A Phase 3 Study Comparing Lenalidomide and Daratumumab Subcutaneous Injection (R-Dara SC) vs Lenalidomide and Dexamethasone (Rd) in Frail Subjects with Previously Untreated Multiple Myeloma who are Ineligible for High Dose Therapy.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Lille

Participant type

Patients

Age range

65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

7 Oct 2019 → ongoing

Decision date (initial)

2024-11-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Janssen Pharmaceutica NV

External identifiers

EU CT number

2024-514088-25-00

EudraCT number

2018-003535-30

ClinicalTrials.gov

NCT03993912

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

The primary objective is to compare the efficacy of daratumumab SC injection when combined with lenalidomide (R-Dara SC) to that of lenalidomide and dexamethasone (Rd), in terms of PFS in frail subjects with newly diagnosed myeloma who are not candidates for high dose chemotherapy and autologous stem cell transplant.

Secondary objectives 12

1. Time-to-treatment failure
2. Time-to-next treatment
3. PFS2 time
4. Overall survival
5. Complete remission (CR)
6. Very good partial response (VGPR) or better
7. Overall response (CR + VGPR + partial response [PR])
8. Occurrence of grade 3 or more side effects
9. Safety and tolerability of Daratumumab SC when administered in combination with R
10. Treatment effects on patient reported outcomes and heath economic/resource utilization
11. Minimal residual disease (MRD) negative rate at 12 months
12. Event Free Survival

Conditions and MedDRA coding

Multiple Myeloma

Study design 1 period

Regulatory references

Plan to share IPD

Yes

IPD plan description

Data will be shared with Janssen CILAG International N.V. as co-owner to capture any security features for other projects they sponsor. All data processing is MR001 compliant. Sharing wil be securely performed.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Subject must be at least 65 years of age
2. Subject must have documented multiple myeloma satisfying the CRAB riteria and measurable disease defined as: 1-Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma 2-Measurable disease as defined by any of the following: - IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL; or - IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein level ≥0.5 g/dL ; or - Light chain multiple myeloma: Serum immunoglobulin free light chain ≥ 10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio (only measurable with freelite® by Binding site); or - Urine M-protein level ≥200 mg/24 hours
3. Newly diagnosed and not considered candidate for high-dose chemotherapy with SCT
4. Subject must have a Frailty Score ≥ 2
5. Subject must have within 5 days prior to first drug intake (C1D1) pretreatment clinical laboratory values meeting the following criteria during the Screening Phase: a) hemoglobin ≥7.5 g/dL (≥4.65 mmol/L; prior red blood cell [RBC] transfusion or recombinant human erythropoietin use is permitted); b) absolute neutrophil count ≥1.0 x 109/L (granulocyte colony stimulating factor [GCSF] use is permitted); c) platelet count ≥70 x 109/L for subjects in whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet count >50 × 109/L (transfusions are not permitted to achieve this minimum platelet count). d) aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN); e) alanine aminotransferase (ALT) ≤2.5 x ULN; f) total bilirubin ≤2.0 x ULN, except in subjects with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin ≤2.0 x ULN); g) creatinine clearance≥30mL/min(for lenalidomide dose adjustment for subjects with creatinine clearance 30-60 mL/min). Creatinine clearance may be calculated using the Cockcroft-Gault formula h) corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L)
6. Measurable ISS with β2-microglobulin and albumin values for randomization
7. A man who is sexually active with a woman of childbearing potential must agree to use a latex or synthetic condom, even if they had a successful vasectomy. All men must also not donate sperm during the study, for 4 weeks after the last dose of lenalidomid, and for 4 months after the last dose of daratumumab. Women participating in this study must be postmenopausal
8. Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF
9. Subjects affiliated with an appropriate social security system

Exclusion criteria 21

1. Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma.
2. Subject has a diagnosis of Waldenström's disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
3. Subject has prior or current systemic therapy or SCT for multiple myeloma, with the exception of an emergency use of a short course of corticosteroids before treatment.
4. Subject has a history of malignancy within 5 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 5 years).
5. Subject has had radiation therapy within 14 days of randomization.
6. Subject has had plasmapheresis within 28 days of randomization.
7. Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
8. Subject has known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume [FEV] in 1 second <60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (intermittent asthma is allowed). Subjects with known or suspected COPD or asthma must have a FEV1 test during screening.
9. Subject is known to be seropositive for history of human immunodeficiency virus (HIV)
10. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
11. (Known to be) seropositive for hepatitis C.
12. Subject has any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
13. Subject has clinically significant cardiac disease, including:  myocardial infarction within 1 year before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV  uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4 Grade ≥ 2) or clinically significant ECG abnormalities  screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec
14. Subject has known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure).
15. Subject has plasma cell leukemia (according to World Health Organization [WHO] criterion: ≥20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
16. Subject is known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Subject is taking any prohibited medications as per Section 8.3.
17. Subject has had major surgery within 2 weeks before randomization or has not fully recovered from surgery.
18. Subject has received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before randomization or is currently enrolled in an interventional investigational study.
19. Refusal to consent or protected by legal regime ( guardianship, trusteeship)
20. Subject has contraindications to required prophylaxis for deep vein thrombosis and pulmonary embolism
21. Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is PFS time, which is defined as the duration from the date of randomization to either progressive disease, or death, whichever occurs first. Disease progression will be determined according to the 2016 IMWG criteria.

Secondary endpoints 12

1. Time-to-treatment failure, defined as time from randomization to discontinuation of therapy for any reason including death, progression, toxicity.
2. Time to next treatment, defined as the time from randomization to the start of the next-line treatment.
3. PFS2 time, defined as the time from randomization to progression on the next line of treatment or death, whichever comes first. Disease progression will be based on investigator judgment. For those subjects who are still alive and not yet progressed on the next line of treatment, they will be censored on the last date of follow-up.
4. Overall survival (OS) time, measured from the date of randomization to the date of the subject's death. If the subject is alive or the vital status is unknown at last contact, then the subject's data will be censored at the date the subject was last known to be alive.
5. CR, defined as: - Negative immunofixation of serum and urine, and - Disappearance of any soft tissue plasmacytomas, and - < 5 % plasma cells (PCs) in bone marrow - For those IgG Kappa myeloma subjects with at least ≤2g/l M-protein on 2 consecutive visits, DIRA test will be utilized to confirm daratumumab interference and rule out false positive immunofixation. Patients who have confirmed daratumumab interference, but meet all other clinical criteria for CR, will be considered CR.
6. VGPR or better, defined as VGPR or CR according to the IMWG criteria during or after the study treatment at the time of data cutoff.
7. Overall response, defined as CR or VGPR or PR, according to the IMWG criteria, during or after the study treatment.
8. Collecting all AE (grade 3 or more) since the beginning of treatment until progression.
9. Evaluation of safety data by type, frequency, severity, relation to study drug, as well as changes in vital signs, physical examinations, incidence of treatment emergent adverse events (TEAEs), serious adverse events, abnormal laboratory test results (according to NCI-CTCAE V4.0).
10. Evaluation of quality of life based on EORTC C30, MY20 and EQ-5D questionnaires filled every 3 months from the C1J1 during the first year then every 6 months until the end of treatment for progression (then 8 and 16 weeks after the end of treatment).
11. MRD negativity, as measured at 12 months.
12. Event Free Survival, defined as time from randomization to discontinuation of therapy for any reason including death, progression or toxicity

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Lille

Sponsor organisation

Centre Hospitalier Universitaire De Lille

Address

2 Avenue Oscar Lambret, Cs 70001 Cs 70001

City

Lille Cedex

Postcode

59037

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Lille

Contact name

Pr Salomon MANIER - Coordinating Clinical Investigator

Public contact point

Organisation

Centre Hospitalier Universitaire De Lille

Contact name

Aomar KEMKEM - Coordonnateur Promotion

Locations

2 EU/EEA countries · 86 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 12 files

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

Application history

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