Clinical trial NCT05556616: A Study of Modakafusp Alfa in Adult Participants With Multiple Myeloma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Multiple Myeloma
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2022-09-27
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 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.

Eligibility criteria: Inclusion Criteria:

1. Group 1 (MM maintenance: modakafusp alfa/lenalidomide) only must have:

   1. MM based on standard IMWG diagnostic criteria.
   2. 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.
   3. 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.
   4. 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).
   5. 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.
   6. No prior allogeneic hematopoietic stem cell transplant or solid organ transplant.
   7. 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.
2. Groups 2 and 3 (RRMM doublets and RRMM triplets) must have:

   1. 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).
   2. A confirmed diagnosis of MM according to IMWG criteria with documented disease progression in need of additional therapy as determined by the investigator.
   3. 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.
3. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at screening
4. 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.
5. 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:

1. 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.
2. Received previous treatment with modakafusp alfa.
3. 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.
4. 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.
5. Has evidence of CNS involvement and/or meningeal involvement due to MM exhibited during screening.
6. 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.
7. 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.
8. Has a known history of seropositivity for HIV.
9. 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.
10. For bortezomib arms: participants received a strong cytochromes P450 (CYP3A4) inducer within 5 half-lives prior to randomization.
11. 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.
12. Has a QTcF (QT interval corrected with Fridericia correction method \>480 millisecond (ms) (Grade \>=2).

Primary outcomes:
measure: Number of Participants With Dose-limiting Toxicities (DLTs)
timeFrame: Cycle 1 (Cycle length is 28 days)
measure: Number of Participants Reporting one or More Treatment Emergent Adverse Events (TEAEs)
timeFrame: Up to approximately 5 years
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Up to approximately 5 years
measure: Overall Response Rate (ORR)
timeFrame: Up to approximately 5 years
measure: Duration of Response (DOR)
timeFrame: Up to approximately 5 years
measure: Groups 2 and 3: Overall Survival (OS)
timeFrame: Up to approximately 5 years
measure: Groups 2 and 3: Time to Progression (TTP)
timeFrame: Up to approximately 5 years
measure: Groups 2 and 3: Time to Next Treatment (TTNT)
timeFrame: Up to approximately 5 years
measure: Groups 2 and 3: Disease Control Rate (DCR)
timeFrame: Up to approximately 5 years
measure: Groups 2 and 3: Event-free Survival
timeFrame: Up to approximately 5 years
measure: Groups 2 and 3: Time to Response (TTR)
timeFrame: Up to approximately 5 years
measure: Group 1: Percentage of Participants with MRD Negativity Status at a Threshold of 10^-5
timeFrame: At 6 months, 1 year, and 2 years after the start of treatment.
measure: 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
timeFrame: Up to approximately 2 years after CR confirmation
measure: Group 1: Duration of MRD Negativity Status at a Threshold of 10^-5 in Participants Achieving MRD Negativity
timeFrame: Up to approximately 2 years after treatment
measure: Group 2 and 3: Percentage of Participants with MRD Negativity Status at a Threshold of 10^-5
timeFrame: Up to approximately 5 years
measure: Groups 2 and 3: Duration of MRD Negativity Status at a Sensitivity Threshold of 10^-5 in Participants Achieving MRD Negativity
timeFrame: Up to approximately 5 years
measure: Number of Participants With Positive Anti-drug Antibodies (ADA) and Neutralizing Antibody (NAb)
timeFrame: Up to approximately 5 years
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: San Diego
country: United States
facility: Scripps Health
state: California
city: Iowa City
country: United States
facility: The University of Iowa Hospitals & Clinics
state: Iowa
city: Baltimore
country: United States
facility: Cancer Center At Greater Baltimore Medical Center
state: Maryland
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Mineola
country: United States
facility: NYU Langone Hospital - Long Island
state: New York
city: New York
country: United States
facility: New York University School of Medicine
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine/New York Presbyterian Hospital
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center - Main Campus
state: New York
city: Charlotte
country: United States
facility: Novant Health Cancer Institute
state: North Carolina
city: Winston-Salem
country: United States
facility: Novant Health Cancer Institute - Forsyth Medical Center
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center Research
state: Ohio
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Yvoir
country: Belgium
facility: CHU UCL Namur site Godinne
state: Namur
city: Roeselare
country: Belgium
facility: AZ Delta
state: Roeselare West-Vlaanderen
city: Haifa
country: Israel
facility: Rambam Health Care Campus (RHCC) - Meyer Children's Hospital - Pediatric Diabetes & Obesity Clinic
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra-Sede Madrid
city: Malaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra, Dept of Oncology
city: Valencia
country: Spain
facility: Hospital Universitario La Fe de Valencia
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: