A Study of Modakafusp Alfa Together With Daratumumab Adults With Relapsed or Refractory Multiple Myeloma (iinnovate-3)

• ClinicalTrials.gov Identifier: NCT05590377
• Recruitment Status: Active, not recruiting
• First Posted: October 21, 2022
• Last Update Posted: April 3, 2024
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Tracking Information

• First Submitted Date: October 19, 2022
• First Posted Date: October 21, 2022
• Last Update Posted Date: April 3, 2024
• Actual Study Start Date: January 26, 2023
• Estimated Primary Completion Date: March 4, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 19, 2022)

• Phase 1: Number of Participants with Dose Limiting Toxicities (DLT) [ Time Frame: Cycle 1 (cycle length=28 days) ]
  DLT will be defined as any of the TEAEs that occur during Cycle 1 and are considered by the investigator to be at least possibly related to modakafusp alfa. Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.
• Phase 1: Number of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs) and Per Severity [ Time Frame: Up to 60 months ]
  An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. Severity grades for TEAEs will be evaluated as per the NCI CTCAE Version 5.0.
• Phase 2a: Overall Response Rate (ORR) [ Time Frame: Up to 60 months ]
  ORR is defined as the percentage of participants who achieve a confirmed partial response (PR) or better during the study in the safety population. ORR will be assessed by the investigator per International Myeloma Working Group (IMWG) criteria.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 19, 2022)

• Phase 1: Cmax: Single-Dose Maximum Observed Serum Concentration for Modakafusp Alfa [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
• Phase 1: Tmax: Time to First Occurrence of Maximum Serum Concentration (Cmax) for Modakafusp Alfa [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
• Phase 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
• Phase 1: AUClast: Area Under the Serum Concentration-time Curve from Time 0 to Time of the Last Quantifiable Concentration [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
• Phase 1: Apparent Serum Terminal Disposition Rate Constant for Modakafusp Alfa [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
• Phase 1: Apparent Serum Terminal Disposition Phase Half-life for Modakafusp Alfa [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
• Phase 1: Total Clearance After Intravenous Administration for Modakafusp Alfa [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
• Phase 1: Volume of Distribution at Steady State After Intravenous Administration for Modakafusp Alfa [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
• Phase 1: Cmax: Single-Dose Maximum Observed Serum Concentration for Daratumumab [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
• Phase 1: Tmax: Time to First Occurrence of Maximum Serum Concentration (Cmax) for Daratumumab [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
• Phase 1: Ctrough: Single-Dose and Multiple-dose Observed Concentration at the End of a Dosing Interval for Daratumumab [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
• Phase 1: AUC∞: Area Under the Serum Concentration-time Curve from Time 0 to Infinity for Daratumumab [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
• Phase 1: AUClast: Area Under the Serum Concentration-time Curve from Time 0 to Time of the Last Quantifiable Concentration for Daratumumab [ Time Frame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days) ]
• Phase 1: Overall Response Rate (ORR) [ Time Frame: Up to 60 months ]
  ORR is defined as the percentage of participants who achieved a confirmed PR or better during the study in the safety population. ORR will be assessed by the investigator per IMWG criteria.
• Phase 1 and Phase 2a: Duration of Response (DOR) [ Time Frame: Up to 60 months ]
  DOR is defined as the time from the date of first documentation of a confirmed PR or better to the date of first documentation of confirmed progressive disease or death due to any cause, whichever occurs first. DOR will be calculated for confirmed responders only (PR or better). DOR will be assessed by the investigator as per IMWG criteria.
• Phase 1 and Phase 2a: Progression Free Survival (PFS) [ Time Frame: up to 60 months ]
  PFS is defined as the time from the date of the first dose administration of any study drug to the first documentation of confirmed progressive disease or death due to any cause, whichever occurs first. PFS will be assessed by the investigator as per IMWG criteria.
• Phase 1 and Phase 2a: Overall Survival (OS) [ Time Frame: Up to 60 months ]
  OS is defined as the time from the date of the first dose administration of any study drug to the documentation of death due to any cause. OS will be assessed by the investigator as per IMWG criteria.
• Phase 1 and Phase 2a: Number of Participants With Anti-drug Antibodies [ Time Frame: Up to 60 months ]
• Phase 1 and Phase 2a: Titer of Anti-drug Antibodies [ Time Frame: Up to 60 months ]
• Phase 1 and Phase 2a: Number of Participants With Neutralizing Antibodies (NAb) Against Study Drug [ Time Frame: Up to 60 months ]
• Phase 1 and Phase 2a: Rate of Measurable [Minimal] Residual Disease Negative (MRD[-]) Complete Response (CR) [ Time Frame: Up to 60 months ]
  MRD[-] CR rate is defined as the percentage of participants who achieve confirmed CR assessed by the investigator and MRD[-] status using a threshold of 10^-5. The analysis will be based on the response-evaluable population.
• Phase 1 and Phase 2a: Duration of Measurable [Minimal] Residual Disease (MRD) Negativity [ Time Frame: Up to 60 months ]
  Duration of MRD negativity for participants achieving MRD negativity is defined as the time from the date of first documentation of MRD negativity to the first documentation of MRD positivity or confirmed progressive disease, whichever occurs first. It will be calculated for participants achieving MRD negativity only.
• Phase 2a: Clinical Benefit Rate (CBR) [ Time Frame: Up to 60 months ]
  CBR is defined as the percentage of participants who had a confirmed response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response based on investigators' disease assessment per IMWG criteria.
• Phase 2a: Duration of Clinical Benefit (DCB) [ Time Frame: Up to 60 months ]
  DCB is defined as the time from the date of first documentation of a minimal response or better to the date of first documentation of confirmed progressive disease or death due to any cause, whichever occurs first. DCB will be calculated for only participants who achieved a minimal response or better. DCB will be assessed by the investigator as per IMWG criteria.
• Phase 2a: Disease Control Rate (DCR) [ Time Frame: Up to 60 months ]
  DCR is defined as the percentage of participants with a confirmed response of sCR, CR, VGPR, PR, minimal response, or stable disease (SD) based on investigators' disease assessment per IMWG criteria.
• Phase 2a: Duration of Disease Control [ Time Frame: Up to 60 months ]
  Duration of disease control is defined as the time from date of first documentation of SD or better to the date of first documentation of confirmed progressive disease or death due to any cause. Duration of disease control will be calculated for only patients who achieved SD or better. It will be assessed by the investigator per IMWG criteria.
• Phase 2a: Time to Progression (TTP) [ Time Frame: Up to 60 months ]
  TTP is defined as the time from the date of randomization to the first documentation of confirmed progressive disease as defined by IMWG criteria, assessed by the investigator. Participants without documentation of confirmed progression will be censored at the date of last adequate disease assessment. The analysis will be based on the intent-to-treat (ITT) population.
• Phase 2a: Time to Response (TTR) [ Time Frame: Up to 60 months ]
  TTR is defined as time from the date of first dose administration of any study drug to the date of the first documentation of a confirmed PR or better. TTR will be calculated for responders only. TTR will be assessed by the investigator per IMWG criteria.
• Phase 2a: Time to Next Treatment (TTNT) [ Time Frame: Up to 60 months ]
  TTNT is defined as the time from the date of first dose administration of any study drug to the date of the first dose initiation of the next line of anticancer therapy for any reason or death from any cause, whichever comes first. Participants who have not started the next-line therapy will be censored at the date last known to be alive before subsequent anticancer therapy.
• Phase 2a: Number of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs) and Per Severity [ Time Frame: Up to 60 months ]
  An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. Severity grades for TEAEs will be evaluated as per the NCI CTCAE Version 5.0.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Modakafusp Alfa Together With Daratumumab Adults With Relapsed or Refractory Multiple Myeloma
• Official Title: A Phase 1/2a Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Modakafusp Alfa in Combination With Daratumumab Subcutaneous in Patients With Relapsed or Refractory Multiple Myeloma
• Brief Summary: The main aim of this study is to determine safety and tolerability of modakafusp alfa given together with daratumumab to find out the best treatment dose. Another aim of this study is to learn more about the characteristics of modakafusp alfa.

Detailed Description

The drug being tested in this study is called modakafusp alfa (TAK-573). Modakafusp alfa is being tested to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy in combination with daratumumab in participants with relapsed or refractory multiple myeloma (RRMM). The study will consist of 2 phases: Phase 1 Dose Escalation and a Phase 2a Dose Finding.

The study will enroll approximately 58 patients. Approximately 18 participants will be enrolled in the Phase 1 Dose Escalation/De-escalation and two dose levels of modakafusp alfa in combination with daratumumab SC will be selected to be further explored in the randomized Phase 2a Dose Finding part of the study wherein, approximately 40 participants will be randomly assigned by chance (like flipping a coin) to one of the two treatment groups:

• Phase 2a Dose Finding: Modakafusp Alfa (DL1) + Daratumumab
• Phase 2a Dose Finding: Modakafusp Alfa (DL2) + Daratumumab This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 60 months. Participants who discontinue study drug treatment for reasons other than progressive disease will continue progression-free survival (PFS) follow-up every 4 weeks from the end of treatment (EOT) visit until the occurrence of progressive disease, death, the start of subsequent systemic antineoplastic therapy, study termination, whichever occurs first.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• Drug: Modakafusp Alfa
  Modakafusp alfa intravenous infusion
  Other Name: TAK-573
• Drug: Daratumumab
  Daratumumab SC injection

Study Arms

• Experimental: Phase 1 Dose Escalation
  Modakafusp alfa 60 to 240 mg, infusion, intravenously, once every 4 weeks (Q4W) with daratumumab 1800 mg, subcutaneously (SC), once weekly (QW) in Cycles 1 and 2, twice weekly (Q2W) in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression.
  Interventions:

  • Drug: Modakafusp Alfa
  • Drug: Daratumumab
• Experimental: Phase 2a Dose Finding: Modakafusp Alfa (DL1) + Daratumumab
  Modakafusp alfa at dose level 1 (DL1) [selected from Phase 1 Dose Escalation] with daratumumab SC 1800 mg, SC, QW in Cycles 1 and 2, Q2W in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression.
  Interventions:

  • Drug: Modakafusp Alfa
  • Drug: Daratumumab
• Experimental: Phase 2a Dose Finding: Modakafusp Alfa (DL2) + Daratumumab
  Modakafusp alfa at dose level 2 (DL2) [selected from Phase 1 Dose Escalation] with daratumumab SC 1800 mg, SC, QW in Cycles 1 and 2, Q2W in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression.
  Interventions:

  • Drug: Modakafusp Alfa
  • Drug: Daratumumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: October 19, 2022): 58
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 4, 2025
• Estimated Primary Completion Date: March 4, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Documented multiple myeloma (MM) diagnosis per IMWG criteria.

2. Measurable disease, defined as at least 1 of the following:

   1. Serum M protein ≥0.5 grams per deciliter [g/dL] (≥5 g/L) on serum protein electrophoresis (SPEP).
   2. Urine M protein ≥200 mg/24 hours on urine protein electrophoresis (UPEP).
   3. Serum free light chain (FLC) assay with involved FLC level ≥10 mg/dL (≥100 mg/L) provided serum FLC ratio is abnormal.

3. For participants in the Phase 1 Dose Escalation only:

   Must have received at least 3 prior lines of therapy, including at least 1 proteosome inhibitor (PI), 1 immunomodulatory imide drug (IMiD), and 1 anti-CD38 monoclonal antibody (mAb) drug; or who are triple refractory to a PI, an IMiD, and an anti-CD38 mAb drug, regardless of the number of prior line(s) or therapy.

4. For participants in Phase 2a Dose Finding only:

   1. Received 1 to 3 prior line(s) of antimyeloma therapy.
   2. Must be refractory to prior lenalidomide treatment.
   3. Participants must be sensitive (nonrefractory) or naïve to prior anti-CD38 mAb treatment.
   4. Documented progressive disease on or after the last regimen.
   5. Participants must have PR or better to at least 1 line of prior therapy.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at screening.

Exclusion Criteria:

1. Prior exposure to modakafusp alfa.
2. Participant has polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, plasma cell leukemia, or lymphoplasmacytic lymphoma.
3. Participant has not recovered from adverse reactions to prior myeloma treatment or procedures (chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE, Version 5 Grade ≤1 or baseline, except for alopecia.
4. Previous allogeneic stem cell transplant at any time or autologous stem cell transplant (ASCT) within 12 weeks of planned start of dosing.
5. Seropositive for hepatitis B, or known history of seropositivity for hepatitis C or of seropositivity for human immunodeficiency virus (HIV).
6. Participant has congestive heart failure (New York Heart Association Grade ≥II), cardiac myopathy, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant arrhythmia requiring therapy including anticoagulants, or clinically significant uncontrolled hypertension.
7. Participant has QT interval corrected by the Fridericia method >480 milliseconds [msec] (Grade ≥2).
8. Participant has a chronic condition that will require the chronic use of systemic corticosteroids >10 milligrams per day (mg/d) of prednisone or equivalent on top of any required corticosteroids for multiple myeloma (MM).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, China, France, Korea, Republic of, Spain, United States
• Removed Location Countries: Czechia, Germany, Hungary, Puerto Rico, United Kingdom

Administrative Information

• NCT Number: NCT05590377
• Other Study ID Numbers: TAK-573-2001; 2022-002169-14 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

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
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: 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/

• Current Responsible Party: Takeda
• Original Responsible Party: Same as current
• Current Study Sponsor: Takeda
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; Takeda

• PRS Account: Takeda
• Verification Date: April 2024