A Study of Modakafusp Alfa in Adult Participants With Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
The main aims of this study are to test for any side effects from modakafusp alfa in combination therapy and to determine the recommended dose of combination therapy with modakafusp. 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. Participants will be given modakafusp alfa through a vein.

Detailed Description
-----------------
The drug being tested in this study is called modakafusp alfa (TAK-573). The study will evaluate the safety, tolerability and determine the recommended dose of modakafusp alfa in combination with lenalidomide in participants with multiple myeloma (MM), or in combination with pomalidomide, bortezomib, carfilzomib, or daratumumab in participants with relapsed/refractory multiple myeloma (RRMM). The study consists of 3 Groups: Group 1: MM Maintenance Therapy, Group 2: RRMM Doublets, Group 3: RRMM Triplets. The study will enroll approximately 18 participants in Group 1, 66 in Group 2, and 36 in Group 3. Participants will be assigned to one of the following treatment groups as given below: Group 1 (MM Maintenance) Arm 1: Modakafusp alfa + Lenalidomide Group 2 (RRMM Doublets) Arm 2: Modakafusp alfa + Pomalidomide Group 2 (RRMM Doublets) Arm 3: Modakafusp alfa + Bortezomib Group 2 (RRMM Doublets) Arm 4: Modakafusp alfa + Carfilzomib Group 3 RRMM Triplets) Arm A: Modakafusp alfa + Pomalidomide + Bortezomib Group 3 (RRMM Triplets) Arm D: Modakafusp alfa + Daratumumab + Pomalidomide Group 2 Arm 4 is closed for enrollment. The study will be conducted worldwide. The maximum treatment duration in this study for Group 1 is until disease progression or unacceptable toxicity, or up to 2 years for minimal/measurable residual disease (MRD) negative [-] participants, whichever occurs first. The maximum treatment duration in this study for Group 2 and Group 3 is until disease progression, unacceptable toxicity or until any other discontinuation criterion is met, whichever occurs first. Overall time to participate in the study is approximately up to 5 years.

Official Title
-----------------
A Phase 1b Open-label Study to Evaluate the Safety and Tolerability of Intravenous Modakafusp Alfa as Part of Combination Therapy in Adult Patients With Multiple Myeloma

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: Modakafusp alfa
* Drug: Lenalidomide
* Drug: Bortezomib
* Drug: Carfilzomib
* Drug: Daratumumab
* Drug: Pomalidomide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Group 1 (MM maintenance: modakafusp alfa/lenalidomide) only must have: MM based on standard IMWG diagnostic criteria. Undergone ASCT for the treatment of MM within 12 months of the start of induction therapy and completed ASCT within 180 days before enrollment- (regardless of the lines of treatment).Consolidation cycles are allowed. Tandem transplant is allowed. Not started lenalidomide maintenance before enrollment. Time to initiation of maintenance therapy: participants may start maintenance therapy as early as 60 days after transplantation and up to 180 days after transplantation or consolidation. MRD positive ( after ASCT (MRD assessed at a threshold of 10^-5 by local SOC methods or central assessment, if a prior local MRD assessment had not been performed). No prior progression after initial therapy (at any time before starting maintenance). Participants whose induction therapy was changed due to suboptimal response or toxicity will be eligible if they do not meet criteria for progression. In addition, no more than 2 regimens will be allowed before ASCT, excluding dexamethasone alone. No prior allogeneic hematopoietic stem cell transplant or solid organ transplant. Recovered to Grade less than or equal to (<=) 1 autologous stem cell transplant (ASCT) -related toxicities from the reversible effects of ASCT (except for alopecia and amenorrhea). ). MM based on standard IMWG diagnostic criteria. Groups 2 and 3 (RRMM doublets and RRMM triplets) must have: Measurable disease, defined as at least 1 of the following: Serum M-protein >=0.5 g/dL (>=5 g/L) on serum protein electrophoresis (SPEP). Urine M-protein >=200 mg/24 hours on urine protein electrophoresis (UPEP). Serum free light chain (FLC) assay result with an involved FLC level >=10 mg/dL (>=100 mg/L), provided the serum FLC ratio is abnormal (per IMWG criteria). A confirmed diagnosis of MM according to IMWG criteria with documented disease progression in need of additional therapy as determined by the investigator. For Group 2 RRMM doublet arms only: Participants who have received at least 3 prior lines of antimyeloma therapy, including at least 1 proteosome inhibitor (PI), 1 immunomodulatory drug (IMiD) and 1 anti-CD38 monoclonal antibody (mAb) drug, or who are triple refractory to a PI, and IMiD, and an anti-CD38 mAb drug regardless of the number of prior line(s) of therapy. d. For Group 3 RRMM triplet arms only: Participants who have received 1 to 3 prior lines of antimyeloma therapy including at least 1 PI and, 1 IMiD, and who are not refractory to the combination partners. e) For anti-CD38 arms, forced expiratory volume in 1second (FEV1) >=50% predicted by pulmonary function testing. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at screening Has adequate organ function at screening as determined by the laboratory values required for enrollment: Absolute neutrophil count (ANC) >=1000 per cubic millimeter (/mm^3) (or >=1*10^9/L); Platelets >=75,000/mm^3 (>=75*10^9/L); Hemoglobin >=8.0 g/dL; estimated creatinine clearance >=30 mL/min (Cockcroft-Gault formula); Total serum bilirubin <=2.0*Upper limit of normal (ULN); an exception for participants with Gilbert's syndrome may be granted after discussion with the sponsor; Liver transaminases (alanine aminotransferase [ALT])/aspartate aminotransferase [AST]) <=3.0*ULN. Has recovered from adverse reactions to prior myeloma treatment or procedures (example, chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE Version 5.0 Grade <=1 or baseline treatment or have the toxicity established as sequela, except for sensory or motor neuropathy, which should have recovered to Grade <=2 or baseline; ; (Grade 1 for the bortezomib arm). Exclusion criteria: Currently participating in another MM interventional study, including other clinical trials with investigational agents (including investigational vaccines or investigational medical device for disease under study) throughout the duration of this study. Received previous treatment with modakafusp alfa. Has a diagnosis of primary amyloidosis, Waldenström disease, monoclonal gammopathy of undetermined significance or smoldering MM per IMWG criteria or standard diagnostic criteria, plasma cell leukemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), lymphoplasmacytic lymphoma. Has been diagnosed with another 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 and that in the opinion of the local investigator, with concurrence with the principal investigator, is considered cured with minimal risk of recurrence within 3 years. Has evidence of CNS involvement and/or meningeal involvement due to MM exhibited during screening. Has a known severe allergic or anaphylactic reactions to human recombinant proteins or excipients used in the modakafusp alfa formulation or to the study combination agents, the study medications, their analogs, or excipients in the various formulations of any agent per the prescribing information. Is 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 and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) and, a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR. Has a known history of seropositivity for HIV. Has a known history of seropositivity for hepatitis C (anti-hepatitis C virus antibody positive or anti-hepatitis C virus-RNA quantitation positive). Exception: Participants with a sustained virologic response with undetectable HCV RNA level at least 12 weeks after completion of antiviral therapy. For bortezomib arms: participants received a strong cytochromes P450 (CYP3A4) inducer within 5 half-lives prior to randomization. The participant has a chronic condition requiring the use of systemic corticosteroids >10 mg/dL of prednisone or equivalent, in addition to any required corticosteroids for the treatment of MM. Has a QTcF (QT interval corrected with Fridericia correction method >480 millisecond (ms) (Grade >=2).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (MM Maintenance) Arm 1: Modakafusp alfa + Lenalidomide<br>Modakafusp alfa, infusion intravenously (IV), once on Day 1, once every 4 weeks (Q4W), in combination with Lenalidomide capsules orally once daily continuously on Days 1 to 28, in a 28-day (4-week) treatment cycle until disease progression, unacceptable toxicity, or to a maximum of 2 years for MRD [-] negative participants, whichever occurs first. Participants who remain MRD positive with demonstrated clinical benefit after 2 years of maintenance therapy may continue treatment beyond 2 years with agreement of the sponsor/designee. | Drug: Modakafusp alfa<br>* Modakafusp alfa intravenous infusion.<br>* Other names: TAK-573;Drug: Lenalidomide<br>* Lenalidomide capsules orally.<br>|
| Experimental: Group 2 (RRMM Doublets) Arm 2: Modakafusp alfa + Pomalidomide<br>Modakafusp alfa, infusion IV, once on Day 1, Q4W in combination with Pomalidomide capsules orally once daily on Days 1 to 21 in a 28-day (4-week) treatment cycle until disease progression, unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. | Drug: Modakafusp alfa<br>* Modakafusp alfa intravenous infusion.<br>* Other names: TAK-573;Drug: Pomalidomide<br>* Pomalidomide capsules orally.<br>|
| Experimental: Group 2 (RRMM Doublets) Arm 3: Modakafusp alfa + Bortezomib<br>Modakafusp alfa, infusion IV, once on Day 1, Q4W in combination with Bortezomib injection subcutaneously on Days 8, 15, and 22 for the first 8 cycles and subsequently on Days 8 and 22 of a 28-day (4-week) treatment cycle until disease progression, unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. | Drug: Modakafusp alfa<br>* Modakafusp alfa intravenous infusion.<br>* Other names: TAK-573;Drug: Bortezomib<br>* Bortezomib injection subcutaneously.<br>|
| Experimental: Group 2 (RRMM Doublets) Arm 4: Modakafusp alfa + Carfilzomib<br>Modakafusp alfa, infusion IV, once on Day 1, Q4W in combination with Carfilzomib IV, on Day 1, 8 and 15 of a 28-day (4-week) treatment cycle until disease progression, unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. This arm is closed for enrollment after 3 participants were enrolled. | Drug: Modakafusp alfa<br>* Modakafusp alfa intravenous infusion.<br>* Other names: TAK-573;Drug: Carfilzomib<br>* Carfilzomib intravenous infusion.<br>|
| Experimental: Group 3 (RRMM Triplets) Arm A: Modakafusp alfa + Pomalidomide + Bortezomib<br>Modakafusp alfa, infusion IV, once on Day 1, Q4W in combination with Pomalidomide capsules orally once daily on Days 1 to 21 in a 28-day (4-week) treatment cycle along with Bortezomib injection subcutaneously on Days 8, 15 and 22 for the first 8 cycles and subsequently on Days 8 and 22 of a 28-day (4-week) treatment cycle until disease progression, unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. | Drug: Modakafusp alfa<br>* Modakafusp alfa intravenous infusion.<br>* Other names: TAK-573;Drug: Bortezomib<br>* Bortezomib injection subcutaneously.<br>Drug: Pomalidomide<br>* Pomalidomide capsules orally.<br>|
| Experimental: Group 3 (RRMM Triplets) Arm D: Modakafusp alfa + Daratumumab + Pomalidomide<br>Modakafusp alfa, infusion IV, once on Day 1, Q4W in combination with Daratumumab injection subcutaneously on Days 1, 8, 15 and 22 of Cycles 1 and 2, further followed by on Days 1 and 15 of Cycles 3 to 6, thereafter on Day 1 on a 28-day (4-week) treatment cycle along with Pomalidomide capsules orally once daily on Days 1 to 21 in a 28-day (4-week) treatment cycle until disease progression, unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. | Drug: Modakafusp alfa<br>* Modakafusp alfa intravenous infusion.<br>* Other names: TAK-573;Drug: Daratumumab<br>* Daratumumab injection subcutaneously.<br>Drug: Pomalidomide<br>* Pomalidomide capsules orally.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities (DLTs) | DLT will be defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0: Grade 5 AE; Hematologic toxicity: Nonfebrile Grade 4 neutropenia lasting more than 7 consecutive days/Grade greater than or equal to (>=) 3 febrile neutropenia; Grade 4 thrombocytopenia lasting more than 14 consecutive days, Grade 3 thrombocytopenia with clinically significant bleeding; any other Grade 4 with exceptions; Nonhematologic Grade 3 or higher toxicities unrelated to the underlying disease with exceptions; Delay in Cycle 2 by more than 14 days due to a lack of adequate recovery of treatment-related hematological or nonhematologic toxicities. | Cycle 1 (Cycle length is 28 days) | 
| Number of Participants Reporting one or More Treatment Emergent Adverse Events (TEAEs) |  | Up to approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the time from the date on which the first dose of study drug is administered to the date of first documentation of confirmed progression of disease (PD) or death due to any cause, whichever occurs first. PD will be determined by International Myeloma Working Group (IMWG) criteria. PD: increase of >=25 percent (%) from lowest response value in any one or more of the following: serum M-component increase >=0.5 gram per deciliter (g/dL) or urine M-component increase >=200 milligram (mg)/24-hour; difference between involved and uninvolved free light chains (FLC) levels increase must be greater than (>) 10 milligram per deciliter (mg/dL); bone marrow plasma cell >=10%; definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder. | Up to approximately 5 years | 
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants who achieved a confirmed partial response rate (PR) or better during the study as defined by IMWG Uniform Response Criteria and the response is determined by investigator. PR: >=50% reduction of serum M-protein and >=90% reduction in urine M-protein or less than (<) 200 mg/24 hour, or >=50% decrease in uninvolved FLC or >=50% reduction in plasma cells. At baseline, a >=50% decrease in size of soft tissue plasmacytomas is required. | Up to approximately 5 years | 
| Duration of Response (DOR) | DOR is defined as the time from the date of first documentation of confirmed PR or better to the date of first documentation of PD or death due to any cause. PR: >=50% reduction of serum M-protein and >=90% reduction in urine M-protein or <200 mg/24 hour, or >=50% decrease in uninvolved FLC or >=50% reduction in plasma cells. At baseline, a >=50% decrease in size of soft tissue plasmacytomas is required. PD: increase of >=25% from lowest response value in any one or more of the following: 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 must be >10 mg/dL; bone marrow plasma cell >=10%; definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder. | Up to approximately 5 years | 
| Groups 2 and 3: Overall Survival (OS) | OS is defined as the time from the first dose of administration to the date of death, due to any cause. Participants without documentation of death at the time of analysis will be censored at the date last known to be alive. | Up to approximately 5 years | 
| Groups 2 and 3: Time to Progression (TTP) | TTP is defined as the time from the date of the first dose until the earliest date of confirmed PD per IMWG, or death due to PD. PD: increase of >=25% from lowest response value in any one or more of the following: 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 must be >10 mg/dL; bone marrow plasma cell >=10%; definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder. | Up to approximately 5 years | 
| Groups 2 and 3: Time to Next Treatment (TTNT) | TTNT is defined as the time from the date of first dose administration to the date of the first dose initiation of the next line of antineoplastic therapy, for any reason. | Up to approximately 5 years | 
| Groups 2 and 3: Disease Control Rate (DCR) | DCR is defined as the percentage of participants who achieved a stable disease (SD) or better during the study based on the investigator's disease assessment as defined by IMWG Uniform Response Criteria. SD is defined as no known evidence of progressive disease or new bone lesions. | Up to approximately 5 years | 
| Groups 2 and 3: Event-free Survival | EFS is defined as the time from the date on which the first dose of study drug is administered to the date of the first documentation of an event that may include confirmed PD, discontinuation of a treatment for an AE (related or not related), or death due to any cause, whichever occurs first. PD will be determined by International Myeloma Working Group (IMWG) criteria. PD: increase of >=25 % from lowest response value in any one or more of the following: serum M-component increase >=0.5 g/dL or urine M-component increase >=200 mg/24-hour; difference between involved and uninvolved free light chains (FLC) levels increase must be > 10 mg/dL; bone marrow plasma cell >=10%; definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder. | Up to approximately 5 years | 
| Groups 2 and 3: Time to Response (TTR) | TTR is defined as the time from the date of the first dose administration to the date of the first documentation of objective confirmed response as defined by IMWG criteria. | Up to approximately 5 years | 
| Group 1: Percentage of Participants with MRD Negativity Status at a Threshold of 10^-5 | Rate of MRD negativity at a sensitivity of 10^-5 is defined as the percentage of participants who have achieved MRD negative status in participants in the MRD-evaluable analysis set. | At 6 months, 1 year, and 2 years after the start of treatment. | 
| Groups 2 and 3: Percentage of Participants with MRD Negativity CR Status at a Threshold of 10^-5 in Participants Achieving CR Assessed by the Investigator | Rate of MRD negativity CR status a sensitivity of 10^-5 is defined as the percentage of participants who have achieved MRD negative CR status in participants achieving CR. CR is defined as negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow; in participants for whom only measurable disease is by serum FLC level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria is required. | Up to approximately 2 years after CR confirmation | 
| Group 1: Duration of MRD Negativity Status at a Threshold of 10^-5 in Participants Achieving MRD Negativity | Duration of MRD negativity (10^-5) is defined as the time from the date of first documentation of MRD [-] to the first documentation of MRD positivity or confirmed PD or death due to any cause, whichever occurs first. PD: increase of >=25% from lowest response value in any one or more of the following: 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 must be >10 mg/dL; bone marrow plasma cell >=10%; definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder. | Up to approximately 2 years after treatment | 
| Group 2 and 3: Percentage of Participants with MRD Negativity Status at a Threshold of 10^-5 | Rate of MRD negativity at a sensitivity of 10^-5 is defined as the percentage of participants who have achieved MRD negative status. | Up to approximately 5 years | 
| Groups 2 and 3: Duration of MRD Negativity Status at a Sensitivity Threshold of 10^-5 in Participants Achieving MRD Negativity | Duration of MRD negativity (10^-5) is defined as the time from the date of first documentation of MRD[-] to the first documentation of MRD positivity or confirmed PD or death due to any cause, whichever occurs first. PD: increase of >=25% from lowest response value in any one or more of the following: 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 must be >10 mg/dL; bone marrow plasma cell >=10%; definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder. | Up to approximately 5 years | 
| Number of Participants With Positive Anti-drug Antibodies (ADA) and Neutralizing Antibody (NAb) |  | Up to approximately 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Drug Therapy