| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Multiple Myeloma: Patients with MM are frequently diagnosed primarily due to renal failure. Up to 40% of the myeloma patients present with renal failure at diagnosis and approximately 10% require dialysis. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Multiple Myeloma: Patients with MM are frequently diagnosed primarily due to renal failure. Up to 40% of the myeloma patients present with renal failure at diagnosis and app. 10% require dialysis. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 determine the safety and toxicity and the rate of renal recovery in newly diagnosed patients with MM induced dialysis-dependent renal failure receiving daratumumab in combination with carfilzomib, pomalidomide and dexamethasone for 4 cycles. |
|
| E.2.2 | Secondary objectives of the trial |
To determine the overall response rate (ORR) in newly diagnosed patients with MM induced renal failure receiving daratumumab in combination with carfilzomib, pomalidomide and dexamethasone for 4 cycles. ORR will be assessed according International Myeloma Working Group (IMWG) criteria,
including Minor Response (MR) according to European Society for Blood and Bone Marrow Transplantation (EBMT) criteria.
To determine progression free survival (1-Year PFS) in newly diagnosed patients with MM induced renal failure receiving daratumumab in combination with carfilzomib, pomalidomide and dexamethasone for 4 cycles. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male or female patients 18 years or older.
• Voluntary written consent must be given before start of antimyeloma treatment, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
• Patients must have measurable disease defined by at least 1 of the following criteria:
- Serum M-protein ≥ 10g/l
- Urine M-protein ≥ 200mg/24h
- sFLC assay: involved serum light chain ≥ 10mg/dl provided that FLC ratio is abnormal
• Life expectancy > 3 months
• ECOG ≤ 3
• Absolute neutrophil count (ANC) > 1.000/mm3 and platelet count > 50.000/mm3. Platelet transfusions to help patients meet eligibility criteria are allowed within 3 days before study enrollment.
• Total bilirubin ≤ 2 x ULN
• ALT and AST ≤ 3 x ULN
• Disease free of prior malignancies for ≥ 2 years with exception of curatively treated basal cell, squamous cell carcinoma of the skin, or carcinoma “in situ” of the cervix or breast if they have undergone complete resection.
Female patients who:
• Are older than 50 years and postmenopausal for at least 1 year before the screening visit, OR
• Are surgically sterile, OR
• If they are of childbearing potential, agree to practice 2 effective methods of contraception at the same time, from 4 weeks before starting study therapy through 90 days after the last dose of study drug, OR
• Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).
• Are informed and understand the possible consequences of the teratogenic potential of
pomalidomide.
Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the
following:
• Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
• Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
• Are informed and understand the possible consequences of the teratogenic potential of pomalidomide |
|
| E.4 | Principal exclusion criteria |
• Previous anti-myeloma treatment within the last 21 days prior to baseline visit (cycle 1 / day 1), except corticosteroid therapy (<=160 mg dexamethasone or corticosteroid dose equivalent for a maximum of 5 days prior to d1c1)
• Major surgery within 14 days before enrollment
• Radiotherapy within 14 days before enrollment, except local radiation for pain and/or
instable bones.
• Clinical evidence of central nervous system involvement
• Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months
• Systemic treatment, within 14 days before the first dose of study medication, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A4 (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A4 inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort (interference with the
metabolization of pomalidomide).
• Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive
• Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol
• Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
• Known gastrointestinal (GI) disease or GI procedure that could interfere with oral absorption or tolerance of difficulty swallowing.
• Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with basal cell, squamous cell carcinoma of the skin, or carcinoma “in situ” of the cervix or breast with are not excluded if they have undergone complete resection
• Patient has ≥ grade 3 peripheral neuropathy.
• Participation in other interventional clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial.
• Pre-existing documented severe renal impairment (before suspected MM diagnosis) with an eGFR of <30 ml/min/1.73 m2 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is renal recovery defined as:
a) becoming independent from hemodialysis
b) renal response in patients with baseline glomerular filtration rate (GFR) 15-30ml/min, defined as follows:
CRrenal = GFR ≥ 60 ml/min
PRrenal = GFR increase >100%, i.e.: from stage V (GFR < 15ml/min) to stage III (GFR 30 – <60 ml/min)
MRrenal = GFR increase >50%, and from stage V (GFR < 15ml/min) to stage IV (GFR 15 - <30 ml/mi 12
Defined by a measurement at baseline (before initiation of hemodialysis) and at the end of treatment (after2 cycles, measurement before hemodialysis in non-responders; or after 4 cycles of treatment in those with a renal response). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints are:
Progression free survival at 1 year (PFS)in months, defined as the time from day 1 of cycle 1 to the date of first documentation of disease progression based on IMWG criteria or death due to any cause, whichever occurs first.
Overall response rate (ORR) being described as complete response, near complete response, very good partial response, partial response, minor response, stable disease, progressive disease. ORR will be assessed according to International Myeloma Working Group (IMWG) criteria, including Minor Response (MR) according to European Society for Blood and Bone Marrow Transplantation (EBMT) criteria.
Time to first response defined as days from day 1 of cycle 1 to the first documented response.
Time to best response defined (days) from day 1 of cycle 1 to the best documented response.
Recording of AE´s, SAE´s, ECOG performance status, assessment of clinical laboratory values.
Minimal residual disease will be performed in bone marrow samples (only in patients achieving complete response after cycle 4) according to the Euroflow-protocol (FACS-Analysis) with a sensitivity of 10-5) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 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 | 2 |
| 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 | 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| 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 |
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