A Phase 3 Study Comparing Daratumumab, VELCADE (bortezomib), Lenalidomide, and Dexamethasone (D-VRd) with VELCADE, Lenalidomide, and Dexamethasone (VRd) in Subjects with Untreated Multiple Myeloma and for Whom Hematopoietic Stem Cell Transplant is Not Planned as Initial Therapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Janssen - Cilag International

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Nov 2018 → 21 Apr 2026

Decision date (initial)

2024-01-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-507312-13-00

EudraCT number

2018-001545-13

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Others, Efficacy, Safety

The primary objective is to determine if the addition of daratumumab to VRd will improve overall minimal residual disease (MRD) negativity rate compared with VRd alone

Conditions and MedDRA coding

Multiple Myeloma

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparecy. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Newly diagnosed and not considered candidate for high-dose chemotherapy with stem cell transplantation due to: ●Being age ≥65years,or ●age 18-65years with presence of comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with SCT or who refuse high-dose chemotherapy with SCT as initial treatment
2. 2. Diagnosis of multiple myeloma as documented per International Myeloma Working Group Criteria: Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma and documented multiple myeloma satisfying at least one of the calcium, renal, anemia, bone (CRAB) criteria or biomarkers of malignancy criteria: CRAB criteria: 1. Hypercalcemia: serum calcium >0.25mmol/L (>1mg/dL) higher than upper limit of normal (ULN) or >2.75mmol/L (>11mg/dL) 2. Renal insufficiency:creatinine clearance <40mL/min or serum creatinine >177 μmol/L (>2mg/dL) 3. Anemia :hemoglobin >2g/dL below the lower limit of normal or hemoglobin <10g/dL 4. Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT Biomarkers of Malignancy: a. Clonal bone marrow plasma cell percentage ≥60% b. Involved: uninvolved serum free light chain (FLC) ratio ≥100 c. >1 focal lesion on magnetic resonance imaging (MRI) studies
3. 3. Must have measurable disease, as assessed by central laboratory, defined by any of the following: - IgG, IgA, IgM, IgD,or IgE multiple myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0g/dL or urine M-protein level ≥ 200mg/24 hours;or - Light chain multiple myeloma without measurable disease in serum or urine: Serum Ig FLC ≥10mg/dL and abnormal serum Ig kappa lambda FLC ratio
4. 4. Eastern cooperative oncology group (ECOG) performance status score of 0, 1 or 2
5. 5. Clinical laboratory values meeting the following criteria during the Screening Phase: a. hemoglobin ≥ 7.5 g/dL (≥ 5 mmol/L) (without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted); b. absolute neutrophil count (ANC) ≥ 1.0 x 109/L (granulocyte colony stimulating factor [G-CSF] use is permitted) c. platelet count ≥ 70x109/L for subjects in whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet count >50×109/L (transfusions are not permitted within 7 days) d. aspartate aminotransferase (AST) ≤2.5 x ULN e. alanine aminotransferase (ALT) ≤2.5 x ULN f. total bilirubin ≤1.5 x ULN, except in subjects with congenital bilirubinemia,such as Gilbert syndrome (direct bilirubin ≤2.0 x ULN) g. Estimated creatinine clearance (CrCl) ≥30 mL/min.Creatinine clearance can be calculated using the Cockcroft-Gault formula or eGFR (MDRD;, or CKD-epi formula or for subjects with over- or underweight, CrCl may be measured from a 24-hours urine collection using the formula provided in Appendix 8 [Section 10.8]). If Cockcroft-Gault formula is used and body mass index (BMI) is ≥30 kg/m2 then adjusted body weight should be used in calculation. h. corrected serum calcium ≤13.5 mg/dL (≤3.4 mM/L); or free ionized calcium ≤6.5 mg/dL (≤1.6 mM/L)
6. 6. Female subjects of reproductive childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously during the Treatment Period,during any dose interruptions, and for 3 months after the last dose of any component of the treatment regimen .Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. This birth control method must include one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy
7. 7. A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 10 to 14 days prior to dosing and the second within 24hours prior to dosing. For requirements during the Treatment Phase, refer to Section 5.3
8. 8. A woman must agree not to donate eggs (ova, oocytes)for the purposes of assisted reproduction during the study and for a period of 3months after receiving the last dose of any component of the treatment regimen
9. 9.Male subjects of reproductive potential who are sexually active with females of reproductive potential must always use a latex or synthetic condom during the study and for 3months after discontinuing study treatment (even after a successful vasectomy)
10. 10. Male subjects of reproductive potential must not donate sperm during the study or for 3months after the last dose of study treatment
11. 11. Must sign an informed consent form (ICF) or their legally designated representative must sign indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study
12. 12. Able to adhere to the prohibitions and restrictions specified in this protocol

Exclusion criteria 14

1. Any potential subject who meets any of the following criteria will be excluded from participating in the study: 1. Frailty index of ≥2 according to Myeloma Geriatric Assessment score
2. 2. Prior therapy for multiple myeloma other than a short course of corticosteroids (not to exceed 40 mg of dexamethasone, or equivalent per day, total of 160 mg dexamethasone or equivalent)
3. 3. Prior or concurrent invasive malignancy (other than multiple myeloma) within 5 years of date of randomization (exceptions are adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other noninvasive lesion that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years)
4. 4. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5
5. 5. Focal radiation therapy within 14 days of randomization with the exception of palliative radiotherapy for symptomatic pain management. Radiotherapy within 14 days prior to randomization on measurable extramedullary plasmacytoma is not permitted even in the setting of palliation for symptomatic management
6. 6. Plasmapheresis within 28 days of randomization
7. 7. Clinical signs of meningeal involvement of multiple myeloma
8. 8. Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted. (FEV1 testing is required for subjects suspected of having COPD)
9. 9. Moderate or severe persistent asthma within the past 2 years, uncontrolled asthma of any classification. (Subjects who have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study)
10. 10. Subject is: a. Known to be seropositive for human immunodeficiency virus (HIV). b. 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 total 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. c. Known to be seropositive for hepatitis C virus (HCV; anti-HCV antibody positive or HCV-RNA quantitation positive), except in the setting of a sustained virologic response (SVR), defined as aviremia at least 12 weeks after completion of antiviral therapy
11. 11. Concurrent medical or psychiatric condition or disease (such as but not limited to, systemic amyloidosis, POEMS, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard if enrolled in the study
12. 12. Has clinically significant cardiac disease, including: ● Myocardial infarction within 6 months before signing the informed consent form (ICF), or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV; Appendix 18) ● Uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormalities ● Screening 12-lead ECG showing a baseline QT interval as corrected by Frederica's formula (QTcF) >470 msec
13. 13. Received a strong CYP3A4 inducer within 5 half-lives prior to randomization
14. 14. Allergy, hypersensitivity, or intolerance to boron or mannitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients, or sensitivity to mammalian-derived products or lenalidomide

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall MRD negativity rate, which is defined as the proportion of subjects who have achieved MRD negative status (at 10^-5) by bone marrow aspirate after randomization and prior to progressive disease (PD) or subsequent anti myeloma therapy. Subjects who have achieved MRD negative status on or after PD or after the switch to subsequent anti-myeloma therapy before PD, will not be considered MRD negative in the primary endpoint analysis

Investigational products

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

Test 1

Auxiliary 11

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Janssen - Cilag International

Sponsor organisation

Janssen - Cilag International

Address

Turnhoutseweg 30

City

Beerse

Postcode

2340

Country

Belgium

Scientific contact point

Organisation

Janssen - Cilag International

Contact name

CTIS Point of Contact

Public contact point

Organisation

Janssen - Cilag International

Contact name

CTIS Point of Contact

Third parties 10

Locations

6 EU/EEA countries · 27 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 58 files

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

Application history

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