E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 |
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. |
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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 determine the ability of daratumumab to reduce minimal residual disease (MRD) in subjects who achieve a CR or stringent complete response (sCR). - To assess the safety and tolerability of daratumumab when administered in combination with Rd. - To assess the immunogenicity of rHuPH20 in subjects receiving daratumumab SC
Please refer to protocol for complete overview of Secondary objectives |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. 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. 2. Subject must have received at least 1 prior line of therapy for multiple myeloma. 3. 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. 4. 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. 5. Subject must have an ECOG Performance Status score of 0, 1, or 2. Please refer to protocol for complete overview of inclusion criteria. |
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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. 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. 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 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) - Corrected Serum calcium >14.0 mg/dL (>3.5 mmol/L) or free ionized calcium >6.5 mg/dL (>1.6 mmol/L). 9. Subject has plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard differential) or Waldenström’s macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis. Please refer to protocol for complete overview of exclusion criteria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS) |
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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 |
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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) |
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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 |
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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 |
United States |
Russian Federation |
Belgium |
France |
Germany |
Greece |
Netherlands |
Poland |
Spain |
Sweden |
Korea, Republic of |
Taiwan |
United Kingdom |
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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
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The end of the study is defined as when one of the following occurs: • when all subjects who are still receiving study treatment after the final OS analysis have access through another source such as commercial availability, continued access through a long-term extension study, or a patient access program, • when all subjects have discontinued study treatment, • if the first 2 are not met, then by 23 August 2024, whichever occurs first. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 9 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 15 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |