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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04776018
Recruitment Status : Recruiting
First Posted : March 1, 2021
Last Update Posted : January 10, 2022
Sponsor:
Information provided by (Responsible Party):
Takeda

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Relapsed and/or Refractory Multiple Myeloma (RRMM) Drug: TAK-981 Drug: Mezagitamab Drug: Daratumumab and Hyaluronidase-fihj Phase 1 Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 81 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : April 20, 2021
Estimated Primary Completion Date : October 15, 2024
Estimated Study Completion Date : October 2, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma
Drug Information available for: Daratumumab

Arm Intervention/treatment
Experimental: Phase 1b, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab

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
TAK-981 IV infusion.

Drug: Mezagitamab
Mezagitamab SC injection.

Experimental: Phase 1b, Part 1 - Dose Escalation: Arm B - TAK-981 Weekly (QW) + Mezagitamab

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
TAK-981 IV infusion.

Drug: Mezagitamab
Mezagitamab SC injection.

Experimental: Phase 1b, Part 2 - Lead-in Cohort: TAK-981 + Daratumumab and Hyaluronidase-fihj

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
TAK-981 IV infusion.

Drug: Daratumumab and Hyaluronidase-fihj
Daratumumab and Hyaluronidase-fihj SC injection.

Experimental: Phase 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab
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
TAK-981 IV infusion.

Drug: Mezagitamab
Mezagitamab SC injection.

Drug: Daratumumab and Hyaluronidase-fihj
Daratumumab and Hyaluronidase-fihj SC injection.




Primary Outcome Measures :
  1. Phase 1b: Number of Participants with Treatment Emergent Adverse Events (TEAEs), By Severity at Each Dose Level [ Time Frame: Up to 24 months ]
    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.

  2. Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Through Cycle 1 (Each cycle is of 28 days) ]
    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.

  3. 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 [ Time Frame: Up to 24 months ]
    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.


Secondary Outcome Measures :
  1. Cmax: Maximum Observed Plasma Concentration for TAK-981 [ Time Frame: Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose ]
  2. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981 [ Time Frame: Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose ]
  3. AUCt: Area Under the Plasma Concentration-time Curve from Time 0 to Time t Over the Dosing Interval for TAK-981 [ Time Frame: Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose ]
  4. AUC∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-981 [ Time Frame: Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose ]
  5. t1/2z: Terminal Disposition Phase Half-life for TAK-981 [ Time Frame: Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose ]
  6. CL: Total Clearance After Intravenous Administration for TAK-981 [ Time Frame: Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose ]
  7. Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981 [ Time Frame: Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose ]
  8. Number of Participants with Anti-mezagitamab or anti-daratumumab antibody (ADA) [ Time Frame: Up to 24 months ]
  9. Serum Sparse Concentration of Mezagitamab or Daratumumab [ Time Frame: Cycles 1 and 2 (cycle = 28 days), on multiple days and at multiple timepoints (Up to 24 hours) post dose ]
    Serum concentrations of mezagitumab and daratumumab will be evaluated during the study.

  10. Phase 1b: Number of Participants With TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation [ Time Frame: Up to 24 months ]
    TAK-981-SUMO adduct formation in blood will be evaluated.

  11. Phase 2: Number of Participants with TEAEs by Severity [ Time Frame: Up to 24 months ]
    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.

  12. Phase 1b: Overall Response Rate (ORR) as Assessed by the Investigator's Based on IMWG Criteria [ Time Frame: Up to 24 months ]
    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.

  13. Phases 1b and 2: Clinical Benefit Rate (CBR) as Assessed by the Investigator's Based on IMWG Criteria [ Time Frame: Up to 24 months ]
    CBR is defined as percentage of participants who achieve at least a stable disease for a least 3 months or better.

  14. Phase 1b: Duration of Response (DOR) as Assessed by the Investigator's Based on IMWG Criteria [ Time Frame: Up to 24 months ]
    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.

  15. Phases 1b and 2: Time to Progression (TTP) as Assessed by the Investigator's Based on IMWG Criteria [ Time Frame: Up to 24 months ]
    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.

  16. Phases 1b and 2: Time to Next Treatment (TTNT) as Assessed by the Investigator's Based on IMWG Criteria [ Time Frame: Up to 24 months ]
    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.

  17. Phases 1b and 2: Progression-free Survival (PFS) as Assessed by the Investigator's Based on IMWG Criteria [ Time Frame: Up to 24 months ]
    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.

  18. Phases 1b and 2: Overall Survival (OS) as Assessed by the Investigator Based on IMWG Criteria [ Time Frame: Up to 24 months ]
    OS is defined as the time from the date of enrollment to the date of death as assessed by the investigator.

  19. Phase 2: Percentage of Participants with MRD Negative Rate [ Time Frame: Up to 1 year ]
    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.

  20. Phase 2: Percentage of Participants with Minimal Residual Disease (MRD) Negative Status As Determined By Next-Generation Sequencing (NGS) [ Time Frame: Up to 24 months ]
    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.

  21. Phase 2: Number of Participants with Durable MRD Negative Rate [ Time Frame: Up to 24 months ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  1. 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.
  2. Has undergone stem cell transplant or is considered transplant ineligible.
  3. 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:

  1. Received treatment with systemic anticancer treatments within 14 days before the first dose of study drug.
  2. 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.
  3. Prior radiation therapy within 14 days of the first dose of TAK-981.
  4. Major surgery within 4 weeks before C1D1. participants should be fully recovered from any surgically related complications.
  5. Plasmapheresis within 28 days of randomization.
  6. 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.
  7. With disease where the only measurable parameter is plasmacytoma.
  8. 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.
  9. Prior treatment with more than 1 anti-CD38 antibody.
  10. Requires the use of drugs known to prolong the corrected QT interval (QTc) (during Phase 1b only).
  11. History of QT interval with Fridericia's correction (QTcF) >480 ms.
  12. History of human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C infection.
  13. Systemic infection requiring systemic antibiotic therapy.
  14. Active or history pneumonitis.
  15. Receipt of any live vaccine (eg, varicella, pneumococcus) within 4 weeks of initiation of study drug.
  16. Receiving strong or moderate Cytochrome P450 (CYP) 3A4/5 inhibitors or inducers.
  17. History of unstable cardiac comorbidities in the following 6 months.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04776018


Contacts
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Contact: Takeda Contact 1-877-825-3327 medinfoUS@takeda.com

Locations
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United States, Arizona
Mayo Clinic Arizona - PPDS Recruiting
Scottsdale, Arizona, United States, 85259-5452
Contact: Site Contact    480-301-4280    larsen.jeremy@mayo.edu   
Principal Investigator: Jeremy Larsen         
United States, Florida
Mayo Clinic Jacksonville - PPDS Recruiting
Jacksonville, Florida, United States, 32224
Contact: Site Contact    904-953-7595    roy.vivek@mayo.edu   
Principal Investigator: Vivek Roy         
United States, Georgia
Winship Cancer Institute, Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Site Contact    404-778-1900    sloni01@emory.edu   
Principal Investigator: Sagar Lonial         
United States, Indiana
Indiana University Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Site Contact    317-274-3515    rabonour@iupui.edu   
Principal Investigator: Rafat Abonour         
United States, Maryland
American Oncology Partners of Maryland, PA Recruiting
Bethesda, Maryland, United States, 20817-1915
Contact: Site Contact    301-571-0019    ralph.boccia@aoncology.com   
Principal Investigator: Ralph Boccia         
United States, Minnesota
Mayo Clinic - Cancer Center - Rochester - PPDS Recruiting
Rochester, Minnesota, United States, 55905-0001
Contact: Site Contact    507-538-0591    kumar.shaji@mayo.edu   
Principal Investigator: Shaji Kumar         
United States, Nebraska
Oncology Hematology West (Omaha) - USOR Recruiting
Omaha, Nebraska, United States, 68130-2042
Contact: Site Contact    402-334-4773    starantolo@nebraskacancer.com   
Principal Investigator: Stefano Tarantolo         
United States, New York
Weill Cornell Medicine Not yet recruiting
New York, New York, United States, 10065-8781
Contact: Site Contact    212-746-3964    car9156@med.cornell.edu   
Principal Investigator: Cara Rosenbaum         
United States, Ohio
TriHealth Cancer Institute Recruiting
Cincinnati, Ohio, United States, 45220-2475
Contact: Site Contact    513-853-1300    saulius_girnius@trihealth.com   
Principal Investigator: Saulius Girnius         
United States, Texas
Baylor Sammons Cancer Center Recruiting
Dallas, Texas, United States, 75246-2003
Contact: Site Contact    214-818-8472    yair.levy@usoncology.com   
Principal Investigator: Moshe Levy         
Texas Oncology (Tyler) - USOR Recruiting
Tyler, Texas, United States, 75702-8363
Contact: Site Contact    903-579-9800    habte.yimer@usoncology.com   
Principal Investigator: Habte Yimer         
United States, Wisconsin
Medical College of Wisconsin Cancer Center Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Site Contact    414-805-4600    memohan@mcw.edu   
Principal Investigator: Meera Mohan         
Sponsors and Collaborators
Takeda
Investigators
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Study Director: Study Director Takeda
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT04776018    
Other Study ID Numbers: TAK-981-1503
First Posted: March 1, 2021    Key Record Dates
Last Update Posted: January 10, 2022
Last Verified: January 2022
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/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Takeda:
Drug Therapy
Additional relevant MeSH terms:
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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
Daratumumab
Antineoplastic Agents