| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Multiple myeloma |
| Myelomatose |
|
| E.1.1.1 | Medical condition in easily understood language |
| Multiple myeloma |
| Myelomatose |
|
| 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 |
|
| 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 |
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 relapsed or refractory multiple myeloma. |
| Det primære formål er at sammenligne effekten af daratumumab, kombineret med lenalidomid og dexamethason (DRd) i forhold til lenalidomid og dexamethason (Rd) i form af progressionsfri overlevelse hos forsøgspersoner med reciditiv eller rekraktær myelomatose. |
|
| E.2.2 | Secondary objectives of the trial |
The major secondary objectives are as follows:
- To compare the 2 treatment groups with respect to time to disease progression (TTP), overall response rate (ORR), and overall survival (OS).
- To compare the 2 treatment groups with respect to the proportion of subjects with a response of very good partial response (VGPR) or better.
- To compare the 2 treatment groups with respect to duration of and time to response.
- To compare the 2 treatment groups with respect to time to subsequent antimyeloma treatment.
- To assess the safety and tolerability of daratumumab when administered in combination with Rd.
Other secondary objectives are as follows:
To assess the pharmacokinetics of daratumumab in combination with
Rd.
To assess the immunogenicity of daratumumab.
To assess the immunogenicity of rHuPH20 in subjects receiving daratumumab SC
|
De vigtigste sekundære mål er som følger:
-At sammenligne de 2 behandlingsgrupper med hensyn til TTP, ORR og OS.
-At sammenligne de 2 behandlingsgrupper med hensyn til andelen af personer med respons af VGPR eller bedre.
-At sammenligne de 2 behandlingsgrupper med hensyn til varigheden af og tid til respons.
-For at sammenligne de 2 behandlingsgrupper med hensyn til tid efterfølgende antimyeloma behandling.
-For at bestemme daratumumab egenskab til at reducere minimal residual sygdom (MRD) i personer, som opnår komplet respons (CR) eller stringent komplet respons (SCR).
-At vurdere sikkerheden og tolerabiliteten af daratumumab, når det gives i kombination med Rd. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject must be at least 18 years of age.
2. Subject must have documented multiple myeloma as defined by the criteria below:
● Monoclonal plasma cells in the bone marrow 10% at some point in their disease history or presence of a biopsy proven plasmacytoma.
● Measurable disease as defined by any of the following:
- IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or
- IgA, IgD, IgE, IgM multiple myeloma: serum M-protein level ≥0.5 g/dL or urine M-protein level ≥200 mg/24 hours; or
- Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
3. Subject must have received at least 1 prior line of therapy for multiple myeloma (refer to Attachment 1).
4. Subject must have achieved a response (PR or better based on investigator's determination of response by the IMWG criteria) to at
least one prior regimen (refer to Attachment 1).
5. Subject must have documented evidence of progressive disease (PD) based on investigator's determination of response by the IMWG criteria on or after their last regimen.
6. Subject must have an ECOG Performance Status score of 0, 1, or 2 (refer to Attachment 2).
7. For subjects experiencing toxicities resulting from previous therapy (including peripheral neuropathy), the toxicities must have resolved or stabilized to ≤Grade 1.
8. 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 [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.
9. 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.
10. 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. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF. |
|
| E.4 | Principal exclusion criteria |
1. Subject has received daratumumab or other anti-CD38 therapies previously
2. Subject's disease shows evidence of refractoriness or intolerance to lenalidomide.If previously treated with a lenalidomide-containing
regimen, the subject is excluded if he or she:
● Discontinued due to any adverse event related to prior lenalidomide
treatment (history of thromboembolism due to lenalidomide is allowed if subject is anticoagulated per the American Society of Clinical Oncology [ASCO] 2013 guideline) (Lyman 2013)26,or
●If, at any time point, the subject was refractory to any dose of lenalidomide. Refractory to lenalidomide is defined either:
-Subjects whose disease progresses within 60 days after the last dose of lenalidomide;or
-Subjects whose disease is nonresponsive while on lenalidomide.Nonresponsive disease is defined as either failure to achieve at least an MR or development of PD while on lenalidomide
3.Subject has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer,before
the date of randomization.The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum 4 days) before treatment. A list of anti-myeloma treatments with the corresponding pharmacokinetic half-lives is
provided in the Site Investigational Product Procedures Manual (IPPM).
4.Subject has received ASCT within 12 weeks before the date of randomization,or the subject has previously received an allogenic stem
cell transplant (regardless of timing)
5.Subjects planning to undergo a stem cell transplant prior to progression of disease on this study,ie, these subjects should not be enrolled in order to reduce disease burden prior to transplant
6.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, carcinoma in situ of the cervix or breast, or other non-invasive 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 5 years)
7. Subject has known meningeal involvement of multiple myeloma
8.Subject has either of the following:
a) 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 is <50% of predicted normal
b) Known moderate or severe persistent asthma, within the past 2 years (see Attachment 9), uncontrolled asthma of any classification. Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study
9.Subject is known to be seropositive for human immunodeficiency virus (HIV), known to have hepatitis B surface antigen positivity, or known to have a history of hepatitis C.
10. Subject has any concurrent medical condition or disease (eg, active systemic infection) that is likely to interfere with 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 6 months before Cycle1,Day1,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)
● Uncontrolled cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] Version 4 Grade 2 or higher) 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 any of the following laboratory test results during the Screening Phase:
-Absolute neutrophil count ≤1.0 × 109/L
- Hemoglobin level ≤7.5 g/dL (≤5 mmol/L) (it is not permissible to transfuse a subject to reach this level)
- Platelet count <75 × 109/L for subjects in whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet count <50 ×
109/L (it is not permissible to transfuse a subject to reach this level)
-Aspartate aminotransferase (AST)or alanine aminotransferase level (ALT) ≥2.5 times the upper limit of normal (ULN)
-Alkaline phosphatase level ≥2.5 × ULN
-Total bilirubin level ≥1.5 × ULN,(except for Gilbert Syndrome: direct bilirubin 1.5 ×ULN)
-Creatinine clearance <30 mL/min (for lenalidomide dose adjustment for subjects with creatinine clearance 30-60 mL/min, please see Section
6.5).Calculated creatinine clearance may be calculated using the Cockcroft-Gault formula, Modification of Diet in Renal Disease (MDRD),or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) (see Attachment 3)
Please refer to protocol for complete overview of 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 randomization to either disease
progression or death whichever occurs first
until 3 years |
|
| E.5.2 | Secondary end point(s) |
1. Time to disease progression (PD)
2. Overall response rate
3. Number of participants who acheive very good partial response (VGPR) or better
4. Time to complete response (CR) or partial response (PR)
5. Overall survival
6. Duration of response
7. Percentage of Participants With Minimal residual disease (MRD) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- for Secondary outcome 1 = From randomization to either disease progression or death whichever occurs first until 3 years
- for Secondary outcome 2 and 3 = From randomization until 3 years
- for Secondary outcome 4 = From randomization up to first documented CR or PR until 3 years
- for Secondary outcome 5 = Up to approximately 5 years (anticipated) after the last participant is randomized
- for Secondary outcome 6 = From randomization to the date of first documented evidence of PD until 3 years
- for Secondary outcome 7 = From randomization to the date of first documented evidence of CR and Month 3 and 6 post CR |
|
| 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 | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Korea, Republic of |
| Russian Federation |
| Taiwan |
| United States |
| Belgium |
| Denmark |
| France |
| Germany |
| Greece |
| Netherlands |
| Poland |
| Spain |
| Sweden |
| 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
|
| the following is included in the protocol : “The study end is defined as when 330 deaths have occurred." |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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