A Study of Modakafusp Alfa on Adult Participants With Relapsed/Refractory Multiple Myeloma (iinnovate-1)

JRCT ID: jRCT2061220078

Registered date:26/12/2022

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Multiple Myeloma
• Date of first enrollment: 04/10/2017
• Target sample size: 336
• Countries of recruitment: United States,Japan,Canada,Japan,China,Japan,Czechia,Japan,France,Japan,Germany,Japan,Greece,Japan,Ireland,Japan,Israel,Japan,Italy,Japan,Korea,Japan,Norway,Japan,Puerto Rico,Japan,Spain,Japan,Taiwan,Japan,Turkey,Japan,United Kingdom,Japan
• Study type: Interventional

Intervention(s)

Part 1 (Dose Escalation) Schedule A: Modakafusp alfa 0.001 Up to 14 mg/kg
Modakafusp alfa 0.001 up to 14 milligram per kilogram (mg/kg), infusion, intravenously (IV), once every week (Q1W) on Days 1, 8, 15 and 22 of each 28-day treatment cycle up to 2 cycles, followed by once on Days 1 and 15 of each 28-day treatment cycle up to 6 cycles, followed by once on Day 1 of each 28-day treatment cycle until treatment discontinuation.

Part 1 (Dose Escalation) Schedule B: Modakafusp alfa TBD
Modakafusp alfa TBD, infusion, IV, once every 2 weeks (Q2W) on Days 1 and 15 of each 28-day treatment cycle until treatment discontinuation. The starting dose will be decided by the investigators and sponsor representatives based on all available clinical information.

Part 1 (Dose Escalation) Schedule C: Modakafusp alfa TBD
Modakafusp alfa TBD, infusion, IV, once every 3 weeks (Q3W) on Day 1 of each 21-day treatment cycle until treatment discontinuation. The starting dose will be decided by the investigators and sponsor representatives based on all available clinical information.

Part 1 (Dose Escalation) Schedule D: Modakafusp alfa TBD
Modakafusp alfa TBD, infusion, IV, once every 4 weeks (Q4W) on Day 1 of each 28-day treatment cycle until treatment discontinuation. The starting dose will be decided by the investigators and sponsor representatives based on all available clinical information.

Part 2 (Dose Expansion): Modakafusp alfa TBD + Dexamethasone 40 mg
Dose(s) for Phase 2 will be based on safety and tolerability results from the preceding Phase 1 dose escalation cohorts. Participants in Phase 2 cohorts will receive modakafusp alfa TBD as a single agent. Participants in at least 1 cohort will receive modakafusp alfa TBD and dexamethasone 40 mg, orally, once weekly of each 28-day treatment cycle until treatment discontinuation.

Part 3 (Dose Extension): Modakafusp alfa 120 mg
Participants will receive modakafusp alfa 120 mg, infusion, IV, Q4W, for each 28-day treatment cycle until disease progression or treatment discontinuation.

Part 3 (Dose Extension): Modakafusp alfa 240 mg
Participants will receive modakafusp alfa 240 mg, infusion, IV, Q4W, for each 28-day treatment cycle until disease progression or treatment discontinuation.

Outcome(s)

Primary Outcome

1.Part 1: Percentage of Participants Reporting one or More Treatment Emergent Adverse Events (TEAEs)
Time Frame: Up to approximately 90 months
An adverse event (AE) is defined as any untoward medical occurrence in a participants administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. A TEAE is defined as any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and within 30 days of the last administration of study drug.

2.Part 1: Percentage of Participants With Dose-limiting Toxicities (DLTs)
Time Frame: Up to Cycle 1 (cycle length is 28 days for Schedule A, B and D; 21 days for Schedule C)
DLTs will be evaluated as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. Nonhematologic TEAEs of NCI CTCAE Grade >=3 clearly unrelated to the underlying disease and occurring during the first cycle will be considered DLTs.

3.Part 1: Percentage of Participants Reporting one or More Grade 3 TEAEs
Time Frame: Up to approximately 90 months
TEAEs Grades will be evaluated as per NCI CTCAE, Version 5.0. Grade 1 scaled as Mild; Grade 2 scaled as Moderate; Grade 3 scaled as severe or medically significant but not immediately life-threatening; Grade 4 scaled as life-threatening consequences; and Grade 5 scaled as death related to AE.

4.Part 1: Percentage of Participants Reporting one or More Serious Adverse Events (SAEs)
Time Frame: Up to approximately 90 months
An SAE is defined as any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is an medically important event that satisfies any of the following: a) May require intervention to prevent items 1 through 5 above. b) May expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization.

5.Part 1: Percentage of Participants Who Discontinue the Treatment Because of TEAE
Time Frame: Up to approximately 90 months
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.

6.Part 1: Percentage of Participants With Dose Modifications: Dose Delay
Time Frame: Up to approximately 90 months

7.Part 1: Percentage of Participants With Dose Modifications: Dose Interruptions
Time Frame: Up to approximately 90 months

8.Part 1: Percentage of Participants With Dose Modifications: Dose Reductions
Time Frame: Up to approximately 90 months

9.Part 1: Percentage of Participants With Clinically Significant Laboratory Values
Time Frame: Up to approximately 90 months
Laboratory values will include hematology, chemistry, and urine analysis.

10.Part 1: Percentage of Participants With Clinically Significant Vital Signs Measurements
Time Frame: Up to approximately 90 months
Vital signs will include temperature, pulse, respiratory rate, oxygen saturation, and blood pressure.

11.Part 2: Overall Response Rate (ORR)
Time Frame: Up to approximately 90 months
ORR is defined as the percentage of participants who achieved a partial response rate (PR) or better during the study as defined by International Myeloma Working Group (IMWG) Uniform Response Criteria.

12.Part 3: Overall Response Rate (ORR) Assessed by Independent Review Committee (IRC)
Time Frame: Up to approximately 90 months
ORR is defined as the percentage of participants who achieved a PR or better during the study as defined by IMWG Uniform Response Criteria assessed by IRC.

Secondary Outcome

1.Part 1 and 2: Percentage of Participants With DLTs- Like Events
Time Frame: Up to approx. 90 months
Percentage of participants with TEAEs meeting DLT definition that occur after phase (P) 1 Cycle (C) 1 will be reported. Toxicity will be evaluated as per the NCI CTCAE, Version 5.0. The hematologic TEAEs of Grade >=3 clearly unrelated to the underlying disease and occur during the first cycle that is considered DLTs with the following exceptions: Grade >=3 hemolysis; Grade 4 neutropenia for >7 consecutive days; Grade 4 thrombocytopenia for >14 consecutive days; Grade 3 thrombocytopenia with clinically significant bleeding; Any other Grade >=4 hematologic toxicity except for Grade 4 lymphopenia. An incomplete recovery from treatment-related toxicity causing >2-week delay in the next scheduled infusion before the initiation of C2 will be considered a DLT. Frequencies and other TEAEs occur over the course of extended treatment with study drug, including dose modification, treatment discontinuation, and clinically significant laboratory values and vital signs.

2.Part 1, 2: Cmax (Maximum Observed Serum Concentration for Modakafusp alfa), Tmax (Time to Reach the Cmax for Modakafusp alfa), AUCinf (Area Under the Serum Concentration-time Curve from Time 0 to Infinity for Modakafusp alfa), AUClast (Area Under the Serum Concentration-time Curve from Time 0 to the Time of the Last Quantifiable Concentration for Modakafusp alfa), Lambda z (Terminal Disposition Rate Constant for Modakafusp alfa), T1/2z (Terminal Elimination Half-life for Modakafusp alfa), CL (Clearance for Modakafusp alfa), Vss (Volume of Distribution at Steady State for Modakafusp alfa)
Time Frame: Part1: Schedule A Cycle(C)1-13,Day(D)1,8,15,22; Schedule B C1-13,D1,15; Schedule C C1-17,D1; Schedule D C1-13,D1: Pre-infusion and at multiple times post-infusion (cycle length is 28 days for Schedule A, B and D; 21 days for Schedule C), Part 2: Up to approx. 90 months
PK blood samples will be collected at the following time points for schedule A: Pre-infusion and at multiple time points (up to 72 hour [h]) C1-2 D1, 15; up to 4h C1-2 D8, 22 and C2 D15; up to 24h C3 D1; up to 4h on C3, 4-6 D15, C4-6 D1, and C7-13 D1; Schedule B: Pre-infusion and at multiple time points (up to 24h) on C1-2 D1, 15; up to 24h C3 D1; up to 4h C3 D15 and C4-13 D1; Schedule C: Pre-infusion and at multiple time points (up to 336h) on C1-2 D1; up to 4h on C3-17 D1; Schedule D: Pre-infusion and at multiple time points (up to 504h) C1-2 D1; up to 4h C3-13 D1 post-infusion (Schedule A, B and D cycle is 28 days and schedule C cycle is 21 days).

3.Parts 1, 2 and 3: Percentage of Participants with Positive Anti-drug Antibodies (ADA)
Time Frame: Up to approx. 90 months

4.Part 1: ORR
Time Frame: Up to approx. 90 months
ORR is defined as the percentage of participants who achieved a PR or better during the study as defined by IMWG Uniform Response Criteria.

5.Parts 1 and 2: Clinical Benefit Rate (CBR)
Time Frame: Up to approx. 90 months
CBR is defined as the percentage of participants who achieved MR or better during the study as defined by IMWG Uniform Response Criteria.

6.Parts 1 and 2: Disease Control Rate (DCR)
Time Frame: Up to approx. 90 months
DCR is defined as the percentage of participants who achieved a stable disease (SD) or better during the study as defined by IMWG Uniform Response Criteria.

7.Parts 1, 2 and 3: Duration of Response (DOR)
Time Frame: Up to approx. 90 months
DOR is defined as the time from the date of first documentation of response PR or better to the time of disease progression or death, whichever occurs first.

8.Parts 1 and 2: Time to Response
Time Frame: Up to approx. 90 months
Time to response is defined as the time from first dose to the date of first documentation of response (PR or better).

9.Parts 1, 2 and 3: Progression Free Survival (PFS)
Time Frame: Up to approx. 90 months
PFS is defined as the time from the date of enrollment until the date of PD or death due to any cause, whichever occurs first as defined by IMWG Criteria.

10.Parts 2 and 3: Overall Survival (OS)
Time Frame: Up to approx. 90 months

11.Part 3: ORR by Investigator Assessment
Time Frame: Up to approx. 90 months

12.Part 3: CBR by IRC and Investigator assessment
Time Frame: Up to approx. 90 months

13.Part 3: Duration of Clinical Benefit
Time Frame: Up to approx. 90 months
Duration of clinical benefit is defined as the time from first documented evidence of confirmed MR or better until the earliest date of a confirmed PD per IMWG, or death among patients who achieve a confirmed MR or better.

14.Part 3: DCR by IRC and Investigator Assessment
Time Frame: Up to approx. 90 months

15.Part 3: Duration of Disease Control
Time Frame: Up to approx. 90 months
Duration of disease control is defined as the time from first documented evidence of SD or better until the earliest date of a confirmed PD per IMWG, or death among patients who achieve a SD or better.

16.Part 3: Time to Progression (TTP) by IRC and Investigator Assessment
Time Frame: Up to approx. 90 months
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.

17.Part 3: Rate of Minimal Residual Disease (MRD) Negativity Status at a Sensitivity of 10^-5 in Participants Achieving CR
Time Frame: Up to approx. 90 months
MRD negativity at a sensitivity of 10^-5 is defined as patients who are MRD negative at a sensitivity of 10^-5 in patients achieving suspected complete response (CR). CR is defined as negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow; in participants for whom only measurable disease is by serum FLC level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria is required.

18.Part 3: Duration of MRD Negativity Status at a Sensitivity of 10^-5 in Participants Achieving CR
Time Frame: Up to approx. 90 months
Duration of MRD negativity (10^-5) is defined as the time from the first MRD negative status (10^-5) to the earliest date of the MRD positive status (10^-5), confirmed PD per IMWG or death.

19.Part 3: Percentage of Participants With AEs
Time Frame: Up to approx. 90 months

20.Part 3: Percentage of Participants With SAEs
Time Frame: Up to approx. 90 months

21.Part 3: Percentage of Participants With Clinically Significant Laboratory Values
Time Frame: Up to approx. 90 months
Laboratory values will include hematology, chemistry, and urine analysis.

22.Part 3: Number of Participants With ECOG Status
Time Frame: Up to approx. 90 months
ECOG is a grade, where grade 0: Normal activity. Grade 1: Symptoms but ambulatory. Grade 2: In bed <50% of the time. Grade 3: In bed >50% of the time. Grade 4: 100% bedridden. Grade 5: Dead.

23.Part 3: Health Care Utilization: Length of Hospital Stays
Time Frame: Up to approx. 90 months

24.Part 3: Percentage of Participants With Neutralizing Antibodies (NAb)
Time Frame: Up to approx. 90 months

25.Part 3: Health Care Utilization: Number of Participants With at Least One Medical Encounter
Time Frame: Up to approx. 90 months
Healthcare resources used during medical encounters included hospitalizations, emergency room stays, or outpatient visits.

26.Part 3: Patient-reported Outcome (PRO): Instrument European Organisation for Research and Treatment of Cancer QLQ Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20)
Time Frame: Up to approx. 90 months
The EORTC QLQ-MY20 has 20 items across 4 independent subscales, 2 functional subscales (body image and future perspective), and 2 symptoms scales (disease symptoms and side effects of treatment). The QLQ-MY20 raw scores are converted into scale scores ranging from 0 to 100. For the symptom scales, lower scores represent better functioning. All items in this questionnaire have a recall period of 1 week.

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

For Parts 1 and 2, and Japan Safety Lead-in:
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:
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.
3.During Part 1 and Japan Safety Lead-in, 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.

Exclude criteria

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 Japan Safety Lead-in and 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.

Related Information

• Primary Sponsor: Asato Takayuki
• Secondary ID(s): NCT03215030,2021-006038-37