A Study of Modakafusp Alfa on Adult Participants With Relapsed/Refractory Multiple Myeloma (iinnovate-1)

• ClinicalTrials.gov Identifier: NCT03215030
• Recruitment Status: Active, not recruiting
• First Posted: July 12, 2017
• Last Update Posted: December 22, 2023
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Study Description

Brief Summary:

The main aims of this 3-part study are as follows:

Part 1: To determine any side effects from modakafusp alfa single treatment and how often they occur. The dose of modakafusp alfa will be increased a little at a time until the highest dose that does not cause harmful side effects is found.

Part 2: To assess clinical activity of one or more dosing schedules of modakafusp alfa alone in participants with relapsed/refractory multiple myeloma. Dexamethasone standard dose will be administered with one or more selected dose of modakafusp alfa in selected group of participants.

Part 3: To find the optimal dose with the more favorable risk-benefit profile of modakafusp alfa.

Participants will receive modakafusp alfa at one of two doses which will be given through a vein.

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma	Drug: Modakafusp alfa; Drug: Dexamethasone	Phase 1; Phase 2

Detailed Description:

The drug being tested in this study, and which will be given through a vein, is called modakafusp alfa (TAK-573 ) as single agent or in combination with dexamethasone. The study will determine the safety, tolerability, and efficacy of modakafusp alfa as single agent and in combination with dexamethasone in participants with relapsed/refractory multiple myeloma (RRMM). The study consists of 3 Parts:

Part 1: Dose Escalation, Part 2: Dose Expansion, Part 3: Dose Extension

The study will enroll approximately 65 participants in Part 1, 35 in Part 2, and 236 in Part 3. Participants will be assigned to one of the following treatment groups in Parts 1 and 2 of the study. Participants will be randomly assigned in Part 3 of the study as given below:

• Part 1 (Dose Escalation) Schedule A: Modakafusp alfa 0.001 Up to 14 mg/kg
• Part 1 (Dose Escalation) Schedule B: Modakafusp alfa TBD
• Part 1 (Dose Escalation) Schedule C: Modakafusp alfa TBD
• Part 1 (Dose Escalation) Schedule D: Modakafusp alfa TBD
• Part 2 (Dose Expansion): Modakafusp alfa TBD + Dexamethasone 40 mg
• Part 3 (Dose Extension): Modakafusp alfa 120 mg
• Part 3 (Dose Extension): Modakafusp alfa 240 mg

The Part 1 (Dose Escalation) portion of the study will follow a 3+3 dose escalation design to evaluate once-weekly up to 4 different schedules of administration of modakafusp alfa starting at 0.001 mg/kg for dose limiting toxicity (DLT) evaluation and to determine the maximum tolerated dose (MTD) or an optimal biological dose (OBD) for assessments in Part 2.

The Part 2 (Dose Expansion) will further assess the safety profile of modakafusp alfa and its efficacy at MTD or OBD.

For Part 3 (Dose Extension) participants will be randomized 1:1 to receive single-agent modakafusp alfa 120 mg or 240 mg Q4W.

Parts 1 and 2 will be conducted at multiple centers in the United States. Part 3 will be conducted worldwide. The maximum treatment duration in this study is up to 12 months (Parts 1 and 2) or until disease progression (Part 3) and overall time to participate in the study is approximately up to 90 months. Participants with clinical benefit may continue treatment after sponsor approval.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 336 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Open-label Study to Investigate the Safety and Tolerability, Efficacy, Pharmacokinetics, and Immunogenicity of Modakafusp Alfa (TAK-573) as a Single Agent in Patients With Relapsed Refractory Multiple Myeloma
• Actual Study Start Date: October 4, 2017
• Estimated Primary Completion Date: March 19, 2024
• Estimated Study Completion Date: September 3, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1 (Dose Escalation) Schedule A: Modakafusp alfa 0.001 Up to 14 mg/kg; Modakafusp alfa 0.001 up to 14 milligram per kilogram (mg/kg), infusion, intravenously (IV), once every week (Q1W) on Days 1, 8, 15 and 22 of each 28-day treatment cycle up to 2 cycles, followed by once on Days 1 and 15 of each 28-day treatment cycle up to 4 cycles, followed by once on Day 1 of each 28-day treatment cycle until treatment discontinuation.	Drug: Modakafusp alfa; Modakafusp alfa intravenous infusion.; Other Names: TAK-573; TEV-48573
Experimental: Part 1 (Dose Escalation) Schedule B: Modakafusp alfa TBD; Modakafusp alfa TBD, infusion, IV, once every 2 weeks (Q2W) on Days 1 and 15 of each 28-day treatment cycle until treatment discontinuation. The starting dose will be decided by the investigators and sponsor representatives based on all available clinical information.	Drug: Modakafusp alfa; Modakafusp alfa intravenous infusion.; Other Names: TAK-573; TEV-48573
Experimental: Part 1 (Dose Escalation) Schedule C: Modakafusp alfa TBD; Modakafusp alfa TBD, infusion, IV, once every 3 weeks (Q3W) on Day 1 of each 21-day treatment cycle until treatment discontinuation. The starting dose will be decided by the investigators and sponsor representatives based on all available clinical information.	Drug: Modakafusp alfa; Modakafusp alfa intravenous infusion.; Other Names: TAK-573; TEV-48573
Experimental: Part 1 (Dose Escalation) Schedule D: Modakafusp alfa TBD; Modakafusp alfa TBD, infusion, IV, once every 4 weeks (Q4W) on Day 1 of each 28-day treatment cycle until treatment discontinuation. The starting dose will be decided by the investigators and sponsor representatives based on all available clinical information.	Drug: Modakafusp alfa; Modakafusp alfa intravenous infusion.; Other Names: TAK-573; TEV-48573
Experimental: Part 2 (Dose Expansion): Modakafusp alfa TBD + Dexamethasone 40 mg; Dose(s) for Phase 2 will be based on safety and tolerability results from the preceding Phase 1 dose escalation cohorts. Participants in Phase 2 cohorts will receive modakafusp alfa TBD as a single agent. Participants in at least 1 cohort will receive modakafusp alfa TBD and modakafusp alfa TBD and dexamethasone 40 mg, orally, once weekly of each 28-day treatment cycle until treatment discontinuation.	Drug: Modakafusp alfa; Modakafusp alfa intravenous infusion.; Other Names: TAK-573; TEV-48573; Drug: Dexamethasone; Dexamethasone.
Experimental: Part 3 (Dose Extension): Modakafusp alfa 120 mg; Participants will receive modakafusp alfa 120 mg, infusion, IV, Q4W, for each 28-day treatment cycle until disease progression or treatment discontinuation.	Drug: Modakafusp alfa; Modakafusp alfa intravenous infusion.; Other Names: TAK-573; TEV-48573
Experimental: Part 3 (Dose Extension): Modakafusp alfa 240 mg; Participants will receive modakafusp alfa 240 mg, infusion, IV, Q4W, for each 28-day treatment cycle until disease progression or treatment discontinuation.	Drug: Modakafusp alfa; Modakafusp alfa intravenous infusion.; Other Names: TAK-573; TEV-48573

Outcome Measures

Primary Outcome Measures :

1. Part 1: Percentage of Participants Reporting one or More Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Up to approximately 90 months ]
   An adverse event (AE) is defined as any untoward medical occurrence in a participants administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. A TEAE is defined as any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and within 30 days of the last administration of study drug.
2. Part 1: Percentage of Participants With Dose-limiting Toxicities (DLTs) [ Time Frame: Up to Cycle 1 (cycle length is 28 days for Schedule A, B and D; 21 days for Schedule C) ]
   DLTs will be evaluated as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. Nonhematologic TEAEs of NCI CTCAE Grade ≥3 clearly unrelated to the underlying disease and occurring during the first cycle will be considered DLTs.
3. Part 1: Percentage of Participants Reporting one or More Grade 3 TEAEs [ Time Frame: Up to approximately 90 months ]
   TEAEs Grades will be evaluated as per NCI CTCAE, Version 5.0. Grade 1 scaled as Mild; Grade 2 scaled as Moderate; Grade 3 scaled as severe or medically significant but not immediately life-threatening; Grade 4 scaled as life-threatening consequences; and Grade 5 scaled as death related to AE.
4. Part 1: Percentage of Participants Reporting one or More Serious Adverse Events (SAEs) [ Time Frame: Up to approximately 90 months ]
   An SAE is defined as any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is an medically important event that satisfies any of the following: a) May require intervention to prevent items 1 through 5 above. b) May expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization.
5. Part 1: Percentage of Participants Who Discontinue the Treatment Because of TEAE [ Time Frame: Up to approximately 90 months ]
   A TEAE is defined as any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and within 30 days of the last administration of study drug.
6. Part 1: Percentage of Participants With Dose Modifications: Dose Delay [ Time Frame: Up to approximately 90 months ]
7. Part 1: Percentage of Participants With Dose Modifications: Dose Interruptions [ Time Frame: Up to approximately 90 months ]
8. Part 1: Percentage of Participants With Dose Modifications: Dose Reductions [ Time Frame: Up to approximately 90 months ]
9. Part 1: Percentage of Participants With Clinically Significant Laboratory Values [ Time Frame: Up to approximately 90 months ]
   Laboratory values will include hematology, chemistry, and urine analysis.
10. Part 1: Percentage of Participants With Clinically Significant Vital Signs Measurements [ Time Frame: Up to approximately 90 months ]
    Vital signs will include temperature, pulse, respiratory rate, oxygen saturation, and blood pressure.
11. Part 2: Overall Response Rate (ORR) [ Time Frame: Up to approximately 90 months ]
    ORR is defined as the percentage of participants who achieved a partial response rate (PR) or better during the study as defined by International Myeloma Working Group (IMWG) Uniform Response Criteria.
12. Part 3: Overall Response Rate (ORR) Assessed by Independent Review Committee (IRC) [ Time Frame: Up to approximately 90 months ]
    ORR is defined as the percentage of participants who achieved a PR or better during the study as defined by IMWG Uniform Response Criteria assessed by IRC.

