A Study Of TAK-981 Given With Monoclonal Antibodies (mAbs) In Adults With Relapsed or Refractory Multiple Myeloma (RRMM)

Study Overview
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Brief Summary
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TAK-981 is being tested in combination with anti-CD38 monoclonal antibodies (mAbs) to treat participants who have relapsed or refractory multiple myeloma (RRMM). The main aims of the study are to evaluate the safety and efficacy of TAK-981 in combination with anti-CD38 (mAbs) and to determine the recommended Phase 2 dose (RP2D). Participants will be on this combination treatment for 28-day cycles. They will continue with this treatment until disease progression or unacceptable toxicity.

Detailed Description
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The drug being tested in this study is called TAK-981. TAK-981 in combination with an anti-CD38 monoclonal antibody (mAbs) is being tested to treat people who have RRMM. The study will include a dose escalation phase and a dose expansion phase. The study will enroll approximately 81 participants; approximately 30 participants in the dose escalation phase (Part 1) approximately 15 participants in (Part 2) and up to 36 participants in dose expansion phase (Part 2). Participants will receive escalating doses of TAK-981 in combination with fixed doses as follows: Phase 1b, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab Phase 1b, Part 1 - Dose Escalation: Arm B - TAK-981 Weekly (QW) + Mezagitamab Phase 1b, Part 2 - Dose Escalation: TAK-981 + Daratumumab and Hyaluronidase-fihj Once RP2D is determined in Phase 1, participants with RRMM will be enrolled in Phase 2. • Phase 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab This multi-center trial will be conducted in North America. The overall time to participate in this study is 2 years. Participants will make multiple visits to the clinic, and progression-free survival follow-up for maximum up to 12 months after last dose of study drug.

Official Title
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A Phase 1b/2 Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of TAK-981 in Combination With Monoclonal Antibodies in Adult Patients With Relapsed and/or Refractory Multiple Myeloma

Conditions
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Relapsed and/or Refractory Multiple Myeloma (RRMM)

Intervention / Treatment
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* Drug: TAK-981
* Drug: Mezagitamab
* Drug: Daratumumab and Hyaluronidase-fihj


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have RRMM with measurable disease: a) Has measurable disease defined as one of the following: Serum M-protein ≥0.5 g/dL (≥5 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 free light chain (FLC) assay result with involved FLC level ≥10 mg/dL (≥100 mg/L), provided serum FLC ratio is abnormal. Has undergone stem cell transplant or is considered transplant ineligible. Has failed at least 3 prior lines of anti-myeloma treatments and is either refractory, or intolerant to at least 1 immunomodulatory drug ( IMiD); (ie, lenalidomide or pomalidomide [thalidomide excluded]), at least 1 proteasome inhibitor (ie, bortezomib, ixazomib or carfilzomib), and refractory to at least 1 anti-CD38 antibody and who have demonstrated disease progression with the last therapy. 5.Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. 6.Have recovered to Grade 1 or baseline from all toxicity associated with previous therapy or have the toxicity established as sequela. Exclusion Criteria: Received treatment with systemic anticancer treatments within 14 days before the first dose of study drug. Current participation in another interventional study, including other clinical trials with investigational agents (including investigational vaccines or investigational medical device for disease under study) within 4 weeks of the first dose of TAK-981 and throughout the duration of this trial. Prior radiation therapy within 14 days of the first dose of TAK-981. Major surgery within 4 weeks before C1D1. participants should be fully recovered from any surgically related complications. Plasmapheresis within 28 days of randomization. Diagnosis of primary amyloidosis, Waldenström's disease, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma (SMM), plasma cell leukemia POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), myelodysplastic syndrome, or myeloproliferative syndrome. With disease where the only measurable parameter is plasmacytoma. Second malignancy within the previous 3 years, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ, resected colorectal adenomatous polyps, breast cancer in situ, or other malignancy for which the participant is not on active anticancer therapy. Prior treatment with more than 1 anti-CD38 antibody. Requires the use of drugs known to prolong the corrected QT interval (QTc) (during Phase 1b only). History of QT interval with Fridericia's correction (QTcF) >480 ms. History of human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C infection. Systemic infection requiring systemic antibiotic therapy. Active or history pneumonitis. Receipt of any live vaccine (eg, varicella, pneumococcus) within 4 weeks of initiation of study drug. Receiving strong or moderate Cytochrome P450 (CYP) 3A4/5 inhibitors or inducers. History of unstable cardiac comorbidities in the following 6 months.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab<br>Mezagitamab: A fixed dose of 600 mg subcutaneous (SC) injection once weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by once every 2 weeks in Cycle 3 through 6, then every 4 weeks up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. TAK-981: Escalating doses of TAK-981 BIW intravenous (IV) infusion on Days 1, 4, 8, 11 and 15 in Cycle 1 and 2 (each Cycle is of 28 days) followed by every 2 weeks in Cycles 3 through 6, followed by once every 4 weeks up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. | Drug: TAK-981<br>* TAK-981 IV infusion.<br>Drug: Mezagitamab<br>* Mezagitamab SC injection.<br>|
| Experimental: Phase 1b, Part 1 - Dose Escalation: Arm B - TAK-981 Weekly (QW) + Mezagitamab<br>Mezagitamab: A fixed dose of 600 mg SC injection once weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by once every 2 weeks from Cycle 3 through 6, then every 4 weeks up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. TAK-981: Escalating doses of TAK-981 QW IV infusion on Days 1, 8, 15, and 22 in Cycles 1 and 2 (each cycle is of 28 days), followed by every 2 weeks in Cycles 3 through 6, followed by once every 4 weeks. up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. | Drug: TAK-981<br>* TAK-981 IV infusion.<br>Drug: Mezagitamab<br>* Mezagitamab SC injection.<br>|
| Experimental: Phase 1b, Part 2 - Lead-in Cohort: TAK-981 + Daratumumab and Hyaluronidase-fihj<br>Daratumumab and hyaluronidase-fihj: 1800 mg SC injection QW once weekly in Cycles 1 and 2 , (each cycle is of 28 days) followed by every 2 weeks in Cycle 3 through 6 , followed by every 4 weeks up to Cycle 24 until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. TAK-981: As per dose and schedule of TAK-981 defined in Phase 1b Part 1. | Drug: TAK-981<br>* TAK-981 IV infusion.<br>Drug: Daratumumab and Hyaluronidase-fihj<br>* Daratumumab and Hyaluronidase-fihj SC injection.<br>|
| Experimental: Phase 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab<br>TAK-981 at RP2D as determined in Phase 1b. Mezagitamab at a fixed dose of 600 mg SC injection or Daratumumab and Hyaluronidase-fihj at a fixed dose of 1800 mg weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by every 2 weeks in Cycle 3 through 6, followed by every 4 weeks up to Cycle 24 or until disease progression unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. | Drug: TAK-981<br>* TAK-981 IV infusion.<br>Drug: Mezagitamab<br>* Mezagitamab SC injection.<br>Drug: Daratumumab and Hyaluronidase-fihj<br>* Daratumumab and Hyaluronidase-fihj SC injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Number of Participants with Treatment Emergent Adverse Events (TEAEs), By Severity at Each Dose Level | An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy. Severity grade will be evaluated as per the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. TEAEs will be graded on a 5-point scale where 1 = mild, 2 = moderate, 3 = severe, 4 = potentially life-threatening and 5 = death. | Up to 24 months | 
| Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs) | DLT will be defined by NCI CTCAE, 5.0, Grade 5 AE. Hematologic toxicity: Nonfebrile Grade 4 neutropenia/Grade ≥3 febrile neutropenia; Significant Grade 3 thrombocytopenia; Grade 4 anemia or thrombocytopenia. Nonhematologic Grade 3 or higher toxicities; Grade 2 nonhematologic toxicities leading to dose reduction/discontinuation. Delay in Cycle 2 by >14 days or missed >1 planned doses of TAK-981/mAb in Cycle 1 due to TEAEs. | Through Cycle 1 (Each cycle is of 28 days) | 
| Phase 2: Overall Response Rate (ORR) (Response of Atleast Partial Response [PR]) as Assessed by the Investigator's Based on International Myeloma Working Group (IMWG) Criteria | ORR is defined as the percentage of participants who achieve complete response (CR) or partial response (PR) or better during the study as assessed by International Myeloma Working Group (IMWG) criteria. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: Maximum Observed Plasma Concentration for TAK-981 |  | Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981 |  | Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose | 
| AUCt: Area Under the Plasma Concentration-time Curve from Time 0 to Time t Over the Dosing Interval for TAK-981 |  | Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose | 
| AUC∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-981 |  | Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose | 
| t1/2z: Terminal Disposition Phase Half-life for TAK-981 |  | Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose | 
| CL: Total Clearance After Intravenous Administration for TAK-981 |  | Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose | 
| Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981 |  | Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose | 
| Number of Participants with Anti-mezagitamab or anti-daratumumab antibody (ADA) |  | Up to 24 months | 
| Serum Sparse Concentration of Mezagitamab or Daratumumab | Serum concentrations of mezagitumab and daratumumab will be evaluated during the study. | Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose | 
| Phase 1b: Number of Participants With TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation | TAK-981-SUMO adduct formation in blood will be evaluated. | Up to 24 months | 
| Phase 2: Number of Participants with TEAEs by Severity | An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy. Severity grade will be evaluated as per the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. TEAEs will be graded on a 5-point scale where 1 = mild, 2 = moderate, 3 = severe, 4 = potentially life-threatening and 5 = death. | Up to 24 months | 
| Phase 1b: Overall Response Rate (ORR) as Assessed by the Investigator's Based on IMWG Criteria | ORR is defined as the proportion of participants who achieve complete response (CR) or partial response (PR) or better (determined by the investigator) during the study as assessed by IMWG criteria. | Up to 24 months | 
| Phases 1b and 2: Clinical Benefit Rate (CBR) as Assessed by the Investigator's Based on IMWG Criteria | CBR is defined as percentage of participants who achieve at least a stable disease for a least 3 months or better. | Up to 24 months | 
| Phase 1b: Duration of Response (DOR) as Assessed by the Investigator's Based on IMWG Criteria | DOR is defined as a time from the time of first documentation of tumor response to the first recorded occurrence of disease progression (PD) or death from any cause (whichever occurs first), through end of study as assessed by the investigator. | Up to 24 months | 
| Phases 1b and 2: Time to Progression (TTP) as Assessed by the Investigator's Based on IMWG Criteria | TTP is defined as the time from the date of first study drug administration to the date of first documented disease progression as assessed by the investigator. | Up to 24 months | 
| Phases 1b and 2: Time to Next Treatment (TTNT) as Assessed by the Investigator's Based on IMWG Criteria | TTNT is defined as the time from the date of first dose of study drug to the date of the first dose of initiation of the next line of antineoplastic therapy, for any reason as assessed by the investigator. | Up to 24 months | 
| Phases 1b and 2: Progression-free Survival (PFS) as Assessed by the Investigator's Based on IMWG Criteria | PFS is defined as time from the date of the first dose administration to the date of first documentation of PD or death due to any cause whichever occurs first, through the end of the study as assessed by the investigator. | Up to 24 months | 
| Phases 1b and 2: Overall Survival (OS) as Assessed by the Investigator Based on IMWG Criteria | OS is defined as the time from the date of enrollment to the date of death as assessed by the investigator. | Up to 24 months | 
| Phase 2: Percentage of Participants with MRD Negative Rate | MRD negativity is defined as the absence of MRD. MRD negativity rate is defined as percentage of participants who have achieved MRD negative status at 1 year. | Up to 1 year | 
| Phase 2: Percentage of Participants with Minimal Residual Disease (MRD) Negative Status As Determined By Next-Generation Sequencing (NGS) | MRD negative rate is defined as the number of participants who have achieved MRD negative status (at 10^-5) at 2 bone marrow aspirates examinations that are a minimum of 1 year apart, without any examination showing MRD positive status in between as determined by NGS. | Up to 24 months | 
| Phase 2: Number of Participants with Durable MRD Negative Rate | Durable MRD negative rate is defined as the number of participants who have achieved MRD negative status (at 10^-5) at 2 bone marrow aspirates examinations that are a minimum of 1 year apart, without any examination showing MRD positive status in between. | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy