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
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| ClinicalTrials.gov Identifier: NCT05137054 |
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Recruitment Status :
Recruiting
First Posted : November 30, 2021
Last Update Posted : April 12, 2024
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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)
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Multiple Myeloma | Drug: Linvoseltamab Drug: Daratumumab Drug: Carfilzomib Drug: Lenalidomide Drug: Bortezomib Drug: Pomalidomide Drug: Isatuximab Drug: Fianlimab Drug: Cemiplimab Drug: Nirogacestat | Phase 1 |
Expanded Access : An investigational treatment associated with this study is available outside the clinical trial. More info ...
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 317 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Sequential Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | August 17, 2022 |
| Estimated Primary Completion Date : | January 13, 2027 |
| Estimated Study Completion Date : | August 7, 2032 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Cohort 1: Linvoseltamab + Daratumumab
Linvoseltamab + Daratumumab
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Drug: Linvoseltamab
Linvoseltamab is administered by intravenous (IV) infusion
Other Name: REGN5458 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 Name: Darzalex®; Darzalex Faspro™ |
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Experimental: Cohort 2: Linvolseltamab + Carfilzomib
Linvoseltamab + Carfilzomib
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Drug: Linvoseltamab
Linvoseltamab is administered by intravenous (IV) infusion
Other Name: REGN5458 Drug: Carfilzomib Carfilzomib is administered by IV infusion
Other Name: Kyprolis® |
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Experimental: Cohort 3: Linvoseltamab + Lenalidomide
Linvoseltamab + Lenalidomide
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Drug: Linvoseltamab
Linvoseltamab is administered by intravenous (IV) infusion
Other Name: REGN5458 Drug: Lenalidomide Lenalidomide is administered by mouth (PO) as a capsule
Other Name: Revlimid® |
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Experimental: Cohort 4: Linvoseltamab + Bortezomib
Linvoseltamab + Bortezomib
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Drug: Linvoseltamab
Linvoseltamab is administered by intravenous (IV) infusion
Other Name: REGN5458 Drug: Bortezomib Bortezomib is administered by IV infusion or SC injection
Other Name: Velcade® |
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Experimental: Cohort 5: Linvoseltamab + Pomalidomide
Linvoseltamab + Pomalidomide
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Drug: Linvoseltamab
Linvoseltamab is administered by intravenous (IV) infusion
Other Name: REGN5458 Drug: Pomalidomide Pomalidomide is administered by mouth (PO) as a capsule
Other Name: Imnovid, Pomalyst® |
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Experimental: Cohort 6: Linvoseltamab + Isatuximab
Linvoseltamab + Isatuximab
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Drug: Linvoseltamab
Linvoseltamab is administered by intravenous (IV) infusion
Other Name: REGN5458 Drug: Isatuximab Isatuximab is administered by IV infusion
Other Name: Sarclisa® |
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Experimental: Cohort 7: Linvoseltamab + Fianlimab
Linvoseltamab + Fianlimab
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Drug: Linvoseltamab
Linvoseltamab is administered by intravenous (IV) infusion
Other Name: REGN5458 Drug: Fianlimab Fianlimab is administered by IV infusion
Other Name: REGN3767 |
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Experimental: Cohort 8: Linvoseltamab + Cemiplimab
Linvoseltamab + Cemiplimab
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Drug: Linvoseltamab
Linvoseltamab is administered by intravenous (IV) infusion
Other Name: REGN5458 Drug: Cemiplimab Cemiplimab is administered by IV infusion
Other Name: LIBTAYO |
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Experimental: Cohort 9: Linvoseltamab + Nirogacestat
Linvoseltamab + Nirogacestat
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Drug: Nirogacestat
Nirogacestat is administered by mouth (PO) as a tablet
Other Name: PF-03084014 |
- Incidence of pre-defined safety criteria or dose-limiting toxicities (DLTs) from the first dose through the end of the DLT observation period [ Time Frame: Up to 28 Days ]Dose finding portion only
- Incidence of treatment-emergent adverse events (TEAEs) [ Time Frame: Up to 5 Years ]
- Severity of TEAEs [ Time Frame: Up to 5 Years ]
- Incidence of serious adverse events (SAEs) [ Time Frame: Up to 5 Years ]
- Severity of SAEs [ Time Frame: Up to 5 Years ]
- Incidence of adverse events of special interest (AESIs) [ Time Frame: Up to 5 Years ]
- Severity of AESIs [ Time Frame: Up to 5 Years ]
- Incidence of laboratory abnormalities [ Time Frame: Up to 5 Years ]≥ grade 3 per National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE v5.0]
- Objective response rate (ORR) as measured by International Myeloma Working Group (IMWG) criteria [ Time Frame: Up to 5 Years ]
- Duration of response (DOR) by IMWG criteria [ Time Frame: Up to 5 Years ]
- Progression-free survival (PFS) as measured by IMWG criteria [ Time Frame: Up to 5 Years ]
- Rate of minimal residual disease (MRD) negative status by IMWG criteria [ Time Frame: Up to 5 Years ]
- Concentrations of total linvoseltamab in serum over time [ Time Frame: Up to 5 Years ]
- Incidence over time of anti-drug antibodies (ADAs) to linvoseltamab [ Time Frame: Up to 5 Years ]
- Overall Survival (OS) [ Time Frame: Up to 5 Years ]
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
General Key Inclusion Criteria:
- Eastern Cooperative Oncology Group (ECOG) performance status ≤1
- Participants must have measurable disease as defined in the protocol according to International Myeloma Working Group (IMWG) consensus criteria
- Adequate creatinine clearance, hematologic function and hepatic function, as defined in protocol
- 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:
- 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)
- Participants with known MM brain lesions or meningeal involvement
- 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
- History of allogeneic stem cell transplantation, or autologous stem cell transplantation within 12 weeks of the start of study drug regimen
- 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)
- 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
- Live or attenuated vaccination within 28 days prior to first study drug regimen administration with a vector that has replicative potential
- 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:
- 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.
- Ongoing or recent (within 2 years) evidence of an autoimmune disease that has required systemic treatment with immunosuppressive agents, as described in the protocol.
- Prior solid organ transplant.
- 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:
- 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.
- Encephalitis or meningitis in the year prior to enrollment.
- 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.
- Ongoing or recent (within 2 years) evidence of an autoimmune disease that has required systemic treatment with immunosuppressive agents, as described in the protocol.
- Prior solid organ transplant.
- 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:
- Abnormal QT interval corrected by Fridericia's formula (QTcF), as described in the protocol
- 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
- 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
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05137054
| Contact: Clinical Trials Administrator | 844-734-6643 | clinicaltrials@regeneron.com |
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| Study Director: | Clinical Trial Management | Regeneron Pharmaceuticals |
| Responsible Party: | Regeneron Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT05137054 |
| Other Study ID Numbers: |
R5458-ONC-2012 2020-004638-39 ( EudraCT Number ) |
| First Posted: | November 30, 2021 Key Record Dates |
| Last Update Posted: | April 12, 2024 |
| Last Verified: | August 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing |
| Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Informed Consent Form (ICF) Clinical Study Report (CSR) Analytic Code |
| 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. |
| 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 |
| URL: | https://vivli.org/ |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Relapsed/Refractory Multiple Myeloma (RRMM) B-cell maturation antigen (BCMA) Anti-CD3 monoclonal antibodies (mAbs) |
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Multiple Myeloma Neoplasms, Plasma Cell Neoplasms by Histologic Type Neoplasms Hemostatic Disorders Vascular Diseases Cardiovascular Diseases Paraproteinemias Blood Protein Disorders Hematologic Diseases Hemorrhagic Disorders Lymphoproliferative Disorders Immunoproliferative Disorders Immune System Diseases Lenalidomide |
Pomalidomide Bortezomib Daratumumab Cemiplimab Nirogacestat Immunologic Factors Physiological Effects of Drugs Angiogenesis Inhibitors Angiogenesis Modulating Agents Growth Substances Growth Inhibitors Antineoplastic Agents Antineoplastic Agents, Immunological Gamma Secretase Inhibitors and Modulators Enzyme Inhibitors |