Multiple Myeloma
Conditions
Keywords
Drug Therapy
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.
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.
Interventions
DRUGModakafusp alfa
Modakafusp alfa intravenous infusion.
DRUGDexamethasone
Dexamethasone.
Sponsors
Teva Branded Pharmaceutical Products R&D LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Percentage of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs) | Up to 54.3 months in Part 1 | 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. 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. |
| Part 1: Number of Participants With Dose-limiting Toxicities (DLTs) | Up to Cycle 1 (cycle length was 28 days for Schedule A, B and D; 21 days for Schedule C) | DLTs were 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 were considered DLTs. |
| Part 1: Percentage of Participants Reporting One or More Grade 3 or Higher TEAEs | Up to 54.3 months in Part 1 | An 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. TEAEs grades were 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. Percentages were rounded off to the nearest decimal. |
| Part 1: Percentage of Participants Reporting One or More Serious Treatment-emergent Adverse Events (Serious TEAEs) | Up to approximately 54.3 months in Part 1 | AE: any untoward medical occurrence in participants administered a pharmaceutical product; untoward medical occurrence does not necessarily have causal relationship with this treatment. AE can therefore be any unfavorable \& unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of medicinal (investigational) product whether or not it is related to medicinal product. TEAE: any AE either reported for first time or worsening of pre-existing event after first dose of study drug \& within 30 days of last administration of study drug. Serious TEAEs: 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 medically important event. Percentages were rounded off to nearest decimal. |
| Part 1: Percentage of Participants Who Discontinued the Treatment Because of TEAE | Up to 54.3 months in Part 1 | An 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. 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. Percentages were rounded off to the nearest decimal. |
| Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Delay | Up to 54.3 months in Part 1 | Percentages were rounded off to the nearest decimal. |
| Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Interruptions | Up to 54.3 months in Part 1 | Percentages were rounded off to the nearest decimal. |
| Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Reductions | Up to 54.3 months in Part 1 | Percentages were rounded off to the nearest decimal. |
| Part 1: Percentage of Participants With Clinically Significant Laboratory Values | Up to 54.3 months in Part 1 | Laboratory values included hematology, chemistry, and urinalysis and were assessed per investigator's interpretation. |
| Part 1: Percentage of Participants With Clinically Significant Vital Signs Measurements | Up to 54.3 months in Part 1 | Vital signs included temperature, pulse, respiratory rate, oxygen saturation, and blood pressure. |
| Part 2: Overall Response Rate (ORR) | Up to 34.7 months in Part 2 | ORR was defined as the percentage of participants who achieved a partial response (PR) rate or better (stringent complete response \[sCR\] + complete response \[CR\] + very good partial response \[VGPR\] + PR) during the study as defined by international myeloma working group (IMWG) uniform response criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal free light chain (FLC) ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR:serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. |
| Part 3: Overall Response Rate (ORR) Assessed by Independent Review Committee (IRC) | Up to 20.5 months in Part 3 | ORR was defined as the percentage of participants who achieved a PR rate or better (sCR + CR + VGPR + PR) during the study as defined by IMWG uniform response criteria. PR :≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR:negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. Scr: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR:serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parts 1 and 2: Percentage of Participants With Dose-limiting Toxicities (DLTs)- Like Events | Up to 54.3 months in Part 1; Up to 34.7 months in Part 2 | Percentage of participants with TEAEs meeting DLT definition were reported. Toxicity was 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 are 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 Cycle 2 were considered a DLT. Percentages were rounded off to the nearest decimal. |
| Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Part 1:Schedule A:Day 1&15 in Cycles 1&2; Schedule B: Day1&15 in Cycles 1&2; Schedule C:Day1 in Cycles 1&2; Schedule D: Day 1 in Cycles 1&2: Pre-infusion&at multiple times post-infusion (cycle length was 28 days for Schedule A, B&D;21 days for Schedule C) | As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule. |
| Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Part 1:Schedule A:Day 1&15 in Cycles 1&2; Schedule B: Day1&15 in Cycles 1&2; Schedule C:Day1 in Cycles 1&2; Schedule D: Day 1 in Cycles 1&2: Pre-infusion&at multiple times post-infusion (cycle length was 28 days for Schedule A, B&D;21 days for Schedule C) | As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule. |
| Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Part1:Schedule A:Day 1 in Cycles1&2&Day15 in Cycle1;Schedule B: Day1&15 in Cycle 1;Schedule C:Day1 in Cycles1&2; Schedule D:Day 1 in Cycles1&2: Pre-infusion&at multiple times post-infusion (cycle length= 28 days for Schedule A, B&D;21 days for Schedule C) | As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule. Given the low exposure at the 0.1 mg/kg dose, there was insufficient data to characterize the terminal phase PK required for calculating this parameter. Consequently, this parameter has been marked as "Not Calculated" - and therefore not reported - for the Part 1, Schedule A, 0.1 mg/kg dose group, in accordance with non-compartmental PK analysis standards. |
| Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Part1:Schedule A:Day 1 in Cycles1&2&Day15 in Cycle1;Schedule B: Day1&15 in Cycle 1;Schedule C:Day1 in Cycles1&2; Schedule D:Day 1 in Cycles1&2: Pre-infusion&at multiple times post-infusion (cycle length= 28 days for Schedule A, B&D;21 days for Schedule C) | As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule. |
| Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Part1:Schedule A:Day 1 in Cycles1&2&Day15 in Cycle1;Schedule B: Day1&15 in Cycle 1;Schedule C:Day1 in Cycles1&2; Schedule D:Day 1 in Cycles1&2: Pre-infusion&at multiple times post-infusion (cycle length= 28 days for Schedule A, B&D;21 days for Schedule C) | As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule. Given the low exposure at the 0.1 mg/kg dose, there was insufficient data to characterize the terminal phase PK required for calculating this parameter. Consequently, this parameter has been marked as "Not Calculated" - and therefore not reported - for the Part 1, Schedule A, 0.1 mg/kg dose group, in accordance with non-compartmental PK analysis standards. |
| Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Part1:Schedule A:Day 1 in Cycles1&2&Day15 in Cycle1;Schedule B: Day1&15 in Cycle 1;Schedule C:Day1 in Cycles1&2; Schedule D:Day 1 in Cycles1&2: Pre-infusion&at multiple times post-infusion (cycle length= 28 days for Schedule A, B&D;21 days for Schedule C) | As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule. |
| Part 1: CL: Clearance for Modakafusp Alfa | Part1:Schedule A:Day 1 in Cycles1&2&Day15 in Cycle1;Schedule B: Day1&15 in Cycle 1;Schedule C:Day1 in Cycles1&2; Schedule D:Day 1 in Cycles1&2: Pre-infusion&at multiple times post-infusion (cycle length= 28 days for Schedule A, B&D;21 days for Schedule C) | Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL = dose/AUC. As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule. |
| Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Part1:Schedule A:Day 1 in Cycles1&2&Day15 in Cycle1;Schedule B: Day1&15 in Cycle 1;Schedule C:Day1 in Cycles1&2; Schedule D:Day 1 in Cycles1&2: Pre-infusion&at multiple times post-infusion (cycle length= 28 days for Schedule A, B&D;21 days for Schedule C) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. V(ss) = (dose/AUC)\*MRT, where MRT is mean residence time. As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule. |
| Parts 1, 2 and 3: Percentage of Participants With Positive Anti-drug Antibody (ADA) at Any Scheduled and Unscheduled Post-Baseline Visit | Up to 54.3 months in Part 1; Up to 34.7 months in Part 2; Up to 20.5 months in Part 3 | ADA samples scoring equal to or above the cut-point (titer of 75) were defined as ADA positive. Percentages were rounded off to the nearest decimal. |
| Part 1: Overall Response Rate (ORR) | Up to 54.3 months in Part 1 | ORR was defined as the percentage of participants who achieved a PR rate or better (sCR + CR + VGPR + PR) during the study as defined by IMWG uniform response criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. Percentages were rounded off to the nearest decimal. |
| Parts 1 and 2: Clinical Benefit Rate (CBR) | Up to 54.3 months in Part 1; Up to 34.7 months in Part 2 | The CBR was defined as the percentage of participants with a confirmed response of sCR, CR, VGPR, PR, or minimal response (MR) during the study per investigator assessment as defined by IMWG Uniform Response Criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. MR: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. Percentages were rounded off to the nearest decimal. |
| Parts 1 and 2: Disease Control Rate (DCR) | Up to 54.3 months in Part 1; Up to 34.7 months in Part 2 | The DCR was defined as the proportion of participants with a confirmed response of sCR, CR, VGPR, PR, MR, or stable disease (SD) during the study per investigator assessment as defined by IMWG Uniform Response Criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. MR: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. SD: no known evidence of progressive or new bone lesions if radiographic studies were performed. Percentages were rounded off to the nearest decimal. |
| Parts 1, 2, and 3: Duration of Response (DOR) | Up to 54.3 months in Part 1; Up to 34.7 months in Part 2; Up to 20.5 months in Part 3 | DOR was defined as the time from the date of first documentation of response PR or better (sCR + CR + VGPR + PR) to the time of disease progression or death, whichever occurs first. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. |
| Parts 1 and 2: Time to Response | Up to 54.3 months in Part 1; Up to 34.7 months in Part 2 | Time to response was defined as the time from first dose to the date of first documentation of response (PR or better \[sCR + CR + VGPR + PR\]) PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. |
| Parts 1, 2, and 3: Progression Free Survival (PFS) | Up to 54.3 months in Part 1; Up to 34.7 months in Part 2; Up to 20.5 months in Part 3 | PFS was defined as the time from the date of enrollment until the date of progressive disease (PD) or death due to any cause, whichever occurs first as defined by IMWG Criteria. Per IMWG criteria, PD: serum M-component increase ≥0.5 g/dl or urine M-component increase ≥ 200 mg/24-hour/ difference between involved and uninvolved FLC levels increase \>10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia. |
| Parts 2 and 3: Overall Survival (OS) | Up to 34.7 months in Part 2; Up to 20.5 months in Part 3 | The OS was defined as the time from the date of first dose to the date of death due to any cause. |
| Part 2: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D) | — |
| Part 2: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D) | — |
| Part 2: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D) | — |
| Part 2: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D) | — |
| Part 2: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D) | — |
| Part 2: CL: Clearance for Modakafusp Alfa | Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D) | Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL = dose/AUC. |
| Part 2: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. V(ss) = (dose/AUC)\*MRT, where MRT is mean residence time. |
| Part 2: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D) | — |
| Part 3: Objective Response Rate (ORR) by Investigator Assessment | Up to 20.5 months in Part 3 | ORR was defined as the percentage of participants who achieved a PR rate or better (sCR + CR + VGPR + PR) during the study as defined by IMWG uniform response criteria. PR :≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR:negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR:serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. Percentages were rounded off to the nearest decimal. |
| Part 3: Clinical Benefit Rate (CBR) by IRC and Investigator Assessment | Up to 20.5 months in Part 3 | The CBR was defined as the percentage of participants with a confirmed response of sCR, CR, VGPR, PR, or minimal response (MR) during the study per investigator assessment as defined by IMWG Uniform Response Criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. MR: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. Percentages were rounded off to the nearest decimal. |
| Part 3: Duration of Clinical Benefit | Up to 20.5 months in Part 3 | Duration of clinical benefit was 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 participants who achieve a confirmed MR or better. MR: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. Per IMWG criteria, PD: serum M-component increase ≥0.5 g/dl or urine M-component increase ≥ 200 mg/24-hour/ difference between involved and uninvolved FLC levels increase \>10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia. |
| Part 3: Disease Control Rate (DCR) by IRC and Investigator Assessment | Up to 20.5 months in Part 3 | The DCR was defined as the proportion of participants with a confirmed response of sCR, CR, VGPR, PR, MR, or stable disease (SD) during the study per investigator assessment as defined by IMWG Uniform Response Criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. MR: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. SD: no known evidence of progressive or new bone lesions if radiographic studies were performed. Percentages were rounded off to the nearest decimal. |
| Part 3: Duration of Disease Control | Up to 20.5 months in Part 3 | Duration of disease control was 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 participants who achieved a SD or better. SD: no known evidence of progressive or new bone lesions if radiographic studies were performed. Per IMWG criteria, PD: serum M-component increase ≥0.5 g/dl or urine M-component increase ≥200 mg/24-hour/ difference between involved and uninvolved FLC levels increase \>10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia. |
| Part 3: Time to Progression (TTP) by IRC and Investigator Assessment | Up to 20.5 months in Part 3 | TTP was 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. Per IMWG criteria, PD: serum M-component increase ≥0.5 g/dl or urine M-component increase ≥200 mg/24-hour/ difference between involved and uninvolved FLC levels increase \>10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia. |
| Part 3: Rate of Minimal Residual Disease (MRD) Negativity Status at a Sensitivity of 10^-5 in Participants Achieving CR | Up to 20.5 months in Part 3 | MRD negativity rate at a sensitivity of 10\^-5 was defined as participants who were MRD negative at a sensitivity of 10\^-5 in participants achieving suspected complete response (CR). CR was 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 was required. |
| Part 3: Duration of MRD Negativity Status at a Sensitivity of 10^-5 in Participants Achieving CR | Up to 20.5 months in Part 3 | Duration of MRD negativity (10\^-5) was 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. |
| Part 3: Percentage of Participants With Treatment -Emergent Adverse Events (TEAEs) | Up to 20.5 months in Part 3 | An 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. 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. Percentages were rounded off to the nearest decimal. |
| Part 3: Percentage of Participants With Serious Treatment-emergent Adverse Events (Serious TEAEs) | Up to 20.5 months in Part 3 | AE: any untoward medical occurrence in participants administered pharmaceutical product; untoward medical occurrence does not necessarily have causal relationship with this treatment. AE can therefore be any unfavorable \& unintended sign (including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal (investigational) product whether or not it is related to medicinal product. TEAE: any AE either reported for first time or worsening of pre-existing event after first dose of study drug \& within 30 days of last administration of study drug. Serious TEAEs: 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 a medically important event. Percentages were rounded off to the nearest decimal. |
| Part 3: Percentage of Participants With Clinically Significant Laboratory Values | Up to 20.5 months in Part 3 | Laboratory values included hematology, chemistry, and urinalysis as interpreted by the investigator. |
| Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Up to 20.5 months in Part 3 | ECOG performance status was measured at baseline and over time. ECOG performance status was measured on a 6 point scale: 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. Reported here is the baseline status and the worst post-baseline status measured. A decrease in grade from baseline indicates an improvement. Only categories for which there was at least 1 participant are reported. |
| Part 3: Health Care Utilization: Length of Hospital Stays | Up to 20.5 months in Part 3 | — |
| Part 3: Percentage of Participants With Neutralizing Antibodies (NAb) at Any Scheduled and Unscheduled Post-Baseline Visit | Up to 20.5 months in Part 3 | Percentages were rounded off to the nearest decimal. |
| Part 3: Health Care Utilization: Number of Participants With at Least One Medical Encounter | Up to 20.5 months in Part 3 | Medical encounters included hospitalizations, emergency room stays, or outpatient visits. |
| Part 3: Patient-reported Outcome (PRO): Change From Baseline to Cycle 9 in Instrument European Organisation for Research and Treatment of Cancer QLQ Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20) | Baseline, Cycle 9 Day 8 [cycle length was 28 days] (up to 7.7 months) | EORTC QLQ-MY20 is a myeloma-specific module developed by the EORTC group specifically to assess quality of life in participants with multiple myeloma. It contains 20 items which can be grouped into a disease symptom subscale (6 items), side effects of treatment subscale (10 items), body image (1 item) and future perspective subscale (3 items). All transformed scale scores range from 0 to 100 with higher scores indicating worse symptoms (Disease Symptoms and Side Effects of Treatment) or better support/functioning (Future Perspective and Body Image). |
Countries
Canada, China, France, Germany, Greece, Israel, Italy, Japan, Norway, Puerto Rico, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at various investigative sites globally from 4 October 2017 to 7 November 2024.
Pre-assignment details
Participants with diagnosis of RRMM were enrolled in this study consisting of Part 1 (Dose Escalation), Part 2 (Dose Expansion), Part 3 (Dose Extension), & Japan Safety Lead-in to receive modakafusp alfa with/without dexamethasone. 4 participants enrolled in study but discontinued without receiving TAK-573 dosing and are thus not presented below.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 (Dose Escalation) Schedule A Participants received modakafusp alfa 0.001 up to 0.75 mg/kg, infusion, IV, Q1W on Days 1, 8, 15 and 22 of each 28-day treatment cycle up to 2 cycles, followed by Q2W on Days 1 and 15 of each 28-day treatment cycle up to 4 cycles, followed by Q4W on Day 1 of each 28-day treatment cycle until treatment discontinuation. | 20 |
| Part 1 (Dose Escalation) Schedule B Participants received modakafusp alfa 0.20 up to 0.30 mg/kg, infusion, IV, Q2W on Days 1 and 15 of each 28-day treatment cycle until treatment discontinuation. | 8 |
| Part 1 (Dose Escalation) Schedule C Participants received modakafusp alfa 0.40 up to 0.75 mg/kg, infusion, IV, Q3W on Day 1 of each 21-day treatment cycle until treatment discontinuation. | 7 |
| Part 1 (Dose Escalation) Schedule D Participants received modakafusp alfa 1.5 up to 6.0 mg/kg, infusion, IV, Q4W on Day 1 of each 28-day treatment cycle until treatment discontinuation. | 21 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa Participants received modakafusp alfa 0.400 mg/kg infusion, IV, Q3W on Day 1 of each 21-day treatment cycle until treatment discontinuation. | 8 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone Participants received modakafusp alfa 0.400 mg/kg infusion, IV, and dexamethasone 40 mg, orally, Q3W on Day 1 of each 21-day treatment cycle until treatment discontinuation. | 3 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa Participants received modakafusp alfa 1.500 mg/kg infusion, IV, Q4W on Day 1 of each 28-day treatment cycle until treatment discontinuation. | 25 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone Participants received modakafusp alfa 1.500 mg/kg infusion, IV, and dexamethasone 40 mg, orally, Q4W on Day 1 of each 28-day treatment cycle until treatment discontinuation. | 25 |
| Part 3 (Dose Extension): Modakafusp Alfa 120 mg Participants received modakafusp alfa 120 mg, infusion, IV, Q4W, for each 28-day treatment cycle until disease progression or treatment discontinuation. | 71 |
| Part 3 (Dose Extension): Modakafusp Alfa 240 mg Participants received modakafusp alfa 240 mg, infusion, IV, Q4W, for each 28-day treatment cycle until disease progression or treatment discontinuation. | 75 |
| Japan Lead-in: Modakafusp Alfa 60 mg Participants received modakafusp alfa 60 mg, infusion, IV, Q4W, for each 28-day treatment cycle until disease progression or treatment discontinuation. | 3 |
| Japan Lead-in: Modakafusp Alfa 120 mg Participants received modakafusp alfa 120 mg, infusion, IV, Q4W, for each 28-day treatment cycle until disease progression or treatment discontinuation. | 2 |
| Total | 268 |
Baseline characteristics
| Characteristic | Total | Part 1 (Dose Escalation) Schedule A | Part 1 (Dose Escalation) Schedule B | Part 1 (Dose Escalation) Schedule C | Part 1 (Dose Escalation) Schedule D | Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 3 (Dose Extension): Modakafusp Alfa 120 mg | Part 3 (Dose Extension): Modakafusp Alfa 240 mg | Japan Lead-in: Modakafusp Alfa 60 mg | Japan Lead-in: Modakafusp Alfa 120 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 65.46 years STANDARD_DEVIATION 9.98 | 60.3 years STANDARD_DEVIATION 10.56 | 61.1 years STANDARD_DEVIATION 7 | 60.4 years STANDARD_DEVIATION 10.47 | 64.7 years STANDARD_DEVIATION 10.34 | 61.9 years STANDARD_DEVIATION 8.63 | 65.7 years STANDARD_DEVIATION 12.58 | 64.1 years STANDARD_DEVIATION 12.17 | 70.2 years STANDARD_DEVIATION 7.77 | 66.2 years STANDARD_DEVIATION 9.76 | 66.5 years STANDARD_DEVIATION 9.61 | 66.66 years STANDARD_DEVIATION 9.71 | 66.00 years STANDARD_DEVIATION 11.31 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants | 3 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 225 Participants | 19 Participants | 8 Participants | 6 Participants | 21 Participants | 8 Participants | 3 Participants | 24 Participants | 23 Participants | 51 Participants | 57 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 33 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 16 Participants | 15 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 23 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 5 Participants | 9 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 34 Participants | 0 Participants | 3 Participants | 1 Participants | 5 Participants | 1 Participants | 0 Participants | 2 Participants | 8 Participants | 10 Participants | 4 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 32 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 18 Participants | 11 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 179 Participants | 20 Participants | 4 Participants | 6 Participants | 14 Participants | 6 Participants | 3 Participants | 20 Participants | 17 Participants | 38 Participants | 51 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 125 Participants | 10 Participants | 3 Participants | 2 Participants | 10 Participants | 1 Participants | 2 Participants | 12 Participants | 10 Participants | 34 Participants | 39 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 143 Participants | 10 Participants | 5 Participants | 5 Participants | 11 Participants | 7 Participants | 1 Participants | 13 Participants | 15 Participants | 37 Participants | 36 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 15 / 20 | 6 / 8 | 6 / 7 | 8 / 21 | 3 / 8 | 1 / 3 | 5 / 25 | 6 / 25 | 19 / 71 | 20 / 75 | 0 / 3 | 0 / 2 |
| other Total, other adverse events | 20 / 20 | 8 / 8 | 7 / 7 | 21 / 21 | 8 / 8 | 3 / 3 | 24 / 25 | 24 / 25 | 70 / 71 | 74 / 75 | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 8 / 20 | 6 / 8 | 2 / 7 | 13 / 21 | 1 / 8 | 1 / 3 | 7 / 25 | 9 / 25 | 28 / 71 | 33 / 75 | 0 / 3 | 0 / 2 |
Outcome results
Primary
Part 1: Number of Participants With Dose-limiting Toxicities (DLTs)
DLTs were 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 were considered DLTs.
