A Window of Opportunity Trial to Learn if Linvoseltamab is Safe and Well Tolerated, and How Well it Works in Adult Participants With Recently Diagnosed Multiple Myeloma Who Have Not Already Received Treatment (LINKER-MM4)

Phase 1/2 Study of Linvoseltamab (Anti-BCMA X Anti-CD3 Bispecific Antibody) in Previously Untreated Patients With Symptomatic Multiple Myeloma

This study is researching an experimental drug called linvoseltamab (called "study drug"). The study is focused on participants with newly diagnosed multiple myeloma (NDMM) who are eligible for high dose chemotherapy with autologous stem cell transplantation (transplant-eligible) or ineligible for autologous stem cell transplantation (transplant-ineligible).

The aim of this clinical trial is to study the safety, tolerability (how the body reacts to the drug), and effectiveness (tumor shrinkage) of linvoseltamab in study participants with NDMM as a first step in determining if the study drug has a role in the treatment of NDMM.

This study consists of 2 phases:

• In Phase 1, the study drug will be given to participants to study the side effects of the study drug and to establish the regimen (initial doses and full dose) of the study drug to be given to participants in Phase 2.
• In Phase 2, the study drug will be given to more participants to continue to assess the side effects of the study drug and to evaluate the ability of the study drug to shrink the tumor (multiple myeloma) in participants with NDMM.

The study is looking at several research questions, including:

• What side effects may happen from taking linvoseltamab?
• What the right dosing regimen is for linvoseltamab?
• How many participants treated with linvoseltamab have improvement of their disease and for how long?
• The effects of linvoseltamab study treatment before and after transplant
• How much linvoseltamab is in the blood at different times?
• Whether the body makes antibodies against linvoseltamab (which could make the drug less effective or could lead to side effects).

Study Overview

• Status: Recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Linvoseltamab

• Study Type: Interventional
• Enrollment (Estimated): 132
• Phase: Phase 2; Phase 1

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

• Study Contact: Name: Clinical Trials Administrator; Phone Number: 844-734-6643; Email: clinicaltrials@regeneron.com

Study Locations

• France
  • Lille, France, 59000
    • Not yet recruiting
    • CHU de Lille
  • Paris, France, 75015
    • Not yet recruiting
    • Hôpital Universitaire Necker Enfants Malades
• United States
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Recruiting
      • Karmanos Cancer Institute
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Recruiting
      • Rutgers Cancer Institute of New Jersey
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
2. Confirmed diagnosis of symptomatic multiple myeloma (MM) by International Myeloma Working Group (IMWG) diagnosis criteria
3. Measurable disease, according to the 2016 IMWG response criteria, as defined in the protocol
4. No prior therapy for MM, with the exception of prior emergent or palliative radiation and up to 1 month of single-agent corticosteroids, with washout periods as per the protocol
5. Participants must have evidence of adequate bone marrow reserves and hepatic, renal and cardiac function as defined in the protocol
6. Participants must be age <70 and have adequate hepatic, renal, pulmonary and cardiac function to be considered transplant-eligible. The specific thresholds for adequate organ function are as per institutional guidance.

Key Exclusion Criteria:

1. Receiving any concurrent investigational agent with known or suspected activity against MM, or agents targeting the A proliferation-inducing ligand (APRIL)/ Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI)/BCMA axis
2. Known central nervous system (CNS) involvement with MM, known or suspected progressive multifocal leukoencephalopathy (PML), a history of neurocognitive conditions, or CNS movement disorder, or history of seizure within 12 months prior to study enrollment
3. Rapidly progressive symptomatic disease, (e.g. progressing renal failure or hypercalcemia not responsive to standard medical interventions), in urgent need of treatment with chemotherapy
4. Diagnosis of non-secretory MM, active plasma cell leukemia, primary light-chain (AL) amyloidosis, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), or known POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)

Note: Other protocol-defined Inclusion/Exclusion criteria apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 cohort; Linvoseltamab dose escalation (part A) and dose expansion (part B) for participants with NDMM who are treatment-naïve.	Drug: Linvoseltamab; Linvoseltamab will be administered by intravenous (IV) infusion; Other Names: REGN5458
Experimental: Phase 2 - transplant ineligible cohort; Transplant-ineligible participants, enrolled in dose expansion, will receive selected Linvoseltamab regimen until disease progression as per protocol.	Drug: Linvoseltamab; Linvoseltamab will be administered by intravenous (IV) infusion; Other Names: REGN5458
Experimental: Phase 2 - transplant eligible cohort; Transplant-eligible participants, enrolled in dose expansion, will receive selected linvoseltamab regimen for a fixed duration of treatment as per protocol	Drug: Linvoseltamab; Linvoseltamab will be administered by intravenous (IV) infusion; Other Names: REGN5458

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of dose-limiting toxicities (DLTs)	Phase 1	End of the Observation period; up to day 28
Incidence of treatment-emergent adverse events (TEAEs)	Phase 1	Post-Last Linvoseltamab Dose, up to 90 days
Incidence of adverse events of special interest (AESIs)	Phase 1	Post-Last Linvoseltamab Dose, up to 90 days
Proportion of participants with a very good partial response (VGPR) or better using the International Myeloma Working Group (IMWG) response criteria	Phase 2	Up to 5 years
Proportion of participants achieving Minimal Residual Disease (MRD) negative status (at 10^-5) after induction with consolidation therapy	Phase 2 Transplant-eligible cohort	Up to 5 years
Proportion of participants achieving MRD-negative status (at 10^-5) after induction without consolidation therapy	Phase 2 Transplant-eligible cohort	Up to 5 years
Proportion of participants achieving MRD-negative status as their best response after treatment period I with continuing to treatment period II	Phase 2 Transplant-ineligible cohort	Up to 5 years
Proportion of participants achieving MRD-negative status as their best response after treatment period I without continuing to treatment period II	Phase 2 Transplant ineligible cohort	Up to 5 years
Severity of TEAEs	Phase 1	Post-Last Linvoseltamab Dose, up to 90 days
Severity of AESIs	Phase 1	Post-Last Linvoseltamab Dose, up to 90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentrations of Linvoseltamab in serum	Phases 1 and 2	Post-Last Linvoseltamab Dose, up to 12 weeks
Concentrations of total soluble B-cell maturation antigen (BCMA)	Phases 1 and 2	Post-Last Linvoseltamab Dose, up to 12 weeks
Incidence of anti-drug antibodies (ADAs) to Linvoseltamab	Phases 1 and 2	Post-Last Linvoseltamab Dose, up to 30 days
Titer of ADAs to Linvoseltamab	Phases 1 and 2	Post-Last Linvoseltamab Dose, up to 30 days
Objective response rate (ORR) measured using the IMWG criteria	Phase 1	Up to 5 years
Duration of Response (DOR) measured using the IMWG criteria	Phase 1	Post-Last Linvoseltamab Dose, up to 90 days
Progression-free survival (PFS) measured using the IMWG criteria	Phase 1	Post-Last Linvoseltamab Dose, up to 90 days
Proportion of participants achieving MRD-negative status (at 10^-5) in participants with NDMM measured using the IMWG criteria	Phase 1	Post-Last Linvoseltamab Dose, up to 90 days
Severity of TEAEs	Phase 2	Post-Last Linvoseltamab Dose, up to 90 days
Severity of AESIs	Phase 2	Post-Last Linvoseltamab Dose, up to 90 days
ORR of participants deemed transplant-eligible and transplant-ineligible by the treating physician	Phase 2	Up to 5 years
MRD-negative status of participants deemed transplant-eligible and transplant-ineligible by the treating physician	Phase 2	Post-Last Linvoseltamab Dose, up to 90 days
DOR of participants deemed transplant-eligible and transplant-ineligible by the treating physician	Phase 2	Post-Last Linvoseltamab Dose, up to 90 days
PFS of participants deemed transplant-eligible and transplant-ineligible by the treating physician	Phase 2	Post-Last Linvoseltamab Dose, up to 90 days
Overall Survival (OS) of participants deemed transplant-eligible and transplant-ineligible by the treating physician	Phase 2	Post-Last Linvoseltamab Dose, up to 90 days
Time to response (TTR) as measured using the IMWG criteria	Phase 2	Post-Last Linvoseltamab Dose, up to 90 days
ORR by risk levels	Phase 2	Post-Last Linvoseltamab Dose, up to 90 days
MRD-negative rstatus by risk levels	Phase 2	Post-Last Linvoseltamab Dose, up to 90 days
DOR by risk levels	Phase 2	Post-Last Linvoseltamab Dose, up to 90 days
TTR by risk levels	Phase 2	Post-Last Linvoseltamab Dose, up to 90 days
PFS by risk levels	Phase 2	Post-Last Linvoseltamab Dose, up to 90 days
Incidence of MRD-negative status	Phase 2	Up to 5 years
Cluster of differentiation 34+ (CD34+) stem cell yield	Phase 2 Transplant-eligible cohort	At cycle 4 of induction (each cycle is 28 days long)
Time to neutrophil engraftment	Phase 2 Transplant-eligible cohort	Up to 100 days post-transplant
Time to platelet engraftment	Phase 2 Transplant-eligible cohort	Up to 100 days post-transplant
PFS after ASCT followed by 3 cycles of linvoseltamab	Phase 2 Transplant-eligible cohort	Up to 5 years
Incidence of TEAEs	Phase 2	Post-Last Linvoseltamab Dose, up to 90 days
Incidence of AESIs	Phase 2	Post-Last Linvoseltamab Dose, up to 90 days

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Investigators: Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2023
• Primary Completion (Estimated): November 2, 2035
• Study Completion (Estimated): November 2, 2035

Study Registration Dates

• First Submitted: April 12, 2023
• First Submitted That Met QC Criteria: April 12, 2023
• First Posted (Actual): April 25, 2023

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: April 4, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: BCMA; Newly diagnosed multiple myeloma (NDMM); Autologous stem cell transplantation (ASCT); Cluster of differentiation 3 (CD3); High dose chemotherapy (HDT); International Myeloma Working Group (IMWG)
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell
• Other Study ID Numbers: R5458-ONC-2158; 2022-500800-24-00 (Registry Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing
• IPD Sharing Time Frame: When Regeneron has received marketing authorization from major health authorities (e.g., FDA, European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), etc.) for the product and indication, has made the study results publicly available (e.g., scientific publication, scientific conference, clinical trial registry), has the legal authority to share the data, and has ensured the ability to protect participant privacy.
• IPD Sharing Access Criteria: Qualified researchers can submit a proposal for access to individual patient or aggregate level data from a Regeneron-sponsored clinical trial through Vivli. Regeneron's Independent Research Request Evaluation Criteria can be found at: https://www.regeneron.com/sites/default/files/Regeneron-External-Data-Sharing-Policy-and-Independent-Research-Request-Evaluation-Criteria.pdf
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No