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)

• ClinicalTrials.gov Identifier: NCT03439280
• Recruitment Status: Active, not recruiting
• First Posted: February 20, 2018
• Last Update Posted: March 19, 2021
• Sponsor: Millennium Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Takeda ( Millennium Pharmaceuticals, Inc. )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Relapsed/Refractory; Multiple Myeloma	Drug: TAK-079; Drug: Pomalidomide; Drug: Dexamethasone	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: April 26, 2018
• Estimated Primary Completion Date: February 28, 2022
• Estimated Study Completion Date: December 30, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1 Dose Escalation Cohort: TAK-079; TAK-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.	Drug: TAK-079; TAK-079 subcutaneously.
Experimental: Phase 1 Dose Confirmation Cohort: TAK-079; TAK-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.	Drug: TAK-079; TAK-079 subcutaneously.
Experimental: Phase 1 Combination Cohort: TAK-079 + PomDex; TAK-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.	Drug: TAK-079; TAK-079 subcutaneously.; Drug: Pomalidomide; Pomalidomide orally.; Drug: Dexamethasone; Dexamethasone orally.
Experimental: Phase 2a: TAK-079 TBD; TAK-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.	Drug: TAK-079; TAK-079 subcutaneously.

Outcome Measures

Primary Outcome Measures :

1. Phase 1: Number of Participants Reporting one or more Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Up to 1 year ]
2. Phase 1: Number of Participants with Dose-limiting Toxicities (DLTs) [ Time Frame: Up to 1 year ]
   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.
3. Phase 1: Number of Participants with Grade 3 or Higher TEAEs [ Time Frame: Up to 1 year ]
   AE Grades will be evaluated as per NCI CTCAE, version 4.03. Grade 1 scaled as Mild; Grade 2 scaled as Moderate; 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.
4. Phase 1: Number of Participants with Serious TEAEs [ Time Frame: Up to 1 year ]
5. Phase 1: Number of Participants with TEAEs Leading to Treatment Discontinuation [ Time Frame: Up to 1 year ]
6. Phase 1: Number of Participants with TEAEs Leading to Dose Modifications [ Time Frame: Up to 1 year ]
7. Phase 2a: Overall Response Rate (ORR) [ Time Frame: Up to 1 year ]
   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 less than (<) 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.

Secondary Outcome Measures :

1. 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) ]
2. 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) ]
3. 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) ]
4. Phase 1: ORR [ Time Frame: Up to 1 year ]
   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.
5. Percentage of Participants with Minimal Response (MR) [ Time Frame: Up to 1 year ]
   MR is defined as >=25% but <=49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%.
6. Percentage of Participants With Positive Anti-drug Antibodies (ADA) [ Time Frame: Up to 1 year ]
7. Phase 2a: Number of Participants with DLTs [ Time Frame: Up to 1 year ]
8. Phase 2a: Number of Participants Reporting one or more TEAEs [ Time Frame: Up to 1 year ]
9. Phase 2a: Number of Participants with TEAEs Leading to Dose Modifications [ Time Frame: Up to 1 year ]
10. Phase 2a: Number of Participants with TEAEs Leading to Treatment Discontinuation [ Time Frame: Up to 1 year ]
11. Phase 2a: Duration of Response (DOR) [ Time Frame: Up to 1 year ]
    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.
12. Phase 2a: Progression Free Survival (PFS) [ Time Frame: Up to 1 year ]
    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.
13. Phase 2a: Overall Survival (OS) [ Time Frame: Up to 1 year ]
    OS is defined as the time from the date of first dose to the date of death due to any cause.
14. Phase 2a: Time to Response (TTR) [ Time Frame: Up to 1 year ]
    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.
15. Phase 1: RP2D of TAK-079 [ Time Frame: Up to 1 year ]

Eligibility Criteria

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

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.

Contacts and Locations

Locations

United States, California

City of Hope - Duarte

Duarte, California, United States, 91010-3012

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, New York

Mount Sinai Hospital-The Donald H. Ruttenberg Cancer Treatment Center

New York, New York, United States, 10011

Weill Cornell Medical Center, Div. of Hematology Medical Oncology

New York, New York, United States, 10065

United States, Oregon

Oregon Health & Science University Knight Cancer Institute

Portland, Oregon, United States, 97239

United States, Texas

The University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030

United States, Wisconsin

Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director; Takeda

More Information

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03439280
• Other Study ID Numbers: TAK-079-1501; U1111-1208-3202 ( Other Identifier: WHO )
• First Posted: February 20, 2018
• Last Update Posted: March 19, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• 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.
• URL: https://vivli.org/ourmember/takeda/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):

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

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Dexamethasone; Pomalidomide; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents