Clinical trial NCT05590377: A Study of Modakafusp Alfa Together With Daratumumab Adults With Relapsed or Refractory Multiple Myeloma
Official title: A Phase 1/2a Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Modakafusp Alfa in Combination With Daratumumab Subcutaneous in Patients With Relapsed or Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2022-10-21
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The main aim of this study is to determine safety and tolerability of modakafusp alfa given together with daratumumab to find out the best treatment dose. Another aim of this study is to learn more about the characteristics of modakafusp alfa.

Detailed description: The drug being tested in this study is called modakafusp alfa (TAK-573). Modakafusp alfa is being tested to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy in combination with daratumumab in participants with relapsed or refractory multiple myeloma (RRMM). The study will consist of 2 phases: Phase 1 Dose Escalation and a Phase 2a Dose Finding.

The study will enroll approximately 58 patients. Approximately 18 participants will be enrolled in the Phase 1 Dose Escalation/De-escalation and two dose levels of modakafusp alfa in combination with daratumumab SC will be selected to be further explored in the randomized Phase 2a Dose Finding part of the study wherein, approximately 40 participants will be randomly assigned by chance (like flipping a coin) to one of the two treatment groups:

* Phase 2a Dose Finding: Modakafusp Alfa (DL1) + Daratumumab
* Phase 2a Dose Finding: Modakafusp Alfa (DL2) + Daratumumab This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 60 months. Participants who discontinue study drug treatment for reasons other than progressive disease will continue progression-free survival (PFS) follow-up every 4 weeks from the end of treatment (EOT) visit until the occurrence of progressive disease, death, the start of subsequent systemic antineoplastic therapy, study termination, whichever occurs first.

Eligibility criteria: Inclusion Criteria:

1. Documented multiple myeloma (MM) diagnosis per IMWG criteria.
2. Measurable disease, defined as at least 1 of the following:

   1. Serum M protein ≥0.5 grams per deciliter \[g/dL\] (≥5 g/L) on serum protein electrophoresis (SPEP).
   2. Urine M protein ≥200 mg/24 hours on urine protein electrophoresis (UPEP).
   3. Serum free light chain (FLC) assay with involved FLC level ≥10 mg/dL (≥100 mg/L) provided serum FLC ratio is abnormal.
3. For participants in the Phase 1 Dose Escalation only:

   Must have received at least 3 prior lines of therapy, including at least 1 proteosome inhibitor (PI), 1 immunomodulatory imide drug (IMiD), and 1 anti-CD38 monoclonal antibody (mAb) drug; or who are triple refractory to a PI, an IMiD, and an anti-CD38 mAb drug, regardless of the number of prior line(s) or therapy.
4. For participants in Phase 2a Dose Finding only:

   1. Received 1 to 3 prior line(s) of antimyeloma therapy.
   2. Must be refractory to prior lenalidomide treatment.
   3. Participants must be sensitive (nonrefractory) or naïve to prior anti-CD38 mAb treatment.
   4. Documented progressive disease on or after the last regimen.
   5. Participants must have PR or better to at least 1 line of prior therapy.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at screening.

Exclusion Criteria:

1. Prior exposure to modakafusp alfa.
2. Participant has polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, plasma cell leukemia, or lymphoplasmacytic lymphoma.
3. Participant has not recovered from adverse reactions to prior myeloma treatment or procedures (chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE, Version 5 Grade ≤1 or baseline, except for alopecia.
4. Previous allogeneic stem cell transplant at any time or autologous stem cell transplant (ASCT) within 12 weeks of planned start of dosing.
5. Seropositive for hepatitis B, or known history of seropositivity for hepatitis C or of seropositivity for human immunodeficiency virus (HIV).
6. Participant 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. Participant has QT interval corrected by the Fridericia method \>480 milliseconds \[msec\] (Grade ≥2).
8. Participant has a chronic condition that will require the chronic use of systemic corticosteroids \>10 milligrams per day (mg/d) of prednisone or equivalent on top of any required corticosteroids for multiple myeloma (MM).

Primary outcomes:
measure: Phase 1: Number of Participants with Dose Limiting Toxicities (DLT)
timeFrame: Cycle 1 (cycle length=28 days)
measure: Phase 1: Number of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs) and Per Severity
timeFrame: Up to 60 months
measure: Phase 2a: Overall Response Rate (ORR)
timeFrame: Up to 60 months
Secondary outcomes:
measure: Phase 1: Cmax: Single-Dose Maximum Observed Serum Concentration for Modakafusp Alfa
timeFrame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days)
measure: Phase 1: Tmax: Time to First Occurrence of Maximum Serum Concentration (Cmax) for Modakafusp Alfa
timeFrame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days)
measure: Phase 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa
timeFrame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days)
measure: Phase 1: AUClast: Area Under the Serum Concentration-time Curve from Time 0 to Time of the Last Quantifiable Concentration
timeFrame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days)
measure: Phase 1: Apparent Serum Terminal Disposition Rate Constant for Modakafusp Alfa
timeFrame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days)
measure: Phase 1: Apparent Serum Terminal Disposition Phase Half-life for Modakafusp Alfa
timeFrame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days)
measure: Phase 1: Total Clearance After Intravenous Administration for Modakafusp Alfa
timeFrame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days)
measure: Phase 1: Volume of Distribution at Steady State After Intravenous Administration for Modakafusp Alfa
timeFrame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days)
measure: Phase 1: Cmax: Single-Dose Maximum Observed Serum Concentration for Daratumumab
timeFrame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days)
measure: Phase 1: Tmax: Time to First Occurrence of Maximum Serum Concentration (Cmax) for Daratumumab
timeFrame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days)
measure: Phase 1: Ctrough: Single-Dose and Multiple-dose Observed Concentration at the End of a Dosing Interval for Daratumumab
timeFrame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days)
measure: Phase 1: AUC∞: Area Under the Serum Concentration-time Curve from Time 0 to Infinity for Daratumumab
timeFrame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days)
measure: Phase 1: AUClast: Area Under the Serum Concentration-time Curve from Time 0 to Time of the Last Quantifiable Concentration for Daratumumab
timeFrame: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days)
measure: Phase 1: Overall Response Rate (ORR)
timeFrame: Up to 60 months
measure: Phase 1 and Phase 2a: Duration of Response (DOR)
timeFrame: Up to 60 months
measure: Phase 1 and Phase 2a: Progression Free Survival (PFS)
timeFrame: up to 60 months
measure: Phase 1 and Phase 2a: Overall Survival (OS)
timeFrame: Up to 60 months
measure: Phase 1 and Phase 2a: Number of Participants With Anti-drug Antibodies
timeFrame: Up to 60 months
measure: Phase 1 and Phase 2a: Titer of Anti-drug Antibodies
timeFrame: Up to 60 months
measure: Phase 1 and Phase 2a: Number of Participants With Neutralizing Antibodies (NAb) Against Study Drug
timeFrame: Up to 60 months
measure: Phase 1 and Phase 2a: Rate of Measurable [Minimal] Residual Disease Negative (MRD[-]) Complete Response (CR)
timeFrame: Up to 60 months
measure: Phase 1 and Phase 2a: Duration of Measurable [Minimal] Residual Disease (MRD) Negativity
timeFrame: Up to 60 months
measure: Phase 2a: Clinical Benefit Rate (CBR)
timeFrame: Up to 60 months
measure: Phase 2a: Duration of Clinical Benefit (DCB)
timeFrame: Up to 60 months
measure: Phase 2a: Disease Control Rate (DCR)
timeFrame: Up to 60 months
measure: Phase 2a: Duration of Disease Control
timeFrame: Up to 60 months
measure: Phase 2a: Time to Progression (TTP)
timeFrame: Up to 60 months
measure: Phase 2a: Time to Response (TTR)
timeFrame: Up to 60 months
measure: Phase 2a: Time to Next Treatment (TTNT)
timeFrame: Up to 60 months
measure: Phase 2a: Number of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs) and Per Severity
timeFrame: Up to 60 months
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology, Inc
state: Indiana
city: Overland Park
country: United States
facility: HCA Midwest Health (Midwest Ventures Group HCA MidAmerica Division)
state: Kansas
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Boston
country: United States
facility: Floating Hospital for Children at Tufts Medical Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Florham Park
country: United States
facility: Summit Medical Group PA
state: New Jersey
city: Bay Shore
country: United States
facility: New York Cancer and Blood Specialists
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Hospital
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati - Vontz Center for Molecular Studies
state: Ohio
city: Webster
country: United States
facility: Tranquil Clinical Research
state: Texas
city: Concord
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Sherbrooke
country: Canada
facility: Centre Hospitalier Universitaire De Sherbrooke (CHUS) - Centre de Recherche Clinique Etienne-Le Bel (CRCELB) Hopital Fleurimont
state: Quebec
city: Guangzhou
country: China
facility: Sun Yat-Sen University Cancer Center
state: Guangdong
city: Wuhan
country: China
facility: Wuhan Union Hospital
state: Hubei
city: Tianjin
country: China
facility: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
state: Tianjin
city: Hangzhou
country: China
facility: Zhejiang University School of Medicine - The First Affiliated Hospital (Zhejiang Provincial First Hospital)
state: Zhejiang
city: Lille
country: France
facility: CHRU Lille
state: Hauts-de-France
city: Marseille
country: France
facility: Institut Paoli-Calmettes
state: Provence-Alpes-Cote d'Azur
city: Hwasun
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
state: Jeollanam-do
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Marys Hospital
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Salamanca
country: Spain
facility: Fundacion Instituto de Estudios Ciencias de la Salud de Castilla y Leon-Investigacion Biomedica de Salamanca (IBSAL)
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: