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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10035226 |
E.1.2 | Term | Plasma cell myeloma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Evaluate the efficacy (overall response rate, ORR according to IMWG recommendations) of the combination of Daratumumab, Bortezomib and Dexamethasone in subjects with relapsed and refractory MM and impaired renal function |
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E.2.2 | Secondary objectives of the trial |
Evaluate safety and tolerability as assessed by the incidence of clinical and laboratory toxicities Evaluate progression-free survival (PFS) Evaluate overall survival (OS) Evaluate renal efficacy according to IMWG (Dimopoulos, MA et al. 2010)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Subjects must be at least 18 years of age 2.Written informed consent 3.Subjects must have had documented multiple myeloma requiring treatment as defined by the criteria below: Monoclonal plasma cells in the bone marrow > 10% and/or presence of a biopsy-proven plasmacytoma at some point in their disease history requiring treatment according diagnostic criteria (IMWG updated criteria 2014, Rajkumar et al. 2014) see appendix I With measurable disease at screening (serum M-protein > 500 mg/dl or urine M-protein > 200 mg/24h, in case of oligosecretory MM serum free light chain > 10 mg/dl and abnormal kappa/lambda free light chain ratio) 4.GFR < 30 ml/min and /or subjects undergoing hemodialysis 5.Subject must have received at least 1 prior treatment line 6.Subjects must have documented evidence of progressive disease after the last treatment line 7.ECOG performance status 0-3 (ECOG 3 is only allowed if due to myeloma disease) 8.Subjects must have certain pretreatment laboratory values meeting the following criteria during the Screening Phase: a)Hemoglobin ≥7.5 g/dl (4,66 mmol/L; prior red blood cells (RBC) transfusion or recombinant human erythropoietin use is permitted). b)Absolute neutrophil count ≥ 1.0 x10^9/L (granulocyte colony stimulating factor (GCSF) use is permitted); c)Platelet count more or equal 70 x10^9/L for subjects in whom < 50% of bone marrow nucleated cells are plasma cells; otherwise platelet count > 50 x 10^9/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)Corrected serum calcium ≤ 14 mg/dl (≤3,5mmol/L); or free ionized calcium < 6,5 mg/dL(˂1,6 mmol/L) 9.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. 10.A woman of childbearing potential must have a negative urine or serum pregnancy test at screening within 14 days prior to treatment start.
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E.4 | Principal exclusion criteria |
1.Subject has received prior Daratumumab or other Anti-CD38 antibodies (previous treatment with Elotuzumab is allowed) 2.Evidence of intolerance to bortezomib or known allergies, hypersensitivity or intolerance to monoclonal antibodies 3.Subject has received anti-myeloma treatment within 2 weeks of Cycle 1, day 1. The only exception is emergency use of a short course of corticosteroids (equivalent of Dexamethasone 40 mg/day for a maximum of 4 days) before treatment. 4.Active graft-versus host disease under immunosuppressive treatment 5.Subject is a woman who is pregnant or breastfeeding 6.Prior invasive malignancy within 5 years before trial inclusion 7.Active, uncontrolled infection. 8.Subject has peripheral neuropathy ≥ 3 or neuropathic pain Grade 2 or higher 9.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 only required for subjects suspected of having COPD b.Known moderate or severe persistent asthma, or currently has 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). 10.Subject has clinically significant cardiac disease, including myocardial infarction within 6 months before date of study entry, unstable angina, cardiac insufficiency New York Heart Association (NYHA) Class III-IV or uncontrolled arrhythmia 11.Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined significant is defined by presence of serum M-protein ˂ 3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia and renal insufficiency related to M-protein; and (if determined) proportion of plasma cells in the bone marrow of 10% or less (Kyle et al. 2003). Smoldering multiple myeloma is defined as asymptomatic multiple myeloma with absence of related organ or tissue impairment and organ damage (Kyle et al., 2003, 2007). 12.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. 13.Subject has had radiation therapy within 14 days of treatment 14.Subject has had plasmapheresis within 14 days of treatment. Screening laboratory values have to be performed after end of plasmapheresis. 15.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 antigen (anti HBs and anti HBc respectively), or hepatitis C (anti-HCV antibody positive or HCV RNA quantitation positive). 16.Subject has had major surgery within 2 weeks before treatment und has not fully recovered from surgery, or has surgery panned during the time the subject is expected to participate in the study. 17.Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs 18.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 the participating in this study. 19.Subject has known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator’s Brochure), or known sensitivity to mammalian-derived products. 20.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 medication as per section 4.8.4
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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 |
evaluation of response at each cycle |
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E.5.2 | Secondary end point(s) |
Evaluate safety and tolerability as assessed by the incidence of clinical and laboratory toxicities Evaluate progression-free survival (PFS) Evaluate overall survival (OS) Evaluate renal efficacy according to IMWG (Dimopoulos, MA et al. 2010)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For the entire Duration of the study
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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 | No |
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) | 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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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2 years after enrollment of the last patient. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |