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NCT05137054PHASE1Recruiting

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

Regeneron Pharmaceuticals

Start Date

8/17/2022

Completion Date

3/24/2032

Summary

This 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 the blood at different times * Whether the body makes antibodies against the study drug(s) (which could make the study drug(s) less effective or could lead to side effects)

Eligibility Criteria

Age Range: 18 years to No maximum

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 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 cohorts 1-6, 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, as described in the protocol Cohort 2: Prior treatment with carfilzomib is allowed if previously tolerated at the approved full dose, as described in the protocol Cohort 3: Prior treatment with lenalidomide is allowed if previously tolerated at the approved full dose, as described in the protocol Cohort 4: Prior treatment with bortezomib is allowed if previously tolerated at the approved full dose, as described in the protocol Cohort 5: Prior treatment with pomalidomide is allowed if previously tolerated at the approved full dose, as described in the protocol Cohort 6: Prior treatment with isatuximab is allowed if previously tolerated, as described in the protocol Cohort 7 and 8: 1. For participants without measurable disease by biochemical parameters \[serum or urine M-protein, or serum involved Free Light Chain (FLC)\], presence of at least 1 soft tissue plasmacytoma with a single diameter of ≥2 cm 2. RRMM with progressive disease and received at least 3 lines of therapy including exposure to at least 1 anti-CD38 antibody, 1 IMiD, and 1 PI or triple-class refractory disease (anti-CD38 antibody, IMiD, PI) Cohort 9: Progressive RRMM in participants with triple-class refractory disease (anti-CD38 antibody, IMiD, PI) after at least 3 lines of therapy Cohort 10: Progressive RRMM after at least 3 lines of therapy including exposure to at least 1 anti-CD38 antibody, 1 IMiD, and 1 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 and autologous stem cell transplantation, as described in the protocol 5. Unless stated otherwise in a specific sub-protocol, prior treatment with a T cell-based immunotherapy directed against B-Cell Maturation Antigen (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 2: Dose expansion: Prior treatment with a BCMA-directed CAR T-cell therapy will not be exclusionary if completed at least 12 weeks prior to first study treatment Cohort 3: Known malabsorption syndrome or pre-existing gastrointestinal (GI) condition that may impair absorption of lenalidomide; delivery of lenalidomide via nasogastric tube or gastrostomy tube is not allowed Cohort 4: Peripheral neuropathy grade ≥2 Cohort 5: Known malabsorption syndrome or pre-existing GI conditions that may impair absorption of pomalidomide; 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 condition that may impair absorption of nirogacestat; delivery of nirogacestat via nasogastric tube or gastrostomy tube is not allowed Cohort 10: 1. Known or suspected active Epstein-Barr Virus (EBV) infection 2. Known history of Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) 3. Prior treatment with cevostamab or another agent with the same target \[Fragment crystallizable Receptor-like 5 (FcRH5)\] Dose finding portion: Prior treatment with any BCMA-directed immunotherapy will not be exclusionary, as described in the protocol Dose expansion portion: Prior treatment with any T cell-engaging bispecific antibody directed against BCMA will be exclusionary, as described in the protocol NOTE: Other protocol defined inclusion/exclusion criteria apply

Interventions

DRUG

Linvoseltamab

DRUG

Daratumumab

DRUG

Carfilzomib

DRUG

Lenalidomide

DRUG

Bortezomib

DRUG

Pomalidomide

DRUG

Isatuximab

DRUG

Fianlimab

DRUG

Cemiplimab

DRUG

Nirogacestat

DRUG

Cevostamab

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Conditions

Multiple Myeloma

Locations

Scripps Clinic Torrey Pines

La Jolla, California 92037

United States

Winship Cancer Institute of Emory University

Atlanta, Georgia 30004

United States

Indiana University Health Simon Cancer Center

Indianapolis, Indiana 46202

United States

Dana Farber/Harvard Cancer Center

Boston, Massachusetts 02215

United States

Karmanos Cancer Institute

Detroit, Michigan 48201

United States

Mayo Clinic

Rochester, Minnesota 55905

United States

Weill Cornell Medicine/New York Presbyterian Hospital

New York, New York 10021

United States

New York Presbyterian Hospital Columbia University Medical Center

New York, New York 10032

United States

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina 27599

United States

Wake Forest University Health Sciences

Winston-Salem, North Carolina 27157

United States

The Ohio State University James Cancer Hospital

Columbus, Ohio 43210

United States

University of Texas Southwestern

Dallas, Texas 75390

United States

VA Puget Sound Health Care System

Seattle, Washington 98108

United States

Centre Hospitalier Universitaire (CHU) de Poitiers

Poitiers, New Aquitaine 86021

France

CHU de Lille - Rue Michel Polonovski

Lille, Nord 59037

France

Nantes University Hospital

Nantes, Pays de la Loire Region 44093

France

Centre Hospitalier Universitaire Angers

Angers, 49933

France

CHU Montpellier - Departement D'Hematologie

Montpellier, 34295

France

Saint Antoine Hospital

Paris, 75571

France

Institut Gustave Roussy

Villejuif, 94805

France

Hospital Henri Mondor

Créteil, Île-de-France Region 94000

France

Saint Louis Hospital

Paris, Île-de-France Region 75010

France

Hopital Necker

Paris, Île-de-France Region 75015

France

Evangelismos General Hospital

Athens, Attica 10676

Greece

General Hospital of Athens Alexandra

Athens, 11528

Greece

Sheba Medical Center

Ramat Gan, Central District 5265601

Israel

Rambam Health Care Campus

Haifa, 3109601

Israel

Hadassah Medical Center

Jerusalem, 91120

Israel

Hospital Clinico Universitario de Santiago

Santiago de Compostela, A Coruna 15706

Spain

Hospital Germans Trias i Pujol

Badalona, Barcelona 08916

Spain

Hospital Universitario Marques de Valdecilla

Santander, Cantabria 39008

Spain

Hospital Universitario Quiron Salud Madrid

Pozuelo de Alarcón, Madrid 28223

Spain

Clinica Universidad de Navarra

Pamplona, Navarre 31008

Spain

Hospital Universitario Vall d'Hebron

Barcelona, 08035

Spain

Hospital Clinic de Barcelona

Barcelona, 08036

Spain

Institut Catala d'Oncologia (ICO) - Hospital Duran i Reynals,

Barcelona, 08908

Spain

Universitaru Hospital La Princesa

Madrid, 28006

Spain

Clinica Universidad de Navarra - Madrid

Madrid, 28027

Spain

Hospital Universitario Ramon y Cajal - Servicio de Psiquiatria

Madrid, 28034

Spain

University Hospital and Research Institute

Madrid, 28041

Spain

Hospital Universitario HM Sanchinarro

Madrid, 28050

Spain

University Hospital of Salamanca

Salamanca, 37007

Spain