| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Young untreated patients with multiple myeloma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| 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 |
| The primary objective of the study is to evaluate the feasibility of the strategy including: 6 cycles of induction consisting of the combination of Carfilzomib/Daratumumab/Lenalidomide/Dexamethasone (KRD-DARA) followed by a first Autologous Stem Cell Transplant (ASCT), followed by 4 cycles of consolidation consisiting of KRD-DARA, followed by a second ASCT. |
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
- Determine the safety and tolerability of the combination of carfilzomib, lenalidomide, dexamethasone and daratumumab as induction prior to Autologous Stem Cell Transplant (ASCT).
- Determine the safety and tolerability of the combination of carfilzomib, lenalidomide, dexamethasone and daratumumab as consolidation following a first ASCT.
- Determine the safety and tolerability in this patient population of the lenalidomide/Daratumumab combination as maintenance therapy.
- Evaluate the Stringent Complete Response, Complete Response and Very Good Partial Response rates, the overall response rate after induction, ASCT n°1, consolidation, ASCT n°2 and maintenance therapies.
- Evaluate Minimal Residual Disease (MRD) by Next Generation Sequencing (NGS) at each step of the program.
- Evaluate progression free survival, overall survival, time to progression and duration of response, time to response.
- Evaluate the quality of stem cell harvest after induction therapy.
- Determine biological prognostic factors influencing outcome and response. |
|
| E.3 | Principal inclusion criteria |
1) Male or female subjects, 18 years of age or older, younger than 66 years (< 66 years)
2) Voluntary written informed consent must be given before performance of any study-related procedure not part of normal medical care, with the understanding that the subject may withdraw consent at any time without prejudice to future medical care.
3) Subject must have documented multiple myeloma satisfying the CRAB and measurable disease as defined by:
• Monoclonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy proven plasmacytoma AND any one or more of the following myeloma defining events:
- Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than ULN or > 2.75 mmol/L (> 11 mg/dL)
- Renal insufficiency: creatinine clearance < 40mL/min or serum creatinine > 177 μmol/L (> 2 mg/dL)
- Anemia: hemoglobin > 2 g/dL below the lower limit of normal or hemoglobin < 10 g/dL
- Bone lesions: one or more osteolytic lesions on skeletal radiography, CT or PET-CT
- Clonal bone marrow plasma cell percentage ≥ 60%
- Involved: uninvolved serum free light chain ratio ≥ 100
- Superior 1 focal lesion on MRI studies
• Measurable disease as defined by the following:
M-component ≥ 5g/l, and/or urine M-component ≥ 200 mg/24h and/or serum FLC ≥ 100 mg/l.
4) Newly diagnosed subjects eligible for high dose therapy and autologous stem cell transplantation
5) Subject must have high risk disease according to FISH analysis: del(17p), or t(14;16) or t(4;14). The FISH-positivity cut-off value for defining the presence of del(17p) in this study is 50%
6) Karnofsky performance status score ≥ 50% (eastern cooperative oncology group performance status ECOG score ≤ 2)
7) Female patients who:
- are postemenopausal for at least 24 months before the screnning visit, OR
- are surgically sterile, OR,
- Women of childbearing potential must have a negative serum or urine pregnancy test (sensitivity of at least 25 mIU/mL) within 10 to 14 days prior to therapy and repeated within 24 hours before starting study drugs. They must commit to continued abstinence from heterosexual intercourse or begin 2 acceptable methods of birth control (One highly effective method and one additional effective method) used at the same time, beginning at least 4 weeks before initiation of lenalidomide treatment and continuing for at least 3 months after the last dose of study drugs. Women must also agree to notify immediately pregnancy or doubt upon pregnancy during the study.
8) Men must agree to not father a child and agree to practice complete abstinence or to use a condom during therapy and for 4 weeks after the last dose of study drug, even if they have had a successful vasectomy, if their partner is of childbearing potential or pregnant.
9) Subject must have pretreatment clinical laboratory values meeting the following criteria during the Screening Phase (Lab tests should be repeated if done more than 15 days before C1D1):
a- Hemoglobin ≥ 7.5 g/dL (≥ 5mmol/L). Prior red blood cell [RBC] transfusion or recombinant human erythropoietin use is permitted;
b- Absolute neutrophil count (ANC) ≥ 1.0 Giga/l (GCSF use is permitted);
c- ASAT ≤ 3 x ULN;
d- ALAT ≤ 3 x ULN;
e- Total bilirubin ≤ 3 x ULN (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubin ≤ 1.5 x ULN);
f- Calculated creatinine clearance ≥ 40 mL/min/1.73 m² ;
g- Corrected serum calcium ≤ 14 mg/dL (< 3.5 mmol/L); or free ionized calcium ≤6.5 mg/dL (≤ 1.6 mmol/L) ;
h- Platelet count ≥ 50 Giga/l for subjects in whom < 50% of bone marrow nucleated cells are plasma cells; otherwise platelet count > 50 Giga/l (transfusions are not permitted to achieve this minimum platelet count).
10) Affiliation with French social security system or beneficiary from such system |
|
| E.4 | Principal exclusion criteria |
1) Subjects must not have been treated previously with any systemic therapy for multiple myeloma. Except of prior treatment with corticosteroids (maximum dose of 160 mg of dexamethasone in a 2-week period) or radiation therapy Two weeks must have elapsed since the date of the last radiotherapy treatment. Enrolment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 2 weeks have elapsed since the last date of therapy
2) Subject has received daratumumab or other anti-CD38 therapies previously
3) Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or solitary plasmacytoma.
4) Subject has a diagnosis of Waldenström’s macroglobulinemia, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
5) Subject has had plasmapheresis within 28 days of C1D1.
6) Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
7) Myocardial infarction within 6 months prior to enrolment according to NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities and LVEF < 40%
8) Uncontrolled hypertension
9) Subjects with 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.
10) Subjects with a history of moderate or severe persistent asthma within the past 2 years, or with uncontrolled asthma of any classification at the time of screening (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
11) Subject has plasma cell leukemia (according to WHO criterion: ≥ 20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
12) Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong inhibitors of CYP3A (as clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (as rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, fosphenytoin phenobarbital), or use of Ginkgo biloba or St. John’s wort within 14 days before the first dose of study treatment.
13) Known intolerance to steroid therapy
14) History of hypersensitivity to any of the study medications, their analogues, or excipients in the various formulations, or to study-required co medication
15) Subject has had major surgery within 2 weeks before the first dose of study treatment or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Kyphoplasty or Vertebroplasty are not considered major surgery.
16) Clinically relevant active infection or serious co-morbid medical conditions
17) Prior malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer free of disease since 5 years.
18) Female subject who is pregnant or breast-feeding + male and female refusing birth control conditions
19) Serious medical or psychiatric illness likely to interfere with participation in study
20) Uncontrolled diabetes mellitus
21) Known HIV infection; Known active hepatitis B or C viral infection; or other ongoing uncontrolled infection
22) Incidence of gastrointestinal disease that may significantly after the absorption of oral drugs
23) Subjects unable or unwilling to undergo antithrombotic prophylactic treatment
24) Person under guardianship, trusteeship or deprived of freedom by a judicial or administrative decision
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the percentage of patients receiving the second ASCT. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Number of adverse events defined by Common Terminology Criteria for Adverse Events (5)
- Evaluate the number of responses according to IMWG, Kumar Lancet Oncol 2016
- Number of MRD at each step of the program
- Number of death, number of patients having survival without progress, time to progression and duration of response time to response
- Number of cells collected after induction therapy
- Value of biological prognostic factors (example: ISS score, LDH rate, cytogenetic ….). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| week 24, 31, 55, 53, 175 and 331 |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
Determine biological pronostic factors influencing outcome and response.
Evaluate MRD by NGS at each step of the program
Evaluate the quality of stem cell harvest after induction therapy |
|
| 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 | No |
| 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.8.3 |
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 | 12 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 96 |
| E.8.9.1 | In the Member State concerned days | |
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