Clinical trial NCT05137054: 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
Official title: Phase 1b Study of REGN5458 (Anti-BCMA x Anti-CD3 Bispecific Antibody) Plus Other Cancer Treatments for Patients With Relapsed/Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Multiple Myeloma
Keywords: Relapsed/Refractory Multiple Myeloma (RRMM)
B-cell maturation antigen (BCMA)
Anti-CD3 monoclonal antibodies (mAbs)
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2021-11-30
Enrollment: 317
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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: 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 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. 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 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: 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 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:

1. Dose expansion: Prior treatment with a B-cell maturation antigen (BCMA) -directed CAR T-cell therapy will not be exclusionary if completed at least 12 weeks prior to first study treatment

Cohort 3:

1. 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:

1. Peripheral neuropathy grade ≥2

Cohort 5:

1. 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 \[Fragment crystallizable receptor-like 5 (FcRH5)\].

NOTE: Other protocol defined inclusion/exclusion criteria apply

Primary outcomes:
measure: Incidence of pre-defined safety criteria or dose-limiting toxicities (DLTs) from the first dose through the end of the DLT observation period
timeFrame: Up to 28 Days
measure: Incidence of treatment-emergent adverse events (TEAEs)
timeFrame: Up to 5 Years
measure: Severity of TEAEs
timeFrame: Up to 5 Years
measure: Incidence of serious adverse events (SAEs)
timeFrame: Up to 5 Years
measure: Severity of SAEs
timeFrame: Up to 5 Years
measure: Incidence of adverse events of special interest (AESIs)
timeFrame: Up to 5 Years
measure: Severity of AESIs
timeFrame: Up to 5 Years
measure: Incidence of laboratory abnormalities
timeFrame: Up to 5 Years
Secondary outcomes:
measure: Objective response rate (ORR) as measured by International Myeloma Working Group (IMWG) criteria
timeFrame: Up to 5 Years
measure: Duration of response (DOR) by IMWG criteria
timeFrame: Up to 5 Years
measure: Progression-free survival (PFS) as measured by IMWG criteria
timeFrame: Up to 5 Years
measure: Rate of minimal residual disease (MRD) negative status by IMWG criteria
timeFrame: Up to 5 Years
measure: Concentrations of total linvoseltamab in serum over time
timeFrame: Up to 5 Years
measure: Incidence over time of anti-drug antibodies (ADAs) to linvoseltamab
timeFrame: Up to 5 Years
measure: Overall Survival (OS)
timeFrame: Up to 5 Years
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Scripps Clinic Torrey Pines
state: California
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Comprehensive Cancer
state: Indiana
city: Boston
country: United States
facility: Dana Farber/Harvard Cancer Center
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Weill Cornell Medicine/New York Presbyterian Hospital
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital Columbia University Medical Center
state: New York
city: Hillsborough
country: United States
facility: UNC Hillsborough
state: North Carolina
city: Winston-Salem
country: United States
facility: Atrium Health Wake Forest Baptist
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University James Cancer Hospital
state: Ohio
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Seattle
country: United States
facility: VA Puget Sound Health Care System
state: Washington
city: Paris
country: France
facility: Hopital Necker
state: Ile-de-France
city: Lille
country: France
facility: CHU de Lille - Rue Michel Polonovski
state: Nord
city: Nantes
country: France
facility: Nantes University Hospital
state: Pays De La Loire
city: Creteil
country: France
facility: Hospital Henri Mondor
state: Val-de-Marne
city: Angers
country: France
facility: Centre Hospitalier Universitaire Angers
city: Montpellier
country: France
facility: CHU Montpellier - Departement D'Hematologie
city: Paris
country: France
facility: Hopital Saint Antoine
city: Poitiers
country: France
facility: CHU de Poitiers
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Paris
country: France
facility: Saint Louis Hospital
state: Île-de-France
city: Athens
country: Greece
facility: Evangelismos General Hospital
city: Athens
country: Greece
facility: General Hospital of Athens Alexandra
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
state: Hamerkaz
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Santiago
country: Spain
facility: Hospital Clínico Universitario de Santiago
state: A Coruña
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
state: Barcelona
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
state: Cantabria
city: Barcelona
country: Spain
facility: Institut Català d'Oncologia
state: Catalonia
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Universitaru Hospital La Princesa
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: University Hospital and Research Institute
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro
city: Madrid
country: Spain
facility: Hospital Universitario Quiron Salud Madrid
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
Study officials:
affiliation: Regeneron Pharmaceuticals
name: Clinical Trial Management
role: STUDY_DIRECTOR
References: