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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Regeneron Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

9 Nov 2020 → ongoing

Decision date (initial)

2024-08-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Regeneron Pharmaceuticals Inc.

External identifiers

EU CT number

2024-511454-45-00

EudraCT number

2018-003188-78

ClinicalTrials.gov

NCT03761108

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Safety, Others, Dose response

PHASE 1
• Part 1 (Intravenous Dose Escalation): To assess the safety, tolerability, and dose-limiting toxicities (DLTs) and to determine one or more recommended phase 2 dose regimens (RP2DRs) of linvoseltamab as intravenous (IV) monotherapy in patients with relapsed or refractory multiple myeloma (RRMM)
• Part 2 (Subcutaneous Administration): To assess the safety, tolerability, and dose-limiting toxicities (DLTs), and pharmacokinetic (PK) properties, and to determine a dosing regimen of subcutaneous linvoseltamab monotherapy in patients with RRMM.
PHASE 2
• Cohorts 1 and 2: To assess the anti-tumor activity of IV linvoseltamab separately in cohorts 1 and 2, as measured by objective response rate (ORR) and as determined by an Independent Review Committee (IRC), in patients who have progressed on or after 3 prior lines of therapy or who are triple-refractory (defined as refractory to a(n) proteasome inhibitor (PI), immunomodulatory imide drug (IMiD), and anti-CD38 monoclonal antibody).
• Cohort 3: To assess the safety and efficacy of anti-IL-6R pre-treatment in preventing CRS in patients treated with IV linvoseltamab, and to assess anti-tumor activity in patients who receive anti-IL-6R pre-treatment as measured by investigator assessed ORR in patients who had previously progressed on or after 3 prior lines of therapy or who are triple-refractory (defined as refractory to a(n) PI, IMiD, and anti-CD38 monoclonal antibody), and in patients who had previously relapsed after receiving BCMA directed chimeric antigen receptor (CAR)-T cellular therapy.

Secondary objectives 16

1. Phase 1- Part 1: To assess the preliminary anti-tumor activity of IV linvoseltamab as determined by the investigator and measured by ORR, duration of response (DOR), progression-free survival (PFS), rate of minimal residual disease (MRD) negative status, and overall survival (OS)
2. Phase 1- Part 1: To evaluate the PK properties of IV linvoseltamab
3. Phase 1- Part 1: To characterize the immunogenicity of IV linvoseltamab
4. Phase 1- Part 1: To assess the anti-tumor activity of IV linvoseltamab in patients treated in phase 1 dose level 7 (full dose) as measured by ORR and as determined by an Independent Review Committee (IRC)
5. Phase 1- Part 2: To assess the preliminary anti-tumor activity of SC linvoseltamab as determined by the investigator and measured by ORR, DOR, PFS, rate of MRD negative status, and OS
6. Phase 1- Part 2: To characterize the immunogenicity of SC linvoseltamab
7. Phase 2- cohorts 1 and 2: To assess the anti-tumor activity of IV linvoseltamab as measured by: ORR, as determined by the investigator; DOR and PFS, as determined by an IRC and the investigator; Rate of MRD negative status; OS
8. Phase 2- cohorts 1 and 2: To evaluate the effects of IV linvoseltamab on health-related quality of life (HRQoL) and patient-reported functions and symptoms
9. Phase 2- cohorts 1 and 2: To evaluate the safety and tolerability of IV linvoseltamab
10. Phase 2- cohorts 1 and 2: To evaluate the PK properties of IV linvoseltamab
11. Phase 2- cohorts 1 and 2: To characterize the immunogenicity of IV linvoseltamab
12. Phase 2- cohorts 3: To assess the anti-tumor activity of IV linvoseltamab as measured by: DOR and PFS, as determined by the investigator; Rate of MRD negative status; OS
13. Phase 2- cohorts 3: To evaluate the effects of IV linvoseltamab on health-related quality of life (HRQoL) and patient-reported functions and symptoms
14. Phase 2- cohorts 3: To evaluate the safety and tolerability of IV linvoseltamab
15. Phase 2- cohorts 3: To evaluate the PK properties of IV linvoseltamab
16. Phase 2- cohorts 3: To characterize the immunogenicity of IV linvoseltamab

Conditions and MedDRA coding

Relapsed or Refractory Multiple Myeloma

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003175-PIP01-21

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
2. Confirmed diagnosis of active Multiple Myeloma (MM) by International Myeloma Working Group (IMWG) diagnostic criteria
3. Patients must have myeloma that is response-evaluable according to the 2016 IMWG response criteria as defined in the protocol.
4. 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 PI, an 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.
5. 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 PI, and an IMiD.
6. 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. *Refractory disease is defined as progression during treatment or within 60 days after completion of therapy, or <25% response to therapy.
7. 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.
8. AND, if patients 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 linvoseltamab
9. Other protocol defined inclusion criteria apply

Exclusion criteria 6

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
3. Cardiac ejection fraction <40% by echocardiogram or multi-gated acquisition scan (MUGA)
4. 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.
5. History of allogeneic stem cell transplantation at any time, or autologous stem cell transplantation within 12 weeks of the start of study treatment
6. Other protocol defined exclusion criteria apply

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

1. Phase 1: Incidence of dose-limiting toxicities (DLTs) from the first dose through the end of the DLT observation period
2. Phase 1: Incidence and severity of treatment-emergent adverse events (TEAEs)
3. Phase 1: Incidence and severity of adverse events of special interest (AESI)
4. Phase 1, Part 2: Assessment of the pharmacokinetics (PK) of linvoseltamab
5. Phase 2, cohorts 1 and 2: Objective response rate (ORR) as determined by an Independent Review Committee (IRC)
6. Phase 2, cohort 3: Incidence and severity of cytokine release syndrome (CRS) with linvoseltamab
7. Phase 2, cohort 3: ORR of IV linvoseltamab as assessed by investigator

Secondary endpoints 22

1. Phase 1 part 1 and Phase 2: Concentrations of linvoseltamab in the serum over time
2. Phase 1 and Phase 2: Incidence over time of anti-drug antibodies (ADAs) to linvoseltamab
3. Phase 1 and Phase 2: Titer of anti-drug antibodies (ADAs) to linvoseltamab over time
4. Phase 1 and Phase 2: Incidence of neutralizing antibodies (Nab) to linvoseltamab over time
5. Phase 2, cohorts 1 and 2: Duration of response (DOR) as determined by an IRC, measured using the IMWG criteria
6. Phase 1 and Phase 2: DOR as determined by an investigator, measured using the International Myeloma Working Group (IMWG) criteria
7. Phase 2: Progression-free survival (PFS) as determined by an IRC, measured using the IMWG criteria
8. Phase 1 and Phase 2: PFS as determined by an investigator, measured using the IMWG criteria
9. Phase 1: Rate of minimal residual disease (MRD) negative status, as determined by the investigator using the IMWG criteria
10. Phase 2: Rate of MRD negative status
11. Phase 1 and Phase 2: Overall survival (OS)
12. Phase 1, part 1 dose level 7 (DL7): ORR as measured as determined by blinded IRC, as measured using the IMWG criteria
13. Phase 1 and Phase 2: ORR as determined by the investigator, measured using the IMWG criteria
14. Phase 2: Effects of linvoseltamab 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)
15. Phase 2: Effects of linvoseltamab on HRQOL and patient-reported symptoms and functioning per Quality of Life Questionnaire-Multiple Myeloma module 20 [QLQ-MY20])
16. Phase 2: Effects of linvoseltamab on HRQOL and patient-reported symptoms and functioning per EuroQoL-5 Dimension-3 Level Scale [EQ-5D-3L])
17. Phase 2: Change in patient-reported global health status/QoL per EORTC QLQ-C30
18. Phase 2: Time to definitive deterioration in patient-reported global health status/QoL per EORTC QLQ-C30
19. Phase 2: Effects of linvoseltamab on patient-reported functions and symptoms per EORTC QLQ-C30
20. Phase 2: Effects of linvoseltamab on patient-reported functions and symptoms per QLQ-MY20
21. Phase 2: Incidence and severity of TEAEs with linvoseltamab
22. Phase 2: Incidence and severity of AESIs with linvoseltamab

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Regeneron Pharmaceuticals Inc.

Sponsor organisation

Regeneron Pharmaceuticals Inc.

Address

777 Old Saw Mill River Road

City

Tarrytown

Postcode

10591-6717

Country

United States

Scientific contact point

Organisation

Regeneron Pharmaceuticals Inc.

Contact name

Medical Affairs

Public contact point

Organisation

Regeneron Pharmaceuticals Inc.

Contact name

Medical Affairs

Third parties 11

Locations

2 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 144 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications