| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| newly diagnosed 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 | 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 |
To compare rate of Minimal Residual Disease (MRD) negativity by NGS between Isa-KRd and KRd in post ASCT consolidation treatment.
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| E.2.2 | Secondary objectives of the trial |
Rate of MRD negativity after induction by NGS
To compare progression-free survival (PFS) in the 2 treatment arms
Rate of MRD negativity
Rate of 1 year sustained MRD negativity by NGS (from post ASCT consolidation to post light consolidation)
Determine:
the overall response rate, VGPR, CR, sCR rate after induction, ASCT, post ASCT consolidation, light consolidation in the 2 treatment arms
the duration of response in the 2 treatment arms
the duration of MRD negativity
the rate of sustained for 1-year MRD negativity
the time to progression in the 2 treatment arms
the overall survival in the 2 treatment arms
the time to next therapy in the 2 treatment arms
the progression-free survival 2 in the 2 treatment arms
whether tumor response and outcome may change in subgroups with different prognosis according to current prognostic factors
safety in the 2 treatment arms
the success of stem cell harvest
the success of engraftment after ASCT
Quality of life. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Patient with newly diagnosed multiple myeloma and eligible to ASCT, for whom the standard treatment it is not, according to investigator, the best treatment available.
2.Patient is, in the investigators opinion, willing and able to comply with the study visits and procedures required per protocol.
3.Patient has provided written informed consent in accordance with federal, local, and institutional guidelines prior to initiation of any study-specific activities or procedures. Subject does not have kind of condition that, in the opinion of the Investigator, may compromise the ability of the subject to give written informed consent and patient is, in the investigator(s) opinion, willing and able to comply with the protocol requirements.
4.Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma and documented multiple myeloma satisfying at least one of the calcium, renal, anemia, bone (CRAB) criteria or biomarkers of malignancy criteria:
CRAB criteria:
- Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than upper limit of normal (ULN) or >2.75 mmol/L (>11 mg/dL)
- Renal insufficiency: creatinine clearance <40mL/min or serum creatinine >177 N>mol/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
Biomarkers of Malignancy:
- Clonal bone marrow plasma cell percentage ≥60%
- Involved: uninvolved serum FLC ratio ≥100
- >1 focal lesion on magnetic resonance imaging (MRI) studies
5.Patient is 18 - 70 years old and is eligible for autologous stem cell transplantation
6.Patient has measurable disease as defined by any one of the following:
- Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or
- Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin FLC ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio.
7.Life expectancy ≥ 3 months
8.ECOG status ≤2
9.Clinical laboratory values meeting the following criteria during the Screening Phase:
-Adequate hepatic function, with serum (alanine aminotransferase) ALT≤ 2.5 times the upper limit of normal (ULN), AST (aspartate transaminase) ≤ 2.5 x the ULN
-Serum direct bilirubin ≤ 1.5 ULN) (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubinemia ≤ 1.5 ULN)
-Absolute neutrophil count (ANC) ≥1.0 109/L
-Platelet count≥ 75 109/L (≥ 50 109/L if myeloma involvement in the bone marrow is > 50%) and no platelet infusion in the 1 week prior to screening platelet count
-Creatinine clearance (CrCl) ≥ 30 mL/minute. Creatinine clearance should be calculated using eGFR (Modified Diet in Renal Disese [MDRD])
-Corrected serum calcium ≤ 13.5 mg/dL (3.4 mmol/L)
-LVEF ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available.
10.Females of childbearing potential (FCBP)* complies with the conditions of the Pregnancy Prevention Plan, including confirmation that she has an adequate level of understanding and must agree to ongoing pregnancy testing and to practice contraception or true abstinence. FCBP must use a highly effective and an additional barrier contraception method simultaneously for 4 weeks before starting therapy, during treatment and dose interruptions and for 5 months after the last dose of study drugs.
11.Male subjects must agree to practice contraception if sexually active with FCBP during the treatment and for at least 5 months after the last dose of study drugs. Males must agree to refrain from donating sperm for at least 90 days after the last dose of carfilzomib and for at least 5 months after the last dose of isatuximab.
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| E.4 | Principal exclusion criteria |
1.Previous treatment with anti-myeloma therapy (does not include radiotherapy, biphosphonates, or a single short course of steroid ≤ to the equivalent of dexamethasone 40 mg/day for 4 days).
2.Patients with non-secretory MM unless serum free light chains are present and the ratio is abnormal or a plasmacytoma with minimum largest diameters of > 2 cm.
3.Patients with plasma cell leukemia, amyloidosis, Waldenstrom Disease, POEMS syndrome
4.Meningeal involvement of multiple myeloma
5.Patient ineligible for autologous transplantation
6.Pregnant or lactating females
7.Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomization
8.Known human immunodeficiency virus infection (HIV)
9.Active hepatitis A, B or C infection. Hepatitis C infection (subjects with hepatitis C that achieve a sustained virologic response after antiviral therapy are allowed), or hepatitis B infection (subjects with hepatitis B surface antigen or core antibody that achieve sustained virologic response with antiviral therapy are allowed). Tests to be performed if required per local country regulations (in Czech Republic testing for HIV and hepatitis B and C is required at screening). In fact it is not possible to avoid the risk of virological reactivation with the study treatments.
Uncontrolled or active HBV infection: Patients with positive HBsAg and/or HBV DNA
Active HCV infection: positive HCV RNA and negative anti-HCV
10.Unstable angina or myocardial infarction within 4 months prior to randomization, NYHA Class III or IV heart failure, uncontrolled angina, uncontrolled hypertension Uncontrolled hypertension, defined as an average systolic blood pressure ≥ 160 mmHg or diastolic ≥ 100 mmHg despite optimal treatment (measured following European Society of Hypertension/European Society of Cardiology 2013 guidelines), in the last 5 years pulmonary embolia, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker
11.Non-hematologic or hematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas
12.Significant neuropathy (Grades 3b4, or Grade 2 with pain) within 14 days prior to randomization as defined by National Cancer Institute Common Toxicity Criteria (NCI CTCAE) 5.0
13.Known history of allergy to CaptisolB. (a cyclodextrin derivative used to solubilize carfilzomib) and to PS80; prior hypersensitivity to sucrose, histidine (as base and hydrochloride salt), or known intolerance or hypersensitivity to infused protein products or any of the components (active substance or excipients) of study treatments that are not amenable to premedication with steroids, or H2 blockers, that would prohibit further treatment with these agents.
14.Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
15.Any other clinically significant medical disease or condition that, in the Investigators opinion, may interfere with protocol adherence or a subjects ability to give informed consent
16.Received any investigational drug within 14 days or 5 half-lives of the investigational drug, prior to initiation of study intervention, whichever is longer.
17.Pregnant or breastfeeding woman or woman who intends to become pregnant during the participation in the study. FCBP unwilling to prevent pregnancy by the use of 2 reliable methods of contraception for ≥4 weeks before the start of study treatment, during treatment (including dose interruptions), and for at least 28 days following discontinuation of study lenalidomide, or 30 days following discontinuation of carfilzomib or for 5 months after discontinuation of isatuximab treatment, whichever occurs last,
18.Male participants who disagree to practice true abstinence or disagree to use a condom during sexual contact with a pregnant woman or a FCBP while participating in the study, during dose interruptions, and for at least 28 days following discontinuation of study lenalidomide, or 3 months following discontinuation of carfilzomib, or for 5 months after discontinuation of isatuximab treatment, whichever occurs last, even if he has undergone a successful vasectomy.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The rate of MRD negativity is determined as the proportion of patients with MRD negativity (≥10 -5 sensitivity level) after ASCT consolidation treatment using ITT principle. For patients who withdraw from the study or are lost to follow up before four post ASCT consolidation cycles, the best MRD assessment will be considered. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
after post ASCT consolidation
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| E.5.2 | Secondary end point(s) |
The rate of MRD negativity after induction is determined as the proportion of patients with MRD negativity after the induction phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment/sample not adequate.
PFS will be measured from the date of randomization to the date of first observation of PD, or death from any cause as an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. All subjects who were lost to FU will also be censored at the time of last complete disease assessment
The rate of MRD negativity after light consolidation is determined as the proportion of patients with MRD negativity after light consolidation phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment/sample not adequate. Patients who withdraw from the study or are lost to follow up before MRD evaluation, the best MRD assessment will be considered.
Rate of 1 year sustained MRD negativity by NGS will be also evaluated.
Response rate will be evaluated according to IMWG Response criteria after induction, ASCT, post ASCT consolidation and light consolidation
PFS2 will be measured from the date of randomization to the date of observation of second disease progression or death to any cause as an event. In case of date of second progression is not available, date of start of third line treatment can be used. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. All subjects who were lost to follow-up prior to the end of the study, have not progressed, and are still alive will also be censored at the time of last contact.
TTP will be measured from the date of randomization to the date of first observation of PD, or deaths for PD. Subjects who have not progressed or who withdraw from the study or die from causes other than PD will be censored at the time of the last complete disease assessment. Subjects lost to FU will also be censored at the time of last complete disease assessment.
DOR is defined as time between first documentation of response and PD with deaths owning to causes other than progression not counted, but censored. Responders without disease progression at the cut-off date of final analysis will be censored either at the time of lost to FU, at the time of death due to other cause than PD, or at the at the time of last contact.
OS is defined as the time between randomization and death, regardless cause of death. Subjects who withdraw consent will be censored at the time of withdrawal. Subjects who are still alive at the cut-off date of final analysis will be censored at the cut-off date. Subjects lost to FU will also be censored at the time of last contact.
TNT will be measured from the date of randomization to the date of next anti-myeloma therapy. Death due to any cause before starting therapy will be considered an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. Subjects lost to FU will also be censored at the time of last contact.
Determine safety in the 2 treatment arms in the different phases
Determine whether tumor response and outcome may change in subgroups with different prognosis according to current prognostic factors.
The rate of MRD negativity after ASCT is determined as the proportion of patients with MRD negativity , NGS using ITT principle. For patients who withdraw from the study or are lost to follow up before ASCT, the best MRD assessment will be considered. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.
The rate of MRD negativity after induction, ASCT, post ASCT consolidation and light consolidation are determined as the proportion of patients with MRD negativity after the specific phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment. Patients who withdraw from the study or are lost to follow up before MRD evaluation phase, the best MRD assessment will be considered.
The duration of MRD Negativity is defined as time between first MRD Negativity and first MRD positivity. Patients without MRD positivity will be censored at last complete assessment.
Determine the rate of sustained for 1-year MRD negativity
Determine the success of stem cell harvest according to baseline characteristics; stem cells will be harvested at a minimum of 4 x 106 CD34+ cells/kg
Determine the success of engraftment after ASCT, defined by the time
needed to achieve: Absolute Neutrophil Count (ANC) and Platelet count
Quality of life defined by EORTC QLQ-C30, EORTC QLQ-MY20 and EQ5D5L. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| after induction therapy (before ASCT) - after ASCT - after post ASCT consolidation - after light consolidation |
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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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| 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) | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 48 |
| 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 |
| Belgium |
| Czechia |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Norway |
| Spain |
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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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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