E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Smoldering multiple myeloma |
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E.1.1.1 | Medical condition in easily understood language |
Smoldering multiple myeloma |
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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 |
- To evaluate if daratumumab can effectively decrease M protein in subjects with intermediate or high-risk SMM as assessed by CR rate - To determine if daratumumab reduces the progression/death rate in subjects with intermediate or high-risk SMM |
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E.2.2 | Secondary objectives of the trial |
- To evaluate preliminary efficacy, including Overall Response Rate (ORR) and progressionfree survival (PFS) - To evaluate the minimal residual disease (MRD) negative rate - To evaluate the pharmacokinetics and immunogenicity of daratumumab - To assess the safety profile of daratumumab given in 3 different dosing schedules - To determine if daratumumab has an effect on QT interval |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A QTc substudy will be conducted in a subpopulation of subjects at selected sites. Blood samples will be drawn for assessment of pharmacokinetic and biomarker parameters. Protocol 54767414SMM2001 provided in section A.4.1 – A.4.3 |
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E.3 | Principal inclusion criteria |
- diagnosis of smoldering multiple myeloma (SMM) for less than 5 years - have a confirmed diagnosis of intermediate or high-risk SMM, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
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E.4 | Principal exclusion criteria |
1. Active MM, requiring treatment, defined by any of the following: a. Bone lesions (one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron-emission tomography [PET]-CT) b. Hypercalcemia (serum calcium >0.25 mmol/L (>1 mg/dL) higher than ULN or >2.75 mmol/L (>11 mg/dL) c. Renal insufficiency (see Section 9.2.1.4; preferably determined by creatinine clearance <40 mL/min measured or estimated using validated equations [MDRD or CKD-EP formulae recommended], or serum creatinine >177 μmol/L [>2 mg/dL]) d. Anemia, defined as hemoglobin <10 g/dL and/or >2 g/dL below LLN in the absence of transfusion support or concurrent treatment with erythropoietin stimulating agents (ESAs) e. Clonal bone marrow plasma cell percentage ≥60% f. Serum free light chain involved:uninvolved ratio ≥100 g. More than 1 focal lesion by magnetic resonance imaging (MRI) 2. Primary systemic AL (immunoglobulin light chain) amyloidosis 3. Prior or concurrent exposure to any of the following: - To approved or investigational treatments for SMM or/and MM (including but not limited to conventional chemotherapies, immunomodulatory drugs (IMiDs), or proteasome inhibitors). - To daratumumab or other anti CD-38 therapies - To concurrent treatment with corticosteroids with a dose >10 mg prednisone per day or equivalent. - To concurrent treatment with bone-protecting agents (eg, bisphosphonates, denosumab) for treatment of SMM or MM. The subjects who are on a stable dose of these medications for a nonmalignant condition are allowed in the study. - Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before Cycle 1, Day 1 4. Subject has a history of malignancy (other than SMM) within 3 years before the date of randomization, except for the following if treated and not active: basal cell or nonmetastatic squamous cell carcinoma of the skin, cervical carcinoma in situ, ductal carcinoma in situ of breast, or International Federation of Gynecology and Obstetrics (FIGO) Stage 1 carcinoma of the cervix. 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 patients suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal. b) Subject has known moderate or severe persistent asthma within the past 2 years (see Attachment 2), 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). 6. Subject is: - known to be seropositive for human immunodeficiency virus (HIV). - known to have a history of hepatitis C. - 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 hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be tested 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 (antiHBs 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. For subjects who enter extension treatment period, HBV serology (HBsAg, anti-HBs, and anti-HBc) testing is to be performed locally prior to re-initiation. HBV serology is not required at re-initiation if this was performed as part of standard of care within 3 months prior to the reinitiation or the start of extension treatment is within 3 months of last daratumumab dose. 7. Subject has any concurrent medical or psychiatric condition or disease (eg, autoimmune disease, active systemic disease, myelodysplasia) 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. 8. Subject has clinically significant cardiac disease, including significant ischemic coronary disease, congestive heart failure (New York Heart Association [NYHA] Class III or IV), unstable arrhythmias, myocardial infarction or unstable angina within 6 months before randomization, a history of additional risk factors for torsades de pointes (eg, electrolyte abnormalities, family history of Long QT Syndrome), or a family history of sudden cardiac death before age 40. 9. Screening QT interval as corrected by Fridericia's formula (QTcF) >470 msec.
For a complete list of the exclusion criteria, please see section 4.2 of the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. The percentage of participants who achieve a complete response (CR) 2. The percentage of participants that have an event (disease progression or death) per patient-year |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to approximately 24 months for point 1. Up to approximately 30 months for point 2. |
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E.5.2 | Secondary end point(s) |
1. The percentage of participants who are minimal residual disease (MRD) negative. 2. Time to next treatment (TNT). 3. The percentage of participants who achieve a Complete Response (CR) or a Partial Response (PR) 4. The median time of progression free survival (PFS) 5. The percentage of participants with symptomatic multiple myeloma 6. Response to first subsequent multiple myeloma treatment 7. Overall survival rate |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 | No |
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) | 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 | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 26 |
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 |
France |
Netherlands |
Czechia |
Germany |
Italy |
Russian Federation |
Turkey |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
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 study is considered completed up to approximately 7 years after the last subject's first dose, following a decision by the sponsor to end the study based on data from the smoldering multiple myeloma Phase 3 study (SMM3001), or for reasons outlined in Section 17.9.2, 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 | 7 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 25 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
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 | 25 |