Phase 1/2 Study of Linvoseltamab in Adult Patients With Relapsed or Refractory Multiple Myeloma

Phase 1

Recruiting

• Conditions: Multiple Myeloma
• Interventions: Drug: Linvoseltamab

• Registration Number: NCT03761108
• Lead Sponsor: Regeneron Pharmaceuticals

Brief Summary

The main purpose of this study is to learn about the safety of linvoseltamab and to find out what is the best dose of linvoseltamab to give to patients with multiple myeloma and to look for any signs that linvoseltamab can effectively treat cancer.

The study is looking at several other research questions, including:

* Side effects that may be experienced by people receiving linvoseltamab

* How linvoseltamab works in the body

* How much linvoseltamab is present in the blood

* How linvoseltamab may work to treat cancer

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-11-29
• Study First Submitted QC: 2018-11-29
• Study First Posted: 2018-12-03
• Study Start: 2019-01-23
• Status Verified: 2025-08
• Last Update Submitted: 2025-10-08
• Last Update Posted: 2025-10-10
• Primary Completion: 2033-03-30
• Study Completion: 2033-06-16

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 387

Inclusion Criteria

1. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

2. Confirmed diagnosis of active Multiple Myeloma (MM) by International Myeloma Working Group (IMWG) diagnostic criteria

3. Patients must have myeloma that is response-evaluable according to the 2016 IMWG response criteria as defined in the protocol.

   • Phase 1, Part 1 (Dose Escalation): Patients with MM who have exhausted all therapeutic options that are expected to provide meaningful clinical benefit, either through disease relapse, treatment refractory disease or intolerance of the therapy and including either:

     a. Progression on or after at least 3 lines of therapy, or intolerance of therapy, including a proteasome inhibitor, an Immunomodulatory agent (IMiD), and an anti-CD38 antibody, OR b. Progression on or after an anti-CD38 antibody and have disease that is "double refractory" to a proteasome inhibitor and an IMiD, or intolerance of therapy. The anti-CD38 antibody may have been administered alone or in combination with another agent such as a proteasome inhibitor (PI). Refractory disease is defined as lack of response or relapse within 60 days of last treatment.

   • Phase 1, Part 2 (SC Administration): Patients with MM whose disease meets the following criteria:

     a. Progression on or after at least 3 prior lines of therapy including a(n) PI, IMiD, and anti-CD38 antibody, OR b. Patients must be triple-refractory, defined as being refractory to prior treatment with at least 1 anti-CD38 antibody, a proteasome inhibitor, and an IMiD.

   • Phase 2 (Cohorts 1 and 2):

   Patients with MM whose disease meets the following criteria:

   a. Progression on or after at least 3 prior lines of therapy including a(n) PI, IMiD, and anti-CD38 antibody, OR b. Patients must be triple- refractory, defined as being refractory* to prior treatment with at least 1 PI, 1 IMiD, and an anti-CD38 antibody.

   • Phase 2 (Cohort 3):

   Patients with MM whose disease meets the following criteria:

   1. Progression on or after at least 3 prior lines of therapy including a(n) PI, IMiD, and anti-CD38 antibody, OR

   2. Patients must be triple- refractory, defined as being refractory* to prior treatment with at least 1 PI, 1 IMiD, and an anti-CD38 antibody.

      • Refractory disease is defined as progression during treatment or within 60 days after completion of therapy, or <25% response to therapy.

   AND, for ALL patients, if they have relapsed after a BCMA-directed CAR-T cellular therapy then:

   • Treatment with a CAR-T must have been associated with a response of PR or better, and

   • If CAR-T cellular therapy was the most recent prior therapy, excluding corticosteroids, then treatment must have been a minimum of 60 days prior to treatment with linvoseltamab.

   Key

Exclusion Criteria

1. Diagnosis of plasma cell leukemia, primary systemic light-chain amyloidosis, (excluding myeloma-associated amyloidosis), Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 2. Patients with known MM brain lesions or meningeal involvement 3. Cardiac ejection fraction <40% by echocardiogram or multi-gated acquisition scan (MUGA) 4. Prior treatment with BCMA-directed immunotherapies, including BCMA bispecific antibodies and BiTEs. Note: BCMA antibody-drug conjugates are not excluded and BCMA-directed CAR-T treatment is not excluded in Phase 2 Cohort 3.

5. History of allogeneic stem cell transplantation at any time, or autologous stem cell transplantation within 12 weeks of the start of study treatment

Note 1: Other protocol defined inclusion / exclusion criteria apply Note 2: US sites are active but currently not enrolling

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Linvoseltamab - Phase 1	Linvoseltamab	Phase 1 has two parts. Part 1, consists of linvoseltamab intravenous (IV) dose escalation and Part 2, consists of subcutaneous (SC) administration. Note: subcutaneous (SC) administration is not applicable for US.
Linvoseltamab - Phase 2 - Cohort 1	Linvoseltamab	Low Dose of linvoseltamab IV monotherapy.
Linvoseltamab - Phase 2 - Cohort 2	Linvoseltamab	High Dose of linvoseltamab IV monotherapy.
Linvoseltamab - Phase 2 - Cohort 3	Linvoseltamab	Anti-interleukin (IL)-6 receptor (R) prophylactic therapy followed by high dose of IV linvoseltamab monotherapy Note: Cohort 3 is not applicable for US.

Primary Outcome Measures

Name	Time	Method
Incidence of dose-limiting toxicities (DLTs) from the first dose through the end of the DLT observation period	Up to 28 days	Phase 1 and Phase 2 for Japanese cohort only
Incidence and severity of treatment-emergent adverse events (TEAEs)	Up to 5 years	Phase 1 Note: Phase 1, part 2 is not applicable for US.
Incidence and severity of adverse events of special interest (AESI)	Up to 5 years	Phase 1 Note: Phase 1, part 2 is not applicable for US.
Assessment of the pharmacokinetics (PK) of linvoseltamab	Up to 5 years	Phase 1 part 2 Note: Phase 1, part 2 is not applicable for US.
Concentrations of linvoseltamab in serum over time	Up to 5 years	Phase 2, for Japanese cohort only
Objective response rate (ORR) as determined by an Independent Review Committee (IRC)	Up to 5 years	Phase 2, cohorts 1 and 2
Incidence and severity of cytokine release syndrome (CRS) with linvoseltamab	Up to 5 years	Phase 2, cohort 3 Note: Phase 2, Cohort 3 is not applicable for US.
ORR of IV linvoseltamab as assessed by investigator	Up to 5 years	Phase 2, cohort 3 Note: Phase 2, Cohort 3 is not applicable for US.

Secondary Outcome Measures

Name	Time	Method
Concentrations of linvoseltamab in the serum over time	Up to 5 years	Phase 1 part 1 and Phase 2 Note: Phase 2, Cohort 3 is not applicable for US.
Incidence over time of anti-drug antibodies (ADAs) to linvoseltamab	Up to 5 years	Phase 1 and Phase 2 Note: Phase 1, part 2 and Phase 2, Cohort 3 is not applicable for US.
Titer of anti-drug antibodies (ADAs) to linvoseltamab over time	Up to 5 years	Phase 1 and Phase 2 Note: Phase 1, part 2 and Phase 2, Cohort 3 is not applicable for US.
Incidence of neutralizing antibodies (NAb) to linvoseltamab over time	Up to 5 years	Phase 1 and Phase 2 Note: Phase 1, part 2 and Phase 2, Cohort 3 is not applicable for US.
Duration of response (DOR) as determined by an IRC, measured using the IMWG criteria	Up to 5 years	Phase 2, cohorts 1 and 2
DOR as determined by an investigator, measured using the International Myeloma Working Group (IMWG) criteria	Up to 5 years	Phase 1 and Phase 2 Note: Phase 1, part 2 is not applicable for US.
Progression-free survival (PFS) as determined by an IRC, measured using the IMWG criteria	Up to 5 years	Phase 2
PFS as determined by an investigator, measured using the IMWG criteria	Up to 5 years	Phase 1 and Phase 2 Note: Phase 1, part 2 is not applicable for US.
Rate of minimal residual disease (MRD) negative status, using the IMWG criteria	Up to 5 years	Phase 1 Note: Phase 1, part 2 is not applicable for US.
Rate of MRD negative status	Up to 5 years	Phase 2 Note: Phase 2, Cohort 3 is not applicable for US.
Overall survival (OS)	Up to 5 years	Phase 1 and Phase 2 Note: Phase 1, part 2 and Phase 2, Cohort 3 is not applicable for US.
ORR as measured as determined by blinded IRC, as measured using the IMWG criteria	Up to 5 years	Phase 1, part 1 dose level 7 (DL7)
ORR as determined by the investigator, measured using the IMWG criteria	Up to 5 years	Phase 1 and Phase 2 Note: Phase 1, part 2 is not applicable for US.
Effects of linvoseltamab on health-related quality of life (HRQoL) and patient-reported symptoms and functioning per European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)	Up to 5 years	Phase 2; The EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including global health status/quality of life, functional Scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Participants rate items on a 4-point scale, with 1 as "not at all" and 4 as "very much."; Note: Phase 2, Cohort 3 is not applicable for US.
Effects of linvoseltamab on HRQOL and patient-reported symptoms and functioning per Quality of Life Questionnaire-Multiple Myeloma module 20 [QLQ-MY20])	Up to 5 years	Phase 2; The EORTC QLQ-MY20 is a self -administered instrument to assess QoL in persons with MM. This 20-item questionnaire measures the following domains: symptom scales, including disease symptoms (6 items) and symptoms related to side effects of treatment (10 items); function scale and future perspective (3 items); and body image (1 item). A high score represents a high level of symptoms or problems.; Note: Phase 2, Cohort 3 is not applicable for US.
Effects of linvoseltamab on HRQOL and patient-reported symptoms and functioning per EuroQoL-5 Dimension-3 Level Scale [EQ-5D-3L])	Up to 5 years	Phase 2; The EQ-5D-3L is a self-administered generic standardized health status measure, consisting of an EQ-5D descriptive system and an EQ visual analog scale. The EQ-5D-3L descriptive system assesses 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a 3-level scale: no problems, some problems, and extreme problems. The EQ visual analog scale component is a vertical visual analog scale used by patients to rate their health.; Note: Phase 2, Cohort 3 is not applicable for US.
Change in patient-reported global health status/QoL per EORTC QLQ-C30	Baseline up to Up to 5 years	Phase 2 Note: Phase 2, Cohort 3 is not applicable for US.
Time to definitive deterioration in patient-reported global health status/QoL per EORTC QLQ-C30	Up to 5 years	Phase 2 Note: Phase 2, Cohort 3 is not applicable for US.
Effects of linvoseltamab on general health status per EQ-5D-3L	Up to 5 years	Phase 2 Note: Phase 2, Cohort 3 is not applicable for US.
Effects of linvoseltamab on patient-reported functions and symptoms per EORTC QLQ-C30	Up to 5 years	Phase 2 Note: Phase 2, Cohort 3 is not applicable for US.
Effects of linvoseltamab on patient-reported functions and symptoms per QLQ-MY20	Up to 5 years	Phase 2 Note: Phase 2, Cohort 3 is not applicable for US.
Incidence and severity of TEAEs with linvoseltamab	Up to 5 years	Phase 2 Note: Phase 2, Cohort 3 is not applicable for US.
Incidence and severity of AESIs with linvoseltamab	Up to 5 years	Phase 2 Note: Phase 2, Cohort 3 is not applicable for US.

Trial Locations

Locations (40)

Sylvester Comprehensive Cancer Center; 🇺🇸 Miami, Florida, United States

Moffitt Cancer Center - McKinley Drive; 🇺🇸 Tampa, Florida, United States

Emory University Hospital; 🇺🇸 Atlanta, Georgia, United States

Indiana University_Michigan Street; 🇺🇸 Indianapolis, Indiana, United States

Norton Cancer Institute; 🇺🇸 Louisville, Kentucky, United States

C. S. Mott_University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

Barbara Ann Karmanos Cancer Center; 🇺🇸 Detroit, Michigan, United States

Rutgers Cancer Institute of New Jersey; 🇺🇸 New Brunswick, New Jersey, United States

Icahn School of Medicine at Mount Sinai; 🇺🇸 New York, New York, United States

Columbia University Medical Center; 🇺🇸 New York, New York, United States

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