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

Phase 1

Terminated

• Conditions: Relapsed and/or Refractory Multiple Myeloma (RRMM)
• Interventions: Drug: TAK-981; Drug: Mezagitamab; Drug: Daratumumab and Hyaluronidase-fihj

• Registration Number: NCT04776018
• Lead Sponsor: 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.

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.

Study Timeline

• Study First Submitted: 2021-02-25
• Study First Submitted QC: 2021-02-25
• Study First Posted: 2021-03-01
• Study Start: 2021-04-20
• Primary Completion: 2023-08-02
• Study Completion: 2023-11-09
• Results First Submitted: 2024-07-30
• Status Verified: 2024-09
• Results First Submitted QC: 2024-09-09
• Last Update Submitted: 2024-09-09
• Results First Posted: 2024-10-02
• Last Update Posted: 2024-10-02

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 27

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1b, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab	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.
Phase 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab	Daratumumab and Hyaluronidase-fihj	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.
Phase 1b, Part 2 - Lead-in Cohort: TAK-981 + Daratumumab and Hyaluronidase-fihj	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.
Phase 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab	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.
Phase 1b, Part 2 - Lead-in Cohort: TAK-981 + Daratumumab and Hyaluronidase-fihj	TAK-981	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.
Phase 1b, Part 1 - Dose Escalation: Arm B - TAK-981 Weekly (QW) + Mezagitamab	TAK-981	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.
Phase 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab	TAK-981	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.
Phase 1b, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab	TAK-981	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.
Phase 1b, Part 1 - Dose Escalation: Arm B - TAK-981 Weekly (QW) + Mezagitamab	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.

Primary Outcome Measures

Name	Time	Method
Phase 1b, Part 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs)	From the first dose of study drug through 30 days after the last dose of study drug (up to 13 months)	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.
Phase 1b, Part 1: Number of Participants With Grade 3 or Higher TEAEs	From the first dose of study drug through 30 days after the last dose of study drug (up to 13 months)	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.
Phase 1b, Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) Based on NCI CTCAE Version 5.0	Cycle 1 (Cycle length = 28 Days)	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.
Phase 2: Overall Response Rate (ORR)	From date of treatment start to until date of first PD or death (whichever occurred first), up to 24 months	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.

Secondary Outcome Measures

Name	Time	Method
Phase 1b, Part 1: Observed Plasma Concentration of TAK-981	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)	Observed plasma concentration of TAK-981 was reported.
Phase 1b, Part 1, Cmax: Maximum Observed Plasma Concentration for TAK-981	Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)	Cmax for TAK-981 was reported.
Phase 1b, Part 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981	Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)	Tmax for TAK-981 was reported.
Phase 1b, Part 1, AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t for TAK-981	Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)	AUC0-t for TAK-981 was reported.
Phase 1b, Part 1, AUC0-inf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981	Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)	AUC0-inf for TAK-981 was reported.
Phase 1b, Part 1, t1/2z: Terminal Disposition Phase Half-life for TAK-981	Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)	t1/2z for TAK-981 was reported.
Phase 1b, Part 1, CL: Total Clearance for TAK-981	Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)	CL for TAK-981 was reported.
Phase 1b, Part 1, Vss: Volume of Distribution at Steady State for TAK-981	Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)	Vss for TAK-981 was reported.
Phase 1b, Part 1: Number of Participants With Positive Anti-drug Antibodies (ADA) for TAK-981 + Mezagitamab and >= 5-fold in ADA Titer	Baseline up to 12 months	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.
Phase 1b, Part 1: Serum Concentration of Mezagitamab	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)	Observed serum concentrations of mezagitumab was reported.
Phase 1b, Part 1: ORR Based on International Myeloma Working Group (IMWG) Criteria	From the first dose of study drug until first disease progression (PD) or death, whichever occurred first (up to 12 months)	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.
Phases 1b, Part 1: Clinical Benefit Rate (CBR) Based on IMWG Criteria	From first dose of study drug until PD or death, whichever occurred first (up to 12 months)	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.
Phase 1b, Part 1: Duration of Response (DOR) Based on IMWG Criteria	From first documented confirmed CR or PR until first documentation of PD or death, whichever occurred first (up to 12 months)	DOR was defined as a time from date of first documentation of a PR or better to the date of first documentation of PD based on IMWG criteria. CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in BM. PR: \>50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by \>90% or to \<200 mg/24 h; If the serum and urine M-protein were unmeasurable, a \>50% decrease in the difference between involved and uninvolved FLC levels was required in place of the 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. DOR was calculated for those participants with a confirmed PR or CR.
Phases 1b, Part 1: Time to Progression (TTP) Based on IMWG Criteria	From first dose of study drug to the date of the first documentation of PD or death, whichever occurred first (up to 12 months)	TTP: time from date of first dose to date of first documentation of PD as defined by standard disease criteria. PD was defined as increase of \>25% from lowest response value in any one or more of following: a) Serum M-component and/or (the absolute increase must be \>0.5 grams per deciliter \[g/dL\]). b) Urine M-component and/or (the absolute increase must be \>200 mg/24 h). c) Only in participants without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be \>10 milligrams per deciliter (mg/dL). d) Bone marrow plasma cell percentage; the absolute percentage must be \>10%. e) Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. f) Development of hypercalcaemia (corrected serum calcium \>11.5 mg/dL or 2.65 millimoles per liter \[mmol/L\]) that can be attributed solely to the plasma cell proliferative disorder.
Phases 1b, Part 1: Time to Next Treatment (TTNT)	From the date of first dose of study drug to the date of the first dose initiation of the next line of antineoplastic therapy (up to 12 months)	TTNT was defined as the time from the date of first dose to the date of the first dose initiation of the next line of antineoplastic therapy, for any reason.
Phases 1b, Part 1: Progression-free Survival (PFS) Based on IMWG Criteria	From the first dose of study drug to date of PD or death, whichever occurred first (up to 12 months)	PFS was 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. PD was defined as increase of \>25% from lowest response value in any one or more of the following: a) Serum M-component and/or (the absolute increase must be \>0.5 g/dL). b) Urine M-component and/or (the absolute increase must be \>200 mg/24h). c) Only in participants without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be \>10 mg/dL. d) Bone marrow plasma cell percentage; the absolute percentage must be \>10%. e) Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. f) Development of hypercalcaemia (corrected serum calcium \>11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder.
Phases 1b, Part 1: Overall Survival (OS)	From date of first dose of study drug up to death from any cause (up to 27 months)	OS was defined as the time from the date of first dose to the date of death. OS was analyzed using Kaplan-Meier (KM) method. Participants were followed for survival after the last dose of study drug.
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	Cycle 1 Day 1: 1, 4, and 24 hours post-dose; Cycle 1 Day 8: Pre-dose, and 1 hour post-dose; Cycle 1 Day 15: Pre-dose (Cycle length = 28 days)	Blood samples were collected to assess TAK-981-SUMO adduct formation. TAK-981-SUMO adduct formation in peripheral blood lymphocytes was tested by flow cytometry with an antibody recognizing the TAK-981-SUMO adduct formation during the inhibition of the SUMO-activating enzyme by TAK-981.
Phases 1b, Part 1: Fold Change From Baseline in SUMO Pathway Inhibition in Peripheral Blood Lymphocytes	Cycle 1 Day 1: 1, 4, and 24 hours post-dose; Cycle 1 Day 8: Pre-dose, and 1 hour post-dose; Cycle 1 Day 15: Pre-dose (Cycle length = 28 days)	Blood samples were collected to assess SUMO inhibition. SUMO pathway inhibition in peripheral blood lymphocytes was tested by flow cytometry with an antibody recognizing SUMO-2/3 chains.
Phase 2: Number of Participants With TEAEs and TEAEs by Severity	Up to 24 months	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. 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. The severity grade was evaluated as per the NCI CTCAE Version 5.0, except for CRS, which was assessed by 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 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.
Phase 2: CBR Based on IMWG Criteria	Up to 24 months	CBR: percentage of participants with response of at least (SD for \>=3 months or better sCR, iCR, 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.
Phase 2: DOR Based on IMWG Criteria	Up to 24 months	DOR was defined as a time from date of first documentation of a PR or better to the date of first documentation of PD based on IMWG criteria. CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in BM. PR: \>50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by \>90% or to \<200 mg/24 h; If the serum and urine M-protein were unmeasurable, a \>50% decrease in the difference between involved and uninvolved FLC levels was required in place of the 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.
Phase 2: Overall Survival (OS)	Up to 24 months	OS was defined as the time from the date of first dose to the date of death.
Phase 2: Percentage of Participants With MRD Negative Status as Determined by Next-Generation Sequencing (NGS)	Up to 24 months
Phase 2: Minimal Residual Disease (MRD) Negative Rate	Up to 12 months
Phase 2: Durable MRD Negative Rate	Up to 12 months
Phase 2: TTP Based on IMWG Criteria	Up to 24 months	TTP: time from date of first dose to date of first documentation of PD as defined by standard disease criteria. PD was defined as increase of \>25% from lowest response value in any one or more of following: a) Serum M-component and/or (the absolute increase must be \>0.5 grams per deciliter \[g/dL\]). b) Urine M-component and/or (the absolute increase must be \>200 mg/24 h). c) Only in participants without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be \>10 milligrams per deciliter (mg/dL). d) Bone marrow plasma cell percentage; the absolute percentage must be \>10%. e) Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. f) Development of hypercalcaemia (corrected serum calcium \>11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder.
Phase 2: Time to Next Treatment (TTNT)	Up to 24 months	TTNT was defined as the time from the date of first dose to the date of the first dose initiation of the next line of antineoplastic therapy, for any reason.
Phase 2: PFS Based on IMWG Criteria	Up to 24 months	PFS was 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. PD was defined as increase of \>25% from lowest response value in any one or more of the following: a) Serum M-component and/or (the absolute increase must be \>0.5 g/dL). b) Urine M-component and/or (the absolute increase must be \>200 mg/24h). c) Only in participants without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be \>10 mg/dL. d) Bone marrow plasma cell percentage; the absolute percentage must be \>10%. e) Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. f) Development of hypercalcaemia (corrected serum calcium \>11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder.

