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

A Phase 1/2 Open-label Study to Investigate the Safety and Tolerability, Efficacy, Pharmacokinetics, and Immunogenicity of Modakafusp Alfa (TAK-573) as a Single Agent in Patients With Relapsed Refractory Multiple Myeloma

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

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

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

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

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

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

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

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

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

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

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

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

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

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.