Clinical Trials /

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), and Efficacy of TAK-169 in Participants With Relapsed or Refractory Multiple Myeloma (RRMM)

NCT04017130

Description:

The purpose of this study is to evaluate the safety and tolerability of TAK-169, establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), and to provide a preliminary evaluation of the clinical activity of TAK-169 monotherapy in participants with RRMM.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), and Efficacy of TAK-169 in Participants With Relapsed or Refractory Multiple Myeloma (RRMM)
  • Official Title: A Phase 1, Open-Label, Dose-Escalation, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of TAK-169 in Patients With Relapsed or Refractory Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: TAK-169-1001
  • SECONDARY ID: U1111-1224-6002
  • SECONDARY ID: 2019-000931-24
  • NCT ID: NCT04017130

Conditions

  • Relapsed and/or Refractory Multiple Myeloma

Interventions

DrugSynonymsArms
TAK-169Part 1: TAK-169 100 mcg/kg Once Weekly

Purpose

The purpose of this study is to evaluate the safety and tolerability of TAK-169, establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), and to provide a preliminary evaluation of the clinical activity of TAK-169 monotherapy in participants with RRMM.

Detailed Description

      The drug being tested in this study is called TAK-169. The study will evaluate the safety,
      tolerability, preliminary efficacy, PK, pharmacodynamic, and immunogenicity of TAK-169
      monotherapy in participants with RRMM.

      The study will be conducted in 2 phases: Dose Escalation Phase (Part 1) and an Expansion
      Phase (Part 2). The study will enroll approximately 81 to 102 participants (39 to 60
      participants in Part 1 and approximately 54 participants in Part 2).

      In the Dose Escalation Phase (Part 1), the starting dose level will be 50 microgram/kilogram
      (mcg/kg), once weekly. On the basis of investigator and sponsor review of available safety,
      PK, pharmacodynamic, and efficacy data from Cohort 1, the dose will be escalated in the
      subsequent cohorts to 100, 200, 335, 500, and 665 mcg/kg, once weekly. A separate dose
      escalation may also occur in which TAK-169 will be administered once every 2 weeks.

      In the Expansion Phase (Part 2), the study will evaluate two types of RRMM cohorts:
      Daratumumab-relapsed or Refractory (RR) Cohorts (once weekly and once every 2 weeks TAK-169
      administration) and an Anti-CD38 Therapy Naive Cohort (once weekly TAK-169 administration).
      The starting dose for each expansion cohort will be the MTD/RP2D (once weekly and once every
      2 weeks) determined in Part 1 after review of the available safety, efficacy, PK, and
      pharmacodynamic data from the dose escalation phase of the study.

      This multi-center trial will be conducted in the United States. The overall duration of the
      study is 34 months. Participants will be followed up for 30 days after the last dose of study
      drug for a follow-up assessment.
    

Trial Arms

NameTypeDescriptionInterventions
Part 1: TAK-169 50 mcg/kg Once WeeklyExperimentalTAK-169 50 microgram per kilogram (mcg/kg), infusion, intravenously, once weekly on Days 1, 8, 15, and 22 in a 28-day treatment cycle until progressive disease (PD), unacceptable toxicity or withdraw from the study for other reasons.
  • TAK-169
Part 1: TAK-169 100 mcg/kg Once WeeklyExperimentalTAK-169 100 mcg/kg, infusion, intravenously, once weekly on Days 1, 8, 15, and 22 in a 28-day treatment cycle until PD, unacceptable toxicity or withdraw from the study for other reasons.
  • TAK-169
Part 1: TAK-169 200 mcg/kg Once WeeklyExperimentalTAK-169 200 mcg/kg, infusion, intravenously, once weekly on Days 1, 8, 15, and 22 in a 28-day treatment cycle until PD, unacceptable toxicity or withdraw from the study for other reasons.
  • TAK-169
Part 1: TAK-169 335 mcg/kg Once WeeklyExperimentalTAK-169 335 mcg/kg, infusion, intravenously, once weekly on Days 1, 8, 15, and 22 in a 28-day treatment cycle until PD, unacceptable toxicity or withdraw from the study for other reasons.
  • TAK-169
Part 1: TAK-169 500 mcg/kg Once WeeklyExperimentalTAK-169 500 mcg/kg, infusion, intravenously, once weekly on Days 1, 8, 15, and 22 in a 28-day treatment cycle until PD, unacceptable toxicity or withdraw from the study for other reasons.
  • TAK-169
Part 1: TAK-169 665 mcg/kg Once WeeklyExperimentalTAK-169 665 mcg/kg, infusion, intravenously, once weekly on Days 1, 8, 15, and 22 in a 28-day treatment cycle until PD, unacceptable toxicity or withdraw from the study for other reasons.
  • TAK-169
Part 1: TAK-169 TBD Once Every Two WeeksExperimentalTAK-169 TBD, infusion, intravenously, once every 2 weeks on Days 1 and 15 in a 28-day treatment cycle until PD, unacceptable toxicity or withdraw from the study for other reasons. Dose escalation of TAK-169 will be based on the investigator and sponsor review of available safety, PK, pharmacodynamic, efficacy data in the previous cohort.
  • TAK-169
Part 2, Daratumumab RR: TAK-169 TBD Once WeeklyExperimentalTAK-169 TBD, infusion, intravenously, once weekly in participants who are relapsed or refractory (RR) to daratumumab until PD, unacceptable toxicity or withdraw from the study for other reasons. Dose for Part 2 will be determined based on the review of the available safety, efficacy, PK, and pharmacodynamic data from Part 1 of this study.
  • TAK-169
Part 2, Daratumumab RR: TAK-169 TBD Once Every Two WeeksExperimentalTAK-169 TBD, infusion, intravenously, once every 2 weeks in participants who are RR to daratumumab until PD, unacceptable toxicity or withdraw from the study for other reasons. Dose for Part 2 will be determined based on the review of the available safety, efficacy, PK, and pharmacodynamic data from Part 1 of this study.
  • TAK-169
Part 2, Anti-CD38 Therapy Naive MM: TAK-169 TBD Once WeeklyExperimentalTAK-169 TBD, infusion, intravenously, once weekly in participants with MM who have never received anti-CD38 therapy until PD, unacceptable toxicity or withdraw from the study for other reasons. Dose for Part 2 will be determined based on the review of the available safety, efficacy, PK, and pharmacodynamic data from Part 1 of this study.
  • TAK-169

Eligibility Criteria

        Inclusion Criteria:

        Inclusion Criteria Part 1

          1. With a confirmed diagnosis of MM.

          2. With RRMM who have failed treatment with, are intolerant to, or are not candidates for
             available therapies that are known to confer clinical benefit in this participant
             population.

          3. Should meet all of the following criteria for prior therapy:

               -  Should be refractory to at least one proteasome inhibitor (PI), at least one
                  immunomodulatory drug (IMiD), and at least 1 steroid.

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

               -  Prior treatment with an anti-CD38 therapy (including daratumumab) is permitted.

          4. With measurable disease, defined as at least 1 of the following:

               -  Serum M-protein >=500 mg/dL (>=5 g/L) on serum protein electrophoresis (SPEP).

               -  Urine M-protein >=200 mg/24 h on urine protein electrophoresis (UPEP).

               -  Serum FLC assay result with an involved FLC level >=10 mg/dL (>=100 milligram per
                  liter [mg/L]), provided the serum FLC ratio is abnormal.

          5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

          6. With normal QT interval corrected by the Fridericia method (QTcF) on screening
             electrocardiogram (ECG), defined as QTcF of <=450 millisecond (ms) in males or <=470
             ms in females

          7. Must meet the following clinical laboratory criteria at study entry:

               -  Total bilirubin <=1.5*the upper limit of the normal range (ULN), except for
                  participant with Gilbert's syndrome, in whom the direct bilirubin must be
                  <2.0*ULN.

               -  Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be
                  <=2.5*ULN.

               -  Estimated glomerular filtration rate (eGFR) >=30 milliliters per minute
                  (mL/min/1.73 square meter [m^2], using the modification of diet in renal disease
                  (MDRD) equation.

               -  Absolute neutrophil count (ANC) >=1000 per cubic millimeter (/mm^3) (>=1.0*10^ 9
                  per liter [/L]); a count of >=750/mm^3 (>=0.75*10^ 9/L) may be acceptable for
                  participants with >50% of plasma cells in bone marrow, after discussion with the
                  sponsor.

               -  Platelet count >=75,000/ mm^3 (>=75*10^ 9/L); a value of >=50,000/ mm^3 (>=50*10^
                  9/L) may be acceptable for participants with >50% of plasma cells in bone marrow,
                  after discussion with the sponsor.

               -  Hemoglobin >=7.5 g/dL (it is not permissible to transfuse a participant to reach
                  this level).

        Inclusion Criteria Part 2

          1. With a confirmed diagnosis of MM.

          2. Should meet all of the following criteria for prior therapy:

               -  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 1 of those lines included a combination of PI
                  and IMiD.

               -  Prior treatment with an anti-CD38 therapy (including daratumumab) is permitted,
                  except for participants enrolled into the anti-CD38-therapy naïve expansion
                  cohort.

               -  Daratumumab-RR cohorts (once weekly and once every two weeks TAK-169 dosing):
                  Participant must be RR to daratumumab at any time during treatment. Of note,
                  participant's RR to other anti-CD38 therapies are excluded.

               -  Anti-CD38 Therapy Naïve cohort (once weekly dosing): Participants must not have
                  received any prior anti-CD38 therapy.

          3. With measurable disease, defined as at least 1 of the following:

               -  Serum M-protein >=500 mg/dL (>=5 g/L) on SPEP.

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

               -  Serum FLC assay result with an involved FLC level >=10 mg/d (>=100 mg/L),
                  provided the serum FLC ratio is abnormal

          4. ECOG performance status score of 0 or 1.

          5. With normal QTcF on screening ECG, defined as QTcF of <=450 ms in males or <=470 ms in
             females

          6. Must meet the following clinical laboratory criteria at study entry:

               -  Total bilirubin <=1.5*the ULN, except for participant with Gilbert's syndrome, in
                  whom the direct bilirubin must be <2.0*ULN.

               -  Serum ALT and ASTmust be <=2.5*ULN.

               -  eGFR >=30 mL/min/1.73 m^2, using the MDRD equation.

               -  ANC >=1000 mm^3 (>=1.0*10^ 9 /L); a count of >=750/mm^3 (>=0.75*10^ 9/L) may be
                  acceptable for participant with >50% of plasma cells in bone marrow, after
                  discussion with the sponsor.

               -  Platelet count >=75,000/ mm^3 (>=75*10^ 9/L); a value of >=50,000/ mm^3 (>=50*10^
                  9/L) may be acceptable for participants with >50% of plasma cells in bone marrow,
                  after discussion with the sponsor.

               -  Hemoglobin >=7.5 g/dL (it is not permissible to transfuse a participant to reach
                  this level).

        Exclusion Criteria:

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

          2. With sensory or motor neuropathy of NCI CTCAE Grade >=3.

          3. Have received a final dose of any of the following treatments/procedures within the
             following minimum interval before the first dose of TAK-169:

               -  Myeloma-specific therapy, including PIs and IMiDs-14 days

               -  Anti-CD38 (a) therapy (Once the MTD/RP2D has been established, the washout period
                  may be adjusted in the expansion phase (Part 2) of the study for participants who
                  have received anti-CD38 therapy )-90 days

               -  Corticosteroid therapy for myeloma- 7 days

               -  Radiation therapy for localized bone lesions- 14 days

               -  Major surgery-30 days

               -  Autologous stem cell transplant- 90 days

               -  Investigational therapy- 30 days

          4. Have received an allogeneic stem cell transplant or organ transplantation.

          5. Have not recovered, to NCI CTCAE V5 Grade <=1 or baseline, from adverse reactions to
             prior myeloma treatment or procedures (chemotherapy, immunotherapy, radiation therapy)
             excluding alopecia.

          6. With clinical signs of central nervous system (CNS) involvement of MM.

          7. With known or suspected light chain amyloidosis of any organ (the presence of amyloid
             on the bone marrow biopsy without other evidence of amyloidosis is acceptable).

          8. With congestive heart failure (New York Heart Association) class >=II or left
             ventricular ejection fraction (LVEF <40%, cardiac myopathy, active ischemia, or any
             other uncontrolled cardiac condition such as angina pectoris or myocardial infarction
             within the past 6 months, clinically significant arrhythmia requiring therapy
             including anticoagulants, or clinically significant uncontrolled hypertension.

          9. With chronic or active infection requiring systemic therapy, as well as a history of
             symptomatic viral infection that has not been fully cured (example, human
             immunodeficiency viruses (HIV) or viral hepatitis B or C).

         10. With a history of systemic inflammatory response syndrome (SIRS)/ cytokine release
             syndrome (CRS) reactions following infusion with any monoclonal antibodies or Chimeric
             Antigen Receptor (CAR) T-cell therapy

         11. With a chronic condition requiring the use of systemic corticosteroids at a dose of
             >10 milligram per day (mg/day) of prednisone or equivalent.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1: Number of Participants With Overall and per Dose Level Treatment-emergent Adverse Events (TEAEs)
Time Frame:Up to 12 months
Safety Issue:
Description:DLTs is defined as any of the events that are considered by the investigator to be at least possibly related to therapy with the study medication. Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE 5.0).

Secondary Outcome Measures

Measure:Part 1 and Part 2, Cmax: Maximum Observed Concentration for TAK-169
Time Frame:Cycles 1 and 2, Day 1: pre-dose, and at multiple time points (up to 168 hours) post-dose (each cycle is 28 days)
Safety Issue:
Description:
Measure:Part 1 and Part 2, Tmax: Time to Reach the Maximum Observed Concentration (Cmax) for TAK-169
Time Frame:Cycles 1 and 2, Day 1: pre-dose, and at multiple time points (up to 168 hours) post-dose (each cycle is 28 days)
Safety Issue:
Description:
Measure:Part 1 and Part 2, AUClast: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-169
Time Frame:Cycles 1 and 2, Day 1: pre-dose, and at multiple time points (up to 168 hours) post-dose (each cycle is 28 days)
Safety Issue:
Description:
Measure:Part 1: ORR
Time Frame:Up to 12 months
Safety Issue:
Description:Percentage of participants who achieved PR or better during study as defined by IMWG Uniform Response Criteria. PR is >=50 % reduction of serum M protein and reduction in 24-hour urinary M protein by >=90% or <200 mg/24 h. If serum and urine M protein are not measurable, >=50% decrease in difference between involved and uninvolved FLC levels is required in place of M protein criteria. If serum and urine M protein and serum FLC assay are not measurable, >=50% reduction in bone marrow plasma cells is required in place of M protein, provided baseline percentage was >=30%. In addition, if present at baseline, >=50% reduction in size of soft tissue plasmacytomas is required. Two consecutive assessments are needed; no known evidence of progressive or new bone lesions if radiographic studies were performed.
Measure:Part 1: Clinical Benefit Rate (CBR)
Time Frame:Up to 12 months
Safety Issue:
Description:CBR is defined as the percentage of participants who achieved a minimal response (MR) or better during study as defined by IMWG Uniform Response Criteria. MR is defined as a >=25% but less than or equal to (<=) 49% reduction of serum M protein and reduction in 24-hour urine M protein by 50% to 89%. In addition, if present at baseline, 25% to 49% reduction in size of soft tissue plasmacytomas is also required. No increase in size or number of lytic bone lesions (development of compression fracture does not exclude response).
Measure:Part 1 and Part 2: Progression-free Survival (PFS)
Time Frame:From date of the dose administration until death due to any cause (up to 12 months)
Safety Issue:
Description:PFS: time from the date of first dose until the date of progressive disease (PD), by IMWG criteria, or the date of death due to any cause. PD: Increase of 25% from lowest response value in: Serum M component with absolute increase >=0.5 gram per deciliter (g/dL); serum M component increases >=1 g/dL, to define relapse if starting M component >=5 g/dL; Urine M component(absolute increase >=200 mg/24 h); Only in participants without measurable serum and urine M protein levels: difference between involved and uninvolved FLC levels(absolute increase >10 milligram per deciliter [mg/dL]); Only in participants without measurable serum and urine M protein levels and without measurable disease by FLC level, bone marrow plasma cell% (absolute% >=10%); Development of new or definite increase in size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia may attributed solely to plasma cell proliferative disorder; Two consecutive assessments before new therapy needed.
Measure:Part 1 and Part 2: Duration of Response (DOR)
Time Frame:From the date of the first documentation of response to the date of the first documented PD (up to 12 months)
Safety Issue:
Description:DOR is time from the date of the first documentation of response to the date of the first documented PD. PD is increase of 25% from lowest response value in: Serum M component with absolute increase >=0.5 g/dL; serum M component increases >=1g/dL, to define relapse if starting M component >=5 g/dL; Urine M component(absolute increase >=200 mg/24 h); Only in participants without measurable serum and urine M protein levels:difference between involved and uninvolved FLC levels (absolute increase >10 mg/dL); Only in participants without measurable serum and urine M protein levels and without measurable disease by FLC level, bone marrow plasma cell% (absolute% >=10%); Development of new or definite increase in size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder; Two consecutive assessments before new therapy needed.
Measure:Part 1 and Part 2: Percentage of Participants who Achieved MR
Time Frame:Up to 12 months
Safety Issue:
Description:Percentage of participants who achieved MR, defined as 25% tumor reduction. MR is defined as a >=25% but <=49% reduction of serum M protein and reduction in 24-hour urine M protein by 50% to 89% as defined by IMWG Uniform Response Criteria.
Measure:Part 1 and Part 2: Number of Participants With Anti-drug Antibodies Following Administration of TAK-169
Time Frame:Up to 12 months
Safety Issue:
Description:
Measure:Part 2: Number of Participants With DLTs and Other TEAEs Including Dose Modifications, Treatment Discontinuation, and Vital signs
Time Frame:Up to 12 months
Safety Issue:
Description:DLTs is defined as any of the events that are considered by the investigator to be at least possibly related to therapy with the study medication. Toxicity will be evaluated according to NCI CTCAE 5.0.
Measure:Part 2: Overall Survival (OS)
Time Frame:From date of the dose administration until death due to any cause (up to 12 months)
Safety Issue:
Description:OS is defined as time from date of the dose administration until death due to any cause.
Measure:Part 2: Time to Response (TTR)
Time Frame:From the date of the first dose of the study treatment to the date of the first documentation of response (up to 12 months)
Safety Issue:
Description:Time from the date of the first dose of the study treatment to the date of the first documentation of response (PR or better). PR is >=50% reduction of serum M protein and reduction in 24-hour urinary M protein by >=90% or to <200 mg/24 hour. If serum and urine M protein are not measurable, >=50% decrease in difference between involved and uninvolved FLC levels is required in place of M protein criteria. If serum and urine M protein and serum FLC assay are not measurable, >=50% reduction in bone marrow plasma cells is required in place of M protein, provided baseline percentage was >=30%. In addition, if present at baseline, >=50% reduction in size of soft tissue plasma cytomas is required. Two consecutive assessments are needed; no known evidence of progressive or new bone lesions if radiographic studies were performed.
Measure:Part 2: Percentage of Participants Who Achieved Complete Response (CR) or Very Good Partial Response (VGPR)
Time Frame:Up to 12 months
Safety Issue:
Description:CR or VGPR is defined by IMWG criteria. CR is defined as Negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow; in participants for whom only measurable disease is by serum FLC level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria is required; Two consecutive assessments are needed. VGPR is defined as serum and urine M component detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M component plus urine M component <100 mg/24 h; in participants for whom only measurable disease is by serum FLC level, >90% decrease in difference between involved and uninvolved FLC levels, in addition to VGPR criteria, is required; Two consecutive assessments are needed.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Millennium Pharmaceuticals, Inc.

Trial Keywords

  • Drug therapy

Last Updated

December 11, 2019