| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| multiple myeloma at the first relaspe of primary refractory disease stage |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 the activity of carfilzomib in combination with cyclophosphamide and low dose dexamethasone (CCD) to that of the control treatment of bortezomib, cyclophosphamide and dexamethasone (CVD) in patients with multiple myeloma at first relapse. Specifically the study will assess whether CVD provides non-inferior activity with regard to the short-term outcome measure of ≥Very Good Partial Response rates at 24 weeks, and superior activity in terms of the longer-term outcome measure of progression-free survival. |
|
| E.2.2 | Secondary objectives of the trial |
To compare the toxicity profile of CCD to CVD overall and specifically in respect to peripheral neuropathy.
To explore the non-inferiority of CCD without maintenance as compared to CVD for the longer term outcome measure of progression free survival.
To further summarise the activity of CCD as compared to CVD overall as well as specifically at 24 weeks and after 12 months with regard to:
Complete response at 24 weeks
Overall response at 24 weeks and 12 months
Maximum response within 12 months
Time to maximum response
Duration of response
Overall survival
Time to next treatment
To dertermine the proportion of participants with MRD negative disease at the end of initial treatment phase (24 weeks of treatment) in both the CVD and CCD arms
To correlate MRD negativity at the end of initial treatment phase (24 weeks) with PFS for all participants
To assess the effect of maintenance Carfilzomib on MRD status at 6 months and at 12 months post second randomisation
To correlate treatmen |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Syptomatic multiple myeloma and requiring therapy for first relapse or primary refractory disease
• Measurable disease
• Age ≥ 18 years
• Life expectancy ≥ 6 months
• Eastern Cooperative Oncology Group (ECOG) performance status 0–2
• Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 14 days prior to randomisation
• Absolute neutrophil count (ANC) ≥ 1.0 × 10^9/L within 14 days prior to randomisation (growth factor support is not permitted). ANC ≥ 0.8 × 109/L is allowed for participaents with racial neutropenia provided the following conditions are met:
i)participant is considered to have racial neutropenia (i.e. is of African or African-Caribbean descent with ANC ≥ 0.8 × 109/L
ii)trial entry has been discussed directly with, and approved by, the CI
• Haemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to randomisation (participants may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines)
• Platelet count ≥ 75 × 10^9/L (≥ 50 × 10^9/L if myeloma involvement in the bone marrow is > 50%) within 14 days prior to randomisation. Platelet support is not permitted.
• Creatinine clearance (CrCl) ≥ 15 mL/minute within 14 days prior to randomisation, either measured or calculated using a standard formula (eg, Cockcroft and Gault)
• Written informed consent
• Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception.
• Male participants must agree to practice contraception
|
|
| E.4 | Principal exclusion criteria |
• Non-secretory multiple myeloma
• Extramedullary plasmacytoma (without evidence of myeloma)
• Received therapy for their first relapsed or primary refractory disease other than local radiotherapy, therapeutic plasma exchange, or dexamethasone up to a maximum of 200mg.
• Previous bortezomib therapy is permitted, providing participant was not refractory (achieved at least a PR, and no disease progression within 6 months of last dose of bortezomib)
Previous carfilzomib therapy
• Pregnant or lactating females
• Major surgery within 21 days prior to randomisation
• Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomisation
• Known human immunodeficiency virus infection
• Active hepatitis B or C infection
• Unstable angina or myocardial infarction within 6 months prior to randomisation, NYHA Class III or IV heart failure, uncontrolled angina, 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 participant has a pacemaker, history of torsade de pointe, QTc prolongation (> 450 msec), LVEF < 40
• Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to randomisation
• Previous or concurrent active 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 localised transitional cell carcinoma of the bladder or benign tumours of the adrenal or pancreas
• Significant neuropathy (Grades 3–4, or Grade 2 with pain) within 14 days prior to randomisation
• Patients with haemorrhagic cystitis
• Known history of hypersensitivity to any of the study medications or excipients
• Participants undergoing active treatment for infiltrative lung disease
• 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 pre-existing pulmonary or cardiac impairment
• Contraindication to IV hydration programme
• Participants with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomisation
• Any other clinically significant medical disease or condition that, in the Investigator’s opinion, may interfere with protocol adherence or a participant’s ability to give informed consent
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
There are two co-primary endpoints in this study as follows:
Proportion of participants achieving at least VGPR 24 weeks post initial randomisation
Progression-free survival |
|
| E.5.2 | Secondary end point(s) |
• Key secondary: proportion of participants experiencing ≥ grade 3 neuropathy or ≥ grade 2 neuropathy with pain during the initial treatment period (8 cycles of CVD or 6 cycles of CCD)
• Total time spent at each grade of toxicity for ≥ grade 3 neuropathy or ≥ grade 2 neuropathy with pain during the initial treatment period (8 cycles of CVD or 6 cycles of CCD)
• Complete response rate 24 weeks post initial randomisation
• Overall response rate 24 weeks post initial randomisation
• Proportion of participants achieving MRD negative disease at the end of initial treatment phase
• Proportion of participants with MRD negative disease at 6 and 12 months following second randomisation
• Overall response rate within 12 months of initial randomisation
• Maximum response within 12 months of initial randomisation
• Maximum response overall
• Time to maximum response
• Duration of response
• Overall survival
• Time to next treatment
• Toxicity overall, and per cycle of treatment during the initial treatment period and throughout the maintenance period
• Treatment compliance
• Safety |
|
| 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 | 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) | 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 | 8 |
| 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 | 5 |
| 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 | 5 |
| 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 |
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