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)

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

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.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma; Relapsed/Refractory
• Intervention / Treatment: Drug: Dexamethasone; Drug: Pomalidomide; Drug: Mezagitamab

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope - Duarte
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10011
      • Mount Sinai Hospital-The Donald H. Ruttenberg Cancer Treatment Center
    • New York, New York, United States, 10065
      • Weill Cornell Medical Center, Div. of Hematology Medical Oncology
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University Knight Cancer Institute
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 Dose Escalation Cohort: Mezagitamab 45 mg; Mezagitamab 45 mg, subcutaneously (SC), 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 progressive disease (PD), unacceptable toxicities or withdrawal due to other reasons.	Drug: Mezagitamab; Mezagitamab subcutaneously.; Other Names: TAK-079
Experimental: Phase 1 Dose Escalation Cohort: Mezagitamab 135 mg; Mezagitamab 135 mg, SC, 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.	Drug: Mezagitamab; Mezagitamab subcutaneously.; Other Names: TAK-079
Experimental: Phase 1 Dose Escalation Cohort: Mezagitamab 300 mg; Mezagitamab 300 mg, SC, 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.	Drug: Mezagitamab; Mezagitamab subcutaneously.; Other Names: TAK-079
Experimental: Phase 1 Dose Escalation Cohort: Mezagitamab 600 mg; Mezagitamab 600 mg, SC, 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.	Drug: Mezagitamab; Mezagitamab subcutaneously.; Other Names: TAK-079
Experimental: Phase 1 Dose Escalation Cohort: Mezagitamab 1200 mg; Mezagitamab 1200 mg, SC, 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.	Drug: Mezagitamab; Mezagitamab subcutaneously.; Other Names: TAK-079
Experimental: Phase 1 Combination Cohort: Mezagitamab 300 mg + PomDex; Mezagitamab 300 mg, SC, once weekly for 8 weeks, then once every 2 weeks for 16 weeks, and then once every 4 weeks thereafter along with pomalidomide, at product-labelled dose, orally, once daily on Days 1 to 21 and dexamethasone, at product-labelled dose, orally, once on Days 1, 8, 15, and 22 in a 28-day treatment cycle until PD.	Drug: Dexamethasone; Dexamethasone orally.; Drug: Pomalidomide; Pomalidomide orally.; Drug: Mezagitamab; Mezagitamab subcutaneously.; Other Names: TAK-079
Experimental: Phase 2a: Mezagitamab; Mezagitamab, SC, 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 was to be determined based on review of the available safety, efficacy, pharmacokinetic, and pharmacodynamic data obtained from the Phase 1 portion of the study. However, Phase 2a of the study was not opened for enrollment due to changes in the Sponsor's overall clinical development plan.	Drug: Mezagitamab; Mezagitamab subcutaneously.; Other Names: TAK-079

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)	TEAEs were any untoward medical occurrence (called an adverse event [AE]) that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug.	From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)	DLTs were defined as any of the following events: Grade 4 laboratory abnormalities, except those events that were 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.	Cycle 1 (cycle length=28 days)
Phase 1: Number of Participants With Grade 3 or Higher TEAEs	AE Grades were evaluated as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. Grade 3 scaled as severe or medically significant but not immediately life-threatening; Grade 4 scaled as life-threatening consequences; and Grade 5 scaled as death related to AE.	From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
Phase 1: Number of Participants With Serious TEAEs	TEAEs were any untoward medical occurrence (called an AE) that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.	From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
Phase 1: Number of Participants With TEAEs Leading to Treatment Discontinuation	TEAEs leading to discontinuation were any untoward medical occurrence (called an AE) that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug leading to discontinuation of any of the study treatment when given in combination.	From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
Phase 1: Number of Participants With TEAEs Leading to Dose Modifications	TEAEs were any untoward medical occurrence (called an AE) that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug. Dose modification includes dose delayed, reduced, and drug discontinued permanently. Dose reduced includes scenarios where the dose was skipped, held, or missed. Dose modifications also refer to a modification of any drug in the study treatment when given in combination.	From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
Phase 2a: Overall Response Rate (ORR)	ORR is defined as the percentage of participants who achieved a partial response (PR) better during the study. PR is defined as >=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >= 90% or to < 200 milligram per (mg/) 24 hours. If serum and urine M protein are not measurable, >= 50% decrease in difference between involved and uninvolved free light chain (FLC) levels is required in place of M protein criteria.	Up to approximately 3.7 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax: Maximum Observed Serum Concentration for TAK-079		Cycles 1 and 2: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (cycle length=28 days)
Tmax: Time to Reach the Maximum Observed Serum Concentration (Cmax) for TAK-079		Cycles 1 and 2: Day 1 pre-dose and at multiple time points (up to 190.95 hours) post-dose (cycle length=28 days)
AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-079		Cycle 1 and 2: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (cycle length=28 days)
Phase 1: Overall Response Rate (ORR)	ORR is defined as the percentage of participants who achieved a partial response (PR) or better during the study. 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. If the serum and urine M-protein were not measurable, a ≥50% decrease in the difference between involved and uninvolved FLC levels was required in place of the M-protein criteria. If serum and urine M-protein were not measurable, and serum FLC was also not measurable, ≥50% reduction in bone marrow plasma cells was required in place of M-protein, provided the baseline percentage was ≥30%. In addition to the above criteria, if present at baseline, ≥50% reduction in the size of soft tissue plasmacytomas was also required. Two consecutive assessments were needed; no known evidence of progressive or new bone lesions if radiographic studies were performed. Percentages are rounded off to whole number at the nearest decimal.	Up to approximately 3.7 years
Percentage of Participants With Minimal Response (MR)	MR is defined as >=25% but <=49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. Percentages are rounded off to whole number at the nearest decimal.	Up to approximately 3.7 years
Percentage of Participants With Positive Anti-drug Antibodies (ADA)	Percentages are rounded off to whole number at the nearest decimal.	Up to approximately 3.7 years
Phase 2a: Number of Participants With DLTs		From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
Phase 2a: Number of Participants Reporting One or More TEAEs		From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
Phase 2a: Number of Participants With TEAEs Leading to Dose Modifications		From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
Phase 2a: Number of Participants With TEAEs Leading to Treatment Discontinuation		From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
Phase 2a: Duration of Response (DOR)	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 deciliter[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.	Up to approximately 3.7 years
Phase 2a: Progression Free Survival (PFS)	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.	Up to approximately 3.7 years
Phase 2a: Overall Survival (OS)	OS is defined as the time from the date of first dose to the date of death due to any cause.	Up to approximately 3.7 years
Phase 2a: Time to Response (TTR)	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.	Up to approximately 3.7 years
Phase 1: RP2D of TAK-079	RP2D was determined by dose escalating monotherapy groups.	From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2018
• Primary Completion (Actual): January 28, 2022
• Study Completion (Actual): January 28, 2022

Study Registration Dates

• First Submitted: February 14, 2018
• First Submitted That Met QC Criteria: February 14, 2018
• First Posted (Actual): February 20, 2018

Study Record Updates

• Last Update Posted (Actual): February 24, 2023
• Last Update Submitted That Met QC Criteria: January 27, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Drug therapy, TAK-079, pomalidomide and dexamethasone, CD38 monoclonal antibody
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dexamethasone; Pomalidomide
• Other Study ID Numbers: TAK-079-1501; U1111-1208-3202 (Other Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No