Time frame: Up to Cycle 1 (cycle length was 28 days for Schedule A, B and D; 21 days for Schedule C)
Population: The DLT-evaluable Analysis Set included participants who received all Cycle 1 doses of modakafusp alfa or experienced a DLT in Cycle 1 in the Part 1 Dose Escalation portion of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 4 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 3 Participants |
| Part 1 (Dose Escalation) Schedule C | Part 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Part 1 (Dose Escalation) Schedule D | Part 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 3 Participants |
Primary
Part 1: Percentage of Participants Reporting One or More Grade 3 or Higher TEAEs
An 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. TEAEs grades were 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. Percentages were rounded off to the nearest decimal.
Time frame: Up to 54.3 months in Part 1
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 1: Percentage of Participants Reporting One or More Grade 3 or Higher TEAEs | 95 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Part 1: Percentage of Participants Reporting One or More Grade 3 or Higher TEAEs | 100 percentage of participants |
| Part 1 (Dose Escalation) Schedule C | Part 1: Percentage of Participants Reporting One or More Grade 3 or Higher TEAEs | 85.7 percentage of participants |
| Part 1 (Dose Escalation) Schedule D | Part 1: Percentage of Participants Reporting One or More Grade 3 or Higher TEAEs | 95.2 percentage of participants |
Primary
Part 1: Percentage of Participants Reporting One or More Serious Treatment-emergent Adverse Events (Serious TEAEs)
AE: any untoward medical occurrence in participants administered a pharmaceutical product; untoward medical occurrence does not necessarily have causal relationship with this treatment. AE can therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of medicinal (investigational) product whether or not it is related to medicinal product. TEAE: any AE either reported for first time or worsening of pre-existing event after first dose of study drug & within 30 days of last administration of study drug. Serious TEAEs: 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 medically important event. Percentages were rounded off to nearest decimal.
Time frame: Up to approximately 54.3 months in Part 1
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 1: Percentage of Participants Reporting One or More Serious Treatment-emergent Adverse Events (Serious TEAEs) | 40 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Part 1: Percentage of Participants Reporting One or More Serious Treatment-emergent Adverse Events (Serious TEAEs) | 75 percentage of participants |
| Part 1 (Dose Escalation) Schedule C | Part 1: Percentage of Participants Reporting One or More Serious Treatment-emergent Adverse Events (Serious TEAEs) | 28.6 percentage of participants |
| Part 1 (Dose Escalation) Schedule D | Part 1: Percentage of Participants Reporting One or More Serious Treatment-emergent Adverse Events (Serious TEAEs) | 61.9 percentage of participants |
Primary
Part 1: Percentage of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs)
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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. 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.
Time frame: Up to 54.3 months in Part 1
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 1: Percentage of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Part 1: Percentage of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Part 1 (Dose Escalation) Schedule C | Part 1: Percentage of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Part 1 (Dose Escalation) Schedule D | Part 1: Percentage of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs) | 100 percentage of participants |
Primary
Part 1: Percentage of Participants Who Discontinued the Treatment Because of TEAE
An 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. 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. Percentages were rounded off to the nearest decimal.
Time frame: Up to 54.3 months in Part 1
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 1: Percentage of Participants Who Discontinued the Treatment Because of TEAE | 15 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Part 1: Percentage of Participants Who Discontinued the Treatment Because of TEAE | 25 percentage of participants |
| Part 1 (Dose Escalation) Schedule C | Part 1: Percentage of Participants Who Discontinued the Treatment Because of TEAE | 0 percentage of participants |
| Part 1 (Dose Escalation) Schedule D | Part 1: Percentage of Participants Who Discontinued the Treatment Because of TEAE | 14.3 percentage of participants |
Primary
Part 1: Percentage of Participants With Clinically Significant Laboratory Values
Laboratory values included hematology, chemistry, and urinalysis and were assessed per investigator's interpretation.
Time frame: Up to 54.3 months in Part 1
Population: SAS:all participants who took ≥1 dose,even if incomplete,of TAK-573.However,clinically significant laboratory values data were not collected \& will never be available to present due to an issue with report form used for data collection(identified after trial completion).Assessments of clinical significance were not included in the report form,making data collection impossible.This issue did not impact participant safety or reliability of study data,particularly primary endpoint.
Primary
Part 1: Percentage of Participants With Clinically Significant Vital Signs Measurements
Vital signs included temperature, pulse, respiratory rate, oxygen saturation, and blood pressure.
Time frame: Up to 54.3 months in Part 1
Population: SAS:all participants who took ≥1 dose,even if incomplete,of TAK-573.However,clinically significant vital signs measurements data were not collected \& will never be available to present due to an issue with report form used for data collection(identified after trial completion).Assessments of clinical significance were not included in the report form,making data collection impossible.This issue did not impact participant safety or reliability of study data,particularly primary endpoint.
Primary
Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Delay
Percentages were rounded off to the nearest decimal.
Time frame: Up to 54.3 months in Part 1
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Delay | 30 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Delay | 12.5 percentage of participants |
| Part 1 (Dose Escalation) Schedule C | Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Delay | 57.1 percentage of participants |
| Part 1 (Dose Escalation) Schedule D | Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Delay | 9.5 percentage of participants |
Primary
Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Interruptions
Percentages were rounded off to the nearest decimal.
Time frame: Up to 54.3 months in Part 1
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Interruptions | 15 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Interruptions | 0 percentage of participants |
| Part 1 (Dose Escalation) Schedule C | Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Interruptions | 0 percentage of participants |
| Part 1 (Dose Escalation) Schedule D | Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Interruptions | 0 percentage of participants |
Primary
Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Reductions
Percentages were rounded off to the nearest decimal.
Time frame: Up to 54.3 months in Part 1
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Reductions | 10 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Reductions | 12.5 percentage of participants |
| Part 1 (Dose Escalation) Schedule C | Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Reductions | 0 percentage of participants |
| Part 1 (Dose Escalation) Schedule D | Part 1: Percentage of Participants With TEAEs Resulting in Dose Modifications: Dose Reductions | 9.5 percentage of participants |
Primary
Part 2: Overall Response Rate (ORR)
ORR was defined as the percentage of participants who achieved a partial response (PR) rate or better (stringent complete response \[sCR\] + complete response \[CR\] + very good partial response \[VGPR\] + PR) during the study as defined by international myeloma working group (IMWG) uniform response criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal free light chain (FLC) ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR:serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours.
Time frame: Up to 34.7 months in Part 2
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573 and with measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 2: Overall Response Rate (ORR) | 0 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Part 2: Overall Response Rate (ORR) | 0 percentage of participants |
| Part 1 (Dose Escalation) Schedule C | Part 2: Overall Response Rate (ORR) | 48 percentage of participants |
| Part 1 (Dose Escalation) Schedule D | Part 2: Overall Response Rate (ORR) | 32 percentage of participants |
Primary
Part 3: Overall Response Rate (ORR) Assessed by Independent Review Committee (IRC)
ORR was defined as the percentage of participants who achieved a PR rate or better (sCR + CR + VGPR + PR) during the study as defined by IMWG uniform response criteria. PR :≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR:negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. Scr: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR:serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours.
Time frame: Up to 20.5 months in Part 3
Population: The FAS included all participants who received at least 1 dose, even an incomplete dose, of modakafusp alfa, in the Part 3 extension cohorts. Due to early termination, IRC was disbanded prior to completing its evaluation and could not be utilized for the assessment, therefore the data for this outcome measure is not available.
Secondary
Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa
As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule. Given the low exposure at the 0.1 mg/kg dose, there was insufficient data to characterize the terminal phase PK required for calculating this parameter. Consequently, this parameter has been marked as Not Calculated - and therefore not reported - for the Part 1, Schedule A, 0.1 mg/kg dose group, in accordance with non-compartmental PK analysis standards.
Time frame: Part1:Schedule A:Day 1 in Cycles1&2&Day15 in Cycle1;Schedule B: Day1&15 in Cycle 1;Schedule C:Day1 in Cycles1&2; Schedule D:Day 1 in Cycles1&2: Pre-infusion&at multiple times post-infusion (cycle length= 28 days for Schedule A, B&D;21 days for Schedule C)
Population: PK Analysis Set; Overall number analyzed: participants with data available for analysis.Number analyzed: participants with data available during specified time-point.Given low exposure at 0.01mg/kg dose,there was insufficient data to characterize terminal phase PK required for calculating this parameter.Consequently,this parameter has been marked as Not Calculated and therefore not reported for Part 1,Schedule A,0.01mg/kg dose group,in accordance with non-compartmental PK analysis standards.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Dose Escalation) Schedule B | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 15 | 2410 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 21.3 |
| Part 1 (Dose Escalation) Schedule C | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 1 | 14900 hour*nanogram per milliliter (h*ng/mL) | — |
| Part 1 (Dose Escalation) Schedule C | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 15 | 24000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 38 |
| Part 1 (Dose Escalation) Schedule C | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 2 Day 1 | 28000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 49.3 |
| Part 1 (Dose Escalation) Schedule D | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 15 | 286000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 66.5 |
| Part 1 (Dose Escalation) Schedule D | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 1 | 209000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 83.4 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 15 | 24300 hour*nanogram per milliliter (h*ng/mL) | — |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 1 | 20500 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 33.2 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 15 | 20100 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 21.7 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 1 | 14100 hour*nanogram per milliliter (h*ng/mL) | — |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 2 Day 1 | 73600 hour*nanogram per milliliter (h*ng/mL) | — |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 1 | 288000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 44.5 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 2 Day 1 | 333000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 54 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 1 | 199000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 104.4 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 2 Day 1 | 243000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 54.5 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 1 | 240000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 109.7 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 2 Day 1 | 215000 hour*nanogram per milliliter (h*ng/mL) | — |
Secondary
Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa
As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule.
