TAK-981 is being tested in combination with anti-CD38 monoclonal antibodies to treat participants who have relapsed or refractory multiple myeloma. The main aims of the study are to evaluate the safety and efficacy of TAK-981 in combination with anti-CD38 monoclonal antibodies. Participants will be on this combination treatment for 28-day cycles. They will continue with this treatment until disease progression or unacceptable toxicity.
Recruiting
Phase 1/Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| TAK-981 | Phase 1, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab | |
| Mezagitamab | Phase 1, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab | |
| Daratumumab and Hyaluronidase-fihj | Phase 1, Part 2 - Lead-in Cohort: TAK-981 + Daratumumab and Hyaluronidase-fihj |
The drug being tested in this study is called TAK-981. TAK-981 in combination with an
anti-CD38 monoclonal antibody 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 patients, 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 of fixed doses as follows:
- Phase 1, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab
- Phase 1, Part 1 - Dose Escalation: Arm B - TAK-981 Weekly (QW) + Mezagitamab
- Phase 1, 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 48 months. 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.
| Name | Type | Description | Interventions |
|---|---|---|---|
| Phase 1, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab | Experimental | Mezagitamab: A fixed dose of 600 mg subcutaneous (SC) injection once weekly x 8 doses, then once every 2 weeks for 8 doses, then monthly 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 for 8 doses, then monthly up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. |
|
| Phase 1, Part 1 - Dose Escalation: Arm B - TAK-981 Weekly (QW) + Mezagitamab | Experimental | Mezagitamab: A fixed dose of 600 mg SC injection once weekly x 8 doses, then once every 2 weeks for 8 doses, then monthly 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 once weekly x 8 doses, then once every 2 weeks x 8 doses, then monthly up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. |
|
| Phase 1, Part 2 - Lead-in Cohort: TAK-981 + Daratumumab and Hyaluronidase-fihj | Experimental | Daratumumab and hyaluronidase-fihj: 1800 mg SC injection QW once weekly x 8 doses, then every 2 weeks x 8 doses, then monthly 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 | Experimental | 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 x 8 doses, then every 2 weeks x 8 doses, then monthly up to Cycle 24 or until disease progression unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. |
|
Inclusion Criteria:
1. Participants must have RRMM with measurable disease:
1. 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 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.
2. Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG)
Performance Scale.
3. 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 1 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 within 4 weeks of initiation of study drug.
16. Receiving strong or moderate Cytochrome P450 (CYP3A4/5) inhibitors or inducers.
17. History of unstable cardiac comorbidities in the following 6 months.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Phase 1: Number of Participants with Treatment Emergent Adverse Events (TEAEs), By Severity at Each Dose Level |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | 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. The severity of TEAEs will be based on the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (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. |
| Measure: | 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 |
| Safety Issue: | |
| Description: |
| Measure: | 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 |
| Safety Issue: | |
| Description: |
| Measure: | 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 |
| Safety Issue: | |
| Description: |
| Measure: | 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 |
| Safety Issue: | |
| Description: |
| Measure: | 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 |
| Safety Issue: | |
| Description: |
| Measure: | 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 |
| Safety Issue: | |
| Description: |
| Measure: | 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 |
| Safety Issue: | |
| Description: |
| Measure: | Phase 1: Number of Participants With TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation and SUMO Pathway Inhibition in Blood |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | TAK-981-SUMO adduct formation and pathway inhibition in blood will be evaluated. |
| Measure: | Phase 2: Number of Participants with TEAEs by Severity |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | 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. The severity of TEAEs will be based on the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (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. |
| Measure: | Phase 1: Overall Response Rate (ORR) as Assessed by the Investigator's Based on IMWG Criteria |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Phases 1 and 2: Clinical Benefit Rate (CBR) as Assessed by the Investigator |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | CBR is defined as percentage of participants who achieve at least a stable disease for a least 3 months or better. |
| Measure: | Phase 1: Duration of Response (DOR) as Assessed by the Investigator |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Phases 1 and 2: Time to Progression (TTP) as Assessed by the Investigator |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Phases 1 and 2: Time to Next Treatment (TTNT) as Assessed by the Investigator |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Phases 1 and 2: Progression-free Survival (PFS) as Assessed by the Investigator |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Phases 1 and 2: Overall Survival (OS) as Assessed by the Investigator |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | OS is defined as the time from the date of enrollment to the date of death as assessed by the investigator. |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Phase 2: Percentage of Participants with MRD Negative Rate |
| Time Frame: | Up to 1 year |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Phase 2: Number of Participants with Durable MRD Negative Rate |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | 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. |
| Phase: | Phase 1/Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Takeda |
July 2, 2021
