Clinical trial NCT03439280: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Relapsed/Refractory
Multiple Myeloma
Keywords: Drug therapy, TAK-079, pomalidomide and dexamethasone, CD38 monoclonal antibody
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2018-02-20
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

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.

Primary outcomes:
measure: Phase 1: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
timeFrame: From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
measure: Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)
timeFrame: Cycle 1 (cycle length=28 days)
measure: Phase 1: Number of Participants With Grade 3 or Higher TEAEs
timeFrame: From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
measure: Phase 1: Number of Participants With Serious TEAEs
timeFrame: From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
measure: Phase 1: Number of Participants With TEAEs Leading to Treatment Discontinuation
timeFrame: From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
measure: Phase 1: Number of Participants With TEAEs Leading to Dose Modifications
timeFrame: From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
measure: Phase 2a: Overall Response Rate (ORR)
timeFrame: Up to approximately 3.7 years
Secondary outcomes:
measure: Cmax: Maximum Observed Serum Concentration for TAK-079
timeFrame: Cycles 1 and 2: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (cycle length=28 days)
measure: Tmax: Time to Reach the Maximum Observed Serum Concentration (Cmax) for TAK-079
timeFrame: Cycles 1 and 2: Day 1 pre-dose and at multiple time points (up to 190.95 hours) post-dose (cycle length=28 days)
measure: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-079
timeFrame: Cycle 1 and 2: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (cycle length=28 days)
measure: Phase 1: Overall Response Rate (ORR)
timeFrame: Up to approximately 3.7 years
measure: Percentage of Participants With Minimal Response (MR)
timeFrame: Up to approximately 3.7 years
measure: Percentage of Participants With Positive Anti-drug Antibodies (ADA)
timeFrame: Up to approximately 3.7 years
measure: Phase 2a: Number of Participants With DLTs
timeFrame: From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
measure: Phase 2a: Number of Participants Reporting One or More TEAEs
timeFrame: From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
measure: Phase 2a: Number of Participants With TEAEs Leading to Dose Modifications
timeFrame: From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
measure: Phase 2a: Number of Participants With TEAEs Leading to Treatment Discontinuation
timeFrame: From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
measure: Phase 2a: Duration of Response (DOR)
timeFrame: Up to approximately 3.7 years
measure: Phase 2a: Progression Free Survival (PFS)
timeFrame: Up to approximately 3.7 years
measure: Phase 2a: Overall Survival (OS)
timeFrame: Up to approximately 3.7 years
measure: Phase 2a: Time to Response (TTR)
timeFrame: Up to approximately 3.7 years
measure: Phase 1: RP2D of TAK-079
timeFrame: From the first dose of study drug through 30 days after the last dose (up to approximately 3.7 years)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope - Duarte
state: California
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Mount Sinai Hospital-The Donald H. Ruttenberg Cancer Treatment Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical Center, Div. of Hematology Medical Oncology
state: New York
city: Portland
country: United States
facility: Oregon Health & Science University Knight Cancer Institute
state: Oregon
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References: