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

Multiple Myeloma Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05137054
• Other study ID #: R5458-ONC-2012
• Secondary ID: 2020-004638-3920
• Status: Recruiting
• Phase: Phase 1
• Start date: August 17, 2022
• Est. completion date: January 23, 2033

Study information

• Verified date: May 2024
• Source: Regeneron Pharmaceuticals
• Contact: Clinical Trials Administrator
• Phone: 844-734-6643
• Email: clinicaltrials[@]regeneron.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 (which could make the drug less effective or could lead to side effects)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 317
• Est. completion date: January 23, 2033
• Est. primary completion date: March 27, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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) 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.

NOTE: Other protocol defined inclusion/exclusion criteria apply

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Linvoseltamab
Linvoseltamab is administered by intravenous (IV) infusion
• 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.
• Carfilzomib
Carfilzomib is administered by IV infusion
• Lenalidomide
Lenalidomide is administered by mouth (PO) as a capsule
• Bortezomib
Bortezomib is administered by IV infusion or SC injection
• Pomalidomide
Pomalidomide is administered by mouth (PO) as a capsule
• Isatuximab
Isatuximab is administered by IV infusion
• Fianlimab
Fianlimab is administered by IV infusion
• Cemiplimab
Cemiplimab is administered by IV infusion
• Nirogacestat
Nirogacestat is administered by mouth (PO) as a tablet

Locations

Country	Name	City	State
France	CHU Angers	Angers
France	CHU Hopital Henri Mondor	Creteil	Val-de-Marne
France	Chu De Lille	Lille
France	CHU de Montpellier	Montpellier
France	CHU Nantes	Nantes	Pays De La Loire Région
France	AP-HP Hôpital Necker - Enfants Malades	Paris
France	Hôpital Saint-Antoine	Paris	Île-de-France
France	Saint Louis Hospital	Paris	Île-de-France
France	CHU de Poitiers	Poitiers
France	Gustave Roussy	Villejuif
Greece	Evangelismos General Hospital	Athens
Greece	General Hospital of Athens Alexandra	Athens
Spain	Hospital Universitari Vall D'Hebron	Barcelona	Catalonia
Spain	Hospital Universitario Germans Trias i Pujol	Barcelona
Spain	Institut Català d'Oncologia	Barcelona	Catalonia
Spain	Institut Clinic de Nefrologia i Urologia - ICNU, Hospital Clinic i Provincial de Barcelona	Barcelona
Spain	Clinica Universidad de Navarra	Madrid
Spain	Hospital Ramon Y Cajal	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario HM Sanchinarro	Madrid
Spain	Hospital Universitario Quiron Salud Madrid	Madrid
Spain	Hospital universitiario de La Princea	Madrid
Spain	Clinica Universidad de Navarra	Pamplona	Navarre
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitario Marqués de Valdecilla (HUMV)	Santander	Cantabria
Spain	Hospital Clínico Universitario de Santiago	Santiago	A Coruña
United States	Ohio State University	Columbus	Ohio
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	UNC Hillsborough	Hillsborough	North Carolina
United States	Columbia University Medical Center	New York	New York
United States	Mayo Clinic	Rochester	Minnesota
United States	VA Puget Sound Health Care System	Seattle	Washington
United States	Atrium Health Wake Forest Baptist	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Regeneron Pharmaceuticals

Countries where clinical trial is conducted

United States,  France,  Greece,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Incidence of treatment-emergent adverse events (TEAEs)		Up to 5 Years
Primary	Severity of TEAEs		Up to 5 Years
Primary	Incidence of serious adverse events (SAEs)		Up to 5 Years
Primary	Severity of SAEs		Up to 5 Years
Primary	Incidence of adverse events of special interest (AESIs)		Up to 5 Years
Primary	Severity of AESIs		Up to 5 Years
Primary	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	Objective response rate (ORR) as measured by International Myeloma Working Group (IMWG) criteria		Up to 5 Years
Secondary	Duration of response (DOR) by IMWG criteria		Up to 5 Years
Secondary	Progression-free survival (PFS) as measured by IMWG criteria		Up to 5 Years
Secondary	Rate of minimal residual disease (MRD) negative status by IMWG criteria		Up to 5 Years
Secondary	Concentrations of total linvoseltamab in serum over time		Up to 5 Years
Secondary	Incidence over time of anti-drug antibodies (ADAs) to linvoseltamab		Up to 5 Years
Secondary	Overall Survival (OS)		Up to 5 Years