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A Study to Investigate the Safety, Tolerability, Efficacy, Pharmacokinetics, and Immunogenicity of TAK-079 Administered Subcutaneously as a Single Agent in Participants With Relapsed/Refractory (r/r) Multiple Myeloma (MM)

NCT03439280

Description:

The purpose of this study is to assess the safety and tolerability, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of TAK-079 monotherapy and when combined with a backbone regimen of pomalidomide and dexamethasone (PomDex) in Phase 1, and to provide a preliminary evaluation of the clinical activity of TAK-079 monotherapy in Phase 2a in participants with r/r MM.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study to Investigate the Safety, Tolerability, Efficacy, Pharmacokinetics, and Immunogenicity of TAK-079 Administered Subcutaneously as a Single Agent in Participants With Relapsed/Refractory (r/r) Multiple Myeloma (MM)
  • Official Title: A Phase 1/2a Open-label, Dose-Escalation Study to Investigate the Safety and Tolerability, Efficacy, Pharmacokinetics, and Immunogenicity of TAK-079 Administered Subcutaneously as a Single Agent in Patients With Relapsed/Refractory Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: TAK-079-1501
  • SECONDARY ID: U1111-1208-3202
  • NCT ID: NCT03439280

Conditions

  • Relapsed/Refractory
  • Multiple Myeloma

Interventions

DrugSynonymsArms
TAK-079Phase 1 Dose Escalation Cohort: TAK-079
PomalidomidePhase 1 Combination Cohort: TAK-079 + PomDex
DexamethasonePhase 1 Combination Cohort: TAK-079 + PomDex

Purpose

The purpose of this study is to assess the safety and tolerability, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of TAK-079 monotherapy and when combined with a backbone regimen of pomalidomide and dexamethasone (PomDex) in Phase 1, and to provide a preliminary evaluation of the clinical activity of TAK-079 monotherapy in Phase 2a in participants with r/r MM.

Detailed Description

      The drug being tested in this study is called TAK-079. TAK-079 is being tested to treat
      people who have relapsed and/or refractory multiple myeloma (RRMM). This study will assess
      the safety, tolerability, efficacy, pharmacokinetics, and immunogenicity of TAK-079
      monotherapy and will provide a preliminary assessment of its activity against MM. The study
      is designed to consist of 2 phases: Phase 1 and Phase 2a.

      The study could enroll approximately 100 participants. The study population of Phase 1 will
      consist of approximately 55 participants. Participants in Phase 1 will be assigned to TAK-079
      and dose-escalation will range from 45 mg to 1800 mg.

      The study population of Phase 2a will consist of approximately 48 participants. Dose for
      Phase 2a will be based upon review of the available safety, efficacy, pharmacokinetic, and
      pharmacodynamic data from the preceding cohorts of Phase 1.

      This multi-center trial will be conducted in the United States. The overall time to
      participate in this study is 42 months (3.5 years). In Phase 1, participants who stop
      treatment for any other reason other than PD will continue to have progression-free survival
      (PFS) follow-up at the site every 4 weeks from the last dose of study drug up to 12 months or
      until PD, death, loss to follow-up, consent withdrawal or study termination. Participants
      will be followed 30 days after last dose of study drug or until the start of subsequent
      alternative anti-cancer therapy, whichever occurs first, for a follow up assessment.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1 Dose Escalation Cohort: TAK-079ExperimentalTAK-079, subcutaneously, once weekly for 8 weeks, then once every 2 weeks for 16 weeks, and then once every 4 weeks thereafter in a 28-day treatment cycle until PD, unacceptable toxicities or withdrawal due to other reasons. Dose escalation of TAK-079 will range from 45 milligram (mg) to 1800 mg and may be done using a 3 + 3 dose escalation design to determine a MTD and/or RP2D.
  • TAK-079
Phase 1 Dose Confirmation Cohort: TAK-079ExperimentalTAK-079, subcutaneously, once weekly for 8 weeks, then once every 2 weeks for 16 weeks, and then once every 4 weeks thereafter in a 28-day treatment cycle until PD. TAK-079 dose will be determined based on review of the available safety, efficacy, pharmacokinetic, and pharmacodynamic data obtained from the previous cohort of Phase 1.
  • TAK-079
Phase 1 Combination Cohort: TAK-079 + PomDexExperimentalTAK-079, subcutaneously, once weekly for 8 weeks, then once every 2 weeks for 16 weeks, and then once every 4 weeks thereafter along with pomalidomide, orally, once daily on Days 1 to 21 and dexamethasone, orally, once on Days 1, 8, 15, and 22 in a 28-day treatment cycle until PD. TAK-079 dose will be determined based on review of the available safety, efficacy, pharmacokinetic, and pharmacodynamic data obtained from the Phase 1.
  • TAK-079
  • Pomalidomide
  • Dexamethasone
Phase 2a: TAK-079 TBDExperimentalTAK-079, subcutaneously, once weekly for 8 weeks, then once every 2 weeks for 16 weeks, and then once every 4 weeks thereafter in a 28-day treatment cycle until PD, unacceptable toxicities or withdrawal due to other reasons. TAK-079 dose for this phase will be determined based on review of the available safety, efficacy, pharmacokinetic, and pharmacodynamic data obtained from the Phase 1 portion of the study.
  • TAK-079

Eligibility Criteria

        Inclusion Criteria:

          1. Eastern Cooperative Oncology Group (ECOG) performance status of <=2.

          2. Has received previous myeloma-specific therapy.

          3. In the Combination Cohort (TAK-079-PomDex) only must be able to take concurrent
             prophylactic anticoagulation per standard clinical practice as directed by the
             investigator and the Pomalyst product information.

          4. Documentation of RRMM as defined by the International Myeloma Working Group (IMWG)
             criteria.

          5. For Participants with MM, measurable disease defined as one of the following:

               -  Serum M-protein >=0.5 g/dL (>=5 gram per liter [g/L]).

               -  Urine M-protein >=200 mg/24 hours.

               -  In participants without measurable M-protein in serum protein electrophoresis
                  (SPEP) or urine protein electrophoresis (UPEP), a serum FLC assay result with
                  involved FLC level >=10 mg/dL (>=100 milligram per liter [mg/L]), provided serum
                  FLC ratio is abnormal.

          6. Prior therapy should meet all the following criteria:

             Participants in the dose Escalation Cohort (escalation phase) and participants in the
             dose Confirmation Cohort;

               -  Should be previously treated with at least a proteasome inhibitor (PI), an
                  immunomodulatory drug (IMiD), and a steroid. Note: Participants who have had a
                  previous autologous stem cell transplant will have additionally been exposed to
                  an alkylating agent; however, participant who have not had a previous autologous
                  stem cell transplant may not have been exposed to an alkylating agent per
                  standard practice.

               -  Should be refractory or intolerant to at least 1 PI and at least 1 IMiD.

               -  Should either have received >= 3 prior lines of therapy or should have received
                  at least 2 prior lines of therapy if one of those lines included a combination of
                  PI and IMiD.

               -  In phase 1, previous exposure to an anti-CD38 agent, as a single agent or in
                  combination, is allowed but is not required. (Participants in the dose Escalation
                  Cohort).

               -  In phase 1 dose Confirmation Cohort, cohorts of participants that are refractory
                  at any time to at least 1 anti-CD38 agent or who are anti-CD38 naïve will be
                  enrolled.

             Participants in the Combination Cohort (TAK-079 added to PomDex cohort only):

               -  Have undergone prior therapy with >=2 prior anti-myeloma therapies (line of
                  therapy defined below).

               -  Has either relapsed or relapsed and refractory disease. Should have progressed on
                  or within 60 days of completing the last anti-myeloma therapy (refractory defined
                  below).

          7. In the phase 2a portion of the study, up to 2 cohorts of participants with RRMM may be
             enrolled: 1 that is refractory to at least 1 anti-CD38 monoclonal antibody (mAb)
             therapy at any time during treatment and 1 that is naïve to daratumumab.

        Note:

        o Refractory is defined as at least a 25% increase in M-protein (response of stable disease
        during prior therapy) or PD during treatment or within 60 days after last dose of prior
        therapy.

        Exclusion Criteria:

          1. Sensory or motor neuropathy of National Cancer Institute Common Terminology Criteria
             for Adverse Events (NCI CTCAE) Grade >=3.

          2. Have received allogeneic stem cell transplant.

          3. Have received anti-CD38 antibody therapy and do not fulfill a 180-day washout period
             before receiving TAK-079.

          4. Not recovered from adverse reactions to prior myeloma treatment or procedures
             (chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE Grade <=1 or baseline,
             excluding alopecia.

          5. Clinical signs of central nervous system (CNS) involvement of MM.

          6. Active chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, active
             HIV, or cytomegalovirus (CMV) infection.

          7. POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin
             changes) syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma,
             solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, or IgM myeloma.

          8. Positive Coombs tests at screening.

          9. For participants in the Combination Cohort (TAK-079-PomDex) only: participant has
             previously received pomalidomide or has hypersensitivity to thalidomide or
             lenalidomide.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Number of Participants Reporting one or more Treatment-emergent Adverse Events (TEAEs)
Time Frame:Up to 1 year
Safety Issue:
Description:DLTs will be defined as any of the following events: Grade 4 laboratory abnormalities, except those events that are clearly due to extraneous causes; nonhematologic TEAEs of grade greater than or equal to (>=3) except grade 3 nausea/vomiting, fatigue lasting less than 72 hours, elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) that resolves to grade less than or equal to (<=)1 or baseline within 7 days, injection reaction (IR) that responds to symptomatic treatment; Hematologic TEAEs of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade >=4, except grade >=3 hemolysis, grade 3 low platelet or higher count with clinically meaningful bleeding; and an incomplete recovery from treatment-related toxicity causing a greater than (>) 2-week delay in the next scheduled injection before the initiation of Cycle 2 will be considered a DLT.

Secondary Outcome Measures

Measure:Cmax: Maximum Observed Serum Concentration for TAK-079
Time Frame:Cycle 1 and 2: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length is equal to [=] 28 days)
Safety Issue:
Description:
Measure:Tmax: Time to Reach the Maximum Observed Serum Concentration (Cmax) for TAK-079
Time Frame:Cycle 1 and 2: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length = 28 days)
Safety Issue:
Description:
Measure:AUClast: Area Under the Serum Concentration-time Curve from Time 0 to the Time of the Last Quantifiable Concentration for TAK-079
Time Frame:Cycle 1 and 2: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length = 28 days)
Safety Issue:
Description:
Measure:Phase 1: ORR
Time Frame:Up to 1 year
Safety Issue:
Description:ORR is defined as the percentage of participants who achieved a partial response (PR) or better during the study. PR is defined as >=50 percent (%) reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg/24 hours.
Measure:Percentage of Participants with Minimal Response (MR)
Time Frame:Up to 1 year
Safety Issue:
Description:MR is defined as >=25% but <=49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%.
Measure:Percentage of Participants With Positive Anti-drug Antibodies (ADA)
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Phase 2a: Number of Participants with DLTs
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Phase 2a: Number of Participants Reporting one or more TEAEs
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Phase 2a: Number of Participants with TEAEs Leading to Dose Modifications
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Phase 2a: Number of Participants with TEAEs Leading to Treatment Discontinuation
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Phase 2a: Duration of Response (DOR)
Time Frame:Up to 1 year
Safety Issue:
Description:DOR is the time from date of first documentation of response to date of first documented PD. PD is increase of >=25% from lowest response value in any of following:Serum M-protein(increase must be >=0.5 gram per decilitre[g/dL];serum M component increases >=1 g/dL are sufficient to define relapse if starting M component is >=5 g/dL),and/or urine M-protein(increase must be >=200 mg/24 hour), and/or only in participants without measurable serum and urine M-protein levels, difference between involved/uninvolved FLC levels (increase must be >10 mg/dL), and only in participants without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow plasma cell percentage (percentage must be >=10%) or definite development of new bone lesions or soft tissue plasmacytomas or increase in size of bone lesions or soft tissue plasmacytomas, and development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder.
Measure:Phase 2a: Progression Free Survival (PFS)
Time Frame:Up to 1 year
Safety Issue:
Description:PFS is time from the date of the first dose until the earliest date of disease progression (PD). PD is increase of >=25% from lowest response value in any of following: Serum M-protein (increase must be >=0.5 g/dL; serum M component increases >=1 g/dL are sufficient to define relapse if starting M component is >=5 g/dL),and/or urine M-protein (increase must be >=200 mg/24 hour), and/or only in participants without measurable serum and urine M-protein levels, difference between involved/uninvolved FLC levels (increase must be >10 mg/dL), and only in participants without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow plasma cell percentage (percentage must be >=10%) or definite development of new bone lesions or soft tissue plasmacytomas or increase in size of bone lesions or soft tissue plasmacytomas, and development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder.
Measure:Phase 2a: Overall Survival (OS)
Time Frame:Up to 1 year
Safety Issue:
Description:OS is defined as the time from the date of first dose to the date of death due to any cause.
Measure:Phase 2a: Time to Response (TTR)
Time Frame:Up to 1 year
Safety Issue:
Description:TTR is defined as the time from the date of the first dose to the date of the first documentation of response (PR [partial response] or better). PR is defined as >=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg/24 hours.
Measure:Phase 1: RP2D of TAK-079
Time Frame:Up to 1 year
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Millennium Pharmaceuticals, Inc.

Trial Keywords

  • Drug therapy, TAK-079, pomalidomide and dexamethasone, CD38 monoclonal antibody

Last Updated

July 12, 2019