A Study to Examine the Effects of Novel Therapy Linvoseltamab in Combination With Other Cancer Treatments for Adult Patients With Multiple Myeloma That is Resistant to Current Standard of Care Treatments

Phase 1b Study of REGN5458 (Anti-BCMA x Anti-CD3 Bispecific Antibody) Plus Other Cancer Treatments for Patients With Relapsed/Refractory Multiple Myeloma

The study is researching an experimental drug called linvoseltamab in combination with other drugs for the treatment of a blood cancer called multiple myeloma. Linvoseltamab has previously been studied as a single agent (without other cancer treatments) in participants with multiple myeloma that returned after prior therapies and needed to be treated again.

In the initial study, some participants treated with linvoseltamab had improvement of their myeloma, including complete responses (no evidence of myeloma in their bodies). This study is the first time linvoseltamab will be combined with other cancer therapies. The main goal is to understand if linvoseltamab can be given safely with other cancer treatments, and if so, what dose of linvoseltamab should be used for each combination.

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

• How many participants treated with linvoseltamab in combination with each of the other cancer treatments have improvement of their multiple myeloma
• What side effects may happen from taking linvoseltamab together with another cancer treatment
• How much study drug is in your blood at different times
• Whether the body makes antibodies against the study drug (which could make the drug less effective or could lead to side effects)

Study Overview

• Status: Recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Daratumumab; Drug: Carfilzomib; Drug: Lenalidomide; Drug: Bortezomib; Drug: Pomalidomide; Drug: Isatuximab; Drug: Nirogacestat; Drug: Linvoseltamab; Drug: Fianlimab; Drug: Cemiplimab

• Study Type: Interventional
• Enrollment (Estimated): 317
• Phase: 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
  • Angers, France, 49100
    • Recruiting
    • CHU Angers
  • Lille, France, 59000
    • Recruiting
    • CHU De Lille
  • Montpellier, France, 340090
    • Recruiting
    • CHU de Montpellier
  • Paris, France, 75015
    • Recruiting
    • AP-HP Hôpital Necker - Enfants Malades
  • Poitiers, France, 86000
    • Recruiting
    • CHU de Poitiers
  • Villejuif, France, 94805
    • Recruiting
    • Gustave Roussy
  • Pays De La Loire Région
    • Nantes, Pays De La Loire Région, France, 44093
      • Recruiting
      • CHU Nantes
  • Val-de-Marne
    • Creteil, Val-de-Marne, France, 94000
      • Recruiting
      • CHU Hôpital Henri Mondor
  • Île-de-France
    • Paris, Île-de-France, France, 75012
      • Recruiting
      • Hôpital Saint-Antoine
    • Paris, Île-de-France, France, 75010
      • Recruiting
      • Saint Louis Hospital
• Greece
  • Athens, Greece, 11528
    • Recruiting
    • General Hospital of Athens Alexandra
  • Athens, Greece, 10676
    • Recruiting
    • Evangelismos General Hospital
• Spain
  • Barcelona, Spain, 08916
    • Recruiting
    • Hospital Universitario Germans Trias i Pujol
  • Barcelona, Spain, 8036
    • Recruiting
    • Institut Clinic de Nefrologia i Urologia - ICNU, Hospital Clinic i Provincial de Barcelona
  • Madrid, Spain, 28041
    • Recruiting
    • Hospital Universitario 12 De Octubre
  • Madrid, Spain, 28027
    • Recruiting
    • Clinica Universidad de Navarra
  • Madrid, Spain, 28034
    • Recruiting
    • Hospital Ramón y Cajal
  • Madrid, Spain, 28050
    • Recruiting
    • Hospital Universitario HM Sanchinarro
  • Madrid, Spain, 28223
    • Recruiting
    • Hospital Universitario Quiron Salud Madrid
  • Madrid, Spain, 28006
    • Recruiting
    • Hospital universitiario de La Princea
  • Salamanca, Spain, 37007
    • Recruiting
    • Hospital Universitario de Salamanca
  • A Coruña
    • Santiago, A Coruña, Spain
      • Recruiting
      • Hospital Clínico Universitario de Santiago
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Recruiting
      • Hospital Universitario Marqués de Valdecilla (HUMV)
  • Catalonia
    • Barcelona, Catalonia, Spain, 08035
      • Recruiting
      • Hospital Universitari Vall d'Hebron
    • Barcelona, Catalonia, Spain, 08908
      • Recruiting
      • Institut Catala d'Oncologia
  • Navarre
    • Pamplona, Navarre, Spain, 31008
      • Recruiting
      • Clinica Universidad de Navarra
• United States
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Recruiting
      • Karmanos Cancer Institute
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Medical Center
  • North Carolina
    • Hillsborough, North Carolina, United States, 27278
      • Recruiting
      • UNC Hillsborough
    • Winston-Salem, North Carolina, United States, 27157
      • Recruiting
      • Atrium Health Wake Forest Baptist
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University
  • Washington
    • Seattle, Washington, United States, 98108
      • Recruiting
      • VA Puget Sound Health Care System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

