| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Primary Objective : The primary objective is to compare the efficacy of daratumumab when combined with lenalidomide and dexamethasone (DRd) to that of lenalidomide and dexamethasone (Rd), in terms of progression-free survival (PFS) in subjects with newly diagnosed myeloma who are not candidates for high dose chemotherapy and autologous stem cell transplant |
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| E.2.2 | Secondary objectives of the trial |
-To evaluate clinical outcomes including:
Time to disease progression (TTP)
CR rate
MRD negativity rate
PFS2 (defined as time from randomization to progression on the next line of therapy or death, whichever comes first)
Overall survival
Time to next treatment
Stringent CR (sCR) rate
Overall response rate (partial response [PR] rate or better)
Proportion of subjects who achieve very good partial response (VGPR) or better
Time to response
Duration of response
-To evaluate the clinical efficacy of daratumumab combination with Rd in high-risk molecular subgroups
-To evaluate treatment effects on patient reported outcomes and heath economic/resource utilization
-To assess the safety and tolerability of daratumumab when administered in combination with Rd.
-To assess the pharmacokinetics of daratumumab in combination with Rd.
-To assess the immunogenicity of daratumumab in Arm B subjects and the immunogenicity of rHuPH20 in subjects receiving daratumumab SC. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject must be at least 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place).
2.Participant must have documented multiple myeloma satisfying the
CRAB (calcium elevation, renal insufficiency, anemia and bone
abnormalities) criteria, monoclonal plasma cells in the bone marrow
greater than or equal to (>=) 10 percent (%) or presence of a biopsy
proven plasmacytoma and measurabl. Measurable disease, as assessed by central laboratory, defined by any of the following:
- immunoglobulin (Ig) G myeloma (serum monoclonal paraprotein
[Mprotein] level >=1.0 gram/deciliter [g/dL] or urine Mprotein level
>=200 milligram[mg]/24 hours[hrs]; or
- IgA, IgM, IgD, or IgE multiple myeloma (serum Mprotein level >=0.5
g/dL or urine Mprotein level >=200 mg/24 hrs); or
- light chain multiple myeloma without measurable disease in serum or urine (serum immunoglobulin free light chain >=10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio)
3.Newly diagnosed and not considered candidate for high-dose
chemotherapy with SCT due to:
Being age ≥65 years, OR
In subjects <65 years: presence of important comorbid condition(s)
likely to have a negative impact on tolerability of high dose chemotherapy with stem cell transplantation. Sponsor review and
approval of subjects under 65 years of age is required before
randomization.
4.Subject must have an ECOG performance status score of 0, 1, or 2
5.Subject must have pretreatment clinical laboratory values meeting the following criteria during the Screening Phase:
a) hemoglobin 7.5 g/dL ( mM/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 ≥30 mL/min (for lenalidomide dose adjustment for subjects with creatinine clearance 30-50 mL/min. Creatinine clearance can be calculated using the Cockcroft-Gault formula; or for subjects with over- or underweight, creatinine clearance may be measured from a 24-hours urine collection using the formula
h) corrected serum calcium ≤14 mg/dL (≤3.5 mM/L); or free ionized
calcium ≤6.5 mg/dL (≤1.6 mM/L)
6. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device [IUD], hormonal [progesterone-only birth control pills or injections 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 and must continue for 3 months after the last dose of daratumumab. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
7. A man who is sexually active with a woman of childbearing potential must agree to use a latex or synthetic condom, even if he had a successful vasectomy. All men must also not donate sperm during the study, for 4 weeks after the last dose of lenalidomide, and for 3 months after the last dose of daratumumab.
8. 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 24 hours prior to dosing. For requirements during the Treatment Phase, please see Section 4.3.
9. Each subject (or their legally acceptable representative) 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.
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|
| E.4 | Principal exclusion criteria |
1.Subject has a diagnosis of primary amyloidosis, monoclonal
gammopathy of undetermined significance, or smoldering multiple
myeloma. Monoclonal gammopathy of undetermined significance is
defined by presence of serum M-protein <3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the Mprotein; and (if determined) proportion of plasma cells in the bone marrow of 10% or less. Smoldering multiple myeloma is defined as asymptomatic multiple myeloma with absence of related organ or tissue impairment end organ damage
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
(equivalent of dexamethasone 40 mg/day for 4 days) of corticosteroids before treatment.
4. Subject has a history of malignancy (other than multiple myeloma)
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.a) Subject has known chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal.
-8.b) Subject has had known moderate or severe persistent asthma
within the last 2 years or currently has uncontrolled asthma of any
classification (Note that subjects who currently have controlled
intermittent asthma or controlled mild persistent asthma are allowed in the study).
9. Subject is known to be seropositive for human immunodeficiency virus (HIV) or hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg] or antibodies to hepatitis B surface and core antigens [Anti-HBs and Anti-HBc, respectively]) or hepatitis C (Anti-HCV antibody positive or HCV-RNA quantitation positive).
10. 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.
11. 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 ≥ 3) or clinically significant ECG abnormalities
screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec
12. Subject has known allergies, hypersensitivity, or intolerance to
corticosteroids, monoclonal antibodies or human proteins, lenalidomide, or their excipients (refer to respective package inserts or Investigator's Brochure), or known sensitivity to mammalian-derived products.
13. 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 × 10^9/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
14. 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.
15. Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study, within 4 weeks after the last dose of lenalidomide, or within 3 months after the last dose of daratumumab. Or, subject is a man who plans to father a child while enrolled in this study, within 4 weeks after the last dose of lenalidomide, or within 3 months after the last dose of daratumumab.
See the protocol for a complete list of the exclusion criteria.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free Survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline for the duration
of disease follow-up, with an
expected average of 40
months |
|
| E.5.2 | Secondary end point(s) |
1-Time to Disease Progression (TTP)
2-Percentage of Participants With Stringent Complete Response (sCR)
3-Percentage of Participants With Complete response (CR)
4-Progression-Free Survival on Next Line of Therapy (PFS2)
5-Percentage of Participants With Negative Minimal Residual Disease (MRD)
6-Time To Next Treatment
7-Percentage of Participants With Overall Response (OR)
8-Percentage of Participants With Very Good Partial Response (VGPR) or Better Response
9-Duration of Response (DR)
10-Overall Survival (OS)Time
11-European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Score
12-Euro Quality of Life (EQ-5D-5L) Health State Profile Utility Score
13-Time to response |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1,2,3,4,6,7, 8 ,9 , 13- From baseline for the duration of disease followup, with an expected average of 40 months
5- From baseline up to 18 months after confirmed CR, with an expected average of 24 months
10- Baseline up to 5 years after last participant is randomized
11 and 12- From baseline up to 16 weeks after disease progression, with an expected average of 44 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| daratumumab plus or minus lenalidomide/dexamethasone |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 84 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Israel |
| New Zealand |
| United States |
| Austria |
| France |
| Sweden |
| Netherlands |
| Germany |
| Italy |
| Denmark |
| Ireland |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
LSLV considered as end of study following below:
1. After last patient has access to other source of dara, LSLV will occur and the study can be ended
2. After last subject has discontinued treatment, LSLV will occur and the study can be ended
3. If there are still patients in the long-term phase shortly before 31
Jan 2026, these will need to be transferred to another source of dara.
After the last patient is transferred, a LSLV will occur and only then the study can be ended on 31 Jan 2026. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 25 |
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