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)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Relapsed/Refractory, Multiple Myeloma

Intervention / Treatment
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* Drug: Mezagitamab
* Drug: Pomalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status of <=2. Has received previous myeloma-specific therapy. 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. Documentation of RRMM as defined by the International Myeloma Working Group (IMWG) criteria. 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. 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). 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: Sensory or motor neuropathy of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade >=3. Have received allogeneic stem cell transplant. Have received anti-CD38 antibody therapy and do not fulfill a 180-day washout period before receiving TAK-079. Not recovered from adverse reactions to prior myeloma treatment or procedures (chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE Grade <=1 or baseline, excluding alopecia. Clinical signs of central nervous system (CNS) involvement of MM. Active chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, active HIV, or cytomegalovirus (CMV) infection. 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. Positive Coombs tests at screening. For participants in the Combination Cohort (TAK-079-PomDex) only: participant has previously received pomalidomide or has hypersensitivity to thalidomide or lenalidomide.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Escalation Cohort: Mezagitamab 45 mg<br>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<br>* Mezagitamab subcutaneously.<br>* Other names: TAK-079;|
| Experimental: Phase 1 Dose Escalation Cohort: Mezagitamab 135 mg<br>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<br>* Mezagitamab subcutaneously.<br>* Other names: TAK-079;|
| Experimental: Phase 1 Dose Escalation Cohort: Mezagitamab 300 mg<br>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<br>* Mezagitamab subcutaneously.<br>* Other names: TAK-079;|
| Experimental: Phase 1 Dose Escalation Cohort: Mezagitamab 600 mg<br>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<br>* Mezagitamab subcutaneously.<br>* Other names: TAK-079;|
| Experimental: Phase 1 Dose Escalation Cohort: Mezagitamab 1200 mg<br>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<br>* Mezagitamab subcutaneously.<br>* Other names: TAK-079;|
| Experimental: Phase 1 Combination Cohort: Mezagitamab 300 mg + PomDex<br>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: Mezagitamab<br>* Mezagitamab subcutaneously.<br>* Other names: TAK-079;Drug: Pomalidomide<br>* Pomalidomide orally.<br>Drug: Dexamethasone<br>* Dexamethasone orally.<br>|
| Experimental: Phase 2a: Mezagitamab<br>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<br>* Mezagitamab subcutaneously.<br>* Other names: TAK-079;|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy, TAK-079, pomalidomide and dexamethasone, CD38 monoclonal antibody