Phase 1/2 Study of REGN5458 in Adult Patients With Relapsed or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The main purpose of this study is to learn about the safety of REGN5458 and to find out what is the best dose of REGN5458 to give to patients with multiple myeloma. An additional purpose is to look for any signs that REGN5458 can treat cancer. The study is looking at several other research questions, including: Side effects that may be experienced by people receiving REGN5458 How REGN5458 works in the body How much REGN5458 is present in the blood How REGN5458 may work to treat cancer

Official Title
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Phase 1/2 FIH Study of REGN5458 (Anti-BCMA x Anti-CD3 Bispecific Antibody) in Patients With Relapsed or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Linvoseltamab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 Confirmed diagnosis of active Multiple Myeloma (MM) by International Myeloma Working Group (IMWG) diagnostic criteria Patients must have myeloma that is response-evaluable according to the 2016 IMWG response criteria as defined in the protocol. Phase 1, Part 1 (Dose Escalation): Patients with MM who have exhausted all therapeutic options that are expected to provide meaningful clinical benefit, either through disease relapse, treatment refractory disease or intolerance of the therapy and including either: a. Progression on or after at least 3 lines of therapy, or intolerance of therapy, including a proteasome inhibitor, an Immunomodulatory agent (IMiD), and an anti-CD38 antibody, OR b. Progression on or after an anti-CD38 antibody and have disease that is double refractory to a proteasome inhibitor and an IMiD, or intolerance of therapy. The anti-CD38 antibody may have been administered alone or in combination with another agent such as a proteasome inhibitor (PI). Refractory disease is defined as lack of response or relapse within 60 days of last treatment. Phase 1, Part 2 (SC Administration): Patients with MM whose disease meets the following criteria: a. Progression on or after at least 3 prior lines of therapy including a(n) PI, IMiD, and anti-CD38 antibody, OR b. Patients must be triple-refractory, defined as being refractory to prior treatment with at least 1 anti-CD38 antibody, a proteasome inhibitor, and an IMiD. Phase 2 (Cohorts 1 and 2): Patients with MM whose disease meets the following criteria: a. Progression on or after at least 3 prior lines of therapy including a(n) PI, IMiD, and anti-CD38 antibody, OR b. Patients must be triple- refractory, defined as being refractory* to prior treatment with at least 1 PI, 1 IMiD, and an anti-CD38 antibody. Phase 2 (Cohort 3): Patients with MM whose disease meets the following criteria: Progression on or after at least 3 prior lines of therapy including a(n) PI, IMiD, and anti-CD38 antibody, OR Patients must be triple- refractory, defined as being refractory* to prior treatment with at least 1 PI, 1 IMiD, and an anti-CD38 antibody. Refractory disease is defined as progression during treatment or within 60 days after completion of therapy, or <25% response to therapy. AND, for ALL patients, if they have relapsed after a BCMA-directed CAR-T cellular therapy then: • Treatment with a CAR-T must have been associated with a response of PR or better, and • If CAR-T cellular therapy was the most recent prior therapy, excluding corticosteroids, then treatment must have been a minimum of 60 days prior to treatment with REGN5458. Key Exclusion Criteria: 1. Diagnosis of plasma cell leukemia, primary systemic light-chain amyloidosis, (excluding myeloma-associated amyloidosis), Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 2. Patients with known MM brain lesions or meningeal involvement -Cardiac ejection fraction <40% by echocardiogram or multi-gated acquisition scan (MUGA) 3. Prior treatment with BCMA-directed immunotherapies, including BCMA bispecific antibodies and BiTEs. Note: BCMA antibody-drug conjugates are not excludedand BCMA-directed CAR-T treatment is not excluded in Phase 2 Cohort 3. 4. History of allogeneic stem cell transplantation at any time, or autologous stem cell transplantation within 12 weeks of the start of study treatment Note 1: Other protocol defined inclusion / exclusion criteria apply Note 2: US enrollment completed

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Linvoseltamab - Phase 1<br>Phase 1 has two parts. Part 1, consists of REGN5458/linvoseltamab intravenous (IV) dose escalation and Part 2, consists of subcutaneous (SC) administration. Note: subcutaneous (SC) administration is not applicable for US. | Drug: Linvoseltamab<br>* Administered by IV infusion and/or SC<br>* Other names: REGN5458;|
| Experimental: Linvoseltamab - Phase 2 - Cohort 1<br>Low Dose of REGN5458/linvoseltamab IV monotherapy. | Drug: Linvoseltamab<br>* Administered by IV infusion and/or SC<br>* Other names: REGN5458;|
| Experimental: Linvoseltamab - Phase 2 - Cohort 2<br>High Dose of REGN5458/linvoseltamab IV monotherapy. | Drug: Linvoseltamab<br>* Administered by IV infusion and/or SC<br>* Other names: REGN5458;|
| Experimental: Linvoseltamab - Phase 2 - Cohort 3<br>Anti-interleukin (IL)-6 receptor (R) prophylactic therapy followed by high dose of IV dose of REGN5458 monotherapy. Note: Cohort 3 is not applicable for US. | Drug: Linvoseltamab<br>* Administered by IV infusion and/or SC<br>* Other names: REGN5458;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) from the first dose through the end of the DLT observation period | Phase 1 and Phase 2 for Japanese cohort only | Up to 28 days | 
| Incidence and severity of treatment-emergent adverse events (TEAEs) | Phase 1 Note: Phase 1, part 2 is not applicable for US. | Up to 5 years | 
| Incidence and severity of adverse events of special interest (AESI) | Phase 1 Note: Phase 1, part 2 is not applicable for US. | Up to 5 years | 
| Concentrations of REGN5458 in serum over time | Phase 1, part 2 and Phase 2, for Japanese cohort only | Up to 5 years | 
| Objective response rate (ORR) as determined by an Independent Review Committee (IRC) | Phase 2, cohorts 1 and 2 | Up to 5 years | 
| Incidence and severity of cytokine release syndrome (CRS) with REGN5458 | Phase 2, cohort 3 Note: Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 
| ORR of IV REGN5458 as assessed by investigator in patients who have progressed | Phase 2, cohort 3 Note: Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations of REGN5458 in the serum over time | Phase 1 part 1 and Phase 2 Note: Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 
| Incidence over time of anti-drug antibodies (ADAs) to REGN5458 | Phase 1 and Phase 2 Note: Phase 1, part 2 and Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 
| Titer of anti-drug antibodies (ADAs) to REGN5458 over time | Phase 1 and Phase 2 Note: Phase 1, part 2 and Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 
| Incidence of neutralizing antibodies (Nab) to REGN5458 over time | Phase 1 and Phase 2 Note: Phase 1, part 2 and Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 
| Duration of response (DOR) as determined by an IRC, measured using the IMWG criteria | Phase 2, cohorts 1 and 2 | Up to 5 years | 
| DOR as determined by an investigator, measured using the International Myeloma Working Group (IMWG) criteria | Phase 1 and Phase 2, cohorts 1 and 2 Note: Phase 1, part 2 is not applicable for US. | Up to 5 years | 
| Progression-free survival (PFS) as determined by an IRC, measured using the IMWG criteria | Phase 2, cohorts 1 and 2 | Up to 5 years | 
| PFS as determined by an investigator, measured using the IMWG criteria | Phase 1 and Phase 2, cohorts 1 and 2 Note: Phase 1, part 2 is not applicable for US. | Up to 5 years | 
| Rate of minimal residual disease (MRD) negative status using the IMWG criteria | Phase 1 Note: Phase 1, part 2 is not applicable for US. | Up to 5 years | 
| Rate of MRD negative status status | Phase 2 Note: Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 
| Overall survival (OS) | Phase 1 and Phase 2 Note: Phase 1, part 2 and Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 
| ORR as measured as determined by blinded IRC, as measured using the IMWG criteria | Phase 1, part 1 dose level 7 (DL7) | Up to 5 years | 
| ORR as determined by the investigator, measured using the IMWG criteria | Phase 1 and Phase 2, cohorts 1 and 2 Note: Phase 1, part 2 is not applicable for US. | Up to 5 years | 
| Effects of REGN5458 on health-related quality of life (HRQoL) and patient-reported symptoms and functioning per European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Phase 2 The EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including global health status/quality of life, functional Scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Participants rate items on a 4-point scale, with 1 as not at all and 4 as very much. Note: Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 
| Effects of REGN5458 on HRQOL and patient-reported symptoms and functioning per Quality of Life Questionnaire-Multiple Myeloma module 20 [QLQ-MY20]) | Phase 2 The EORTC QLQ-MY20 is a self -administered instrument to assess QoL in persons with MM. This 20-item questionnaire measures the following domains: symptom scales, including disease symptoms (6 items) and symptoms related to side effects of treatment (10 items); function scale and future perspective (3 items); and body image (1 item). A high score represents a high level of symptoms or problems. Note: Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 
| Effects of REGN5458 on HRQOL and patient-reported symptoms and functioning per EuroQoL-5 Dimension-3 Level Scale [EQ-5D-3L]) | Phase 2 The EQ-5D-3L is a self-administered generic standardized health status measure, consisting of an EQ-5D descriptive system and an EQ visual analog scale. The EQ-5D-3L descriptive system assesses 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a 3-level scale: no problems, some problems, and extreme problems. The EQ visual analog scale component is a vertical visual analog scale used by patients to rate their health. Note: Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 
| Change in patient-reported global health status/QoL per EORTC QLQ-C30 | Phase 2 Note: Phase 2, Cohort 3 is not applicable for US. | Baseline up to Up to 5 years | 
| Time to definitive deterioration in patient-reported global health status/QoL per EORTC QLQ-C30 | Phase 2 Note: Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 
| Effects of REGN5458 on general health status per EQ-5D-3L | Phase 2 Note: Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 
| Effects of REGN5458 on patient-reported functions and symptoms per EORTC QLQ-C30 | Phase 2 Note: Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 
| Effects of REGN5458 on patient-reported functions and symptoms per QLQ-MY20 | Phase 2 Note: Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 
| Incidence and severity of TEAEs with REGN5458 | Phase 2 Note: Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 
| Incidence and severity of AESIs with REGN5458 | Phase 2 Note: Phase 2, Cohort 3 is not applicable for US. | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed, Refractory