Clinical trial NCT04776018: A Study Of TAK-981 Given With Monoclonal Antibodies (mAbs) In Adults With Relapsed or Refractory Multiple Myeloma (RRMM)
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Relapsed and/or Refractory Multiple Myeloma (RRMM)
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2021-03-01
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Phase 1b, Part 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs)
timeFrame: From the first dose of study drug through 30 days after the last dose of study drug (up to 13 months)
measure: Phase 1b, Part 1: Number of Participants With Grade 3 or Higher TEAEs
timeFrame: From the first dose of study drug through 30 days after the last dose of study drug (up to 13 months)
measure: Phase 1b, Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) Based on NCI CTCAE Version 5.0
timeFrame: Cycle 1 (Cycle length = 28 Days)
measure: Phase 2: Overall Response Rate (ORR)
timeFrame: From date of treatment start to until date of first PD or death (whichever occurred first), up to 24 months
Secondary outcomes:
measure: Phase 1b, Part 1: Observed Plasma Concentration of TAK-981
timeFrame: 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)
measure: Phase 1b, Part 1, Cmax: Maximum Observed Plasma Concentration for TAK-981
timeFrame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)
measure: Phase 1b, Part 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981
timeFrame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)
measure: Phase 1b, Part 1, AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t for TAK-981
timeFrame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)
measure: Phase 1b, Part 1, AUC0-inf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981
timeFrame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)
measure: Phase 1b, Part 1, t1/2z: Terminal Disposition Phase Half-life for TAK-981
timeFrame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)
measure: Phase 1b, Part 1, CL: Total Clearance for TAK-981
timeFrame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)
measure: Phase 1b, Part 1, Vss: Volume of Distribution at Steady State for TAK-981
timeFrame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days)
measure: Phase 1b, Part 1: Number of Participants With Positive Anti-drug Antibodies (ADA) for TAK-981 + Mezagitamab and >= 5-fold in ADA Titer
timeFrame: Baseline up to 12 months
measure: Phase 1b, Part 1: Serum Concentration of Mezagitamab
timeFrame: 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)
measure: Phase 1b, Part 1: ORR Based on International Myeloma Working Group (IMWG) Criteria
timeFrame: From the first dose of study drug until first disease progression (PD) or death, whichever occurred first (up to 12 months)
measure: Phases 1b, Part 1: Clinical Benefit Rate (CBR) Based on IMWG Criteria
timeFrame: From first dose of study drug until PD or death, whichever occurred first (up to 12 months)
measure: Phase 1b, Part 1: Duration of Response (DOR) Based on IMWG Criteria
timeFrame: From first documented confirmed CR or PR until first documentation of PD or death, whichever occurred first (up to 12 months)
measure: Phases 1b, Part 1: Time to Progression (TTP) Based on IMWG Criteria
timeFrame: From first dose of study drug to the date of the first documentation of PD or death, whichever occurred first (up to 12 months)
measure: Phases 1b, Part 1: Time to Next Treatment (TTNT)
timeFrame: 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)
measure: Phases 1b, Part 1: Progression-free Survival (PFS) Based on IMWG Criteria
timeFrame: From the first dose of study drug to date of PD or death, whichever occurred first (up to 12 months)
measure: Phases 1b, Part 1: Overall Survival (OS)
timeFrame: From date of first dose of study drug up to death from any cause (up to 27 months)
measure: 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
timeFrame: 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)
measure: Phases 1b, Part 1: Fold Change From Baseline in SUMO Pathway Inhibition in Peripheral Blood Lymphocytes
timeFrame: 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)
measure: Phase 2: Number of Participants With TEAEs and TEAEs by Severity
timeFrame: Up to 24 months
measure: Phase 2: CBR Based on IMWG Criteria
timeFrame: Up to 24 months
measure: Phase 2: DOR Based on IMWG Criteria
timeFrame: Up to 24 months
measure: Phase 2: TTP Based on IMWG Criteria
timeFrame: Up to 24 months
measure: Phase 2: Time to Next Treatment (TTNT)
timeFrame: Up to 24 months
measure: Phase 2: PFS Based on IMWG Criteria
timeFrame: Up to 24 months
measure: Phase 2: Overall Survival (OS)
timeFrame: Up to 24 months
measure: Phase 2: Percentage of Participants With MRD Negative Status as Determined by Next-Generation Sequencing (NGS)
timeFrame: Up to 24 months
measure: Phase 2: Minimal Residual Disease (MRD) Negative Rate
timeFrame: Up to 12 months
measure: Phase 2: Durable MRD Negative Rate
timeFrame: Up to 12 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Arizona - PPDS
state: Arizona
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville - PPDS
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute, Emory University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Bethesda
country: United States
facility: American Oncology Partners of Maryland, PA
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic - Cancer Center - Rochester - PPDS
state: Minnesota
city: Omaha
country: United States
facility: Oncology Hematology West (Omaha) - USOR
state: Nebraska
city: New York
country: United States
facility: Weill Cornell Medical Center
state: New York
city: Cincinnati
country: United States
facility: TriHealth Cancer Institute
state: Ohio
city: Dallas
country: United States
facility: Baylor Sammons Cancer Center
state: Texas
city: Tyler
country: United States
facility: Northeast Texas Cancer and Research Institute
state: Texas
city: Milwaukee
country: United States
facility: Medical College of Wisconsin Cancer Center
state: Wisconsin
city: Montreal
country: Canada
facility: Hopital Maisonneuve-Rosemont
state: Quebec
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
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.