Time frame: Part1:Schedule A:Day 1 in Cycles1&2&Day15 in Cycle1;Schedule B: Day1&15 in Cycle 1;Schedule C:Day1 in Cycles1&2; Schedule D:Day 1 in Cycles1&2: Pre-infusion&at multiple times post-infusion (cycle length= 28 days for Schedule A, B&D;21 days for Schedule C)
Population: The PK Analysis Set included participants from the SAS who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis during the specified time-point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 128 h*ng/mL | Geometric Coefficient of Variation 113.1 |
| Part 1 (Dose Escalation) Schedule A | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 29.5 h*ng/mL | Geometric Coefficient of Variation 19 |
| Part 1 (Dose Escalation) Schedule A | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 15 | 76.3 h*ng/mL | Geometric Coefficient of Variation 34.8 |
| Part 1 (Dose Escalation) Schedule B | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 15 | 1270 h*ng/mL | Geometric Coefficient of Variation 88.4 |
| Part 1 (Dose Escalation) Schedule B | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 550 h*ng/mL | Geometric Coefficient of Variation 111.6 |
| Part 1 (Dose Escalation) Schedule B | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 584 h*ng/mL | — |
| Part 1 (Dose Escalation) Schedule C | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 15 | 23900 h*ng/mL | Geometric Coefficient of Variation 38.2 |
| Part 1 (Dose Escalation) Schedule C | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 30100 h*ng/mL | Geometric Coefficient of Variation 67.9 |
| Part 1 (Dose Escalation) Schedule C | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 27700 h*ng/mL | Geometric Coefficient of Variation 48.5 |
| Part 1 (Dose Escalation) Schedule D | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 15 | 285000 h*ng/mL | Geometric Coefficient of Variation 66.1 |
| Part 1 (Dose Escalation) Schedule D | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 208000 h*ng/mL | Geometric Coefficient of Variation 83.2 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 15 | 8710 h*ng/mL | Geometric Coefficient of Variation 514 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 2 Day 15 | 22200 h*ng/mL | — |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 7090 h*ng/mL | Geometric Coefficient of Variation 263.7 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 2 Day 15 | 5090 h*ng/mL | — |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 15 | 19200 h*ng/mL | Geometric Coefficient of Variation 17 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 10600 h*ng/mL | Geometric Coefficient of Variation 98 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 6020 h*ng/mL | — |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 17900 h*ng/mL | Geometric Coefficient of Variation 106.8 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 15600 h*ng/mL | Geometric Coefficient of Variation 225.4 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 287000 h*ng/mL | Geometric Coefficient of Variation 44.5 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 332000 h*ng/mL | Geometric Coefficient of Variation 54 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 197000 h*ng/mL | Geometric Coefficient of Variation 83.9 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 190000 h*ng/mL | Geometric Coefficient of Variation 77.5 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 582000 h*ng/mL | Geometric Coefficient of Variation 250.5 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 229000 h*ng/mL | Geometric Coefficient of Variation 107.7 |
Secondary
Part 1: CL: Clearance for Modakafusp Alfa
Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL = dose/AUC. As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule.
Time frame: Part1:Schedule A:Day 1 in Cycles1&2&Day15 in Cycle1;Schedule B: Day1&15 in Cycle 1;Schedule C:Day1 in Cycles1&2; Schedule D:Day 1 in Cycles1&2: Pre-infusion&at multiple times post-infusion (cycle length= 28 days for Schedule A, B&D;21 days for Schedule C)
Population: PK Analysis Set; Overall number analyzed: participants with data available for analysis.Number analyzed: participants with data available during specified time-point.Given low exposure at 0.01mg/kg dose,there was insufficient data to characterize terminal phase PK required for calculating this parameter.Consequently,this parameter has been marked as Not Calculated and therefore not reported for Part 1,Schedule A,0.01mg/kg dose group,in accordance with non-compartmental PK analysis standards.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Dose Escalation) Schedule B | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 15 | 0.0415 liters per hour per kilogram (L/h/kg) | Geometric Coefficient of Variation 21.3 |
| Part 1 (Dose Escalation) Schedule C | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 1 | 0.0268 liters per hour per kilogram (L/h/kg) | — |
| Part 1 (Dose Escalation) Schedule C | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 15 | 0.0167 liters per hour per kilogram (L/h/kg) | Geometric Coefficient of Variation 37.9 |
| Part 1 (Dose Escalation) Schedule C | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 2 Day 1 | 0.0143 liters per hour per kilogram (L/h/kg) | Geometric Coefficient of Variation 49.2 |
| Part 1 (Dose Escalation) Schedule D | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 15 | 0.00261 liters per hour per kilogram (L/h/kg) | Geometric Coefficient of Variation 66.5 |
| Part 1 (Dose Escalation) Schedule D | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 1 | 0.00358 liters per hour per kilogram (L/h/kg) | Geometric Coefficient of Variation 83.7 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 15 | 0.00820 liters per hour per kilogram (L/h/kg) | — |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 1 | 0.0147 liters per hour per kilogram (L/h/kg) | Geometric Coefficient of Variation 32.9 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 15 | 0.0149 liters per hour per kilogram (L/h/kg) | Geometric Coefficient of Variation 22 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 1 | 0.0283 liters per hour per kilogram (L/h/kg) | — |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 2 Day 1 | 0.00540 liters per hour per kilogram (L/h/kg) | — |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 1 | 0.00258 liters per hour per kilogram (L/h/kg) | Geometric Coefficient of Variation 45.3 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 2 Day 1 | 0.00226 liters per hour per kilogram (L/h/kg) | Geometric Coefficient of Variation 52.1 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 1 | 0.00380 liters per hour per kilogram (L/h/kg) | Geometric Coefficient of Variation 102.9 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 2 Day 1 | 0.00306 liters per hour per kilogram (L/h/kg) | Geometric Coefficient of Variation 55.3 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 1 | 0.00628 liters per hour per kilogram (L/h/kg) | Geometric Coefficient of Variation 108.4 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: CL: Clearance for Modakafusp Alfa | Cycle 2 Day 1 | 0.00700 liters per hour per kilogram (L/h/kg) | — |
Secondary
Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa
As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule.
Time frame: Part 1:Schedule A:Day 1&15 in Cycles 1&2; Schedule B: Day1&15 in Cycles 1&2; Schedule C:Day1 in Cycles 1&2; Schedule D: Day 1 in Cycles 1&2: Pre-infusion&at multiple times post-infusion (cycle length was 28 days for Schedule A, B&D;21 days for Schedule C)
Population: The Pharmacokinetic (PK) Analysis Set included participants from the SAS who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis during the specified time-point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 47.5 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 175.1 |
| Part 1 (Dose Escalation) Schedule A | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 14.7 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 47.6 |
| Part 1 (Dose Escalation) Schedule A | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 15 | 16.9 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 75.4 |
| Part 1 (Dose Escalation) Schedule B | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 15 | 289 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 71.8 |
| Part 1 (Dose Escalation) Schedule B | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 154 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 95.5 |
| Part 1 (Dose Escalation) Schedule B | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 158 nanograms per milliliter (ng/mL) | — |
| Part 1 (Dose Escalation) Schedule C | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 15 | 2750 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 18.1 |
| Part 1 (Dose Escalation) Schedule C | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 2980 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 29 |
| Part 1 (Dose Escalation) Schedule C | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 3030 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 10.1 |
| Part 1 (Dose Escalation) Schedule D | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 15 | 11900 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 40.8 |
| Part 1 (Dose Escalation) Schedule D | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 11800 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 33.5 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 15 | 1030 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 183.5 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 2 Day 15 | 1730 nanograms per milliliter (ng/mL) | — |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 1260 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 106.1 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 2 Day 15 | 1270 nanograms per milliliter (ng/mL) | — |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 15 | 2600 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 37.9 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 2230 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 53.8 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 1970 nanograms per milliliter (ng/mL) | — |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 2460 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 38.6 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 2490 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 41.5 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 15000 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 20 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 15100 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 2.3 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 11600 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 30.9 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 9690 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 21.3 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 16800 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 31.3 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 15900 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 27.1 |
Secondary
Part 1: Overall Response Rate (ORR)
ORR was defined as the percentage of participants who achieved a PR rate or better (sCR + CR + VGPR + PR) during the study as defined by IMWG uniform response criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. Percentages were rounded off to the nearest decimal.
Time frame: Up to 54.3 months in Part 1
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573 and with measurable disease at baseline. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 1: Overall Response Rate (ORR) | 15.8 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Part 1: Overall Response Rate (ORR) | 0 percentage of participants |
| Part 1 (Dose Escalation) Schedule C | Part 1: Overall Response Rate (ORR) | 0 percentage of participants |
| Part 1 (Dose Escalation) Schedule D | Part 1: Overall Response Rate (ORR) | 23.8 percentage of participants |
Secondary
Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa
As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule.
Time frame: Part1:Schedule A:Day 1 in Cycles1&2&Day15 in Cycle1;Schedule B: Day1&15 in Cycle 1;Schedule C:Day1 in Cycles1&2; Schedule D:Day 1 in Cycles1&2: Pre-infusion&at multiple times post-infusion (cycle length= 28 days for Schedule A, B&D;21 days for Schedule C)
Population: PK Analysis Set; Overall number analyzed: participants with data available for analysis.Number analyzed: participants with data available during specified time-point.Given low exposure at 0.01mg/kg dose,there was insufficient data to characterize terminal phase PK required for calculating this parameter.Consequently,this parameter has been marked as Not Calculated and therefore not reported for Part 1,Schedule A,0.01mg/kg dose group,in accordance with non-compartmental PK analysis standards.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Dose Escalation) Schedule B | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 15 | 4.28 hours | Geometric Coefficient of Variation 4.3 |
| Part 1 (Dose Escalation) Schedule C | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 1 | 2.24 hours | — |
| Part 1 (Dose Escalation) Schedule C | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 2 Day 1 | 3.52 hours | Geometric Coefficient of Variation 12.8 |
| Part 1 (Dose Escalation) Schedule C | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 15 | 3.36 hours | Geometric Coefficient of Variation 34.6 |
| Part 1 (Dose Escalation) Schedule D | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 1 | 7.43 hours | Geometric Coefficient of Variation 26.2 |
| Part 1 (Dose Escalation) Schedule D | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 15 | 8.14 hours | Geometric Coefficient of Variation 20.6 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 15 | 6.01 hours | — |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 15 | 3.87 hours | Geometric Coefficient of Variation 59.7 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 1 | 2.36 hours | Geometric Coefficient of Variation 3.1 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 2 Day 1 | 7.64 hours | — |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 1 | 2.61 hours | — |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 2 Day 1 | 13.1 hours | Geometric Coefficient of Variation 10.1 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 1 | 7.50 hours | Geometric Coefficient of Variation 0.4 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 1 | 6.51 hours | Geometric Coefficient of Variation 88.6 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 2 Day 1 | 8.37 hours | Geometric Coefficient of Variation 14.6 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 2 Day 1 | 7.22 hours | — |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 1 | 6.16 hours | Geometric Coefficient of Variation 117.7 |
Secondary
Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa
As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule.
Time frame: Part 1:Schedule A:Day 1&15 in Cycles 1&2; Schedule B: Day1&15 in Cycles 1&2; Schedule C:Day1 in Cycles 1&2; Schedule D: Day 1 in Cycles 1&2: Pre-infusion&at multiple times post-infusion (cycle length was 28 days for Schedule A, B&D;21 days for Schedule C)
Population: The PK Analysis Set included participants from the SAS who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis during the specified time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 2 Day 1 | 2.97 hours |
| Part 1 (Dose Escalation) Schedule A | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 15 | 3.93 hours |
| Part 1 (Dose Escalation) Schedule A | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 1 | 4.03 hours |
| Part 1 (Dose Escalation) Schedule B | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 2 Day 1 | 4.23 hours |
| Part 1 (Dose Escalation) Schedule B | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 15 | 4.02 hours |
| Part 1 (Dose Escalation) Schedule B | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 1 | 3.99 hours |
| Part 1 (Dose Escalation) Schedule C | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 15 | 4.25 hours |
| Part 1 (Dose Escalation) Schedule C | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 1 | 4.40 hours |
| Part 1 (Dose Escalation) Schedule C | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 2 Day 1 | 3.98 hours |
| Part 1 (Dose Escalation) Schedule D | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 15 | 5.87 hours |
| Part 1 (Dose Escalation) Schedule D | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 1 | 4.27 hours |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 1 | 4.75 hours |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 2 Day 15 | 5.65 hours |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 15 | 4.28 hours |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 2 Day 15 | 4.00 hours |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 15 | 4.00 hours |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 1 | 4.03 hours |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 2 Day 1 | 4.45 hours |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 2 Day 1 | 4.00 hours |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 1 | 4.78 hours |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 1 | 3.07 hours |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 2 Day 1 | 3.21 hours |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 2 Day 1 | 4.13 hours |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 1 | 4.94 hours |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 2 Day 1 | 5.52 hours |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 1 | 4.03 hours |
Secondary
Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. V(ss) = (dose/AUC)\*MRT, where MRT is mean residence time. As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule.
Time frame: Part1:Schedule A:Day 1 in Cycles1&2&Day15 in Cycle1;Schedule B: Day1&15 in Cycle 1;Schedule C:Day1 in Cycles1&2; Schedule D:Day 1 in Cycles1&2: Pre-infusion&at multiple times post-infusion (cycle length= 28 days for Schedule A, B&D;21 days for Schedule C)
Population: PK Analysis Set; Overall number analyzed: participants with data available for analysis.Number analyzed: participants with data available during specified time-point.Given low exposure at 0.01mg/kg dose,there was insufficient data to characterize terminal phase PK required for calculating this parameter.Consequently,this parameter has been marked as Not Calculated and therefore not reported for Part 1,Schedule A,0.01mg/kg dose group,in accordance with non-compartmental PK analysis standards.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Dose Escalation) Schedule B | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 15 | 0.150 liters/kg | Geometric Coefficient of Variation 24.6 |
| Part 1 (Dose Escalation) Schedule C | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 1 | 0.104 liters/kg | — |
| Part 1 (Dose Escalation) Schedule C | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 15 | 0.0675 liters/kg | Geometric Coefficient of Variation 36.9 |
| Part 1 (Dose Escalation) Schedule C | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 2 Day 1 | 0.0678 liters/kg | Geometric Coefficient of Variation 31.1 |
| Part 1 (Dose Escalation) Schedule D | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 15 | 0.0319 liters/kg | Geometric Coefficient of Variation 43.3 |
| Part 1 (Dose Escalation) Schedule D | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 1 | 0.0352 liters/kg | Geometric Coefficient of Variation 23.4 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 15 | 0.0660 liters/kg | — |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 1 | 0.0575 liters/kg | Geometric Coefficient of Variation 26.4 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 15 | 0.0624 liters/kg | Geometric Coefficient of Variation 14.2 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 1 | 0.117 liters/kg | — |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 2 Day 1 | 0.0640 liters/kg | — |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 1 | 0.0329 liters/kg | Geometric Coefficient of Variation 32.1 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 2 Day 1 | 0.0456 liters/kg | Geometric Coefficient of Variation 36.9 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 1 | 0.0390 liters/kg | Geometric Coefficient of Variation 27.1 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 2 Day 1 | 0.0404 liters/kg | Geometric Coefficient of Variation 26.8 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 1 | 0.0536 liters/kg | Geometric Coefficient of Variation 24.3 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 2 Day 1 | 0.0716 liters/kg | — |
Secondary
Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa
As per planned analysis, data for this outcome measure was collected and reported dose-wise for each treatment schedule. Given the low exposure at the 0.1 mg/kg dose, there was insufficient data to characterize the terminal phase PK required for calculating this parameter. Consequently, this parameter has been marked as Not Calculated - and therefore not reported - for the Part 1, Schedule A, 0.1 mg/kg dose group, in accordance with non-compartmental PK analysis standards.
Time frame: Part1:Schedule A:Day 1 in Cycles1&2&Day15 in Cycle1;Schedule B: Day1&15 in Cycle 1;Schedule C:Day1 in Cycles1&2; Schedule D:Day 1 in Cycles1&2: Pre-infusion&at multiple times post-infusion (cycle length= 28 days for Schedule A, B&D;21 days for Schedule C)
Population: PK Analysis Set; Overall number analyzed: participants with data available for analysis.Number analyzed: participants with data available during specified time-point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Dose Escalation) Schedule B | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 15 | 0.162 per hour (1/hour) | Geometric Coefficient of Variation 4.3 |
| Part 1 (Dose Escalation) Schedule C | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 2 Day 1 | 0.197 per hour (1/hour) | Geometric Coefficient of Variation 12.7 |
| Part 1 (Dose Escalation) Schedule C | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 1 | 0.309 per hour (1/hour) | — |
| Part 1 (Dose Escalation) Schedule C | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 15 | 0.207 per hour (1/hour) | Geometric Coefficient of Variation 34.6 |
| Part 1 (Dose Escalation) Schedule D | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 15 | 10.0852 per hour (1/hour) | Geometric Coefficient of Variation 20.6 |
| Part 1 (Dose Escalation) Schedule D | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 1 | 0.0933 per hour (1/hour) | Geometric Coefficient of Variation 26.2 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 15 | 0.115 per hour (1/hour) | — |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 1 | 0.294 per hour (1/hour) | Geometric Coefficient of Variation 3.1 |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 15 | 0.179 per hour (1/hour) | Geometric Coefficient of Variation 59.7 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 2 Day 1 | 0.0907 per hour (1/hour) | — |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 1 | 0.265 per hour (1/hour) | — |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 2 Day 1 | 0.0528 per hour (1/hour) | Geometric Coefficient of Variation 10.1 |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 1 | 0.0924 per hour (1/hour) | Geometric Coefficient of Variation 0.5 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 1 | 0.107 per hour (1/hour) | Geometric Coefficient of Variation 88.7 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 2 Day 1 | 0.0828 per hour (1/hour) | Geometric Coefficient of Variation 14.6 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 1 | 0.113 per hour (1/hour) | Geometric Coefficient of Variation 117.8 |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Part 1: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 2 Day 1 | 0.0961 per hour (1/hour) | — |
Secondary
Part 2: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa
Time frame: Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D)
Population: The PK Analysis Set included participants from the SAS who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis during the specified time-point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 2: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 1 | 24900 h*ng/mL | Geometric Coefficient of Variation 77.1 |
| Part 1 (Dose Escalation) Schedule A | Part 2: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 2 Day 1 | 37200 h*ng/mL | Geometric Coefficient of Variation 35.4 |
| Part 1 (Dose Escalation) Schedule B | Part 2: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 2 Day 1 | 43700 h*ng/mL | Geometric Coefficient of Variation 118.5 |
| Part 1 (Dose Escalation) Schedule B | Part 2: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 1 | 42700 h*ng/mL | Geometric Coefficient of Variation 19.2 |
| Part 1 (Dose Escalation) Schedule C | Part 2: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 1 | 1020000 h*ng/mL | Geometric Coefficient of Variation 89.1 |
| Part 1 (Dose Escalation) Schedule C | Part 2: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 2 Day 1 | 1520000 h*ng/mL | Geometric Coefficient of Variation 60.7 |
| Part 1 (Dose Escalation) Schedule D | Part 2: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 1 Day 1 | 1280000 h*ng/mL | Geometric Coefficient of Variation 70.4 |
| Part 1 (Dose Escalation) Schedule D | Part 2: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa | Cycle 2 Day 1 | 2070000 h*ng/mL | Geometric Coefficient of Variation 33.9 |
Secondary
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: Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D)
Population: The PK Analysis Set included participants from the SAS who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis during the specified time-point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 2: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 40800 h*ng/mL | Geometric Coefficient of Variation 93.6 |
| Part 1 (Dose Escalation) Schedule A | Part 2: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 42300 h*ng/mL | Geometric Coefficient of Variation 64.8 |
| Part 1 (Dose Escalation) Schedule B | Part 2: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 45600 h*ng/mL | Geometric Coefficient of Variation 74.7 |
| Part 1 (Dose Escalation) Schedule B | Part 2: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 34600 h*ng/mL | Geometric Coefficient of Variation 40 |
| Part 1 (Dose Escalation) Schedule C | Part 2: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 975000 h*ng/mL | Geometric Coefficient of Variation 90.8 |
| Part 1 (Dose Escalation) Schedule C | Part 2: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 1510000 h*ng/mL | Geometric Coefficient of Variation 62.5 |
| Part 1 (Dose Escalation) Schedule D | Part 2: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 1280000 h*ng/mL | Geometric Coefficient of Variation 70.4 |
| Part 1 (Dose Escalation) Schedule D | Part 2: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 1650000 h*ng/mL | Geometric Coefficient of Variation 56.3 |
Secondary
Part 2: CL: Clearance for Modakafusp Alfa
Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL = dose/AUC.
Time frame: Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D)
Population: The PK Analysis Set included participants from the SAS who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. Overall number of participants analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis during the specified time-point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 2: CL: Clearance for Modakafusp Alfa | Cycle 2 Day 1 | 0.0107 L/h/kg | Geometric Coefficient of Variation 35.6 |
| Part 1 (Dose Escalation) Schedule A | Part 2: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 1 | 0.0160 L/h/kg | Geometric Coefficient of Variation 77.4 |
| Part 1 (Dose Escalation) Schedule B | Part 2: CL: Clearance for Modakafusp Alfa | Cycle 2 Day 1 | 0.00912 L/h/kg | Geometric Coefficient of Variation 118.7 |
| Part 1 (Dose Escalation) Schedule B | Part 2: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 1 | 0.00937 L/h/kg | Geometric Coefficient of Variation 19 |
| Part 1 (Dose Escalation) Schedule C | Part 2: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 1 | 0.00147 L/h/kg | Geometric Coefficient of Variation 89.9 |
| Part 1 (Dose Escalation) Schedule C | Part 2: CL: Clearance for Modakafusp Alfa | Cycle 2 Day 1 | 0.000995 L/h/kg | Geometric Coefficient of Variation 61.2 |
| Part 1 (Dose Escalation) Schedule D | Part 2: CL: Clearance for Modakafusp Alfa | Cycle 1 Day 1 | 0.00119 L/h/kg | Geometric Coefficient of Variation 67.9 |
| Part 1 (Dose Escalation) Schedule D | Part 2: CL: Clearance for Modakafusp Alfa | Cycle 2 Day 1 | 0.000737 L/h/kg | Geometric Coefficient of Variation 36.5 |
Secondary
Part 2: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa
Time frame: Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D)
Population: The PK Analysis Set included participants from the SAS who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis during the specified time-point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 2: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 3540 ng/mL | Geometric Coefficient of Variation 83.7 |
| Part 1 (Dose Escalation) Schedule A | Part 2: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 3450 ng/mL | Geometric Coefficient of Variation 51.2 |
| Part 1 (Dose Escalation) Schedule B | Part 2: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 3870 ng/mL | Geometric Coefficient of Variation 26.6 |
| Part 1 (Dose Escalation) Schedule B | Part 2: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 4330 ng/mL | Geometric Coefficient of Variation 23.7 |
| Part 1 (Dose Escalation) Schedule C | Part 2: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 32100 ng/mL | Geometric Coefficient of Variation 25.4 |
| Part 1 (Dose Escalation) Schedule C | Part 2: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 34200 ng/mL | Geometric Coefficient of Variation 24.6 |
| Part 1 (Dose Escalation) Schedule D | Part 2: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 1 Day 1 | 35700 ng/mL | Geometric Coefficient of Variation 20 |
| Part 1 (Dose Escalation) Schedule D | Part 2: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa | Cycle 2 Day 1 | 36100 ng/mL | Geometric Coefficient of Variation 25.6 |
Secondary
Part 2: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa
Time frame: Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D)
Population: The PK Analysis Set included participants from the SAS who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. Overall number of participants analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis during the specified time-point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 2: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 1 | 6.08 hours | Geometric Coefficient of Variation 67 |
| Part 1 (Dose Escalation) Schedule A | Part 2: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 2 Day 1 | 5.46 hours | Geometric Coefficient of Variation 80.1 |
| Part 1 (Dose Escalation) Schedule B | Part 2: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 2 Day 1 | 4.07 hours | Geometric Coefficient of Variation 64 |
| Part 1 (Dose Escalation) Schedule B | Part 2: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 1 | 6.22 hours | Geometric Coefficient of Variation 31 |
| Part 1 (Dose Escalation) Schedule C | Part 2: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 1 | 14.5 hours | Geometric Coefficient of Variation 63.6 |
| Part 1 (Dose Escalation) Schedule C | Part 2: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 2 Day 1 | 18.2 hours | Geometric Coefficient of Variation 36.9 |
| Part 1 (Dose Escalation) Schedule D | Part 2: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 1 Day 1 | 14.8 hours | Geometric Coefficient of Variation 62.8 |
| Part 1 (Dose Escalation) Schedule D | Part 2: T1/2z: Terminal Elimination Phase Half-life for Modakafusp Alfa | Cycle 2 Day 1 | 25.1 hours | Geometric Coefficient of Variation 54.2 |
Secondary
Part 2: Tmax: Time to Reach the Cmax for Modakafusp Alfa
Time frame: Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D)
Population: The PK Analysis Set included participants from the SAS who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. Overall number of participants analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis during the specified time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 2: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 1 | 5.70 hours |
| Part 1 (Dose Escalation) Schedule A | Part 2: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 2 Day 1 | 5.68 hours |
| Part 1 (Dose Escalation) Schedule B | Part 2: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 2 Day 1 | 3.30 hours |
| Part 1 (Dose Escalation) Schedule B | Part 2: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 1 | 3.27 hours |
| Part 1 (Dose Escalation) Schedule C | Part 2: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 1 | 1.18 hours |
| Part 1 (Dose Escalation) Schedule C | Part 2: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 2 Day 1 | 1.29 hours |
| Part 1 (Dose Escalation) Schedule D | Part 2: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 1 Day 1 | 1.68 hours |
| Part 1 (Dose Escalation) Schedule D | Part 2: Tmax: Time to Reach the Cmax for Modakafusp Alfa | Cycle 2 Day 1 | 1.63 hours |
Secondary
Part 2: Vss: Volume of Distribution at Steady State for Modakafusp Alfa
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. V(ss) = (dose/AUC)\*MRT, where MRT is mean residence time.
Time frame: Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D)
Population: The PK Analysis Set included participants from the SAS who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis during the specified time-point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 2: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 1 | 0.114 L/kg | Geometric Coefficient of Variation 32.8 |
| Part 1 (Dose Escalation) Schedule A | Part 2: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 2 Day 1 | 0.0779 L/kg | Geometric Coefficient of Variation 32.2 |
| Part 1 (Dose Escalation) Schedule B | Part 2: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 2 Day 1 | 0.0501 L/kg | Geometric Coefficient of Variation 41.8 |
| Part 1 (Dose Escalation) Schedule B | Part 2: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 1 | 0.0646 L/kg | Geometric Coefficient of Variation 4.7 |
| Part 1 (Dose Escalation) Schedule C | Part 2: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 1 | 0.0260 L/kg | Geometric Coefficient of Variation 67.6 |
| Part 1 (Dose Escalation) Schedule C | Part 2: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 2 Day 1 | 0.0289 L/kg | Geometric Coefficient of Variation 39.6 |
| Part 1 (Dose Escalation) Schedule D | Part 2: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 1 Day 1 | 0.0276 L/kg | Geometric Coefficient of Variation 16.7 |
| Part 1 (Dose Escalation) Schedule D | Part 2: Vss: Volume of Distribution at Steady State for Modakafusp Alfa | Cycle 2 Day 1 | 0.0260 L/kg | Geometric Coefficient of Variation 13.7 |
Secondary
Part 2: λz: Terminal Disposition Rate Constant for Modakafusp Alfa
Time frame: Schedule C and D: Pre-infusion and at multiple times post-infusion on Day 1 of Cycles 1 and 2: (cycle length was 21 days for Schedule C and 28 days for Schedule D)
Population: The PK Analysis Set included participants from the SAS who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. Overall number of participants analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis during the specified time-point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 2: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 1 | 0.114 1/h | Geometric Coefficient of Variation 67 |
| Part 1 (Dose Escalation) Schedule A | Part 2: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 2 Day 1 | 0.127 1/h | Geometric Coefficient of Variation 80.1 |
| Part 1 (Dose Escalation) Schedule B | Part 2: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 2 Day 1 | 0.171 1/h | Geometric Coefficient of Variation 64 |
| Part 1 (Dose Escalation) Schedule B | Part 2: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 1 | 0.111 1/h | Geometric Coefficient of Variation 31 |
| Part 1 (Dose Escalation) Schedule C | Part 2: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 1 | 0.0478 1/h | Geometric Coefficient of Variation 63.6 |
| Part 1 (Dose Escalation) Schedule C | Part 2: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 2 Day 1 | 0.0381 1/h | Geometric Coefficient of Variation 36.9 |
| Part 1 (Dose Escalation) Schedule D | Part 2: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 1 Day 1 | 0.0468 1/h | Geometric Coefficient of Variation 62.8 |
| Part 1 (Dose Escalation) Schedule D | Part 2: λz: Terminal Disposition Rate Constant for Modakafusp Alfa | Cycle 2 Day 1 | 0.0276 1/h | Geometric Coefficient of Variation 54.4 |
Secondary
Part 3: Clinical Benefit Rate (CBR) by IRC and Investigator Assessment
The CBR was defined as the percentage of participants with a confirmed response of sCR, CR, VGPR, PR, or minimal response (MR) during the study per investigator assessment as defined by IMWG Uniform Response Criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. MR: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. Percentages were rounded off to the nearest decimal.
Time frame: Up to 20.5 months in Part 3
Population: The FAS included all participants who received at least 1 dose, even an incomplete dose, of modakafusp alfa, in the Part 3 extension cohorts.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 3: Clinical Benefit Rate (CBR) by IRC and Investigator Assessment | 38.0 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Clinical Benefit Rate (CBR) by IRC and Investigator Assessment | 48.0 percentage of participants |
Secondary
Part 3: Disease Control Rate (DCR) by IRC and Investigator Assessment
The DCR was defined as the proportion of participants with a confirmed response of sCR, CR, VGPR, PR, MR, or stable disease (SD) during the study per investigator assessment as defined by IMWG Uniform Response Criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. MR: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. SD: no known evidence of progressive or new bone lesions if radiographic studies were performed. Percentages were rounded off to the nearest decimal.
Time frame: Up to 20.5 months in Part 3
Population: The FAS included all participants who received at least 1 dose, even an incomplete dose, of modakafusp alfa, in the Part 3 extension cohorts.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 3: Disease Control Rate (DCR) by IRC and Investigator Assessment | 74.6 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Disease Control Rate (DCR) by IRC and Investigator Assessment | 68.0 percentage of participants |
Secondary
Part 3: Duration of Clinical Benefit
Duration of clinical benefit was 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 participants who achieve a confirmed MR or better. MR: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. Per IMWG criteria, PD: serum M-component increase ≥0.5 g/dl or urine M-component increase ≥ 200 mg/24-hour/ difference between involved and uninvolved FLC levels increase \>10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia.
Time frame: Up to 20.5 months in Part 3
Population: The FAS included all participants who received at least 1 dose, even an incomplete dose, of modakafusp alfa, in the Part 3 extension cohorts. Overall number of participants analyzed is the number of participants with events. Participants with no post baseline response assessment were censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 3: Duration of Clinical Benefit | NA months |
| Part 1 (Dose Escalation) Schedule B | Part 3: Duration of Clinical Benefit | 9.2 months |
Secondary
Part 3: Duration of Disease Control
Duration of disease control was 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 participants who achieved a SD or better. SD: no known evidence of progressive or new bone lesions if radiographic studies were performed. Per IMWG criteria, PD: serum M-component increase ≥0.5 g/dl or urine M-component increase ≥200 mg/24-hour/ difference between involved and uninvolved FLC levels increase \>10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia.
Time frame: Up to 20.5 months in Part 3
Population: The FAS included all participants who received at least 1 dose, even an incomplete dose, of modakafusp alfa, in the Part 3 extension cohorts. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 3: Duration of Disease Control | 6.5 months |
| Part 1 (Dose Escalation) Schedule B | Part 3: Duration of Disease Control | 5.6 months |
Secondary
Part 3: Duration of MRD Negativity Status at a Sensitivity of 10^-5 in Participants Achieving CR
Duration of MRD negativity (10\^-5) was 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.
Time frame: Up to 20.5 months in Part 3
Population: The ITT Analysis Set included all randomized participants regardless of whether they received study drug or adhered to the assigned dose. Overall number of participants analyzed is the number of participants from ITT analysis set who achieved CR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 3: Duration of MRD Negativity Status at a Sensitivity of 10^-5 in Participants Achieving CR | NA months |
| Part 1 (Dose Escalation) Schedule B | Part 3: Duration of MRD Negativity Status at a Sensitivity of 10^-5 in Participants Achieving CR | NA months |
Secondary
Part 3: Health Care Utilization: Length of Hospital Stays
Time frame: Up to 20.5 months in Part 3
Population: The FAS included all participants who received at least 1 dose, even an incomplete dose, of modakafusp alfa, in the Part 3 extension cohorts. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 3: Health Care Utilization: Length of Hospital Stays | 14 days |
| Part 1 (Dose Escalation) Schedule B | Part 3: Health Care Utilization: Length of Hospital Stays | 11 days |
Secondary
Part 3: Health Care Utilization: Number of Participants With at Least One Medical Encounter
Medical encounters included hospitalizations, emergency room stays, or outpatient visits.
Time frame: Up to 20.5 months in Part 3
Population: The FAS included all participants who received at least 1 dose, even an incomplete dose, of modakafusp alfa, in the Part 3 extension cohorts. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 3: Health Care Utilization: Number of Participants With at Least One Medical Encounter | Hospitalizations | 29 Participants |
| Part 1 (Dose Escalation) Schedule A | Part 3: Health Care Utilization: Number of Participants With at Least One Medical Encounter | Emergency Room Stays | 7 Participants |
| Part 1 (Dose Escalation) Schedule A | Part 3: Health Care Utilization: Number of Participants With at Least One Medical Encounter | All Outpatient Visits | 10 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Health Care Utilization: Number of Participants With at Least One Medical Encounter | Hospitalizations | 31 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Health Care Utilization: Number of Participants With at Least One Medical Encounter | Emergency Room Stays | 8 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Health Care Utilization: Number of Participants With at Least One Medical Encounter | All Outpatient Visits | 18 Participants |
Secondary
Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status
ECOG performance status was measured at baseline and over time. ECOG performance status was measured on a 6 point scale: 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. Reported here is the baseline status and the worst post-baseline status measured. A decrease in grade from baseline indicates an improvement. Only categories for which there was at least 1 participant are reported.
Time frame: Up to 20.5 months in Part 3
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 0; Worst Post-baseline: 0 | 11 Participants |
| Part 1 (Dose Escalation) Schedule A | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 0; Worst Post-baseline: 1 | 5 Participants |
| Part 1 (Dose Escalation) Schedule A | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 0; Worst Post-baseline: 2 | 2 Participants |
| Part 1 (Dose Escalation) Schedule A | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 0; Worst Post-baseline: 3 | 0 Participants |
| Part 1 (Dose Escalation) Schedule A | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 1; Worst Post-baseline: 0 | 1 Participants |
| Part 1 (Dose Escalation) Schedule A | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 1; Worst Post-baseline: 1 | 31 Participants |
| Part 1 (Dose Escalation) Schedule A | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 1; Worst Post-baseline: 2 | 6 Participants |
| Part 1 (Dose Escalation) Schedule A | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 1; Worst Post-baseline: 3 | 3 Participants |
| Part 1 (Dose Escalation) Schedule A | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 1; Worst Post-baseline: 4 | 1 Participants |
| Part 1 (Dose Escalation) Schedule A | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 2; Worst Post-baseline: 2 | 6 Participants |
| Part 1 (Dose Escalation) Schedule A | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 2; Worst Post-baseline: 3 | 1 Participants |
| Part 1 (Dose Escalation) Schedule A | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 2; Worst Post-baseline: 4 | 1 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 2; Worst Post-baseline: 3 | 1 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 0; Worst Post-baseline: 0 | 6 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 1; Worst Post-baseline: 2 | 12 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 0; Worst Post-baseline: 1 | 12 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 2; Worst Post-baseline: 2 | 4 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 0; Worst Post-baseline: 2 | 1 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 1; Worst Post-baseline: 3 | 1 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 0; Worst Post-baseline: 3 | 1 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 2; Worst Post-baseline: 4 | 0 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 1; Worst Post-baseline: 0 | 0 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 1; Worst Post-baseline: 4 | 0 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Number of Participants at Baseline and at Worst Post-baseline Status as Categorized by Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline: 1; Worst Post-baseline: 1 | 25 Participants |
Secondary
Part 3: Objective Response Rate (ORR) by Investigator Assessment
ORR was defined as the percentage of participants who achieved a PR rate or better (sCR + CR + VGPR + PR) during the study as defined by IMWG uniform response criteria. PR :≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR:negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR:serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. Percentages were rounded off to the nearest decimal.
Time frame: Up to 20.5 months in Part 3
Population: The FAS included all participants who received at least 1 dose, even an incomplete dose, of modakafusp alfa, in the Part 3 extension cohorts.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 3: Objective Response Rate (ORR) by Investigator Assessment | 32.4 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Objective Response Rate (ORR) by Investigator Assessment | 41.3 percentage of participants |
Secondary
Part 3: Patient-reported Outcome (PRO): Change From Baseline to Cycle 9 in Instrument European Organisation for Research and Treatment of Cancer QLQ Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20)
EORTC QLQ-MY20 is a myeloma-specific module developed by the EORTC group specifically to assess quality of life in participants with multiple myeloma. It contains 20 items which can be grouped into a disease symptom subscale (6 items), side effects of treatment subscale (10 items), body image (1 item) and future perspective subscale (3 items). All transformed scale scores range from 0 to 100 with higher scores indicating worse symptoms (Disease Symptoms and Side Effects of Treatment) or better support/functioning (Future Perspective and Body Image).
Time frame: Baseline, Cycle 9 Day 8 [cycle length was 28 days] (up to 7.7 months)
Population: The PRO Analysis Set included all participants with a baseline and at least one post-baseline measurement of any PRO measure (EORTC QLQ-MY20 or EQ-5D-5L). Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 3: Patient-reported Outcome (PRO): Change From Baseline to Cycle 9 in Instrument European Organisation for Research and Treatment of Cancer QLQ Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20) | Disease Symptoms | -7.9 score on a scale | Standard Deviation 22.63 |
| Part 1 (Dose Escalation) Schedule A | Part 3: Patient-reported Outcome (PRO): Change From Baseline to Cycle 9 in Instrument European Organisation for Research and Treatment of Cancer QLQ Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20) | Side Effects of Treatment | 4.7 score on a scale | Standard Deviation 11.62 |
| Part 1 (Dose Escalation) Schedule A | Part 3: Patient-reported Outcome (PRO): Change From Baseline to Cycle 9 in Instrument European Organisation for Research and Treatment of Cancer QLQ Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20) | Body Image | 4.8 score on a scale | Standard Deviation 35.63 |
| Part 1 (Dose Escalation) Schedule A | Part 3: Patient-reported Outcome (PRO): Change From Baseline to Cycle 9 in Instrument European Organisation for Research and Treatment of Cancer QLQ Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20) | Future Perspective | 11.1 score on a scale | Standard Deviation 9.06 |
| Part 1 (Dose Escalation) Schedule B | Part 3: Patient-reported Outcome (PRO): Change From Baseline to Cycle 9 in Instrument European Organisation for Research and Treatment of Cancer QLQ Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20) | Future Perspective | 7.4 score on a scale | Standard Deviation 34.92 |
| Part 1 (Dose Escalation) Schedule B | Part 3: Patient-reported Outcome (PRO): Change From Baseline to Cycle 9 in Instrument European Organisation for Research and Treatment of Cancer QLQ Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20) | Disease Symptoms | -7.4 score on a scale | Standard Deviation 10.93 |
| Part 1 (Dose Escalation) Schedule B | Part 3: Patient-reported Outcome (PRO): Change From Baseline to Cycle 9 in Instrument European Organisation for Research and Treatment of Cancer QLQ Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20) | Body Image | 0.0 score on a scale | Standard Deviation 21.06 |
| Part 1 (Dose Escalation) Schedule B | Part 3: Patient-reported Outcome (PRO): Change From Baseline to Cycle 9 in Instrument European Organisation for Research and Treatment of Cancer QLQ Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20) | Side Effects of Treatment | 7.0 score on a scale | Standard Deviation 5.45 |
Secondary
Part 3: Percentage of Participants With Clinically Significant Laboratory Values
Laboratory values included hematology, chemistry, and urinalysis as interpreted by the investigator.
Time frame: Up to 20.5 months in Part 3
Population: FAS:all participants who took ≥1 dose,even if incomplete,of TAK-573 in Part 3 extension cohorts.However,clinically significant laboratory values data were not collected\&will never be available to present due to issue with report form used for data collection(identified after trial completion).Assessments of clinical significance were not included in report form,making data collection impossible.This issue did not impact participant safety/reliability of study data,particularly primary endpoint.
Secondary
Part 3: Percentage of Participants With Neutralizing Antibodies (NAb) at Any Scheduled and Unscheduled Post-Baseline Visit
Percentages were rounded off to the nearest decimal.
Time frame: Up to 20.5 months in Part 3
Population: Immunogenicity-Evaluable Set Analysis included participants with a baseline assessment and at least 1 post-baseline immunogenicity assessment. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 3: Percentage of Participants With Neutralizing Antibodies (NAb) at Any Scheduled and Unscheduled Post-Baseline Visit | 47.7 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Percentage of Participants With Neutralizing Antibodies (NAb) at Any Scheduled and Unscheduled Post-Baseline Visit | 44.6 percentage of participants |
Secondary
Part 3: Percentage of Participants With Serious Treatment-emergent Adverse Events (Serious TEAEs)
AE: any untoward medical occurrence in participants administered pharmaceutical product; untoward medical occurrence does not necessarily have causal relationship with this treatment. AE can therefore be any unfavorable & unintended sign (including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal (investigational) product whether or not it is related to medicinal product. TEAE: any AE either reported for first time or worsening of pre-existing event after first dose of study drug & within 30 days of last administration of study drug. Serious TEAEs: 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 a medically important event. Percentages were rounded off to the nearest decimal.
Time frame: Up to 20.5 months in Part 3
Population: The FAS included all participants who received at least 1 dose, even an incomplete dose, of modakafusp alfa, in the Part 3 extension cohorts.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 3: Percentage of Participants With Serious Treatment-emergent Adverse Events (Serious TEAEs) | 39.4 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Percentage of Participants With Serious Treatment-emergent Adverse Events (Serious TEAEs) | 44.0 percentage of participants |
Secondary
Part 3: Percentage of Participants With Treatment -Emergent Adverse Events (TEAEs)
An 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. 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. Percentages were rounded off to the nearest decimal.
Time frame: Up to 20.5 months in Part 3
Population: The FAS included all participants who received at least 1 dose, even an incomplete dose, of modakafusp alfa, in the Part 3 extension cohorts.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 3: Percentage of Participants With Treatment -Emergent Adverse Events (TEAEs) | 98.6 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Percentage of Participants With Treatment -Emergent Adverse Events (TEAEs) | 100 percentage of participants |
Secondary
Part 3: Rate of Minimal Residual Disease (MRD) Negativity Status at a Sensitivity of 10^-5 in Participants Achieving CR
MRD negativity rate at a sensitivity of 10\^-5 was defined as participants who were MRD negative at a sensitivity of 10\^-5 in participants achieving suspected complete response (CR). CR was 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 was required.
Time frame: Up to 20.5 months in Part 3
Population: The Intent-to-Treat (ITT) Analysis Set included all randomized participants regardless of whether they received study drug or adhered to the assigned dose. Overall number of participants analyzed is the number of participants from ITT analysis set who achieved CR.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 3: Rate of Minimal Residual Disease (MRD) Negativity Status at a Sensitivity of 10^-5 in Participants Achieving CR | 1 Participants |
| Part 1 (Dose Escalation) Schedule B | Part 3: Rate of Minimal Residual Disease (MRD) Negativity Status at a Sensitivity of 10^-5 in Participants Achieving CR | 1 Participants |
Secondary
Part 3: Time to Progression (TTP) by IRC and Investigator Assessment
TTP was 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. Per IMWG criteria, PD: serum M-component increase ≥0.5 g/dl or urine M-component increase ≥200 mg/24-hour/ difference between involved and uninvolved FLC levels increase \>10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia.
Time frame: Up to 20.5 months in Part 3
Population: The FAS included all participants who received at least 1 dose, even an incomplete dose, of modakafusp alfa, in the Part 3 extension cohorts. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Part 3: Time to Progression (TTP) by IRC and Investigator Assessment | 4.7 months |
| Part 1 (Dose Escalation) Schedule B | Part 3: Time to Progression (TTP) by IRC and Investigator Assessment | 5.5 months |
Secondary
Parts 1, 2, and 3: Duration of Response (DOR)
DOR was defined as the time from the date of first documentation of response PR or better (sCR + CR + VGPR + PR) to the time of disease progression or death, whichever occurs first. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours.
Time frame: Up to 54.3 months in Part 1; Up to 34.7 months in Part 2; Up to 20.5 months in Part 3
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Parts 1, 2, and 3: Duration of Response (DOR) | 2.1 months |
| Part 1 (Dose Escalation) Schedule D | Parts 1, 2, and 3: Duration of Response (DOR) | 7.4 months |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Parts 1, 2, and 3: Duration of Response (DOR) | 24.4 months |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Parts 1, 2, and 3: Duration of Response (DOR) | 10.3 months |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Parts 1, 2, and 3: Duration of Response (DOR) | NA months |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Parts 1, 2, and 3: Duration of Response (DOR) | 9.2 months |
Secondary
Parts 1, 2 and 3: Percentage of Participants With Positive Anti-drug Antibody (ADA) at Any Scheduled and Unscheduled Post-Baseline Visit
ADA samples scoring equal to or above the cut-point (titer of 75) were defined as ADA positive. Percentages were rounded off to the nearest decimal.
Time frame: Up to 54.3 months in Part 1; Up to 34.7 months in Part 2; Up to 20.5 months in Part 3
Population: The Immunogenicity-evaluable Analysis Set included participants from the SAS with a baseline assessment and at least 1 postbaseline immunogenicity assessment. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Parts 1, 2 and 3: Percentage of Participants With Positive Anti-drug Antibody (ADA) at Any Scheduled and Unscheduled Post-Baseline Visit | 41.2 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Parts 1, 2 and 3: Percentage of Participants With Positive Anti-drug Antibody (ADA) at Any Scheduled and Unscheduled Post-Baseline Visit | 83.3 percentage of participants |
| Part 1 (Dose Escalation) Schedule C | Parts 1, 2 and 3: Percentage of Participants With Positive Anti-drug Antibody (ADA) at Any Scheduled and Unscheduled Post-Baseline Visit | 83.3 percentage of participants |
| Part 1 (Dose Escalation) Schedule D | Parts 1, 2 and 3: Percentage of Participants With Positive Anti-drug Antibody (ADA) at Any Scheduled and Unscheduled Post-Baseline Visit | 66.7 percentage of participants |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Parts 1, 2 and 3: Percentage of Participants With Positive Anti-drug Antibody (ADA) at Any Scheduled and Unscheduled Post-Baseline Visit | 57.1 percentage of participants |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Parts 1, 2 and 3: Percentage of Participants With Positive Anti-drug Antibody (ADA) at Any Scheduled and Unscheduled Post-Baseline Visit | 66.7 percentage of participants |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Parts 1, 2 and 3: Percentage of Participants With Positive Anti-drug Antibody (ADA) at Any Scheduled and Unscheduled Post-Baseline Visit | 61.9 percentage of participants |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Parts 1, 2 and 3: Percentage of Participants With Positive Anti-drug Antibody (ADA) at Any Scheduled and Unscheduled Post-Baseline Visit | 14.3 percentage of participants |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Parts 1, 2 and 3: Percentage of Participants With Positive Anti-drug Antibody (ADA) at Any Scheduled and Unscheduled Post-Baseline Visit | 52.3 percentage of participants |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Parts 1, 2 and 3: Percentage of Participants With Positive Anti-drug Antibody (ADA) at Any Scheduled and Unscheduled Post-Baseline Visit | 61.5 percentage of participants |
Secondary
Parts 1, 2, and 3: Progression Free Survival (PFS)
PFS was defined as the time from the date of enrollment until the date of progressive disease (PD) or death due to any cause, whichever occurs first as defined by IMWG Criteria. Per IMWG criteria, PD: serum M-component increase ≥0.5 g/dl or urine M-component increase ≥ 200 mg/24-hour/ difference between involved and uninvolved FLC levels increase \>10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia.
Time frame: Up to 54.3 months in Part 1; Up to 34.7 months in Part 2; Up to 20.5 months in Part 3
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573. The FAS included all participants who received at least 1 dose, even an incomplete dose, of modakafusp alfa, in the Part 3 extension cohorts. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Parts 1, 2, and 3: Progression Free Survival (PFS) | 2.6 months |
| Part 1 (Dose Escalation) Schedule B | Parts 1, 2, and 3: Progression Free Survival (PFS) | 1.5 months |
| Part 1 (Dose Escalation) Schedule C | Parts 1, 2, and 3: Progression Free Survival (PFS) | 1.4 months |
| Part 1 (Dose Escalation) Schedule D | Parts 1, 2, and 3: Progression Free Survival (PFS) | 3.6 months |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Parts 1, 2, and 3: Progression Free Survival (PFS) | 1.1 months |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Parts 1, 2, and 3: Progression Free Survival (PFS) | 1.4 months |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Parts 1, 2, and 3: Progression Free Survival (PFS) | 8.0 months |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Parts 1, 2, and 3: Progression Free Survival (PFS) | 3.4 months |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 0.75 mg/kg | Parts 1, 2, and 3: Progression Free Survival (PFS) | 4.1 months |
| Part 1 (Dose Escalation) Schedule D: Modakafusp Alfa 1.5 mg/kg | Parts 1, 2, and 3: Progression Free Survival (PFS) | 5.3 months |
Secondary
Parts 1 and 2: Clinical Benefit Rate (CBR)
The CBR was defined as the percentage of participants with a confirmed response of sCR, CR, VGPR, PR, or minimal response (MR) during the study per investigator assessment as defined by IMWG Uniform Response Criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. MR: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. Percentages were rounded off to the nearest decimal.
Time frame: Up to 54.3 months in Part 1; Up to 34.7 months in Part 2
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573 and with measurable disease at baseline. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Parts 1 and 2: Clinical Benefit Rate (CBR) | 15.8 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Parts 1 and 2: Clinical Benefit Rate (CBR) | 0 percentage of participants |
| Part 1 (Dose Escalation) Schedule C | Parts 1 and 2: Clinical Benefit Rate (CBR) | 0 percentage of participants |
| Part 1 (Dose Escalation) Schedule D | Parts 1 and 2: Clinical Benefit Rate (CBR) | 38.1 percentage of participants |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Parts 1 and 2: Clinical Benefit Rate (CBR) | 0 percentage of participants |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Parts 1 and 2: Clinical Benefit Rate (CBR) | 0 percentage of participants |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Parts 1 and 2: Clinical Benefit Rate (CBR) | 52.0 percentage of participants |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Parts 1 and 2: Clinical Benefit Rate (CBR) | 32.0 percentage of participants |
Secondary
Parts 1 and 2: Disease Control Rate (DCR)
The DCR was defined as the proportion of participants with a confirmed response of sCR, CR, VGPR, PR, MR, or stable disease (SD) during the study per investigator assessment as defined by IMWG Uniform Response Criteria. PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours. MR: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. SD: no known evidence of progressive or new bone lesions if radiographic studies were performed. Percentages were rounded off to the nearest decimal.
Time frame: Up to 54.3 months in Part 1; Up to 34.7 months in Part 2
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573 and with measurable disease at baseline. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Parts 1 and 2: Disease Control Rate (DCR) | 57.9 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Parts 1 and 2: Disease Control Rate (DCR) | 37.5 percentage of participants |
| Part 1 (Dose Escalation) Schedule C | Parts 1 and 2: Disease Control Rate (DCR) | 42.9 percentage of participants |
| Part 1 (Dose Escalation) Schedule D | Parts 1 and 2: Disease Control Rate (DCR) | 61.9 percentage of participants |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Parts 1 and 2: Disease Control Rate (DCR) | 62.5 percentage of participants |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Parts 1 and 2: Disease Control Rate (DCR) | 66.7 percentage of participants |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Parts 1 and 2: Disease Control Rate (DCR) | 64.0 percentage of participants |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Parts 1 and 2: Disease Control Rate (DCR) | 68.0 percentage of participants |
Secondary
Parts 1 and 2: Percentage of Participants With Dose-limiting Toxicities (DLTs)- Like Events
Percentage of participants with TEAEs meeting DLT definition were reported. Toxicity was 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 are 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 Cycle 2 were considered a DLT. Percentages were rounded off to the nearest decimal.
Time frame: Up to 54.3 months in Part 1; Up to 34.7 months in Part 2
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Parts 1 and 2: Percentage of Participants With Dose-limiting Toxicities (DLTs)- Like Events | 10 percentage of participants |
| Part 1 (Dose Escalation) Schedule B | Parts 1 and 2: Percentage of Participants With Dose-limiting Toxicities (DLTs)- Like Events | 0 percentage of participants |
| Part 1 (Dose Escalation) Schedule C | Parts 1 and 2: Percentage of Participants With Dose-limiting Toxicities (DLTs)- Like Events | 0 percentage of participants |
| Part 1 (Dose Escalation) Schedule D | Parts 1 and 2: Percentage of Participants With Dose-limiting Toxicities (DLTs)- Like Events | 9.5 percentage of participants |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Parts 1 and 2: Percentage of Participants With Dose-limiting Toxicities (DLTs)- Like Events | 12.5 percentage of participants |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Parts 1 and 2: Percentage of Participants With Dose-limiting Toxicities (DLTs)- Like Events | 66.7 percentage of participants |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Parts 1 and 2: Percentage of Participants With Dose-limiting Toxicities (DLTs)- Like Events | 24 percentage of participants |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Parts 1 and 2: Percentage of Participants With Dose-limiting Toxicities (DLTs)- Like Events | 25 percentage of participants |
Secondary
Parts 1 and 2: Time to Response
Time to response was defined as the time from first dose to the date of first documentation of response (PR or better \[sCR + CR + VGPR + PR\]) PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. CR: negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow. sCR: CR+normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein \<100 mg/24 hours.
Time frame: Up to 54.3 months in Part 1; Up to 34.7 months in Part 2
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Parts 1 and 2: Time to Response | 1.15 months |
| Part 1 (Dose Escalation) Schedule D | Parts 1 and 2: Time to Response | 1.87 months |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa | Parts 1 and 2: Time to Response | 1.07 months |
| Part 2 (Dose Expansion): Schedule D: Modakafusp Alfa + Dexamethasone | Parts 1 and 2: Time to Response | 1.08 months |
Secondary
Parts 2 and 3: Overall Survival (OS)
The OS was defined as the time from the date of first dose to the date of death due to any cause.
Time frame: Up to 34.7 months in Part 2; Up to 20.5 months in Part 3
Population: The SAS included all enrolled participants who received at least 1 dose, even if incomplete, of TAK-573. The FAS included all participants who received at least 1 dose, even an incomplete dose, of modakafusp alfa, in the Part 3 extension cohorts. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (Dose Escalation) Schedule A | Parts 2 and 3: Overall Survival (OS) | NA months |
| Part 1 (Dose Escalation) Schedule B | Parts 2 and 3: Overall Survival (OS) | NA months |
| Part 1 (Dose Escalation) Schedule C | Parts 2 and 3: Overall Survival (OS) | NA months |
| Part 1 (Dose Escalation) Schedule D | Parts 2 and 3: Overall Survival (OS) | 3.4 months |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa | Parts 2 and 3: Overall Survival (OS) | NA months |
| Part 2 (Dose Expansion): Schedule C: Modakafusp Alfa + Dexamethasone | Parts 2 and 3: Overall Survival (OS) | NA months |