day 1 through Day 14 of Cycles 1 to 4 and dexamethasone 20 mg orally or intravenously on Days 1, 2 ,8, 9, 15 and 16 of Cycle 1 to 4.
  • Daratumumab
  • Bortezomib
  • Lenalidomide
  • Dexamethasone
D + Bortezomib + Melphalan + Prednisone (D-VMP)ExperimentalParticipants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15, 22, 29 and 36 of Cycle 1 then on Days 1 and 22 in Cycles 2 to 9 and Day 1 of Cycle 10 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; bortezomib 1.3 mg/m^2 SC injection on Day 1, 4, 8, 11, 22, 25, 29 and 32 of Cycle 1 and on Days 1, 8, 22 and 29 of Cycles 2 to 9; melphalan 9 mg/m^2 orally on Day 1 through Day 4 of Cycles 1 to 9; prednisone 60 mg/m^2 orally on Days 1 to 4 of cycles 1 to 9.
  • Daratumumab
  • Bortezomib
  • Melphalan
  • Prednisone
Daratumumab + Lenalidomide + Dexamethasone (D-Rd)ExperimentalParticipants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2 then on Day 1 and 15 of Cycles 3 to 6 and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; lenalidomide 25 mg orally on Day 1 through Day 21 of each cycle until documented progression of disease, unacceptable toxicity, or end of study and dexamethasone 40 mg orally or intravenously weekly until documented progression of disease, unacceptable toxicity, or end of study.
  • Daratumumab
  • Lenalidomide
  • Dexamethasone
Daratumumab + Carfilzomib + Dexamethasone (D-Kd)ExperimentalParticipants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2 (each cycle is of 28 days) then on Day 1 and 15 of Cycles 3 to 6 and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; Carfilzomib 20 mg/m^2 intravenously (IV) on Day 1 of Cycle 1 only then 70 mg/m^2 IV on Days 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2 and thereafter until documented progression of disease, unacceptable toxicity, or end of study and dexamethasone 40 mg orally or IV weekly for Cycles 1-9 then on Days 1, 8, 15 of each cycle for Cycles 10 and thereafter until documented progression of disease, unacceptable toxicity, or end of study.
  • Daratumumab
  • Dexamethasone
  • Carfilzomib

Eligibility Criteria

        Inclusion Criteria:

          -  Multiple myeloma diagnosed according to the International Myeloma Working Group (IMWG)
             diagnostic criteria

          -  Measurable, secretory disease as defined by any of the following:

               1. Serum monoclonal paraprotein (M-protein) level greater than or equal to (>=) 1.0
                  gram per deciliter (g/dL); or

               2. Urine M-protein level >= 200 milligram per 24 hours (mg/24 hours); or

               3. Light chain multiple myeloma (MM), for participants without measurable disease in
                  the serum or urine: serum Immunoglobulin (Ig) free light chain (FLC) >= 10 mg/dL
                  and abnormal FLC ratio

          -  Meets one of the sets of the following criteria:

               1. For Daratumumab + bortezomib + lenalidomide + dexamethasone (D-VRd) and
                  Daratumumab + bortezomib + melphalan + prednisone + dexamethasone (D-VMP)
                  regimen: newly diagnosed myeloma

               2. For Daratumumab + lenalidomide + dexamethasone (D-Rd) and Daratumumab +
                  Carfilzomib + Dexamethasone (D-Kd) regimen: relapsed or refractory disease

               3. D-Kd cohort: Participants must have received only 1 prior line of therapy for MM
                  which included at least 2 consecutive cycles of lenalidomide therapy

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status grade of 0, 1, or 2

          -  During the study, and for 3 months after receiving the last dose of daratumumab, a
             woman must agree not to donate eggs (ova, oocytes) and men must agree not to donate
             sperm for the purposes of assisted reproduction

        Exclusion Criteria:

          -  History of malignancy (other than MM) unless all treatment of that malignancy was
             completed at least 2 years before consent and the participant has no evidence of
             disease further exceptions are squamous and basal cell carcinomas of the skin and
             carcinoma in situ of the cervix, or breast, or other non-invasive lesion, that in the
             opinion of the investigator, with concurrence with the sponsor's medical monitor, is
             considered cured with minimal risk of recurrence within 3 years

          -  Exhibits clinical signs of meningeal involvement of MM

          -  Either of the following: a) Chronic obstructive pulmonary disease with a forced
             expiratory volume in 1 second (FEV1) is less than (<) 50 percentage (%) of predicted
             normal b) Moderate or severe persistent asthma, or a history of asthma within the last
             2 years, or currently has uncontrolled asthma of any classification c) For D-Kd
             cohort: Known infiltrative pulmonary disease or known pulmonary hypertension

          -  Any of the following: a) Known to be seropositive for human immunodeficiency virus; b)
             Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
             antigen [HBsAg]). Participants with resolved infection (participants who are HBsAg
             negative but positive for antibodies to hepatitis B core antigen [Anti-HBc] and/or
             antibodies to hepatitis B surface antigen [Anti-HBs]) must be screened using real-time
             polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels.
             Those who are polymerase chain reaction (PCR) positive will be excluded

          -  Known to be seropositive for hepatitis C (Anti-HCV antibody positive or HCV-RNA
             quantitation positive) except in the setting of a sustained virologic response [SVR],
             defined as aviremia at least 12 weeks after completion of antiviral therapy

          -  For D-Kd cohort only: Transthoracic echocardiogram showing left ventricular ejection
             fraction (LVEF) <40%; uncontrolled hypertension, defined as an average systolic blood
             pressure greater than (>)159 millimeters of mercury (mmHg) or diastolic >99 mmHg
             despite optimal treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:D-VMP, D-Kd, and D-Rd Cohort: Overall Response Rate (ORR)
Time Frame:18 months after the last participant enrolled (approximately 2.5 years)
Safety Issue:
Description:The ORR is defined as the percentage of participants who achieve partial response (PR) or better according to international myeloma working group (IMWG) criteria, during or after study treatment for D-VMP, D-Kd and D-Rd cohorts. IMWG criteria for PR: greater than or equal to (>=) 50 percent (%) reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to less than (<) 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 free light chain (FLC) levels is required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, >=50% reduction in bone marrow plasma cells (PCs) is required in place of M-protein, provided baseline bone marrow plasma cell percentage was >=30%. In addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required.

Secondary Outcome Measures

Measure:Maximum Observed Serum Concentrations (Cmax) of Daratumumab
Time Frame:D-VRd: Day 4 of Cycles 1 and 4 and post treatment 4 weeks and at week 8; D-VMP and D-Rd: Day 4 of Cycles 1 and 2 and post treatment 4 weeks and at week 8; D-Kd: Day 4 of Cycles 1 and 3 and post treatment 4 weeks and at week 8
Safety Issue:
Description:Cmax is defined as maximum concentration observed following daratumumab administration.
Measure:Minimum Observed Serum Concentrations (Cmin) of Daratumumab
Time Frame:D-VRd: predose on Day 1 of Cycles 1, 3, and 4; D-VMP: predose on Day 1 of Cycles 1, 2, 3, 6 and 9; D-Rd: predose on Day 1 of Cycles 1, 3, 6, 9 and 12 and D-Kd: predose on Day 1 of Cycles 1, 3, 6, 9, and 12
Safety Issue:
Description:Cmin is defined as the minimum concentration observed immediately before daratumumab administration.
Measure:Percentage of Participants with Infusion-Related Reactions (IRR)
Time Frame:18 months after the last participant enrolled (approximately 2.5 years)
Safety Issue:
Description:The Percentage of Participants with infusion reactions will be reported.
Measure:D-Kd, D-VMP, and D-Rd Cohort: Very Good Partial Response (VGPR) or Better Rate
Time Frame:18 months after the last participant enrolled (approximately 2.5 years)
Safety Issue:
Description:The VGPR or better rate, defined as the percentage of participants achieving VGPR or better rate according IMWG criteria during or after the study treatment for Daratumumab + Carfilzomib + Dexamethasone (D-Kd), Daratumumab + Bortezomib + Melphalan + Prednisone (D-VMP), and Daratumumab + Lenalidomide + Dexamethasone (D-Rd) cohorts. IMWG criteria for VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis, or greater than equal to (>=) 90 percent (%) reduction in serum M-protein plus urine M-protein <100 milligram (mg)/24 hours.
Measure:D-VRd Cohort: Overall Response Rate (ORR)
Time Frame:18 months after the last participant enrolled (approximately 2.5 years)
Safety Issue:
Description:The ORR is defined as the proportion of participants who achieve partial response (PR) or better according to IMWG criteria, during or after study treatment for D-VRd cohort. IMWG criteria for PR: greater than or equal to (>=) 50 percent (%) reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to less than (<) 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 free light chain (FLC) levels is required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, >=50% reduction in bone marrow plasma cells (PCs) is required in place of M-protein, provided baseline bone marrow plasma cell percentage was >=30%. In addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required.
Measure:Complete Response or Better Rate
Time Frame:18 months after the last participant enrolled (approximately 2.5 years)
Safety Issue:
Description:Complete response is based on serum M-Protein assessments. IMWG criteria for CR: Negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow. Stringent complete response (sCR): CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4 color flow cytometry.
Measure:Duration of Response (DOR)
Time Frame:18 months after the last participant enrolled (approximately 2.5 years)
Safety Issue:
Description:Duration of response is defined as the time from the date of initial documented response (PR or better for D-Kd, D-VMP, D-Rd, and D-VRd cohorts) to the date of first documented evidence of progressive disease or death due to progressive disease (PD).
Measure:Number of Participants with Anti-Drug Antibodies Against Daratumumab or Recombinant Human Hyaluronidase (rHuPH20)
Time Frame:Up to 8 weeks after the last dose of study drug (approximately 1 year)
Safety Issue:
Description:Participants with anti-drug antibodies against daratumumab or rHuPH20 will be analyzed.
Measure:D-Kd, D-VMP, and D-Rd Cohorts: Percentage of Participants who are Minimal Residual Disease (MRD) Negative
Time Frame:18 months after the last participant enrolled (approximately 2.5 years)
Safety Issue:
Description:Percentage of participants who are MRD negative will be assessed for D-Kd, D-VMP, and D-Rd cohorts. MRD negative is defined as less than (<) 0.01% abnormal population counts to total event counts when measured by flow.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Janssen Research & Development, LLC

Last Updated

January 30, 2020