| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| A cancer arising from plasma cells, a type of white blood cell which is made in the bone marrow |
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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 | 100000004864 |
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| 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 | 100000004864 |
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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 |
The purpose of the CARDAMON study is:
• To determine the efficacy of the triple regimen Carfilzomib, Cyclophosphamide and Dexamethasone (CarCyDex) as induction in untreated patients with symptomatic multiple myeloma (MM) who are candidates for autologous stem cell transplantation (ASCT).
• To evaluate the benefit (progression free survival at 2 years) of upfront ASCT in patients achieving at least a partial response (PR) to induction with CarCyDex.
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| E.2.2 | Secondary objectives of the trial |
• To determine the efficacy of an upfront protocol incorporating induction with CarCyDex, ASCT and then carfilzomib maintenance in patients with untreated symptomatic MM who are candidates for ASCT (ASCT arm).
• To assess toxicity and tolerability of CarCyDex as induction and carfilzomib as maintenance therapy in untreated patients with symptomatic MM.
• To determine the efficacy of maintenance therapy in deepening disease response, in the ASCT and non-ASCT setting.
• To determine the efficacy (PFS) of an upfront protocol incorporating 8 cycles of CarCyDex followed by carfilzomib maintenance in patients with untreated symptomatic MM who are candidates for ASCT (non-ASCT arm).
• To determine rate of MRD (minimal residual disease) following 4 cycles of induction with CarCyDex.
• To determine the increase in negative MRD rates following ASCT versus consolidation with 4 further cycles of CarCyDex.
• To investigate the effects of CarCyDex treatment and of withholding ASCT on patient qualit |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PET-CT Sub-study
Objectives:
• To investigate the association between PET-CT parameters at baseline with other disease markers and with disease response (all response categories, PFS, OS)
• To investigate the association between CMR on PET-CT with IMWG response and with MRD-negative response by flow cytometry
• To compare the CMR rate in ASCT versus consolidation chemotherapy arms
• To investigate the effect of achieving a CMR on PFS, and on OS
• To investigate the activity of 6 months of maintenance Carfilzomib in terms of conversion of PET-positive disease to PET-negative disease (CMR)
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| E.3 | Principal inclusion criteria |
• Previously untreated patients with symptomatic MM (see appendix 2) eligible for stem cell transplantation, with the exception of the following treatments:
o local radiotherapy to relieve bone pain and/or spinal cord compression
o bisphosphonates
o corticosteroids within the last 3 months. Within 14 days prior to study entry, the maximum permitted dose is 160mg (i.e. 4 days of Dexamethasone at 40mg, or equivalent), unless otherwise agreed by the TMG.
• Suitable for high dose therapy and ASCT
• Age ≥ 18 years
• Life expectancy ≥ 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status 0–2), except:
o ECOG >2 is permissible if resulting from complications related to myeloma (i.e. due to spinal cord compression). Please check with UCL CTC if unsure as to whether this exception may be applicable.
• Measurable disease as defined by one of the following:
o Secretory myeloma:
• Either monoclonal protein in the serum (≥10 g/L)
• Or monoclonal light chain in the urine (Bence Jones protein ≥200mg/24hours)
• Or serum free light chain (SFLC, involved light chain ≥100mg/L provided the FLC ratio is abnormal)
o Non-secretory myeloma:
• Either ≥30% clonal plasma cells in bone marrow (aspirate or trephine)
• Or 10-30% clonal plasma cells in the marrow and >1 soft tissue or extra-osseous plasmacytoma ≥ 2 cm that is measurable for response assessment by CT or MRI
• 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 registration
• Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to registration and subject has not received any growth factor support within 7 days of testing. ANC≥0.8x109/L allowed for patients with racial neutropenia.
• Haemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to registration (subjects may be receiving red blood cell (RBC) transfusions in accordance with institutional guidelines)
• Platelet count ≥ 75 × 109/L (≥ 50 × 109/L if myeloma involvement in the bone marrow is > 50%) within 14 days prior to registration and subject has not received any platelet transfusions within 7 days prior to testing
• Creatinine clearance (CrCl) ≥ 30 mL/minute within 14 days prior to registration, either measured or calculated using a standard formula (e.g. Cockcroft and Gault)
• Written informed consent
• Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception
• Male subjects must agree to practice contraception
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| E.4 | Principal exclusion criteria |
• Pregnant or breast-feeding females (lactating women may participate if breastfeeding ceases for the duration of trial treatment and until 12 months after last treatment)
• Previous systemic chemotherapy for myeloma, with the exception of steroids, as detailed above (see section 6.3.1)
• Any major surgery within 21 days prior to registration which in the investigator’s opinion would compromise trial treatment and/or the patient’s ability to comply with trial visits. Surgery to relieve spinal cord compression or for treatment of bone fractures is permitted
• Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) 7 days prior to planned start of treatment, unless otherwise agreed by the TMG
• Known human immunodeficiency virus (HIV) infection
• Active hepatitis B or C infection (refer to appendix 4)
• Unstable angina or myocardial infarction within 4 months prior to registration, 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 subject has a pacemaker
• Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to registration
• Non-haematologic 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 tumors of the adrenal or pancreas
• Significant neuropathy (Grades 3–4, or Grade 2 with pain) within 14 days prior to registration
• Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilise carfilzomib)
• 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, cardiac or renal impairment
• Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to registration
• Any other clinically significant medical disease or condition that, in the Investigator’s opinion, may interfere with protocol adherence or a subject’s ability to give informed consent
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Major response rate (CR+VGPR) to 4 cycles of CarCyDex
• Progression free survival at 2 years, taken from the date of randomisation, for both ASCT and non-ASCT (consolidation) arms
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Major response rate to be evaluated following the completion of induction treatment (4 cycles of CarCyDex)
2 year PFS measured from the date of randomisation until date of progression or death |
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| E.5.2 | Secondary end point(s) |
• Toxicity: AEs (including peripheral neuropathy), dose reductions and delays, tolerability of the induction and maintenance regimens (treatment delays, discontinuation rates)
• Disease response rate (sCR, CR, VGPR, PR) to CarCyDex induction
• PFS in both ASCT and non-ASCT arms
• Improvement in disease response and conversion from MRD-positive to MRD-negative post ASCT and post Consolidation
• Improvement of disease response and conversion from MRD-positive to MRD-negative following maintenance therapy
• Overall survival
- PFS2 defined as the time from initial randomisation to second progression or death from any cause
PET-CT endpoints (exploratory) for patients participating in PET-CT sub study
• CMR rate after consolidation/ASCT
• CMR conversion rate after 6 months of maintenance in patients who are PET positive after consolidation/ASCT
• PET response association with IMWG and MRD response
• PFS association with baseline PET-CT parameters and PET-CT response
• OS association with baseline PET-CT parameters and PET-CT response
• Disease response (as measured by PET-CT) association with baseline PET-CT parameters
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Toxicity will be presented by trial arm with adverse events collected from the start of trial treatment until 30 days post the last trial treatment.
The number and percentage of patient that achieve a disease response (sCR, CR, VGPR, PR)at the end of induction treatment.
Overall and progression free survival will be measured from the date of randomisation until progression or death
Bone marrow aspirate samples will be performed at baseline, Post PBSCH, 100 days post ASCT or after 4 cycles of consolidation, and after 6 months of maintenance therapy. This is used to measure the disease response rate and the MRD-positive to MRD-negative rate in the ASCT and non-ASCT setting
PET CT endpoints:
At registration, after consolidation/ ASCT and 6 months after the start of maintenance |
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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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Autologous stem cell transplantation with melphalan conditioning |
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| 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 | 25 |
| 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
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| 10 years after the last patient completes induction treatment |
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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 | 14 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 19 |
| E.8.9.2 | In all countries concerned by the trial years | 14 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 19 |
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