Clinical Trials /

Daratumumab Retreatment in Participants With Multiple Myeloma Who Have Been Previously Treated With Daratumumab Intravenous (Dara-IV)

NCT03871829

Description:

The purpose of this study is to compare the efficacy (rate of very good partial response [VGPR] or better as best response as defined by the International Myeloma Working Group [IMWG] criteria) of daratumumab subcutaneous (Dara-SC) in combination with carfilzomib and dexamethasone (Kd) with the efficacy of Kd in participants with relapsed refractory multiple myeloma who were previously exposed to daratumumab intravenous (Dara-IV) to evaluate daratumumab retreatment.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Daratumumab Retreatment in Participants With Multiple Myeloma Who Have Been Previously Treated With Daratumumab Intravenous (Dara-IV)
  • Official Title: A Phase 2 Study of Daratumumab Subcutaneous (Dara-SC) Administration in Combination With Carfilzomib and Dexamethasone (DKd) Compared With Carfilzomib and Dexamethasone (Kd) in Participants With Multiple Myeloma Who Have Been Previously Treated With Daratumumab Intravenous (Dara-IV) to Evaluate Daratumumab Retreatment

Clinical Trial IDs

  • ORG STUDY ID: CR108598
  • SECONDARY ID: 2018-004185-34
  • SECONDARY ID: 54767414MMY2065
  • NCT ID: NCT03871829

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
Carfilzomib 20 mg/m^2Arm A: Carfilzomib+Dexamethasone (Kd)
Carfilzomib 70 mg/m^2Arm A: Carfilzomib+Dexamethasone (Kd)
Dexamethasone 40 mgArm A: Carfilzomib+Dexamethasone (Kd)
Dara-SC 1800 mgArm B: Dara-SC in combination with Kd (DKd)
Dexamethasone 20 mgArm A: Carfilzomib+Dexamethasone (Kd)

Purpose

The purpose of this study is to compare the efficacy (rate of very good partial response [VGPR] or better as best response as defined by the International Myeloma Working Group [IMWG] criteria) of daratumumab subcutaneous (Dara-SC) in combination with carfilzomib and dexamethasone (Kd) with the efficacy of Kd in participants with relapsed refractory multiple myeloma who were previously exposed to daratumumab intravenous (Dara-IV) to evaluate daratumumab retreatment.

Detailed Description

      For relapsed or refractory multiple myeloma, the treatment is determined on an individual
      basis. Common standard of care regimens use either a proteasome inhibitor (PI) or an
      immunomodulatory agent (IMiD) in combination with dexamethasone with or without a monoclonal
      antibody (mAb) such as daratumumab. After relapse from PIs or IMiDs, patients are often
      retreated with drugs that have same mechanism of action to which they have been sensitive.
      The disease becomes refractory and all effective treatment options are exhausted. Daratumumab
      is a human IgG1 mAb that binds with high affinity to unique epitope on cluster of
      differentiation 38 (CD38) and attacks tumor cells that overexpress CD38. Study is to
      determine the efficacy of Dara-SC in combination with carfilzomib and dexamethasone (DKd) in
      adult participants with relapsed refractory MM who had 1 or 2 prior line(s) of treatment
      including a line containing Dara-IV to evaluate daratumumab retreatment. The MM treatment is
      determined on an individual basis where patient's age, prior therapy, bone marrow function,
      co-morbidities, patient preference and time to relapse are considered. Common standard of
      care regimens use either PI or an IMiD in combination with dexamethasone with or without a
      mAb. It is a targeted immunotherapy that attacks tumor cells that overexpress CD38, a
      transmembrane glycoprotein, in a variety of hematological malignancies including multiple
      myeloma. The study will be conducted in 3 phases: Screening (28 days), Treatment, and
      Follow-Up. Assessments like chest X-ray, spirometry test, electrocardiogram (ECG), will be
      performed during Screening phase. During the Treatment Phase, participants will be randomized
      to receive Kd or DKd. Efficacy assessments like bone marrow examination will be performed.
      Follow-up will continue until the end of study.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: Carfilzomib+Dexamethasone (Kd)Active ComparatorParticipants will receive carfilzomib 20 milligram per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1 and then 70 mg/m^2 on Days 8 and 15 of Cycle 1 and thereafter on Days 1, 8, 15 of Cycle 2 onwards. Participants will receive dexamethasone 20 mg on Cycle 1 Day 1, a second dose of 20 milligram (mg) will be given on Cycle 1 Day 2 and 40 mg IV or orally on Days 8, 15, 22 for Cycle 1. Patients will then receive dexamethasone 40mg on days 1, 8, 15 and 22 for cycles 2-9, then on Days 1, 8, 15 for Cycle 10 onwards, until death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study. The total duration of each cycle is 28 Days.
  • Carfilzomib 20 mg/m^2
  • Carfilzomib 70 mg/m^2
  • Dexamethasone 40 mg
  • Dexamethasone 20 mg
Arm B: Dara-SC in combination with Kd (DKd)ExperimentalParticipants will receive daratumumab subcutaneous (Dara-SC) 1800 mg by SC injection on Days 1, 8, 15, 22 for Cycle 1 and 2, Days 1 and 15 for Cycle 3-6, Day 1 for Cycle 7 onwards. Participants will receive carfilzomib 20 mg/m^2 IV on Cycle 1 Day 1 and then 70 mg/m^2 on Day 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2. Participants will receive dexamethasone 20 mg on Cycle 1 Day 1, a second dose of 20 milligram (mg) will be given on Cycle 1 Day 2 and 40 mg IV or orally on Days 8, 15, 22 for Cycle 1. Patients will then receive dexamethasone 40mg on days 1, 8, 15 and 22 for cycles 2-9, then on Days 1, 8, 15 for Cycle 10 onwards, until death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study. The total duration of each cycle is 28 Days.
  • Carfilzomib 20 mg/m^2
  • Carfilzomib 70 mg/m^2
  • Dexamethasone 40 mg
  • Dara-SC 1800 mg
  • Dexamethasone 20 mg

Eligibility Criteria

        Inclusion Criteria:

          -  Evidence of a response (partial response or better based on investigator's
             determination of response by International Myeloma Working Group [IMWG] criteria) to
             daratumumab-containing intravenously (IV) therapy with response duration of at least 4
             months

          -  Participants must have progressed from or be refractory to their last line of
             treatment. Relapsed or refractory disease as defined as: a) Relapsed disease is
             defined as an initial response to previous treatment, followed by confirmed
             progressive disease (PD) by IMWG criteria greater than (>) 60 days after cessation of
             treatment. b) Refractory disease is defined as less than (<) 25 percent (%) reduction
             in M-protein or confirmed PD by IMWG criteria during previous treatment or >60 days
             after cessation of treatment

          -  Received 1 or 2 prior line(s) of treatment of which one contained Dara IV, and
             completed Dara IV at least 3 months prior to randomization. A single line of therapy
             may consist of 1 or more agents, and may include induction, hematopoietic stem cell
             transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single
             short course of corticosteroids (no more than the equivalent of dexamethasone 40
             milligram per day [mg/day] for 4 days) would not be considered prior lines of therapy

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

          -  Women of childbearing potential must have a negative urine or serum pregnancy test at
             screening within 14 days prior to randomization

        Exclusion Criteria:

          -  Previous treatment with daratumumab within the last 3 months prior to randomization

          -  Discontinuation of Dara IV due to a daratumumab-related adverse event (AE)

          -  History of malignancy (other than multiple myeloma) unless all treatment of that
             malignancy was completed at least 2 years before consent and the patient 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

          -  Allergies, hypersensitivity, or intolerance to daratumumab, hyaluronidase, monoclonal
             antibodies (mAbs), human proteins, or their excipients, or known sensitivity to
             mammalian-derived products. Known history of allergy to Captisol (a cyclodextrin
             derivative used to solubilize carfilzomib)

          -  Participant is: 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 (example: 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)
             deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded. c)
             Known to be seropositive for hepatitis C (except in the setting of a sustained
             virologic response [SVR], defined as aviremia at least 12 weeks after completion of
             antiviral therapy)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants Achieving Very Good Partial Response (VGPR) or Better Response
Time Frame:Approximately 2 years
Safety Issue:
Description:Percentage of participants achieving VGPR or better response according IMWG criteria for VGPR will be reported. IMWG criteria for VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis, or greater than or equal to (>=) 90 percent (%) reduction in serum M-protein plus urine M-protein less than (<) 100 milligram (mg)/24 hours.

Secondary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:Approximately 2 years
Safety Issue:
Description:ORR is defined as percentage of participants who achieve partial response (PR) or better (including VGPR, CR, sCR) responses prior to subsequent anti-myeloma therapy. IMWG criteria for 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 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%; additionally, if present at baseline, a >=50% reduction in the size of soft tissue PCs is also required.
Measure:Percentage of Participants Achieving Complete Response (CR) or Stringent Complete Response (sCR)
Time Frame:Approximately 2 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 (PCs), and <5% PCs in bone marrow. IMWG criteria for sCR defined as, CR plus normal free light chain (FLC) ratio, and Absence of clonal PCs by immunohistochemistry, immunofluorescencea or 2- to 4- color flow cytometry.
Measure:Progression Free Survival (PFS)
Time Frame:Up to approximately 3.3 years
Safety Issue:
Description:PFS is time from date of randomization to date of documented progressive disease (PD) on first line treatment given for multiple myeloma (MM) or death, whichever comes first. IMWG criteria for PD: >=25% from lowest response level in serum M-component (the absolute increase must be >=0.5 gram per deciliter [g/dL]) and/or in urine M-component (the absolute increase must be >=200 mg/24 hour); only in participants without measurable serum and urine M-protein levels: increase of >=25% in the difference between involved and uninvolved free light chain levels and the absolute increase must be >10 mg/dL. BMPC%: the absolute % must be >=10%; definite increase in size of existing bone lesions or soft tissue plasmacytomas; definite development of new bone lesions or soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium >11.5 milligrams per deciliter (mg/dL) or 2.65 millimoles per liter [mmol/L]) that can be attributed solely to PC proliferative disorder.
Measure:Overall Survival (OS)
Time Frame:Up to approximately 3.3 years
Safety Issue:
Description:OS is defined as the time from the date of first dose of study drug to date of death due to any cause. If the participant is alive or the vital status is unknown, the participant will be censored at the date the participant will be last known to be alive.
Measure:Percentage of Participants With Negative Minimal Residual Disease (MRD)
Time Frame:Approximately 2 years
Safety Issue:
Description:Percentage of participants who have achieved MRD negative status will be assessed.
Measure:Time to Next Treatment
Time Frame:Up to approximately 3.3 years
Safety Issue:
Description:Time to next treatment is defined as the time from randomization to the start of the next-line treatment.
Measure:Serum Concentrations of Daratumumab
Time Frame:Arm A: Cycle 1 (each cycle of 28 days) Day 1 (Cycle 1 Day 1), Cycle 3 Day 1; Arm B: Cycle 1 Day1, Cycle 3 Day 1, Cycle 7 Day 1 and Follow Up (post treatment Week 8)
Safety Issue:
Description:Serum concentrations of daratumumab will be assessed.
Measure:Number of Participants with Anti-Daratumumab Antibodies
Time Frame:Arm A: Cycle 1 (each cycle of 28 days) Day 1 (Cycle 1 Day 1), Cycle 3 Day 1; Arm B: Cycle 1 Day1, Cycle 3 Day 1, Cycle 7 Day 1 and Follow Up (post treatment Week 8)
Safety Issue:
Description:Number of participants who test positive for anti-daratumumab antibodies will be reported.
Measure:Number of Participants with Anti-recombinant Human Hyaluronidase (rHuPH20) Antibodies
Time Frame:Arm A: Cycle 1 (each cycle of 28 days) Day 1 (Cycle 1 Day 1), Cycle 3 Day 1; Arm B: Cycle 1 Day1, Cycle 3 Day 1, Cycle 7 Day 1 and Follow Up (post treatment Week 8)
Safety Issue:
Description:Number of participants who test positive for anti-rHuPH20 antibodies will be reported.

Details

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

Last Updated

January 2, 2020