ixazomib citrate for Multiple myeloma

Inclusion criteria

• {"criterion_text":"- Patient at least 18 years of age and ≤ 65 years.\n- 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.\n- 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.\n- Patient with an ECOG performance status score of 0, 1, or 2 or Karnofsky performance status ≥ 60%.\n- Pretreatment clinical laboratory values within 30 days of enrolment: - Platelet count ≥75 x 10^9 /L; - Absolute neutrophil count (ANC) ≥ 1 x 10^9 /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\n- Patient has a life-expectancy >3 months.\n- Patient eligible for ASCT.\n- LVEF ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available.\n- Newly diagnosed multiple myeloma patient.\n- 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of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.\n- Patient with documented multiple myeloma and measurable disease as defined by: 1) Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma. 2) Measurable disease as defined by at least one of the following: 2.1) serum M-protein level ≥1 g/dL or urine M-protein level ≥200 mg/24 hours; or 2.2) Light chain multiple myeloma: involved serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.\n- Evidence of end organ damage/presence of biomarkers of malignancies, specifically: 1) 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). 2) Renal insufficiency: creatinine clearance <40 mL per minute (measured or estimated by validated equations) or serum creatinine >177 μmol/L (>2 mg/dL). 3) Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or haemoglobin value <100 g/L. 4) 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.\n- Any one or more of the following biomarkers of malignancy: 1) 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). 2) 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). 3) or >1 focal lesion on MRI studies (each focal lesion must be 5 mm or more in size)\n- Patient is, in the investigator(s) opinion willing and able to comply with the protocol requirements."}

Exclusion criteria

• {"criterion_text":"- 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 endorgan damage or amyloidosis. Plasma cell leukemia is defined as the presence of circulating plasmacells (PCs) >2×10^9 /L in peripheral blood or a peripheral blood plasmacytosis >20%.\n- Contraindication to any of the required concomitant drugs or supportive treatments.\n- Pregnant or lactating females.\n- Acute active infection requiring antibiotics or infiltrative pulmonary disease.\n- 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.\n- Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.\n- Invasive malignancy within the past 5 years.\n- Major surgery within 14 days before enrollment.\n- Radiotherapy within 14 days before enrollment.\n- Live vaccine 30 days before start of treatment and 90 days after the end of study treatment\n- Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.\n- 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.\n- 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.\n- Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not.\n- 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.\n- Patient has peripheral neuropathy of grade 2 or higher as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 5.0.\n- Patient is exhibiting clinical signs of meningeal involvement of multiple myeloma.\n- Known to be: - seropositive for human immunodeficiency virus (HIV) - seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. - seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).\n- Subject has known chronic obstructive pulmonary disease (COPD), persistent asthma, or a history of asthma within the last 2 years with a forced expiratory volume in 1 second [FEV1] <60%. Subjects with known or suspected COPD or asthma must have a FEV1 test during screening.\n- 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.\n- Known allergy to any of the study medications, their analogues, or excipients in the various formulations."}

Primary endpoints

• {"endpoint_text":"- Progression free survival (PFS): PFS in part 1 and part 2 of the study will be measured from the date of first or second randomization to the date of first observation of disease progression or death to any cause as an event. In the first part the efficacy of Dara VCd will be compared with VTd at 3 years from the first randomization; in the second part the efficacy of daratumumab-ixazomib will be compared with ixazomib at 2 years from the second randomization.","definition_or_measurement_approach":"PFS will be measured from date of first or second randomization to date of first observation of disease progression or death from any cause. Comparison planned at 3 years from first randomization for part 1 and at 2 years from second randomization for part 2."}
• {"endpoint_text":"- MRD negativity: MRD evaluation by clonotypic analysis of immunoglobulin heavy chain (IgH) VDJ gene rearrangement will be performed on bone marrow samples obtained by the end of induction and consolidation therapy and thereafter every 6 months after the first maintenance treatment dose. For this purpose, the ClonoSEQ TM assay (Adaptive Biotechnologies, Seattle) will be used at sensitivity thresholds of 10 -3 (1 cancer cell per 1,000 nucleated cells), 10 -4 and ≥10 –5 .","definition_or_measurement_approach":"MRD assessed by clonotypic analysis (IgH VDJ) on bone marrow using the ClonoSEQ assay at sensitivity thresholds of 10^-3, 10^-4 and ≥10^-5. Samples collected end of induction, end of consolidation and every 6 months during maintenance."}

Secondary endpoints

• {"endpoint_text":"- Overall response rate (ORR): ORR will include at least PR using the International Response Criteria reported by Durie et al. Categories of response will include stringent Complete Response (sCR), CR, VGPR, PR, SD and PD. If, during the course of the study, other relevant categories are identified in the literature, then these categories may be added. Responders are defined as subjects with at least a PR.","definition_or_measurement_approach":"ORR includes at least PR per International Response Criteria (Durie et al.); response categories include sCR, CR, VGPR, PR, SD, PD. Responders defined as subjects with ≥ PR."}
• {"endpoint_text":"- Progression free survival 2 (PFS2): PFS2 will be measured from the date of first randomization to the date of observation of second disease progression (i.e. progression after the second line of therapy) or death to any cause as an event.","definition_or_measurement_approach":"Measured from date of first randomization to date of second disease progression or death from any cause."}
• {"endpoint_text":"- Duration of response (DoR): Time between first documentation of response and PD.","definition_or_measurement_approach":"Time between first documented response and progressive disease."}
• {"endpoint_text":"- Overall survival (OS): OS is defined as the time between the date of first randomization and death.","definition_or_measurement_approach":"Time from first randomization to death from any cause."}
• {"endpoint_text":"- Time to progression (TTP): TTP will be measured from the date of randomization to the date of first observation of PD, or deaths due to PD.","definition_or_measurement_approach":"Measured from randomization to first observation of progressive disease or death due to progression."}
• {"endpoint_text":"- Time to the next anti-myeloma therapy (TNT): TNT will be measured from the date of first randomization to the date of next anti-myeloma therapy.","definition_or_measurement_approach":"Measured from first randomization to start date of next anti-myeloma therapy."}
• {"endpoint_text":"- MRD by NGF and PET/CT ✓ Immunophenotypic CR is defined as CR plus absence of phenotypically aberrant PCs (clonal) in bone marrow with a minimum of 1 million total bone marrow cells analyzed by multiparametric flow cytometry (with 2 tubes of 8 colors) ✓ PET/CT negativity is defined as the complete disappearance of any area of FDG uptake, according to the IMWG criteria.","definition_or_measurement_approach":"MRD by next-generation flow cytometry (NGF) on bone marrow (≥1 million cells, multiparametric flow cytometry) and imaging negativity by PET/CT per IMWG criteria; immunophenotypic CR defined as CR plus absence of phenotypically aberrant clonal plasma cells."}
• {"endpoint_text":"- Definition of prognostic factors, as assessed by NGS (MM-panel): NGS will be employed to deeply characterize MM CD138+ clone(s) both at diagnosis and at time of first progression. NGS data will be analyzed to describe patients genomic profile at baseline and to identify prognostic factors related to disease progression. A stratification of patients will be performed according to the evolution patterns, and eventual clinical correlations will be searched.","definition_or_measurement_approach":"NGS (MM-panel) profiling of CD138+ clone(s) at diagnosis and at progression to identify genomic prognostic factors and correlate genomic profiles with outcomes."}

Italy

Earliest CTIS Part Ii Submission Date

22-05-2024

Latest Decision Or Authorization Date

19-09-2025

Processing Time Days

485

Number Of Sites

16

Number Of Participants

260

Greece

Earliest CTIS Part Ii Submission Date

26-07-2024

Latest Decision Or Authorization Date

16-09-2025

Processing Time Days

417

Number Of Sites

2

Number Of Participants

69

Czechia

Earliest CTIS Part Ii Submission Date

22-05-2024

Latest Decision Or Authorization Date

26-11-2025

Processing Time Days

553

Number Of Sites

6

Number Of Participants

72

Primary sponsor

Full Name

European Myeloma Network B.V.

Organisation Type

Patient organisation/association

Country Of Registered Address

Netherlands

Contract research organisations

Name

Clinigen Clinical Supplies Management

Responsibilities

Clinical supplies management; specific labelling and packaging for the clinical trial

Name

Health Data Specialists Ireland Limited

Responsibilities

site payments

Name

Fisher Clinical Services GmbH

Third parties

• {"country":"Greece","full_name":"Genotypos Private Diagnostic Laboratory Of Molecular And Cytogenetic Analysis S.A","duties_or_roles":"FISH assessment","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Greece","full_name":"Iatropolis Magnitiki Tomografia Idiotiko Polyiatreio A.E.","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Greece","full_name":"National And Kapodistrian University Of Athens","duties_or_roles":"NGF; local laboratory duties (codes indicate NGF and other laboratory roles)","organisation_type":"Educational Institution"}
• {"country":"Belgium","full_name":"Clinigen Clinical Supplies Management","duties_or_roles":"Clinical supplies management; specific labelling and packaging for the clinical trial","organisation_type":"Pharmaceutical company"}
• {"country":"Greece","full_name":"Bioiatriki Private Medical Polyclinic S.A.","duties_or_roles":"DIRA test","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Ireland","full_name":"Health Data Specialists Ireland Limited","duties_or_roles":"site payments","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Greece","full_name":"Health Data Specialists Consulting Services Organization And Conduct Of Studies Single Member S.A.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Czechia","full_name":"Fakultni Nemocnice Ostrava","duties_or_roles":"Local laboratory for collecting, processing and sending samples to the Central laboratory","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Czechia","full_name":"Spadia Lab a.s.","duties_or_roles":"Local lab for FISH / local lab for NGF (different locations listed)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Italy","full_name":"Azienda Ospedaliero-Universitaria Di Bologna IRCCS Istituto Di Ricerca E Di Cura A Carattere Scientifico","duties_or_roles":"NGS","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Italy","full_name":"Emn Trial Office S.r.l. Impresa Sociale","duties_or_roles":"FISH, Immunophenotype, MRD negativity con NGF; central lab duties","organisation_type":"Laboratory/Research/Testing facility"}

Co-sponsors

• Ceska Myelomova Skupina z.s.
• Emn Trial Office S.r.l. Impresa Sociale