General Key Inclusion Criteria:

1. Eastern Cooperative Oncology Group (ECOG) performance status ≤1
2. Participants must have measurable disease as defined in the protocol according to International Myeloma Working Group (IMWG) consensus criteria
3. Adequate creatinine clearance, hematologic function and hepatic function, as defined in protocol
4. Life expectancy of at least 6 months.

Cohort Specific Inclusion Criteria:

For the below cohorts, each participant must have RRMM with progression following at least 3 lines of therapy, or at least 2 lines of therapy and either prior exposure to at least 1 anti-CD38 antibody, 1 immunomodulatory imide drug (IMiD) and 1 proteasome inhibitor (PI), or double-refractory to 1 PI and 1 IMiD, or the combination of 1 PI and 1 IMiD.

Cohort 1: Prior treatment with daratumumab is allowed if previously tolerated. However, participants enrolled in the expansion portion cannot be refractory to an anti-CD38 antibody containing regimen. In addition, all participants must have at least a 6-month washout from prior anti-CD38 antibody therapy.

Cohort 2: Prior treatment with carfilzomib is allowed if previously tolerated at the approved full dose. Carfilzomib-refractory participants may enroll in the dose finding portion provided they are triple-class refractory (PI, IMiD, anti-CD38 antibody). However, participants enrolled in the dose expansion portion cannot be refractory to carfilzomib. In addition, all participants must have at least a 6-month washout from prior carfilzomib therapy.

Cohort 3: Prior treatment with lenalidomide is allowed if previously tolerated at the approved full dose. However, a participant cannot be refractory to any combination regimen that included 25 mg of lenalidomide. In addition, participants must have at least a 6-month washout from any prior lenalidomide therapy (including maintenance therapy).

Cohort 4: Prior treatment with bortezomib is allowed if previously tolerated at the approved full dose. Bortezomib-refractory participants may enroll in the dose finding portion provided they are triple-class refractory (PI, IMiD, anti-CD38 antibody). However, participants enrolled in the dose expansion portion cannot be refractory to bortezomib. In addition, all participants must have at least a 6-month washout from prior bortezomib therapy.

Cohort 5: Prior treatment with pomalidomide is allowed if previously tolerated at the approved full dose. Additionally, participants must undergo at least a 6-month washout following prior pomalidomide therapy before enrollment.

Cohort 6: Prior treatment with isatuximab is allowed if previously tolerated. Additionally, participants must undergo at least a 3-month washout following prior anti-CD38 antibody therapy before enrollment.

Cohort 7 and 8: RRMM with progressive disease and one of the following:

• Received at least 3 lines of therapy including exposure to at least 1 anti-CD38 antibody, 1IMiD, and 1 PI or
• Triple-class refractory disease (anti-CD38 antibody, IMiD, PI)

Cohort 9: each participant must have progressive RRMM and the following:

• Received at least 3 lines of therapy and
• Triple-class refractory disease (anti-CD38 antibody, IMiD, PI)

General Key Exclusion Criteria:

1. Diagnosis of plasma cell leukemia, primary light-chain amyloidosis (excluding myeloma associated amyloidosis), Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
2. Participants with known MM brain lesions or meningeal involvement
3. Treatment with any systemic anti-myeloma therapy within 5 half-lives or within 21 days prior to first administration of study drug regimen, whichever is shorter
4. History of allogeneic stem cell transplantation, or autologous stem cell transplantation within 12 weeks of the start of study drug regimen
5. Unless stated otherwise in a specific sub-protocol, prior treatment with BCMA-directed immunotherapies, including BCMA bispecific antibodies and bispecific T-cell engagers (BiTEs), and BCMA chimeric antigen receptor (CAR) T cells (Note: BCMA antibody-drug conjugates are not excluded)
6. History of progressive multifocal leukoencephalopathy, neurodegenerative condition or central nervous system (CNS) movement disorder or participants with a history of seizure within 12 months prior to study enrollment are excluded
7. Live or attenuated vaccination within 28 days prior to first study drug regimen administration with a vector that has replicative potential
8. Cardiac ejection fraction <40% by echocardiogram (Echo) or multigated acquisition (MUGA) scan.

