E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or Relapsed and Refractory Multiple myeloma |
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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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To establish the safety profile of daratumumab when given in combination with Len/Dex in subjects with relapsed or relapsed and refractory multiple myeloma |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of daratumumab when given in combination with Len/Dex in subjects with relapsed or relapsed and refractory multiple myeloma • To evaluate the PK profile of daratumumab when given in combination with Len/Dex in subjects with relapsed or relapsed and refractory multiple myeloma • To assess the immunogenicity of daratumumab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Before entering Phase 1 of the study, subjects must: 1. Have relapsed multiple myeloma after receiving a minimum of 2 and a maximum of 4 prior lines of therapy and be eligible for treatment with Len/Dex. 2. Have measurable levels of M component, defined as serum M component≥ 1.0 g/dL and/or urine M component ≥ 200 mg/24 hour sample. 3. Be ≥ 18 years of age. 4. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (Attachment 1). 5. Have a life expectancy of ≥ 3 months. 6. Provide signed informed consent after receipt of oral and written information about the study and before any study-related activity is performed. Before entering Phase 2 of the study, subjects must: 1.-Have received at least 1 prior line of therapy for multiple myeloma (refer to Attachment 2). - Have achieved a response (PR or better) to at least one prior regimen. - Have documented evidence of progressive disease (PD) as defined by the IMWG criteria on or after their last regimen. 2. Have measurable levels of M component, defined as serum M component ≥ 1.0 g/dL and/or urine M component ≥ 200 mg/24 hour sample. 3. Be ≥ 18 years of age. 4. Have an ECOG performance status score of 0, 1, or 2 (Attachment 1). 5. Have a life expectancy of ≥ 3 months. 6. Provide signed informed consent after receipt of oral and written information about the study and before any study-related activity is performed. |
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E.4 | Principal exclusion criteria |
1. Have previously received an allogenic stem cell transplant. 2. Have received auto SCT within 12 weeks before the first infusion. 3. Have received antimyeloma treatment, radiotherapy, or any experimental drug or therapy within 2 weeks before the first infusion. 4.Have discontinued lenalidomide due to any treatment-related adverse event or be refractory to any dose of lenalidomide. Refractory to lenalidomide is defined as either: - Subjects whose disease progresses within 60 days of lenalidomide, or - Subjects whose disease is nonresponsive while on any dose of lenalidomide. Nonresponsive disease is defined as either failure to achieve at least an MR or development of PD while on lenalidomide. 5. Have experienced prior DVT of Grade ≥ 3 according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE). 6. Have experienced prior PE. 7. Have had past or current malignancy, except for: -cervical carcinoma of Stage 1B or less; -noninvasive basal cell or squamous cell skin carcinoma; -malignant melanoma with a CR of > 10 years duration; -prostate cancer with a current prostate-specific antigen level < 0.1 ng/mL; -any curable cancer with a CR of > 5 years duration. 8. Have any current serious infectious disease requiring systemic treatment. 9. Have clinically significant cardiac disease, including: -unstable angina; -acute myocardial infarction within 6 months of the Screening Visit (before the first infusion); -congestive heart failure (Class III or IV as classified by the New York Heart Association; Attachment 3); -a known decreased cardiac ejection fraction of < 50%; -a screening 12-lead electrocardiogram (ECG) reading showing a baseline QT interval as corrected by Fridericia's formula (QTcF) > 470 msec for females or > 450 msec for males or a complete left bundle branch block (defined as a QRS interval ≥ 120 msec in left bundle branch block form). 10. Have a significant, concurrent, uncontrolled medical condition including, but not limited to, renal (except as related to multiple myeloma), hepatic, hematologic (except as related to multiple myeloma), gastrointestinal, endocrine, pulmonary, neurologic, cerebral, or psychiatric disease. 11. Be exhibiting clinical signs of meningeal involvement of multiple myeloma. 12. Have known severe chronic obstructive pulmonary disease or asthma (defined as a forced expiratory volume in 1 second [FEV1] <60% of predicted normal) or persistent asthma. 13. Have a history of significant cerebrovascular disease. 14. Have known to be seropositive for human immunodeficiency virus (HIV) or have active hepatitis B or hepatitis C. 15. Have screening laboratory test results as the following: -absolute neutrophil count ≤ 1.5 10^9/L; -hemoglobin level ≤ 80 g/L (≤ 5 mmol/L); -platelet count < 75 10^9/L -alanine aminotransferase (ALT) ≥ 2.5 times the upper limit of normal (ULN); -alkaline phosphatase level ≥ 2.5 × ULN; -direct bilirubin level ≥ 2 × ULN; -creatinine clearance (CrCl) ≤ 60 mL/min within 7 days before the Screening Visit (before the first infusion); -potassium level < 3.0 mEq/L. 16. Have received granulocyte-colony stimulating factor (G-CSF) or granulocyte/macrophage-colony stimulating factor support for < 1 week or pegylated G-CSF for < 2 weeks before the Screening Visit or before the first infusion. 17. Have received a cumulative dose of corticosteroid ≥ 200 mg (dexamethasone, or equivalent doses of prednisone) within 2 weeks before the first infusion. 18. Have a known hypersensitivity to components of the study drug or combination therapy, or have known allergies, hypersensitivity, or intolerance to monoclonal antibodies or human proteins, or their excipients (refer to Investigator Brochure 2013), or have known sensitivity to mammalian-derived products. 19. Have plasma cell leukemia or Waldenström's macroglobulinemia. 20. Have previously received daratumumab, or other anti-CD38 therapies. 21. Be known to have any contraindications to receiving lenalidomide (as specified in the lenalidomide label). 22. Have received treatment with any nonmarketed drug substance within 4 weeks before the first infusion. 23. Be currently participating in any other interventional clinical study. 24. Be known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). 25. Be breastfeeding female. 26. Have a positive pregnancy test at the Screening Visit or before the first infusion.
Please see the protocol for a full list of the exclusion criteria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At end of trial and as part of preparations for subsequent trials, exploratory analysis of subsets of data may be performed. |
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E.5.2 | Secondary end point(s) |
- The rate of response - Pharmacokinetic parameters - Time to progression - Duration of response- Survival |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At end of trial and as part of preparations for subsequent trials, exploratory analysis of subsets of data may be performed. |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
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 | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 |
Denmark |
France |
Italy |
Netherlands |
United Kingdom |
United States |
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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 trial is the last patient last visit. |
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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 | 11 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 26 |
E.8.9.2 | In all countries concerned by the trial years | 11 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 26 |