MagnetisMM-5: A Phase 3 Study of Elranatamab (PF-06863135) Monotherapy and Elranatamab + Daratumumab Versus Daratumumab + Pomalidomide + Dexamethasone in Participants With Relapsed/Refractory Multiple Myeloma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pfizer Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

28 Sep 2021 → ongoing

Decision date (initial)

2024-09-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pfizer Inc.

External identifiers

EU CT number

2023-509208-14-00

EudraCT number

2021-000044-22

ClinicalTrials.gov

NCT05020236

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacokinetic, Pharmacodynamic, Dose response, Safety, Efficacy

PART 1:
To assess DLTs, safety and tolerability of elranatamab + daratumumab in order to select a RP3D for the combination to be used in Part 2 of this study.

PART 2:
To compare the efficacy of elranatamab (Arm A) vs daratumumab + pomalidomide + dexamethasone (Arm C) as measured by PFS

PART 3:
To assess the safety of elranatamab (Arm D) and elranatamab + daratumumab (Arm E) with increased risk minimization for serious infection, including required infection prophylaxis

Secondary objectives 17

1. Part 1: To assess the rate of Grade ≥2 cytokine release syndrome (CRS) when elranatamab is administered with a 2 step-up priming regimen along with premedication.
2. Part 1: To evaluate the overall safety profile of elranatamab using 2 stepup priming doses and in combination with daratumumab.
3. Part 1: To evaluate the efficacy of elranatamab + daratumumab as measured by PFS, ORR, DOR, CRR, DOCR, TTR, OS, and % MRD negative.
4. Part 1: To evaluate the PK of elranatamab.
5. Part 1: To evaluate the immunogenicity of elranatamab.
6. Part 1: To evaluate the PK of daratumumab.
7. Part 2 Key secondary: To compare the efficacy of Arm A vs Arm C as measured by OS.
8. Part 2: To compare the efficacy of Arm A vs Arm C as measured by PFS, PFS2, ORR, DOR, CRR, DOCR, TTR, % MRD negative, and % Sustained MRD negative.
9. Part 2: To determine the safety and tolerability of elranatamab monotherapy.
10. Part 2: To evaluate the PK of elranatamab in Arm A
11. Part 2: To evaluate the immunogenicity of elranatamab in Arm A
12. Part 2: To evaluate the impact of treatment on participant HRQoL in Arm A and Arm C.
13. Part 3: To evaluate the overall safety profile of elranatamab (Arm D) and elranatamab plus daratumumab (Arm E) with increased risk minimization for serious infection, including required infection prophylaxis
14. Part 3: To evaluate the efficacy of elranatamab (Arm D) and elranatamab plus daratumumab (Arm E) as measured by PFS, ORR, DOR, CRR, DOCR, TTR, OS, % MRD negative, and % Sustained MRD negative.
15. Part 3: To evaluate the PK of elranatamab in Arm D and Arm E
16. Part 3: To evaluate the immunogenicity of elranatamab in Arm D and Arm E
17. Part 3: To evaluate the PK of daratumumab

Conditions and MedDRA coding

MULTIPLE MYELOMA

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003083-PIP01-21

Plan to share IPD

Yes

IPD plan description

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. Participants age ≥18 years (or the minimum country-specific age of consent if >18).
2. 2. Prior diagnosis of multiple myeloma (MM) as defined according to IMWG criteria (Rajkumar et al, 2014).
3. 3. Measurable disease based on IMWG criteria as defined by at least 1 of the following:  Serum M-protein ≥0.5 g/dL;  Urinary M-protein excretion ≥200 mg/24 hours;  Serum immunoglobulin free light chain (FLC) ≥10 mg/dL (≥100 mg/L) AND abnormal serum immunoglobulin kappa to lambda FLC ratio (<0.26 or >1.65).
4. 4. Prior anti-MM therapy: Part 1: At least 3 prior lines of anti-MM therapy including treatment with lenalidomide and a PI. Part 2: At least 1, but not more than 3, prior lines of anti-MM therapy including treatment with lenalidomide and a PI. Part 3 Arm D: At least 1, but not more than 3, prior lines of anti-MM therapy including treatment with lenalidomide and an anti-CD38-directed therapy. Part 3 Arm E: At least 1, but not more than 3, prior lines of anti-MM therapy including treatment with lenalidomide.
5. 5. Eastern Cooperative Oncology Group (ECOG) performance status <2.
6. 6. Left ventricular ejection fraction (LVEF) ≥40% as determined by a multiple gated acquisition (MUGA) scan or echocardiogram (ECHO).
7. 7. Adequate hepatic, renal and bone marrow (BM) function.
8. 8. Corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L), or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L).
9. 9. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1.

Exclusion criteria 21

1. 1. Smoldering MM.
2. 19. Administration with an investigational product (eg, drug or vaccine) concurrent with study intervention or within 30 days (or as determined by the local requirement) preceding the first dose of study intervention used in this study. A participant may be eligible if they are in the follow-up phase of an investigational study if they meet the criterion for time elapsed from previous administration of investigational product. Cases must be discussed with sponsor’s medical monitor to judge eligibility.
3. 2. Plasma cell leukemia.
4. 20. For women of childbearing potential: Pregnancy test positive at screening.
5. 21. Part 2: Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease or previous gastric resection or lap band surgery. Gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed (assuming no drug interaction potential).
6. 3. Amyloidosis, Waldenström’s macroglobulinemia, or POEMS Syndrome.
7. 4. Known active CNS involvement or clinical signs of myelomatous meningeal involvement.
8. 5. Stem cell transplant within 12 weeks prior to enrollment, active GVHD (other than Grade 1 skin involvement), or GVHD requiring treatment.
9. 6. Impaired cardiovascular function or clinically significant cardiovascular diseases within 6 months prior to enrollment.
10. 7. Ongoing Grade 3 or higher peripheral sensory or motor neuropathy.
11. 10. Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ, or Stage 0/1 malignancy with minimal risk of recurrence per investigator.
12. 8. History of Guillain-Barrė syndrome (GBS) or GBS variants, or history of any Grade ≥3 peripheral motor polyneuropathy.
13. 9. Active hepatitis B virus (HBV), hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus (HIV), or any active, uncontrolled bacterial, fungal, or viral infection.
14. 15. Part 3 Arm E: Refractory to prior anti-CD38-directed therapy (disease progression while on or within 60 days of the last dose of any anti-CD38-directed therapy).
15. 11. Participants with known or suspected hypersensitivity to the study interventions or any of their excipients.
16. 12. Previous treatment with a BCMA-directed therapy or a CD3-redirecting therapy.
17. 13. Parts 1 and 2: Anti-CD38-directed therapy within 6 months preceding the first dose of treatment in this study.
18. 14. Part 2: Refractory to prior anti-CD38-directed therapy (disease progression while on or within 60 days of the last dose of any anti-CD38-directed therapy or failure to achieve at least MR).
19. 16. Part 2: Previous pomalidomide therapy.
20. 17. Part 3: Any anti-myeloma drug therapy within 14 days of the first dose of study intervention (includes dexamethasone).
21. 18. Live attenuated vaccine must not be administered within 4 weeks of the first dose of study intervention. Refer to Section 6.8 Concomitant Therapy.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Part 1: DLTs during the DLT observation period (14 days from first elranatamab dose + first 28 days following first dose of elranatamab + daratumumab).
2. Part 2: PFS by blinded independent central review (BICR) per IMWG
3. Part 3: AEs as characterized by type, frequency, severity (as graded by NCI CTCAE v5.0), timing, and seriousness, and relationship to study treatment during the first 84 days following first elranatamab dose. Severity of CRS and ICANS will be assessed according to ASTCT criteria

Secondary endpoints 17

1. Part 1: Grade ≥2 CRS rate during the 28 days following the first dose of elranatamab.
2. Part 1: Adverse events (AEs) as characterized by type, frequency, severity (as graded by NCI CTCAE v5.0), timing, seriousness, and relationship to elranatamab in combination with daratumumab. Severity of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) will be assessed according to ASTCT criteria; •Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v5.0), and timing.
3. Part1: ORR and CRR, per IMWG (International Myeloma Working Group) response criteria as determined by investigator; • Time to event endpoints: TTR, DOR, DOCR and PFS per IMWG response criteria as determined by investigator, and OS; • MRD negativity rate (central lab) per IMWG sequencing criteria.
4. Part 1: Predose and postdose concentrations of elranatamab
5. Part 1: Anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) against elranatamab.
6. Part 1: Predose concentrations of daratumumab.
7. Part 2 Key secondary: OS.
8. Part 2: •PFS and PFS2 by Investigator per IMWG •ORR by BICR per IMWG •DOR by BICR per IMWG •CRR by BICR per IMWG •DOCR by BICR per IMWG •TTR by BICR per IMWG •MRD negativity rate (central lab) per IMWG •Sustained MRD negativity rate (central lab) per IMWG
9. Part 2: • AEs as characterized by type, frequency, severity (as graded by NCI CTCAE v5.0), timing, seriousness, and relationship to study treatment. The severity of CRS and ICANS will be assessed according to ASTCT criteria. • Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v5.0), and timing.
10. Part 2: Predose and postdose concentrations of elranatamab.
11. Part 2: ADAs and NAbs against elranatamab.
12. Part 2: of Cancer Quality of Life Questionnaire – Core 30 (EORTC QLQ-C30) and myeloma quality of life questionnaire (MY20).
13. Part 3: • AEs as characterized by type, frequency, severity (as graded by NCI CTCAE v5.0), timing, seriousness, and relationship to study treatment. Severity of CRS and ICANS will be assessed according to ASTCT criteria • Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v5.0), and timing
14. Part 3: • ORR and CRR per IMWG • Time to event endpoints: TTR, DOR, DOCR and PFS per IMWG response criteria, and OS • MRD negativity rate (central lab) per IMWG • Sustained MRD negativity rate (central lab) per IMWG
15. Part 3: Predose and postdose concentrations of elranatamab
16. Part 3: ADAs and NAbs against elranatamab
17. Part 3: Predose concentrations of daratumumab

Investigational products

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

Test 1

Comparator 6

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pfizer Inc.

Sponsor organisation

Pfizer Inc.

Address

66 Hudson Boulevard East

City

New York

Postcode

10001-2189

Country

United States

Scientific contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Public contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Third parties 13

Locations

13 EU/EEA countries · 77 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 150 files

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

Application history

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