Carfilzomib for Multiple myeloma

Inclusion criteria

• {"criterion_text":"- Newly diagnosed symptomatic MM based on either standard CRAB criteria (at least 10% of bone marrow plasma cells plus CRAB defined as the onset of any of the following clinical symptoms: hypercalcemia, renal failure, anemia and bone lesions) or at least 10% of bone marrow plasma cells plus the presence of at least one of the following biomarkers of malignancy: 60% or greater clonal plasma cells on bone marrow examination; Serum involved/uninvolved free light chain (FLC) ratio of 100 or greater; More than one focal lesion on magnetic resonance imaging (MRI) that is at least 5 mm or greater in size.\n- LVEF (left ventricular ejection fraction) ≥ 40%: 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation; multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available\n- Pre-treatment blood pressure value < 140/90 mmHg even with adequate therapy: 24 hours blood pressure monitoring is the preferred method of evaluation; blood pressure diary at home for 2 weeks is acceptable.\n- Females of childbearing potential (FBCP) comply with the conditions of the Pregnancy Prevention Plan, including confirmation that she has an adequate level of understanding\n- FBCP must follow the Pregnancy Prevention Plan and use a highly effective and an additional barrier contraception method simultaneously for 4 weeks before starting therapy, during treatment and dose interruptions and for at least 30 days after the last dose of study drugs.\n- Males must use an effective barrier method of contraception if sexually active with FCBP during the treatment and for at least 90 days after the last administration of study drug/s. Male subjects must agree to refrain from sperm donation for at least 90 days after the last dose of carfilzomib.\n- Patient not eligible for ASCT (age ≥ 65 years or abnormal cardiac, pulmonary and liver function).\n- Patient defined as fit or intermediate according to the IMWG (International Myeloma Working Group) frailty score.\n- Patient has given voluntary written informed consent.\n- Patient is able to be compliant with hospital visits and procedures required per protocol.\n- Patient agrees to use acceptable methods for contraception.\n- Patient has measurable disease according to IMWG criteria.\n- Patient has ECOG (Eastern Cooperative Oncology Group) performance status < 3.\n- Pre-treatment clinical laboratory values within 30 days before randomization: Platelet count ≥50 x 10^9/L (≥30 x 10^9 /L if myeloma involvement in the bone marrow is > 50%), Absolute neutrophil count (ANC) ≥ 1 x 10^9/L without the use of growth factors, Corrected serum calcium ≤14 mg/dL (3.5 mmol/L), Alanine transaminase (ALT): ≤ 3 x the ULN, Total bilirubin: ≤ 2 x the UL, Calculated or measured creatinine clearance: ≥ 30 mL/minute."}

Exclusion criteria

• {"criterion_text":"- Serious medical condition, laboratory abnormality or psychiatric illness that prevented the subject from the screening or place the subject at unacceptable risk.\n- Presence of peripheral neuropathy or neuropathic pain grade 2 or higher, as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 5.0.\n- Presence of incontrolled hypertension defined as persistent hypertension (>140/90 mmHg) regardless treatment with 3 drugs, including a diuretic.\n- Contraindication to any of the required drugs or supportive treatments and hypersensitivity to any excipient of the study drugs.\n- Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib).\n- Invasive malignancy within the past 3 years.\n- Administration of any experimental drug within 4 weeks prior to the baseline or within 5 drug half-lives.\n- Patient defined as frail according to the IMWG frailty score (pts with age >80 years old).\n- Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid < to the equivalent of dexamethasone 40 mg/day for 4 days)\n- Pregnant or lactating females.\n- Presence of clinical active infectious hepatitis type A, B, C or HIV.\n- Presence of acute active infection requiring antibiotics or infiltrative pulmonary disease.\n- Presence of pulmonary hypertension and interstitial lung disease.\n- Presence of uncontrolled arrhythmias or history of QT prolongation.\n- Presence of myocardial infarction or unstable angina ≤ 6 months or other clinically significant heart disease."}

Primary endpoints

• {"endpoint_text":"- MRD evaluation will be performed on bone marrow samples obtained after 1 and 2 years of treatment in patients who achieved at least a VGPR during the first year of study treatment. The rate of MRD negativity is determined as the patients with MRD negativity at 2 years of treatment. For patients who withdraw or are lost to follow up before two years of treatment, the best MRD assessment will be considered.","definition_or_measurement_approach":"MRD measured on bone marrow samples after 1 and 2 years in patients with ≥VGPR in year 1; primary rate is MRD negativity at 2 years. For early withdrawals/lost to follow-up, best MRD assessment considered."}
• {"endpoint_text":"- 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 withdraw from the study will be censored at the time of the last complete disease assessment. Subjects who complete the study, have not progressed, and are still alive at the cut-off date of final analysis will be censored at the cut-off date. All subjects who were lost to FU will also be censored at the time of last contact.","definition_or_measurement_approach":"PFS defined as time from randomization to first documented progression (PD) or death from any cause. Censoring rules specified for withdrawals, study completion, and lost to follow-up."}

