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Multiple Myeloma

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Antineoplastic Agents

All Drugs and Chemicals

Daratumumab

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.

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.

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.

Modakafusp Alfa

Study Director

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.

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.

A Study of Modakafusp Alfa Together With Daratumumab Adults With Relapsed or Refractory Multiple Myeloma

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Takeda

Anti-Inflammatory Agents

Antiemetics

Gastrointestinal Agents

Dexamethasone

Dexamethasone acetate

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

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.

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.

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.

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.

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.

Participants will receive modakafusp alfa 120 mg, infusion, IV, Q4W, for each 28-day treatment cycle until disease progression or treatment discontinuation.

Participants will receive modakafusp alfa 240 mg, infusion, IV, Q4W, for each 28-day treatment cycle until disease progression or treatment discontinuation.

Modakafusp alfa

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.

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.

A Study of Modakafusp Alfa on Adult Participants With Relapsed/Refractory Multiple Myeloma

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

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.

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.

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.

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.

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.

Laboratory values will include hematology, chemistry, and urine analysis.

Vital signs will include temperature, pulse, respiratory rate, oxygen saturation, and blood pressure.

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.

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.

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.

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).

ORR is defined as the percentage of participants who achieved a PR or better during the study as defined by IMWG Uniform Response Criteria.

CBR is defined as the percentage of participants who achieved MR or better during the study as defined by IMWG Uniform Response Criteria.

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.

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.

Time to response is defined as the time from first dose to the date of first documentation of response (PR or better).

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.

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.

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.

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.

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.

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.

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.

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.

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.

Healthcare resources used during medical encounters included hospitalizations, emergency room stays, or outpatient visits.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study of Modakafusp Alfa Together With Daratumumab Adults With Relapsed or Refractory Multiple Myeloma	NCT05590377	Multiple Myelom...	Modakafusp Alfa Daratumumab	18 Years -	Takeda
A Study of Modakafusp Alfa on Adult Participants With Relapsed/Refractory Multiple Myeloma	NCT03215030	Multiple Myelom...	Modakafusp alfa Dexamethasone	18 Years -	Takeda

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