Relapsed/Refractory Multiple Myeloma MedDRA version: 21.0 Level: LLT Classification code 10028228 Term: Multiple myeloma System Organ Class: 100000004864
Conditions
Interventions
Product Name: Modakafusp Alfa
Product Code: TAK-573
Pharmaceutical Form: Injection
INN or Proposed INN: Modakafusp alfa
Current Sponsor code: TAK-573
Concentration unit: mg/ml milligram(s)/millilitre
Sponsors
Takeda Development Center Americas, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: For Parts 1 and 2: 1. MM defined by the IMWG criteria with evidence of disease progression and: a) Is in need of additional myeloma therapy as determined by the investigator. b) Has previously received at least 3 lines of myeloma therapy (eg, containing an IMiD, a PI, an alkylating agent, and/or an anti-CD38 as single agents or in combination). c) Is either refractory to, or intolerant of, at least 1 PI and at least 1 IMiD (see NOTE below). For Part 3: 1. MM defined by the IMWG criteria with evidence of disease progression and: a) Is in need of additional myeloma therapy as determined by the investigator. b) Has previously received at least 3 lines of myeloma therapy. c) 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 who have demonstrated disease progression with the last therapy (see NOTE below). Patients who are primary refractory, meaning they never achieved at least a MR with any previous treatment line, are not eligible. NOTE: Refractory is defined as ?25% reduction in M-protein or progression of disease during treatment or within 60 days after cessation of treatment. A line of therapy is defined as 1 or more cycles of a planned treatment program. This may consist of 1 or more planned cycles of single-agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. A new line of therapy starts when a planned course of therapy is modified to include other treatment agents (alone or in combination) as a result of disease progression, relapse, or toxicity. A new line of therapy also starts when a planned period of observation off therapy is interrupted by a need for additional treatment for the disease (Rajkumar et al. 2011). 2. Aged 18 years or older. 3. For patients in Parts 2 and 3 only: Measurable disease defined as one of the following: a) Serum M-protein =500 mg/dL (=5 g/L). b) Urine M-protein =200 mg/24 hours. c) Serum free light chain (FLC) assay with involved FLC level =10 mg/dL (=100 mg/L) provided serum FLC ratio is abnormal. 4. During Part 1 only, patients not meeting the above criteria for measurable disease should, at least, have measurable bone marrow plasmacytosis (=10%) and/or plasmacytoma (=1 cm in diameter) detected by physical examination or imaging. 5. ECOG performance status of =2. 6. Patient has adequate organ function as determined by the following laboratory values. See Protocol for values. 7. Patient has received the final dose of any of the following treatments/procedures within the specified minimum intervals before the first dose of modakafusp alfa. See Protocol for values. 8. Female patients who: Are postmenopausal for at least 2 years before the screening visit, OR Are surgically sterile, OR If they are of childbearing potential: – Agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 7 days after the last dose of study drug, OR – Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject, from the time of signing the informed consent through 7 days after the last dose of study drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and la
Exclusion criteria
Exclusion criteria: 1. Patient has polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia or IgM myeloma, or lymphoplasmacytic lymphoma. 2. Patients who have received autologous SCT 60 days before first infusion of modakafusp alfa or patients who have received allogeneic SCT 6 months before first infusion. 3. Graft-versus-host disease that is active or requires ongoing systemic immunosuppression. 4. Part 1: Until the MTD/OBD is defined, patients who have received daratumumab (or other investigational anti-CD38 antibody) for at least 5 months (steady state) require a 90-day wash-out period before receiving modakafusp alfa. For patients who have received less than 5 months of daratumumab or who have received another anti-CD38 monoclonal antibody, the necessary wash-out period needs to be discussed and approved by the sponsor. Once the MTD/OBD has been confirmed, these patients can be enrolled in the trial (Parts 2 and 3). Parts 2 and 3: No washout from daratumumab or isatuximab is required. 5. Patient has not recovered from adverse reactions to prior myeloma treatment or procedures (chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE Grade =1 or baseline, except for sensory or motor neuropathy which should have recovered to Grade =2 or baseline. 6. Patient has congestive heart failure (New York Heart Association Grade =II), cardiac myopathy, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant arrhythmia requiring therapy including anticoagulants, or clinically significant uncontrolled hypertension. 7. Patient has a history of acute myocardial infarction within 5 months from enrollment or has ECG abnormalities during screening that are deemed medically relevant by the investigator. 8. Patient has QT interval corrected by the Fridericia method (QTcF) >480 msec (Grade =2). 9. Patient has a concurrent illness that would preclude study conduct and assessment including, but not limited to, uncontrolled medical conditions, uncontrolled and active infection (considered opportunistic, life-threatening, or clinically significant), uncontrolled risk of bleeding, uncontrolled diabetes mellitus, pulmonary disease (including obstructive pulmonary disease, pulmonary fibrosis, and history of symptomatic bronchospasm), alcoholic liver disease, or primary biliary cirrhosis. 10. Patient has a chronic condition requiring the use of systemic corticosteroids >10 mg/day of prednisone or equivalent. 11. Patient has clinical signs of central nervous system involvement of MM. 12. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug if applicable. 13. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol. 14. Infection with HIV: Screening for HIV infection will be performed, and patients who have a positive result will be excluded. 15. Parts 1 and 2: Known chronic hepatitis C and/or positive serology (unless due to vaccination or passive immunization due to Ig therapy) for chronic hepatitis B. Part 3: Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Screening for HBV and HCV
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: *Part 1 and Part 2 is conducted in the US only. Part 1 Dose Escalation: To determine the safety and tolerability of single-agent modakafusp alfa in patients with RRMM. Part 2 Expansion Cohorts: To provide a prelim. evaluation of the clinical activity of modakafusp alfa as a single agent and in comb. with dexamethasone in patients with RRMM. Part 3 Extension Cohorts: To determine the objective response rate (ORR) as assessed by IRC according to IMWG criteria (App. F) of modakafusp alfa in patients who have MM defined by the IMWG criteria with evidence of disease progression and are in need of additional myeloma therapy as determined by the investigator, have previously received at least 3 lines of myeloma therapy, and are 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 and who have demonstrated disease progression with the last therapy.;Secondary Objective: Please see Protocol for full list of secondary objectives Part 1 Dose Escalation: To determine the MTD/OBD of modakafusp alfa with 1 or more schedules of administration. To characterize the PK profile of modakafusp alfa. To evaluate the immunogenicity of modakafusp alfa. To provide a preliminary evaluation of the clinical activity of modakafusp alfa. Part 2 Expansion: To further evaluate safety and to determine the suitability of MTD/OBD of modakafusp alfa as a single agent and in combination with dexamethasone for further trials as the recommended dose and schedule. To further characterize the PK profile of modakafusp alfa as a single agent and in combination with dexamethasone. To further characterize the immunogenicity of modakafusp alfa as a single agent and in combination with dexamethasone. Part 3 Extension: To determine ORR by investigator assessment, duration of response (DOR), clinical benefit rate (CBR), duration of clinical benefit, disease c | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part 1 Secondary Endpoints DLT-like (TEAEs meeting DLT definition that occur after phase 1 Cycle 1) frequencies and other TEAEs occurring over the course of extended treatment with modakafusp alfa, including information about dose modification, treatment discontinuation, and clinically significant laboratory values and vital signs. Summary statistics by dose level and cycle day for the following PK parameters: – Single-dose Cmax. – Time of first occurrence of Cmax (tmax). – Area under the serum concentration-time curve from time 0 to infinity (AUC8). – Area under the serum concentration-time curve from time 0 to time of the last quantifiable concentration (AUClast). Apparent serum modakafusp alfa terminal disposition rate constant (?z). – Apparent serum modakafusp alfa terminal elimination phase half-life (t1/2z). – CL. – Volume of distribution at steady state (Vss). Antimodakafusp alfa-antibody incidence and characteristics (eg, titer and specificity). Preliminary evaluation of antitumor activity of modakafusp alfa: – For patients with measurable disease only: ORR, defined as the proportion of patients who achieved a P or better during the study; sCR, CR, very good partial response (VGPR), and PR as defined by IMWG Uniform Response Criteria (Appendix F), CBR (includes patients with a response of sCR, CR, VGPR, PR, or minimal response); DCR (includes patients with a response of sCR, CR, VGPR, PR, minimal response, or stable disease). – For patients with measurable disease only: median DOR, with DoR defined as the time from the date of first documentation of response PR or better to the time of disease progression or death, whichever occurs first. – For patients with measurable disease only: time to response, defined as the time from first dose to the date of first documentation of response (PR or better). – Progression-free survival (PFS), defined as the time from the date of first dose until the sooner of the date of PD, defined by IMWG crit | — |
Countries
Canada, China, Czechia, France, Germany, Greece, Ireland, Israel, Italy, Japan, Korea, Republic of, Norway, Spain, Taiwan, Turkey, United Kingdom, United States
Contacts
Public ContactTed Preston
Takeda Development Center Americas, Inc.
Outcome results
None listed