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

• ClinicalTrials.gov Identifier: NCT05137054
• Recruitment Status: Recruiting
• First Posted: November 30, 2021
• Last Update Posted: April 12, 2024
• Sponsor: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Regeneron Pharmaceuticals

Tracking Information

• First Submitted Date: November 18, 2021
• First Posted Date: November 30, 2021
• Last Update Posted Date: April 12, 2024
• Actual Study Start Date: August 17, 2022
• Estimated Primary Completion Date: January 13, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 12, 2023)

• 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]

Original Primary Outcome Measures (submitted: November 18, 2021)

• Incidence of pre-defined safety criteria (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 and severity of treatment-emergent adverse events (TEAEs) [ Time Frame: Up to 5 Years ]
  Dose finding portion Dose expansion portion
• Incidence and severity of serious adverse events (SAEs) [ Time Frame: Up to 5 Years ]
  Dose finding portion Dose expansion portion
• Incidence and severity of adverse events of special interest (AESIs) [ Time Frame: Up to 5 Years ]
  Dose finding portion Dose expansion portion
• Incidence of laboratory abnormalities [ Time Frame: Up to 5 Years ]
  As measured by chemistry, hematology, urinalysis and pregnancy testing Dose finding portion Dose expansion portion

Current Secondary Outcome Measures (submitted: January 11, 2024)

• 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 ]

Original Secondary Outcome Measures (submitted: November 18, 2021)

• Objective response rate (ORR) as measured using the International Myeloma Working Group (IMWG) criteria [ Time Frame: Up to 5 Years ]
  Dose finding portion Dose expansion portion
• Duration of response (DOR) using the IMWG criteria [ Time Frame: Up to 5 Years ]
  Dose finding portion Dose expansion portion
• Progression-free survival (PFS) as measured using the IMWG criteria [ Time Frame: Up to 5 Years ]
  Dose finding portion Dose expansion portion
• Rate of minimal residual disease (MRD) negative status using the IMWG criteria [ Time Frame: Up to 5 Years ]
  Dose finding portion Dose expansion portion
• Concentrations of REGN5458 in the serum over time [ Time Frame: Up to 5 Years ]
  Dose finding portion Dose expansion portion
• Incidence over time of anti-drug antibodies (ADAs) to REGN5458 [ Time Frame: Up to 5 Years ]
  Dose finding portion Dose expansion portion
• Overall Survival (OS) [ Time Frame: Up to 5 Years ]
  Dose finding portion Dose expansion portion

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

Brief Summary

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)

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• 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™
• Drug: Carfilzomib
  Carfilzomib is administered by IV infusion
  Other Name: Kyprolis®
• Drug: Lenalidomide
  Lenalidomide is administered by mouth (PO) as a capsule
  Other Name: Revlimid®
• Drug: Bortezomib
  Bortezomib is administered by IV infusion or SC injection
  Other Name: Velcade®
• Drug: Pomalidomide
  Pomalidomide is administered by mouth (PO) as a capsule
  Other Name: Imnovid, Pomalyst®
• Drug: Isatuximab
  Isatuximab is administered by IV infusion
  Other Name: Sarclisa®
• Drug: Fianlimab
  Fianlimab is administered by IV infusion
  Other Name: REGN3767
• Drug: Cemiplimab
  Cemiplimab is administered by IV infusion
  Other Name: LIBTAYO
• Drug: Nirogacestat
  Nirogacestat is administered by mouth (PO) as a tablet
  Other Name: PF-03084014

Study Arms

• Experimental: Cohort 1: Linvoseltamab + Daratumumab
  Linvoseltamab + Daratumumab
  Interventions:

  • Drug: Linvoseltamab
  • Drug: Daratumumab
• Experimental: Cohort 2: Linvolseltamab + Carfilzomib
  Linvoseltamab + Carfilzomib
  Interventions:

  • Drug: Linvoseltamab
  • Drug: Carfilzomib
• Experimental: Cohort 3: Linvoseltamab + Lenalidomide
  Linvoseltamab + Lenalidomide
  Interventions:

  • Drug: Linvoseltamab
  • Drug: Lenalidomide
• Experimental: Cohort 4: Linvoseltamab + Bortezomib
  Linvoseltamab + Bortezomib
  Interventions:

  • Drug: Linvoseltamab
  • Drug: Bortezomib
• Experimental: Cohort 5: Linvoseltamab + Pomalidomide
  Linvoseltamab + Pomalidomide
  Interventions:

  • Drug: Linvoseltamab
  • Drug: Pomalidomide
• Experimental: Cohort 6: Linvoseltamab + Isatuximab
  Linvoseltamab + Isatuximab
  Interventions:

  • Drug: Linvoseltamab
  • Drug: Isatuximab
• Experimental: Cohort 7: Linvoseltamab + Fianlimab
  Linvoseltamab + Fianlimab
  Interventions:

  • Drug: Linvoseltamab
  • Drug: Fianlimab
• Experimental: Cohort 8: Linvoseltamab + Cemiplimab
  Linvoseltamab + Cemiplimab
  Interventions:

  • Drug: Linvoseltamab
  • Drug: Cemiplimab
• Experimental: Cohort 9: Linvoseltamab + Nirogacestat
  Linvoseltamab + Nirogacestat
  Intervention: Drug: Nirogacestat

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 12, 2023): 317
• Original Estimated Enrollment (submitted: November 18, 2021): 256
• Estimated Study Completion Date: August 7, 2032
• Estimated Primary Completion Date: January 13, 2027 (Final data collection date for primary outcome measure)

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 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Clinical Trials Administrator; 844-734-6643; clinicaltrials@regeneron.com

• Listed Location Countries: France, Greece, Spain, United States

Administrative Information

• NCT Number: NCT05137054
• Other Study ID Numbers: R5458-ONC-2012; 2020-004638-39 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Supporting Materials: 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/

• Current Responsible Party: Regeneron Pharmaceuticals
• Original Responsible Party: Same as current
• Current Study Sponsor: Regeneron Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trial Management; Regeneron Pharmaceuticals

• PRS Account: Regeneron Pharmaceuticals
• Verification Date: August 2023