Secondary Outcome Measures :

1. Part 1 and 2: Percentage of Participants With Dose-limiting Toxicities (DLTs)- Like Events [ Time Frame: Up to approximately 90 months ]
   Percentage of participants with TEAEs meeting DLT definition that occur after phase (P) 1 Cycle (C) 1 will be reported. Toxicity will be evaluated as per the NCI CTCAE, Version 5.0. The hematologic TEAEs of Grade ≥3 clearly unrelated to the underlying disease and occur during the first cycle that is considered DLTs: Grade ≥3 hemolysis; Grade 4 neutropenia for >7 consecutive days; Grade 4 thrombocytopenia for >14 consecutive days; Grade 3 thrombocytopenia with clinically significant bleeding; Any other Grade ≥4 hematologic toxicity except for Grade 4 lymphopenia. An incomplete recovery from treatment-related toxicity causing >2-week delay in the next scheduled infusion before the initiation of C2 will be considered a DLT. Frequencies and other TEAEs occur over the course of extended treatment with study drug, including dose modification, treatment discontinuation, and clinically significant laboratory values and vital signs.
2. Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp alfa [ Time Frame: Schedule A Cycle(C)1-13,Day(D)1,8,15,22; Schedule B C1-13,D1,15; Schedule C C1-17,D1; Schedule D C1-13,D1: Pre-infusion and at multiple times post-infusion (cycle length is 28 days for Schedule A, B and D; 21 days for Schedule C) ]
   PK blood samples will be collected at the following time points for schedule A: Pre-infusion and at multiple time points (up to 72 hour [h]) C1-2 D1, 15; up to 4h C1-2 D8, 22 and C2 D15; up to 24h C3 D1; up to 4h on C3, 4-6 D15, D1, C4-6 and C7-13 D1; Schedule B: Pre-infusion and at multiple time points (up to 24h) on C1-2 D1, 15; up to 24h C3 D1; up to 4h C3 D15 and C4-13 D1; Schedule C: Pre-infusion and at multiple time points (up to 336h) on C1-2 D1; up to 4h on C3-17 D1; Schedule D: Pre-infusion and at multiple time points (up to 504h) C1-2 D1; up to 4h C3-13 D1 post-infusion (Schedule A, B and D cycle is 28 days and schedule C cycle is 21 days).
3. Part 1: Tmax: Time to Reach the Cmax for Modakafusp alfa [ Time Frame: Schedule A Cycle(C)1-13,Day(D)1,8,15,22; Schedule B C1-13,D1,15; Schedule C C1-17,D1; Schedule D C1-13,D1: Pre-infusion and at multiple times post-infusion (cycle length is 28 days for Schedule A, B and D; 21 days for Schedule C) ]
   PK blood samples will be collected at the following time points for schedule A: Pre-infusion and at multiple time points (up to 72 hour [h]) C1-2 D1, 15; up to 4h C1-2 D8, 22 and C2 D15; up to 24h C3 D1; up to 4h on C3, 4-6 D15, D1, C4-6 and C7-13 D1; Schedule B: Pre-infusion and at multiple time points (up to 24h) on C1-2 D1, 15; up to 24h C3 D1; up to 4h C3 D15 and C4-13 D1; Schedule C: Pre-infusion and at multiple time points (up to 336h) on C1-2 D1; up to 4h on C3-17 D1; Schedule D: Pre-infusion and at multiple time points (up to 504h) C1-2 D1; up to 4h C3-13 D1 post-infusion (Schedule A, B and D cycle is 28 days and schedule C cycle is 21 days).
4. Part 1: AUC∞: Area Under the Serum Concentration-time Curve from Time 0 to Infinity for Modakafusp alfa [ Time Frame: Schedule A Cycle(C)1-13,Day(D)1,8,15,22; Schedule B C1-13,D1,15; Schedule C C1-17,D1; Schedule D C1-13,D1: Pre-infusion and at multiple times post-infusion (cycle length is 28 days for Schedule A, B and D; 21 days for Schedule C) ]
   PK blood samples will be collected at the following time points for schedule A: Pre-infusion and at multiple time points (up to 72 hour [h]) C1-2 D1, 15; up to 4h C1-2 D8, 22 and C2 D15; up to 24h C3 D1; up to 4h on C3, 4-6 D15, D1, C4-6 and C7-13 D1; Schedule B: Pre-infusion and at multiple time points (up to 24h) on C1-2 D1, 15; up to 24h C3 D1; up to 4h C3 D15 and C4-13 D1; Schedule C: Pre-infusion and at multiple time points (up to 336h) on C1-2 D1; up to 4h on C3-17 D1; Schedule D: Pre-infusion and at multiple time points (up to 504h) C1-2 D1; up to 4h C3-13 D1 post-infusion (Schedule A, B and D cycle is 28 days and schedule C cycle is 21 days).
5. Part 1: AUClast: Area Under the Serum Concentration-time Curve from Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp alfa [ Time Frame: A Cycle(C)1-13,Day(D)1,8,15,22; Schedule B C1-13,D1,15; Schedule C C1-17,D1; Schedule D C1-13,D1: Pre-infusion and at multiple times post-infusion (cycle length is 28 days for Schedule A, B and D; 21 days for Schedule C) ]
   PK blood samples will be collected at the following time points for schedule A: Pre-infusion and at multiple time points (up to 72 hour [h]) C1-2 D1, 15; up to 4h C1-2 D8, 22 and C2 D15; up to 24h C3 D1; up to 4h on C3, 4-6 D15, D1, C4-6 and C7-13 D1; Schedule B: Pre-infusion and at multiple time points (up to 24h) on C1-2 D1, 15; up to 24h C3 D1; up to 4h C3 D15 and C4-13 D1; Schedule C: Pre-infusion and at multiple time points (up to 336h) on C1-2 D1; up to 4h on C3-17 D1; Schedule D: Pre-infusion and at multiple time points (up to 504h) C1-2 D1; up to 4h C3-13 D1 post-infusion (Schedule A, B and D cycle is 28 days and schedule C cycle is 21 days).
6. Part 1: λz: Terminal Disposition Rate Constant for Modakafusp alfa [ Time Frame: Schedule A Cycle(C)1-13,Day(D)1,8,15,22; Schedule B C1-13,D1,15; Schedule C C1-17,D1; Schedule D C1-13,D1: Pre-infusion and at multiple times post-infusion (cycle length is 28 days for Schedule A, B and D; 21 days for Schedule C) ]
   PK blood samples will be collected at the following time points for schedule A: Pre-infusion and at multiple time points (up to 72 hour [h]) C1-2 D1, 15; up to 4h C1-2 D8, 22 and C2 D15; up to 24h C3 D1; up to 4h on C3, 4-6 D15, D1, C4-6 and C7-13 D1; Schedule B: Pre-infusion and at multiple time points (up to 24h) on C1-2 D1, 15; up to 24h C3 D1; up to 4h C3 D15 and C4-13 D1; Schedule C: Pre-infusion and at multiple time points (up to 336h) on C1-2 D1; up to 4h on C3-17 D1; Schedule D: Pre-infusion and at multiple time points (up to 504h) C1-2 D1; up to 4h C3-13 D1 post-infusion (Schedule A, B and D cycle is 28 days and schedule C cycle is 21 days).
7. Part 1: T1/2: Terminal Elimination Half-life for Modakafusp alfa [ Time Frame: Schedule A Cycle(C)1-13,Day(D)1,8,15,22; Schedule B C1-13,D1,15; Schedule C C1-17,D1; Schedule D C1-13,D1: Pre-infusion and at multiple times post-infusion (cycle length is 28 days for Schedule A, B and D; 21 days for Schedule C) ]
   PK blood samples will be collected at the following time points for schedule A: Pre-infusion and at multiple time points (up to 72 hour [h]) C1-2 D1, 15; up to 4h C1-2 D8, 22 and C2 D15; up to 24h C3 D1; up to 4h on C3, 4-6 D15, D1, C4-6 and C7-13 D1; Schedule B: Pre-infusion and at multiple time points (up to 24h) on C1-2 D1, 15; up to 24h C3 D1; up to 4h C3 D15 and C4-13 D1; Schedule C: Pre-infusion and at multiple time points (up to 336h) on C1-2 D1; up to 4h on C3-17 D1; Schedule D: Pre-infusion and at multiple time points (up to 504h) C1-2 D1; up to 4h C3-13 D1 post-infusion (Schedule A, B and D cycle is 28 days and schedule C cycle is 21 days).
8. Part 1: CL: Clearance for Modakafusp alfa [ Time Frame: Schedule A Cycle(C)1-13,Day(D)1,8,15,22; Schedule B C1-13,D1,15; Schedule C C1-17,D1; Schedule D C1-13,D1: Pre-infusion and at multiple times post-infusion (cycle length is 28 days for Schedule A, B and D; 21 days for Schedule C) ]
   PK blood samples will be collected at the following time points for schedule A: Pre-infusion and at multiple time points (up to 72 hour [h]) C1-2 D1, 15; up to 4h C1-2 D8, 22 and C2 D15; up to 24h C3 D1; up to 4h on C3, 4-6 D15, D1, C4-6 and C7-13 D1; Schedule B: Pre-infusion and at multiple time points (up to 24h) on C1-2 D1, 15; up to 24h C3 D1; up to 4h C3 D15 and C4-13 D1; Schedule C: Pre-infusion and at multiple time points (up to 336h) on C1-2 D1; up to 4h on C3-17 D1; Schedule D: Pre-infusion and at multiple time points (up to 504h) C1-2 D1; up to 4h C3-13 D1 post-infusion (Schedule A, B and D cycle is 28 days and schedule C cycle is 21 days).
9. Part 1: Vss: Volume of Distribution at Steady State for Modakafusp alfa [ Time Frame: Schedule A Cycle(C)1-13,Day(D)1,8,15,22; Schedule B C1-13,D1,15; Schedule C C1-17,D1; Schedule D C1-13,D1: Pre-infusion and at multiple times post-infusion (cycle length is 28 days for Schedule A, B and D; 21 days for Schedule C) ]
   PK blood samples will be collected at the following time points for schedule A: Pre-infusion and at multiple time points (up to 72 hour [h]) C1-2 D1, 15; up to 4h C1-2 D8, 22 and C2 D15; up to 24h C3 D1; up to 4h on C3, 4-6 D15, D1, C4-6 and C7-13 D1; Schedule B: Pre-infusion and at multiple time points (up to 24h) on C1-2 D1, 15; up to 24h C3 D1; up to 4h C3 D15 and C4-13 D1; Schedule C: Pre-infusion and at multiple time points (up to 336h) on C1-2 D1; up to 4h on C3-17 D1; Schedule D: Pre-infusion and at multiple time points (up to 504h) C1-2 D1; up to 4h C3-13 D1 post-infusion (Schedule A, B and D cycle is 28 days and schedule C cycle is 21 days).
10. Parts 1, 2 and 3: Percentage of Participants with Positive Anti-drug Antibodies (ADA) [ Time Frame: Up to approximately 90 months ]
11. Part 1: Objective Response Rate (ORR) [ Time Frame: Up to approximately 90 months ]
    ORR is defined as the percentage of participants who achieved a PR or better during the study as defined by IMWG Uniform Response Criteria.
12. Parts 1 and 2: Clinical Benefit Rate (CBR) [ Time Frame: Up to approximately 90 months ]
    CBR is defined as the percentage of participants who achieved MR or better during the study as defined by IMWG Uniform Response Criteria.
13. Parts 1 and 2: Disease Control Rate (DCR) [ Time Frame: Up to approximately 90 months ]
    DCR is defined as the percentage of participants who achieved a stable disease (SD) or better during the study as defined by IMWG Uniform Response Criteria.
14. Parts 1, 2 and 3: Duration of Response (DOR) [ Time Frame: Up to approximately 90 months ]
    DOR is defined as the time from the date of first documentation of response PR or better to the time of disease progression or death, whichever occurs first.
15. Parts 1 and 2: Time to Response [ Time Frame: Up to approximately 90 months ]
    Time to response is defined as the time from first dose to the date of first documentation of response (PR or better).
16. Parts 1, 2 and 3: Progression Free Survival (PFS) [ Time Frame: Up to approximately 90 months ]
    PFS is defined as the time from the date of enrollment until the date of PD or death due to any cause, whichever occurs first as defined by IMWG Criteria.
17. Parts 2 and 3: Overall Survival (OS) [ Time Frame: Up to approximately 90 months ]
18. Part 2: Cmax: Maximum Observed Serum Concentration for Modakafusp alfa [ Time Frame: Up to approximately 90 months ]
19. Part 2: AUC∞: Area Under the Serum Concentration-time Curve from Time 0 to Infinity for Modakafusp alfa [ Time Frame: Up to approximately 90 months ]
20. Part 2: AUClast: Area Under the Serum Concentration-time Curve from Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp alfa [ Time Frame: Up to approximately 90 months ]
21. Part 2: λz: Terminal Disposition Rate Constant for Modakafusp alfa [ Time Frame: Up to approximately 90 months ]
22. Part 2: Tmax: Time to Reach the Cmax for Modakafusp alfa [ Time Frame: Up to approximately 90 months ]
23. Part 2: CL: Clearance for Modakafusp alfa [ Time Frame: Up to approximately 90 months ]
24. Part 2: Vss: Volume of Distribution at Steady State for Modakafusp alfa [ Time Frame: Up to approximately 90 months ]
25. Part 2: T1/2z: Terminal Elimination Half-life for Modakafusp alfa [ Time Frame: Up to approximately 90 months ]
26. Part 3: Objective Response Rate (ORR) by Investigator Assessment [ Time Frame: Up to approximately 90 months ]
    ORR is defined as the percentage of participants who achieved a PR or better during the study as defined by IMWG Uniform Response Criteria assessed by investigators.
27. Part 3: Clinical Benefit Rate (CBR) by IRC and Investigator assessment [ Time Frame: Up to approximately 90 months ]
    CBR is defined as the percentage of participants who achieved MR or better during the study as defined by IMWG Uniform Response Criteria.
28. Part 3: Duration of Clinical Benefit [ Time Frame: Up to approximately 90 months ]
    Duration of clinical benefit is defined as the time from first documented evidence of confirmed MR or better until the earliest date of a confirmed PD per IMWG, or death among patients who achieve a confirmed MR or better.
29. Part 3: Disease Control Rate (DCR) by IRC and Investigator Assessment [ Time Frame: Up to approximately 90 months ]
    DCR is defined as the percentage of participants who achieved a stable disease (SD) or better during the study as defined by IMWG Uniform Response Criteria.
30. Part 3: Duration of Disease Control [ Time Frame: Up to approximately 90 months ]
    Duration of disease control is defined as the time from first documented evidence of SD or better until the earliest date of a confirmed PD per IMWG, or death among patients who achieve a SD or better.
31. Part 3: Time to Progression (TTP) by IRC and Investigator Assessment [ Time Frame: Up to approximately 90 months ]
    TTP is defined as the time from the date of the first dose until the earliest date of confirmed PD per IMWG, or death due to PD.
32. Part 3: Rate of Minimal Residual Disease (MRD) Negativity Status at a Sensitivity of 10^-5 in Participants Achieving CR [ Time Frame: Up to approximately 90 months ]
    MRD negativity at a sensitivity of 10^-5 is defined as patients who are MRD negative at a sensitivity of 10^-5 in patients achieving suspected complete response (CR). CR is defined as negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow; in participants for whom only measurable disease is by serum FLC level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria is required.
33. Part 3:Duration of MRD Negativity Status at a Sensitivity of 10^-5 in Participants Achieving CR [ Time Frame: Up to approximately 90 months ]
    Duration of MRD negativity (10^-5) is defined as the time from the first MRD negative status (10^-5) to the earliest date of the MRD positive status (10^-5), confirmed PD per IMWG or death.
34. Part 3: Percentage of Participants With Adverse Events (AEs) [ Time Frame: Up to approximately 90 months ]
    An adverse event (AE) is defined as any untoward medical occurrence in a participants administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment.
35. Part 3: Percentage of Participants With Serious Adverse Events (SAEs) [ Time Frame: Up to approximately 90 months ]
    An SAE is defined as any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is an medically important event that satisfies any of the following: a) May require intervention to prevent items 1 through 5 above. b) May expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization.
36. Part 3: Percentage of Participants With Clinically Significant Laboratory Values [ Time Frame: Up to approximately 90 months ]
    Laboratory values will include hematology, chemistry, and urine analysis.
37. Part 3: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Status [ Time Frame: Up to approximately 90 months ]
    ECOG is a grade, where grade 0: Normal activity. Grade 1: Symptoms but ambulatory. Grade 2: In bed <50% of the time. Grade 3: In bed >50% of the time. Grade 4: 100% bedridden. Grade 5: Dead.
38. Part 3: Health Care Utilization: Length of Hospital Stays [ Time Frame: Up to approximately 90 months ]
39. Part 3: Percentage of Participants With Neutralizing Antibodies (NAb) [ Time Frame: Up to approximately 90 months ]
40. Part 3: Health Care Utilization: Number of Participants With at Least One Medical Encounter [ Time Frame: Up to approximately 90 months ]
    Healthcare resources used during medical encounters included hospitalizations, emergency room stays, or outpatient visits.
41. Part 3: Patient-reported Outcome (PRO): Instrument European Organisation for Research and Treatment of Cancer QLQ Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20) [ Time Frame: Up to approximately 90 months ]
    The EORTC QLQ-MY20 has 20 items across 4 independent subscales, 2 functional subscales (body image and future perspective), and 2 symptoms scales (disease symptoms and side effects of treatment). The QLQ-MY20 raw scores are converted into scale scores ranging from 0 to 100. For the symptom scales, lower scores represent better functioning. All items in this questionnaire have a recall period of 1 week.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

For Parts 1 and 2:

1. Has MM defined by the IMWG criteria with evidence of disease progression and:

• In need of additional myeloma therapy as determined by the investigator.
• Has previously received at least 3 lines of myeloma therapy (for example, containing an Immunomodulatory imide drug [IMiD], a proteasome inhibitor [PI], an alkylating agent, and/or an anti-CD38 as single agents or in combination).
• Is either refractory to or intolerant of at least 1 PI and a least 1 IMiD.

For Part 3:

1. Has MM defined by the IMWG criteria with evidence of disease progression and:

   • In need of additional myeloma therapy as determined by the investigator.
   • Has previously received at least 3 lines of myeloma therapy.
   • Is refractory to at least 1 IMiD (ie, lenalidomide or pomalidomide [thalidomide excluded]), at least 1 PI (ie, bortezomib, ixazomib, or carfilzomib), and refractory to at least 1 anti-CD38 antibody (ie, daratumumab or isatuximab) and has demonstrated disease progression with the last therapy. Participants who are primary refractory, meaning they never achieved at least a MR with any previous treatment line, are not eligible.

2. For participants in Part 2 and 3 only: Measurable disease is defined as :

   1. Serum M-protein ≥500 mg/dL (≥5 g/L)
   2. Urine M-protein ≥200 mg/24 hours.
   3. Serum free light chain (FLC) assay, with involved FLC level ≥10 mg/dL (≥100 mg/L) provided serum FLC ratio is abnormal.
3. During Part 1 only, participants not meeting the above criteria for measurable disease should, at least, have measurable bone marrow plasmacytosis (greater than or equal to [≥ ] 10 percent [%]) and/or plasmacytoma (≥1 centimeter [cm] in diameter) detected by physical examination or imaging.
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.

Exclusion Criteria:

For Parts 1 and 2:

1. Has polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma, solitary plasmacytoma, amyloidosis, Waldenstrom macroglobulinemia or immunoglobulin M (IgM) myeloma, or lymphoplasmacytic lymphoma (LPL).
2. Who have received autologous stem cell transplant (SCT) 60 days before first infusion of modakafusp alfa or participants who have received allogeneic SCT 6 months before first infusion. Graft-versus-host disease that is active or requires ongoing systemic immunosuppression.
3. Has not recovered from adverse reactions to prior myeloma treatment or procedures (chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE less than or equal to (≤) Grade 1 or baseline, except for sensory or motor neuropathy which should have recovered to ≤ Grade 2 or baseline.
4. Has clinical signs of central nervous system involvement of MM.

For Part 3:

• Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]. Participants with resolved infection (that is, participants who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of HBV DNA levels. Those who are PCR positive will be excluded.
• In addition to the above criteria, participants must not have plasma cell leukemia or have had primary refractory MM, current central nervous system involvement of MM, myelodysplastic syndrome, myeloproliferative syndrome, or have had a 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.

Contacts and Locations

Locations

United States, Arkansas

Highlands Oncology Group

Springdale, Arkansas, United States, 72762

United States, California

Los Angeles Cancer Network - Glendale Adventist Medical Center

Glendale, California, United States, 91204

University of California Irvine

Orange, California, United States, 92868

Office of James R. Berenson MD

West Hollywood, California, United States, 90069

United States, Connecticut

Smilow Cancer Hospital at Yale New Haven

New Haven, Connecticut, United States, 06520

United States, Georgia

Winship Cancer Institute of Emory University

Atlanta, Georgia, United States, 30322

United States, Illinois

Northwestern Medicine - Northwestern Medical Group

Chicago, Illinois, United States, 60611

Loyola University Medical Center

Maywood, Illinois, United States, 60153

United States, Indiana

Investigative Clinical Research of Indiana, LLC

Noblesville, Indiana, United States, 46062

United States, Iowa

June E. Nylen Cancer Center

Sioux City, Iowa, United States, 51101

United States, Maryland

Johns Hopkins Hospital

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Boston Medical Center

Boston, Massachusetts, United States, 02118

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Nebraska

Univeristy of Nebraska Medical Center

Omaha, Nebraska, United States, 68198

United States, Nevada

USOR - Comprehensive Cancer Centers of Nevada - Central Valley

Las Vegas, Nevada, United States, 89119

United States, New Jersey

John Theurer Cancer Center

Hackensack, New Jersey, United States, 07601

United States, New York

Montefiore Medical Center

Bronx, New York, United States, 10467

University of Rochester

Rochester, New York, United States, 14627

United States, North Carolina

Levine Cancer Center

Charlotte, North Carolina, United States, 28402

Levine Cancer Institute - Concord

Concord, North Carolina, United States, 28205

Duke University Medical Center

Durham, North Carolina, United States, 27710

United States, Ohio

Gabrail Cancer Center

Canton, Ohio, United States, 44718-2566

The Ohio State University

Columbus, Ohio, United States, 43210

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Tennessee

Baptist Cancer Center - Memphis - Walnut Grove

Memphis, Tennessee, United States, 38120

United States, Texas

Lumi Research

Houston, Texas, United States, 77002

Canada, British Columbia

British Columbia Cancer Agency Vancouver Centre

Vancouver, British Columbia, Canada, V5Z 4E6

Canada, Ontario

Juravinski Cancer Centre

Hamilton, Ontario, Canada, L8V 5C2

Canada, Quebec

Centre de Recherche du CHUM

Montreal, Quebec, Canada, H2X 0C1

Sir Mortimer B. Davis Jewish General Hospital

Montreal, Quebec, Canada, H3T 1E2

China, Beijing

Peking University People's Hospital

Beijing, Beijing, China, 100044

Peking University Third Hospital

Beijing, Beijing, China, 100089

China, Guangdong

Sun Yat-Sen University Cancer Center

Guangzhou, Guangdong, China, 510060

China, Henan

Henan Cancer Hospital

Zhengzhou, Henan, China, 450003

China, Hubei

Wuhan Union Hospital

Wuhan, Hubei, China, 430023

Zhongnan Hospital of Wuhan University

Wuhan, Hubei, China, 430071

China, Jiangsu

Nanjing Drum Tower Hospital

Nanjing, Jiangsu, China, 210008

The First Affiliated Hospital of Soochow University - Suzhou First People's Hospital

Suzhou, Jiangsu, China, 215006

China, Shanghai

Shanghai Fourth People's Hospital

Shanghai, Shanghai, China, 200003

China, Tianjin

Tianjin Medical University Cancer Institute & Hospital

Tianjin, Tianjin, China, 300060

China, Zhejiang

The First Affiliated Hospital, Zhejiang University

Hangzhou, Zhejiang, China, 310003

France

Institut de cancerologie Strasbourg Europe

Strasbourg, Alsace, France, 67200

Centre Hospitalier Universitaire Henri Mondor

Creteil Cedex, Ile-de-france, France, 91010

Hopital Saint-Antoine

Paris Cedex 12, Ile-de-france, France, 75012

Hopital Necker-Enfants Malades

Paris, Ile-de-france, France, 75015

Centre Hospitalier Universitaire de Toulouse Hopital Purpan

Toulouse, Midi-pyrenees, France, 31059

Hopital Saint-Vincent de Paul - Lille

Lille Cedex, NORD Pas-de-calais, France, 59020

Centre Hospitalier Regional Universitaire de Lille

Lille Cedex, NORD Pas-de-calais, France, 59037

Centre Hospitalier Universitaire Nantes - Hotel Dieu

Nantes Cedex 1, PAYS DE LA Loire, France, 44093

Centre Hospitalier Universitaire de Poitiers

Poitiers, Poitou-charentes, France, 86000

Centre Hospitalier d'Argenteuil - Centre Hospitalier Victor Dupouy

Argenteuil Cedex, France, 95107

Germany

Universitatsklinik Tubingen

Tuebingen, Baden-wuerttemberg, Germany, 72076

Universitatsklinikum Leipzig

Leipzig, Sachsen, Germany, 04103

Greece

Evaggelismos General Hospital

Athens, Attica, Greece, 10676

Alexandra General Hospital of Athens

Athens, Attica, Greece, 11528

University Regional General Hospital of Patras

Patra, Peloponnese, Greece, 26504

Israel

The Chaim Sheba Medical Center

Ramat Gan, Tel Aviv, Israel, 52621

Hadassah Medical Center

Jerusalem, Israel, 9112001

Tel Aviv Sourasky Medical Center

Tel Aviv, Israel, 6423906

Italy

AON SS Antonio e Biagio e Cesare Arrigo

Alessandria, Italy, 15121

Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona

Ancona, Italy, 60126

Azienda Ospedaliero-Universitaria di Bologna - Policlinico Sant'Orsola-Malpighi

Bologna, Italy, 40138

Azienda Ospedaliero - Universitaria Policlinico - Vittorio Emanuele

Catania, Italy, 95125

Fondazione IRCCS Policlinico San Matteo

Pavia, Italy, 27100

Japan

Nagoya City University Hospital

Nagoya, Aichi, Japan, 467-8601

Ogaki Municipal Hospital

Gifu-shi, Gifu, Japan, 503-8502

University Hospital Kyoto Prefectural University of Medicine

Kyoto-City, Kyoto, Japan, 602-855

National Hospital Organization Okayama Medical Center

Okayama-city, Okayama, Japan, 701-1192

Japanese Red Cross Medical Center

Tokyo, Japan, 150-8935

Korea, Republic of

Chonnam National University Hwasun Hospital

Hwasun, Jeollanam-do, Korea, Republic of, 58128

Seoul National University Hospital

Seoul, Korea, Republic of, 03080

The Catholic University of Korea - Seoul St. Mary's Hospital

Seoul, Korea, Republic of, 06591

Norway

Oslo Universitetssykehus-Ulleval Hospital

Oslo, Norway, 0450

Puerto Rico

Ad-Vance Medical Research

Ponce, Puerto Rico, 00730

Hospital Espanol Auxilio Mutuo

San Juan, Puerto Rico, 00919

Spain

Hospital Universitari Germans Trias i Pujol

Badalona, Barcelona, Spain, 08916

Hospital Universitari Vall d'Hebron

Barcelona, Spain, 08035

Hospital Clinic de Barcelona

Barcelona, Spain, 08036

Hospital Universitario 12 de Octubre

Madrid, Spain, 28041

Hospital Universitario Virgen de la Arrixaca

Murcia, Spain, 30120

Hospital Universitario de Salamanca

Salamanca, Spain, 37007

Hospital Universitario Marques de Valdecilla

Santander, Spain, 39008

Taiwan

Tri-Service General Hospital

Taipei, Taipei CITY, Taiwan, 11490

National Taiwan University Hospital

Taipei, Taiwan, 100

Turkey

Ankara Universitesi

Yenimahalle, Ankara, Turkey, 06560

Ondokuz Mayis Universitesi Tp Fakultesi

Samsun, Turkey, 55139

United Kingdom

University Hospitals Birmingham NHS Foundation Trust

Birmingham, England, United Kingdom, B9 5SS

Royal Cornwall Hospital NHS Trust

Cornwell, England, United Kingdom, TR1 3LI

University College London Hospitals NHS Foundation Trust

London, England, United Kingdom, NW1 2BU

Genesis Care - Milton Keynes

Milton Keynes, England, United Kingdom, MK14 6LS

Oxford University Hospitals NHS Foundation Trust

Oxford, England, United Kingdom, OX3 7LE

The Royal Marsden NHS Foundation Trust

Sutton, England, United Kingdom, SM2 5PT

Genesis Care Windsor - Genesis Care UK Ltd.

Windsor, England, United Kingdom, SL43HD

Sponsors and Collaborators

Takeda

Investigators

• Study Director: Study Director; Takeda

More Information

Additional Information:

To obtain more information about this study, click this link. 

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT03215030
• Other Study ID Numbers: TAK-573-1501; TV48573-ONC-10128 ( Other Identifier: Former Id ); U1111-1195-8134 ( Registry Identifier: WHO ); 2021-006038-37 ( EudraCT Number ); jRCT2061220078 ( Registry Identifier: jRCT )
• First Posted: July 12, 2017
• Last Update Posted: December 22, 2023
• Last Verified: December 2023

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/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda:

Drug Therapy

Additional relevant MeSH terms:

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; Dexamethasone; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents