NCT04776018 · REGISTRY CONDITION SEARCH

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

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase: PHASE1, PHASE2
Status at capture: TERMINATED
Registry last update: 2024-10-02

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Phase 1b, Part 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs)

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outcome · POSTED

Phase 1b, Part 1: Number of Participants With Grade 3 or Higher TEAEs

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outcome · POSTED

Phase 1b, Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) Based on NCI CTCAE Version 5.0

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outcome · POSTED

Phase 2: Overall Response Rate (ORR)

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outcome · POSTED

Phase 1b, Part 1: Observed Plasma Concentration of TAK-981

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outcome · POSTED

Phase 1b, Part 1, Cmax: Maximum Observed Plasma Concentration for TAK-981

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outcome · POSTED

Phase 1b, Part 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981

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outcome · POSTED

Phase 1b, Part 1, AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t for TAK-981

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outcome · POSTED

Phase 1b, Part 1, AUC0-inf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981

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outcome · POSTED

Phase 1b, Part 1, t1/2z: Terminal Disposition Phase Half-life for TAK-981

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outcome · POSTED

Phase 1b, Part 1, CL: Total Clearance for TAK-981

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outcome · POSTED

Phase 1b, Part 1, Vss: Volume of Distribution at Steady State for TAK-981

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outcome · POSTED

Phase 1b, Part 1: Number of Participants With Positive Anti-drug Antibodies (ADA) for TAK-981 + Mezagitamab and >= 5-fold in ADA Titer

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outcome · POSTED

Phase 1b, Part 1: Serum Concentration of Mezagitamab

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outcome · POSTED

Phase 1b, Part 1: ORR Based on International Myeloma Working Group (IMWG) Criteria

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outcome · POSTED

Phases 1b, Part 1: Clinical Benefit Rate (CBR) Based on IMWG Criteria

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outcome · POSTED

Phase 1b, Part 1: Duration of Response (DOR) Based on IMWG Criteria

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outcome · POSTED

Phases 1b, Part 1: Time to Progression (TTP) Based on IMWG Criteria

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outcome · POSTED

Phases 1b, Part 1: Time to Next Treatment (TTNT)

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outcome · POSTED

Phases 1b, Part 1: Progression-free Survival (PFS) Based on IMWG Criteria

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outcome · POSTED

Phases 1b, Part 1: Overall Survival (OS)

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outcome · POSTED

Phases 1b, Part 1: Fold Change From Baseline in Level of TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation in Peripheral Blood Lymphocytes

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outcome · POSTED

Phases 1b, Part 1: Fold Change From Baseline in SUMO Pathway Inhibition in Peripheral Blood Lymphocytes

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outcome · POSTED

Phase 2: Number of Participants With TEAEs and TEAEs by Severity

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outcome · POSTED

Phase 2: CBR Based on IMWG Criteria

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outcome · POSTED

Phase 2: DOR Based on IMWG Criteria

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outcome · POSTED

Phase 2: TTP Based on IMWG Criteria

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outcome · POSTED

Phase 2: Time to Next Treatment (TTNT)

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outcome · POSTED

Phase 2: PFS Based on IMWG Criteria

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outcome · POSTED

Phase 2: Overall Survival (OS)

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outcome · POSTED

Phase 2: Percentage of Participants With MRD Negative Status as Determined by Next-Generation Sequencing (NGS)

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outcome · POSTED

Phase 2: Minimal Residual Disease (MRD) Negative Rate

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outcome · POSTED

Phase 2: Durable MRD Negative Rate

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility 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.
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
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.
intervention Names
Drug: TAK-981
Drug: Mezagitamab
label
Phase 1b, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab
type
EXPERIMENTAL
description
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.
intervention Names
Drug: TAK-981
Drug: Mezagitamab
label
Phase 1b, Part 1 - Dose Escalation: Arm B - TAK-981 Weekly (QW) + Mezagitamab
type
EXPERIMENTAL
description
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.
intervention Names
Drug: TAK-981
Drug: Daratumumab and Hyaluronidase-fihj
label
Phase 1b, Part 2 - Lead-in Cohort: TAK-981 + Daratumumab and Hyaluronidase-fihj
type
EXPERIMENTAL
description
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.
intervention Names
Drug: TAK-981
Drug: Mezagitamab
Drug: Daratumumab and Hyaluronidase-fihj
label
Phase 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab
type
EXPERIMENTAL

interventions

arm Group Labels
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 - Lead-in Cohort: TAK-981 + Daratumumab and Hyaluronidase-fihj
Phase 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab
description
TAK-981 IV infusion.
name
TAK-981
type
DRUG
arm Group Labels
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 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab
description
Mezagitamab SC injection.
name
Mezagitamab
type
DRUG
arm Group Labels
Phase 1b, Part 2 - Lead-in Cohort: TAK-981 + Daratumumab and Hyaluronidase-fihj
Phase 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab
description
Daratumumab and Hyaluronidase-fihj SC injection.
name
Daratumumab and Hyaluronidase-fihj
type
DRUG

Study design

allocation

NON_RANDOMIZED

intervention Model

SEQUENTIAL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 27
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
TEAEs were adverse events (AEs) that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug. Adverse event (AE) means any untoward medical occurrence in a participant administered a pharmaceutical product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product.
measure
Phase 1b, Part 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs)
time Frame
From the first dose of study drug through 30 days after the last dose of study drug (up to 13 months)
description
The severity grade was evaluated as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0, except for Cytokine Release Syndrome (CRS), which was assessed by American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. Where Grade 3 was severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living (ADL), Grade 4 was 4 Life-threatening consequences; urgent intervention indicated. and Grade 5 was death related to AE. TEAEs were AEs that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug.
measure
Phase 1b, Part 1: Number of Participants With Grade 3 or Higher TEAEs
time Frame
From the first dose of study drug through 30 days after the last dose of study drug (up to 13 months)
description
DLTs were evaluated according to NCI CTCAE version 5.0. Grade 5 AE. Hematologic toxicity: Nonfebrile Grade 4 neutropenia/Grade greater than or equal to (\>=) 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 greater than (\>) 14 days or missed \>1 planned doses of TAK-981/monoclonal antibody (mAb) in Cycle 1 due to TEAEs.
measure
Phase 1b, Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) Based on NCI CTCAE Version 5.0
time Frame
Cycle 1 (Cycle length = 28 Days)
description
ORR: percentage of participants who achieve complete response (CR) or partial response (PR) or better per investigator assessment by IMWG.CR: Negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and \<5 percent (%) plasma cells in bone marrow (BM). PR: \>50 percent (%) reduction of serum M-protein and reduction in 24 hours (h) urinary M-protein by \>90% or to less than (\<) 200 milligrams per 24 hour (mg/24 h); If serum and urine M-protein were unmeasurable, \>50% decrease in difference between involved and uninvolved free light chain (FLC) levels was required in place of M-protein criteria; If serum and urine M-protein are not measurable, and serum free light assay was also not measurable, \>50% reduction in plasma cells is required in place of M-protein, provided baseline BM plasma cell percentage was \>30%. In addition to the above listed criteria, if present at baseline, a \>50% reduction in the size of soft tissue plasmacytomas is also required.
measure
Phase 2: Overall Response Rate (ORR)
time Frame
From date of treatment start to until date of first PD or death (whichever occurred first), up to 24 months

secondary Outcomes

description
Observed plasma concentration of TAK-981 was reported.
measure
Phase 1b, Part 1: Observed Plasma Concentration of TAK-981
time Frame
Cycle 1 Day 1: Pre-dose, at end of infusion (EOI), 2, 4, 6, and 24 hours post-dose; Cycle 1 Days 8 and 15: Pre-dose and EOI; Cycle 2 Days 1 and 15: Pre-dose and EOI (Cycle length = 28 days)
description
Cmax for TAK-981 was reported.
measure
Phase 1b, Part 1, Cmax: Maximum Observed Plasma Concentration for TAK-981
time Frame
Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)
description
Tmax for TAK-981 was reported.
measure
Phase 1b, Part 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981
time Frame
Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)
description
AUC0-t for TAK-981 was reported.
measure
Phase 1b, Part 1, AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t for TAK-981
time Frame
Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)
description
AUC0-inf for TAK-981 was reported.
measure
Phase 1b, Part 1, AUC0-inf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981
time Frame
Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)
description
t1/2z for TAK-981 was reported.
measure
Phase 1b, Part 1, t1/2z: Terminal Disposition Phase Half-life for TAK-981
time Frame
Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)
description
CL for TAK-981 was reported.
measure
Phase 1b, Part 1, CL: Total Clearance for TAK-981
time Frame
Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)
description
Vss for TAK-981 was reported.
measure
Phase 1b, Part 1, Vss: Volume of Distribution at Steady State for TAK-981
time Frame
Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)
description
ADA positive was defined as participants who had confirmed positive ADA status in at least 1 post-baseline assessments. \>=5-fold in ADA titer was defined as increase in the ADA titer value post-baseline of at least 5-fold from the positive ADA titer value at baseline.
measure
Phase 1b, Part 1: Number of Participants With Positive Anti-drug Antibodies (ADA) for TAK-981 + Mezagitamab and >= 5-fold in ADA Titer
time Frame
Baseline up to 12 months
description
Observed serum concentrations of mezagitumab was reported.
measure
Phase 1b, Part 1: Serum Concentration of Mezagitamab
time Frame
Cycles 1, 2, 3, 4, 6, 7 and 12: Day 1 pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)
description
ORR: percentage of participants who achieve complete response (CR) or partial response (PR) or better per investigator assessment by IMWG.CR: Negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow (BM). PR: \>50 percent (%) reduction of serum M-protein and reduction in 24 hours (h) urinary M-protein by \>90% or to less than (\<) 200 milligrams per 24 hour (mg/24 h); If the serum and urine M-protein were unmeasurable, \>50% decrease in the difference between involved and uninvolved free light chain (FLC) levels was required in place of M-protein criteria; If serum and urine M-protein are not measurable, and serum free light assay was also not measurable, \>50% reduction in plasma cells is required in place of M-protein, provided baseline BM plasma cell percentage was \>30%. In addition to the above listed criteria, if present at baseline, a \>50% reduction in the size of soft tissue plasmacytomas is also required.
measure
Phase 1b, Part 1: ORR Based on International Myeloma Working Group (IMWG) Criteria
time Frame
From the first dose of study drug until first disease progression (PD) or death, whichever occurred first (up to 12 months)
description
CBR: % of participants with response of at least stable disease (SD) for \>=3 months or better (stringent CR \[sCR\], immunophenotypic CR \[iCR\], molecular CR \[mCR\], CR, very good partial response \[VGPR\], PR, minimal response \[MR\] or SD) per investigator assessment by IMWG. sCR: CR plus normal FLC ratio, absence of clonal cells in BM. iCR: sCR plus absence of phenotypical aberrant plasma in BM with minimum of 1 million total BM cells. mCR: CR plus negative allele-specific oligonucleotide polymerase chain reaction. CR: Negative immunofixation on serum, urine, disappearance soft tissue plasmacytomas, \<5% plasma cells in BM. VGPR: Serum, urine M-protein detectable by immunofixation but not on electrophoresis or \>90% reduction in serum M-protein+urine M-protein level \<100mg/24h. PR: \>50% reduction of serum M-protein and in 24h urinary M-protein by \>90% or to \<200mg/24h. MR: \>=25% but \<=49% reduction in serum M-protein, reduction in 24h urine M-protein by 50 to 89%. SD: No CR, VGPR, PR or PD.
measure
Phases 1b, Part 1: Clinical Benefit Rate (CBR) Based on IMWG Criteria
time Frame
From first dose of study drug until PD or death, whichever occurred first (up to 12 months)

Full study description

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.
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.

Source references

references

citation
Nakamura A, Grossman S, Song K, Xega K, Zhang Y, Cvet D, Berger A, Shapiro G, Huszar D. The SUMOylation inhibitor subasumstat potentiates rituximab activity by IFN1-dependent macrophage and NK cell stimulation. Blood. 2022 May 5;139(18):2770-2781. doi: 10.1182/blood.2021014267.
pmid
35226739
type
DERIVED