Trial Locations

Locations (13)

Mayo Clinic Arizona - PPDS; 🇺🇸 Scottsdale, Arizona, United States

Mayo Clinic Jacksonville - PPDS; 🇺🇸 Jacksonville, Florida, United States

Weill Cornell Medical Center; 🇺🇸 New York, New York, United States

Northeast Texas Cancer and Research Institute; 🇺🇸 Tyler, Texas, United States

Hopital Maisonneuve-Rosemont; 🇨🇦 Montreal, Quebec, Canada

Winship Cancer Institute, Emory University; 🇺🇸 Atlanta, Georgia, United States

Indiana University; 🇺🇸 Indianapolis, Indiana, United States

American Oncology Partners of Maryland, PA; 🇺🇸 Bethesda, Maryland, United States

Mayo Clinic - Cancer Center - Rochester - PPDS; 🇺🇸 Rochester, Minnesota, United States

Oncology Hematology West (Omaha) - USOR; 🇺🇸 Omaha, Nebraska, United States

TriHealth Cancer Institute; 🇺🇸 Cincinnati, Ohio, United States

Baylor Sammons Cancer Center; 🇺🇸 Dallas, Texas, United States

Medical College of Wisconsin Cancer Center; 🇺🇸 Milwaukee, Wisconsin, United States