| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| YOUNG PATIENTS AFFECTED BY MULTIPLE MYELOMA (MM) TO THE DIAGNOSIS ELIGIBLE TO THE AUTOLOGOUS TRANSMISSION OF STEM CELLS |
|
| E.1.1.1 | Medical condition in easily understood language |
| YOUNG PATIENTS WITH NEW DIAGNOSIS OF MULTIPLE MYELOMA ELIGIBLE TO THE AUTOLOGOUS TRANSMISSION OF STEM CELLS |
|
| 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) |
|
| 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 |
-Determine the progression free survival (PFS) at 36 months from first randomization (24 months from second).
-Determine minimal residual disease (MRD) negativity rate after consolidation according to IMWG criteria, by means of next generation sequencing (NGS)
-Determine MRD negativity rate during maintenance according to IMWG criteria, by means of next generation sequencing (NGS) |
|
| E.2.2 | Secondary objectives of the trial |
Determine:
overall response rate
VGPR rate
Determine the CR and sCR rate.
PFS2
the safety
the duration of response
the overall survival
the time to progression
the time to next therapy
MRD negativity rate by next generation flow cytometry (NGF) and
PET/CT after induction, consolidation and during maintenance
the role of MRD on OS
the prognostic role of different sensitivity levels of MRD
the MRD duration
the conversion rate of MRD negativity in MRD positivity and viceversa
whether tumor response and outcome may change in subgroups with
different prognosis according to current prognostic factors
whether tumor response and outcome may change in subgroups with
different prognosis according to new prognostic factors
the impact of maintenance treatment on MRD
Determine whether tumor response and outcome may change in subgroups with different prognosis according to new prognostic factors, as evaluated by NGS.
Definition of prognostic factors, as assessed by NGS
Evaluate QoL |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
➢ Patient at least 18 years of age and ≤ 65 years.
➢ Patient eligible for ASCT.
➢ LVEF ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation.
Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available.
➢ Newly diagnosed multiple myeloma patient.
➢ Patient has given voluntary written informed consent before performance of any study related
procedure not part of standard medical care, with the understanding that consent may be
withdrawn by the patient at any time without prejudice to future medical care.
➢ Patient with documented multiple myeloma and measurable disease as defined by:
- Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven
plasmacytoma
- Measurable disease as defined by at least one of the following:
➢ serum M-protein level ≥1 g/dL or urine M-protein level ≥200 mg/24 hours; or
➢ Light chain multiple myeloma: involved serum immunoglobulin free light chain
≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
➢ Evidence of end organ damage/presence of biomarkers of malignancies, specifically:
- Hypercalcaemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal
or >2.75 mmol/L (>11 mg/dL)
- Renal insufficiency: creatinine clearance <40 mL per minute (measured or estimated by validated
equations) or serum creatinine >177 μmol/L (>2 mg/dL)
- Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or haemoglobin value
<100 g/L
- Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT. If bone
marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish
from solitary plasmacytoma with minimal marrow involvement.
➢ Any one or more of the following biomarkers of malignancy:
• Clonal bone marrow plasma cell percentage ≥ 60% (clonality should be established by
showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or
immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated
from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy,
the highest value should be used)
• Involved/uninvolved serum free light chain ratio ≥100 (values based on the serum Freelite
assay. The involved free light chain must be ≥100 mg/L)
• or >1 focal lesion on MRI studies (each focal lesion must be 5 mm or more in size)
➢ Patient is, in the investigator(s) opinion willing and able to comply with the protocol requirements.
➢ Women of childbearing potential must commit to either abstain continuously from heterosexual
intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly
effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills,
hormonal patches, vaginal rings or implants] or partner’s vasectomy through a medical assessment
of success of the procedure, according to local procedure) and one additional effective contraceptive
method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin
prior to dosing and for at least 4 weeks before starting thalidomide through 90 days after the last
dose of study drugs and 6 months after the last dose of cyclophosphamide. Reliable
contraception is indicated even where there has been a history of infertility, unless due to
hysterectomy or bilateral oophorectomy.
➢ Male patient agrees to use an acceptable method for contraception (i.e., condom or abstinence)
during study drug therapy (including dose interruption) and for 90 days after the last dose of study
drugs and 6 months after the last dose of cyclophosphamide.
➢ Patient with an ECOG performance status score of 0, 1, or 2 or Karnofsky performance status ≥
60%.
➢ Pretreatment clinical laboratory values within 30 days of enrolment:
- Platelet count ≥75 x 109/L;
- Absolute neutrophil count (ANC) ≥ 1 x 109/L (G-CSF use is permitted);
- Corrected serum calcium <14 mg/dL (<3.5 mmol/L);
- Aspartate transaminase (AST) ≤ 2.5 x the upper limit of normal (ULN);
- Alanine transaminase (ALT) ≤ 2.5 x the ULN;
- Total bilirubin ≤ 1.5 x the ULN;
- Calculated or measured creatinine clearance ≥ 30 mL/minute.
➢ Patient has a life-expectancy >3 months.
|
|
| E.4 | Principal exclusion criteria |
Patient with a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, plasma cell leukemia or smoldering multiple myeloma. Monoclonal gammopathy of undetermined significance is defined by presence of serum M-protein <3 g/dL; clonal bone marrow plasma cells <10%, and absence of end-organ damage; or amyloidosis that can be attributed to the plasma cell proliferative disorder. Smoldering multiple myeloma is defined as serum monoclonal protein ≥ 30 g/L or urinary monoclonal protein ≥ 500 mg per 24 h and/or clonal bone marrow plasma cell 10-60% with absence of related organ or tissue impairment or end-organ damage or amyloidosis. Plasma cell leukemia is defined as the presence of circulating plasmacells (PCs) >2×109/L in peripheral blood or a peripheral blood plasmacytosis >20%.
Patient with 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.
Patient has prior or current systemic therapy or SCT for multiple myeloma, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.
Patient has peripheral neuropathy of grade 2 or higher as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 4.0.Patient has peripheral neuropathy of grade 2 or higher as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 5.0.
Patient is exhibiting clinical signs of meningeal involvement of multiple myeloma.
Clinical active infectious hepatitis type A, B, C or HIV.
Subject has known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume in 1 second [FEV1] <60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years. Subjects with known or suspected COPD or asthma must have a FEV1 test during screening.
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.
Known allergy to any of the study medications, their analogues, or excipients in the various formulations.
Contraindication to any of the required concomitant drugs or supportive treatments.
Pregnant or lactating females.
Acute active infection requiring antibiotics or infiltrative pulmonary disease.
Serious medical condition, laboratory abnormality or psychiatric illness that prevented the subject from the enrolment or place the subject at unacceptable risk, including acute diffuse infiltrative pericardial and pulmonary disease.
Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.
Invasive malignancy within the past 5 years.
Major surgery within 14 days before enrollment.
Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the ixazomib.
Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.
Live vaccine 30 days before start of treatment and 90 days after the end of study treatment
Participation in other 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.Participation in other clinical trials 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. Participation to observational study is allowed.
Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
-Progression free survival (PFS)
-MRD negativity |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Overall response rate (ORR)
-Progression free survival 2 (PFS2)
- Duration of response (DoR)
- Overall survival (OS)
- Time to progression (TTP)
- Time to the next anti-myeloma therapy (TNT)
-MRD by NGF and PET/CT
-Definition of prognostic factors, as assessed by NGS (MM-panel) |
|
| 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 | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 | 12 |
| 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 | 12 |
| 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 |
Print