Secondary endpoints

• {"endpoint_text":"- Response rate (sCR, CR, VGPR, PR) of experimental KRd regimen vs Rd regimen.","definition_or_measurement_approach":"Response rate assessed by standard response categories (sCR, CR, VGPR, PR) comparing KRd vs Rd."}
• {"endpoint_text":"- PFS2 will be measured from the date of first 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 withdraw from the study will be considered at the time of the last complete disease assessment. Subjects who complete the study or were lost to follow-up, have no progressed, and are still alive at final analysis will be censored","definition_or_measurement_approach":"PFS2 = time from first randomization to second progression or death; if date of second progression unavailable, start date of third-line therapy may be used; censoring rules specified."}
• {"endpoint_text":"- TTP will be measured from the date of randomization to the date of first observation of PD, or deaths related to PD. Subjects 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 who complete the study, have not progressed, and 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.","definition_or_measurement_approach":"Time to progression from randomization to PD or death related to PD; censoring rules provided."}
• {"endpoint_text":"- DOR is defined as time between first documentation of response and PD. Responders without disease progression 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 end of the study.","definition_or_measurement_approach":"Duration of response from first documented response to PD; censoring for lost to follow-up, death from other causes, or end of study."}
• {"endpoint_text":"- OS is defined as the time between randomization and death. Subjects who die will be censored at time of death as an event, regardless cause of death. Subjects who withdraw consent will be censored at the time of withdrawal. Subjects who complete the study and 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.","definition_or_measurement_approach":"Overall survival from randomization to death; censoring rules specified."}
• {"endpoint_text":"- 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 withdraw from the study will be censored at the time of the last complete disease assessment. Subjects who complete the study, have not progressed, and 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.","definition_or_measurement_approach":"Time to next therapy from randomization to start of next anti-myeloma therapy; death before therapy considered event; censoring rules specified."}
• {"endpoint_text":"- Toxicity","definition_or_measurement_approach":"Adverse events/toxicities recorded and compared between arms (no further detail in JSON)."}
• {"endpoint_text":"- Quality of life defined by EOCTC QLQ-C30 and QLQ-MY20.","definition_or_measurement_approach":"QoL measured using EORTC QLQ-C30 and QLQ-MY20 instruments."}
• {"endpoint_text":"- To determine the incidence of dose reduction and drug discontinuation in both treatment arms.","definition_or_measurement_approach":"Incidence of dose reductions and discontinuations will be recorded and compared between arms."}
• {"endpoint_text":"- To determine the benefit of proper cardiovascular baseline assessment and monitoring in both treatment arms: to mitigate major cardiovascular adverse event incidence, to prolong duration of treatment, to improve efficacy.","definition_or_measurement_approach":"Cardiovascular baseline assessment and monitoring outcomes tracked to assess impact on major CV adverse events, treatment duration and efficacy."}
• {"endpoint_text":"- To determine the impact of MRD negativity on PFS, PFS2, TTP, TNT and OS.","definition_or_measurement_approach":"Correlation analyses between MRD negativity and survival/outcome endpoints."}
• {"endpoint_text":"- To determine difference of response and outcome (PFS, PFS2, TTP, TNT and OS) in subgroups analysis with different prognostic factors.","definition_or_measurement_approach":"Subgroup analyses by prognostic factors to evaluate differences in response and outcome endpoints."}

Italy

Earliest CTIS Part Ii Submission Date

10-04-2024

Latest Decision Or Authorization Date

17-04-2026

Processing Time Days

737

Number Of Sites

28

Number Of Participants

340

Primary sponsor

Full Name

Fondazione European Myeloma Network Italy O.N.L.U.S.

Organisation Type

Patient organisation/association

Country Of Registered Address

Italy

Contract research organisations

Name

Almac Clinical Services Limited

Responsibilities

sponsorDuties codes: [14]

Name

Almac Clinical Services (Ireland) Limited

Responsibilities

sponsorDuties codes: [14]

Third parties

• {"country":"Switzerland","full_name":"Amgen (Europe) GmbH","duties_or_roles":"sponsorDuties codes: [14]","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Celgene International II SARL","duties_or_roles":"sponsorDuties codes: [14]","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Emn Trial Office S.r.l. Impresa Sociale","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"sponsorDuties codes: [14]","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Mipharm S.p.A.","duties_or_roles":"sponsorDuties codes: [14]","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Almac Clinical Services (Ireland) Limited","duties_or_roles":"sponsorDuties codes: [14]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Adaptive Biotechnologies Corp.","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Pharmaceutical company"}