Cohort Specific Exclusion Criteria:

Cohort 3:

1. Known malabsorption syndrome or pre-existing gastrointestinal (GI) conditions that may impair absorption of lenalidomide (eg, gastric bypass, lap band, or other gastric procedures that would alter absorption); delivery of lenalidomide via nasogastric tube or gastrostomy tube is not allowed.

Cohort 4:

1. Peripheral neuropathy grade ≥2

Cohort 5:

1. Known malabsorption syndrome or pre-existing GI conditions that may impair absorption of pomalidomide (eg, gastric bypass, lap band, or other gastric procedures that would alter absorption); delivery of pomalidomide via nasogastric tube or gastrostomy tube is not allowed.

Cohort 7:

1. Prior treatment with anti-lymphocyte activation gene 3 (LAG-3) agents. Prior exposure to vaccine therapies or other immune checkpoint modulating therapies such as anti-programmed cell death protein 1 (PD-1) antibodies is permitted, as described in the protocol.
2. Ongoing or recent (within 2 years) evidence of an autoimmune disease that has required systemic treatment with immunosuppressive agents, as described in the protocol.
3. Prior solid organ transplant.
4. History of grade ≥3 immune-mediated adverse events (with the exclusion of endocrinopathies that are fully controlled by hormone replacement) from prior checkpoint inhibitor therapies.

Cohort 8:

1. Prior treatment with anti-PD-1 or anti-PD-L1 agents. Prior exposure to vaccine therapies or other immune checkpoint modulating therapies such as anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibodies is permitted, as described in the protocol.
2. Encephalitis or meningitis in the year prior to enrollment.
3. History of interstitial lung disease (eg, idiopathic pulmonary fibrosis or organizing pneumonia), of active, noninfectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management, or of pneumonitis within the last 5 years. A history of radiation pneumonitis in the radiation field is permitted as long as pneumonitis resolved ≥6 months prior to enrollment.
4. Ongoing or recent (within 2 years) evidence of an autoimmune disease that has required systemic treatment with immunosuppressive agents, as described in the protocol.
5. Prior solid organ transplant.
6. History of grade ≥3 immune-mediated adverse events (with the exclusion of endocrinopathies that are fully controlled by hormone replacement) from prior checkpoint inhibitor therapies.

Cohort 9:

1. Abnormal QT interval corrected by Fridericia's formula (QTcF), as described in the protocol
2. Use of concomitant medications that are known to prolong the QT/QTcF interval including Class Ia and Class III antiarrhythmics at the time of informed consent
3. Ongoing use or anticipated use of food or drugs that are known strong/moderate cytochrome P450 (CYP)3A4 inhibitors, or strong CYP3A inducers within 14 days prior to first dose of nirogacestat
4. Known malabsorption syndrome or existing gastrointestinal GI conditions that may impair absorption of nirogacestat (eg, gastric bypass, lap band, or other gastric procedures that would alter absorption); delivery of nirogacestat via nasogastric tube or gastrostomy tube is not allowed.

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

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: Linvoseltamab + Daratumumab; Linvoseltamab + Daratumumab	Drug: Daratumumab; Daratumumab is administered by IV infusion and/or subcutaneous (SC) injection; SC injection may be used after a minimum of 2 cycles of IV administration at the investigator's discretion.; Other Names: Darzalex®; Darzalex Faspro™; Drug: Linvoseltamab; Linvoseltamab is administered by intravenous (IV) infusion; Other Names: REGN5458
Experimental: Cohort 2: Linvolseltamab + Carfilzomib; Linvoseltamab + Carfilzomib	Drug: Carfilzomib; Carfilzomib is administered by IV infusion; Other Names: Kyprolis®; Drug: Linvoseltamab; Linvoseltamab is administered by intravenous (IV) infusion; Other Names: REGN5458
Experimental: Cohort 3: Linvoseltamab + Lenalidomide; Linvoseltamab + Lenalidomide	Drug: Lenalidomide; Lenalidomide is administered by mouth (PO) as a capsule; Other Names: Revlimid®; Drug: Linvoseltamab; Linvoseltamab is administered by intravenous (IV) infusion; Other Names: REGN5458
Experimental: Cohort 4: Linvoseltamab + Bortezomib; Linvoseltamab + Bortezomib	Drug: Bortezomib; Bortezomib is administered by IV infusion or SC injection; Other Names: Velcade®; Drug: Linvoseltamab; Linvoseltamab is administered by intravenous (IV) infusion; Other Names: REGN5458
Experimental: Cohort 5: Linvoseltamab + Pomalidomide; Linvoseltamab + Pomalidomide	Drug: Pomalidomide; Pomalidomide is administered by mouth (PO) as a capsule; Other Names: Imnovid, Pomalyst®; Drug: Linvoseltamab; Linvoseltamab is administered by intravenous (IV) infusion; Other Names: REGN5458
Experimental: Cohort 6: Linvoseltamab + Isatuximab; Linvoseltamab + Isatuximab	Drug: Isatuximab; Isatuximab is administered by IV infusion; Other Names: Sarclisa®; Drug: Linvoseltamab; Linvoseltamab is administered by intravenous (IV) infusion; Other Names: REGN5458
Experimental: Cohort 7: Linvoseltamab + Fianlimab; Linvoseltamab + Fianlimab	Drug: Linvoseltamab; Linvoseltamab is administered by intravenous (IV) infusion; Other Names: REGN5458; Drug: Fianlimab; Fianlimab is administered by IV infusion; Other Names: REGN3767
Experimental: Cohort 8: Linvoseltamab + Cemiplimab; Linvoseltamab + Cemiplimab	Drug: Linvoseltamab; Linvoseltamab is administered by intravenous (IV) infusion; Other Names: REGN5458; Drug: Cemiplimab; Cemiplimab is administered by IV infusion; Other Names: LIBTAYO
Experimental: Cohort 9: Linvoseltamab + Nirogacestat; Linvoseltamab + Nirogacestat	Drug: Nirogacestat; Nirogacestat is administered by mouth (PO) as a tablet; Other Names: PF-03084014

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of pre-defined safety criteria or dose-limiting toxicities (DLTs) from the first dose through the end of the DLT observation period	Dose finding portion only	Up to 28 Days
Incidence of treatment-emergent adverse events (TEAEs)		Up to 5 Years
Severity of TEAEs		Up to 5 Years
Incidence of serious adverse events (SAEs)		Up to 5 Years
Severity of SAEs		Up to 5 Years
Incidence of adverse events of special interest (AESIs)		Up to 5 Years
Severity of AESIs		Up to 5 Years
Incidence of laboratory abnormalities	≥ grade 3 per National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE v5.0]	Up to 5 Years

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall Survival (OS)	Up to 5 Years
Objective response rate (ORR) as measured by International Myeloma Working Group (IMWG) criteria	Up to 5 Years
Duration of response (DOR) by IMWG criteria	Up to 5 Years
Progression-free survival (PFS) as measured by IMWG criteria	Up to 5 Years
Rate of minimal residual disease (MRD) negative status by IMWG criteria	Up to 5 Years
Concentrations of total linvoseltamab in serum over time	Up to 5 Years
Incidence over time of anti-drug antibodies (ADAs) to linvoseltamab	Up to 5 Years

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2022
• Primary Completion (Estimated): January 13, 2027
• Study Completion (Estimated): August 7, 2032

Study Registration Dates

• First Submitted: November 18, 2021
• First Submitted That Met QC Criteria: November 18, 2021
• First Posted (Actual): November 30, 2021

Study Record Updates

• Last Update Posted (Actual): April 12, 2024
• Last Update Submitted That Met QC Criteria: April 10, 2024
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: B-cell maturation antigen (BCMA); Relapsed/Refractory Multiple Myeloma (RRMM); Anti-CD3 monoclonal antibodies (mAbs)
• 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Gamma Secretase Inhibitors and Modulators; Pomalidomide; Lenalidomide; Daratumumab; Bortezomib; Cemiplimab; Nirogacestat
• Other Study ID Numbers: R5458-ONC-2012; 2020-004638-39 (EudraCT 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