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 |
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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 | 14.0 |
E.1.2 | Level | PT |
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) |
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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 |
The primary objective of this study is to compare overall survival (OS) in patients with refactory multiple myeloma relapsed after at least 3 prior regimens who are randomized to receive either carfilzomib alone or best supportive care. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives include investigating the effect of carfilzomib on other standard efficacy variables including PFS, overall response rate (ORR) (stringent complete response [sCR] + CR + very good PR [VGPR] + PR), clinical benefit rate (CBR) (ORR + MR), disease control rate (DCR) (CBR + stable disease lasting for at least 8 weeks), duration of response (DOR; calculated separately for overall response, clinical benefit, and disease control endpoints), and safety. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Disease-related:
* Multiple myeloma
* Measurable disease based on central laboratory values, as defined by one or both of the following criteria (assessed within 21 days prior to randomization):
- Serum M-protein
SPEP: ≥ 0.5 g/dL
For IgA patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA): > 750 mg/dL (0.75 g/dL)
- Urine Bence-Jones protein ≥ 200 mg/24 h
* Responsive (defined by a 25% or greater decrease in M-protein or total protein) to at least one line of prior therapy
*Relapsed multiple myeloma, defined as disease progression while on or after at least 1 prior treatment regimen
* Refractory multiple myeloma, defined as meeting one or more of the following:
• Nonresponsive to most recent therapy (eg, stable disease only, or progressive disease while on treatment), or
• Disease progression within 60 days of discontinuation from most recent therapy
* Received 3 or more prior therapeutic regimens for multiple myeloma
* Adequate prior treatment with bortezomib (if less than 4 complete cycles, the reason for discontinuation must be reviewed by the Medical Monitor and the reason documented)
* Prior treatment with an immunomodulatory agent (lenalidomide if available, and/or thalidomide)
* Prior treatment with an alkylating agent (standard or high-dose)
* Prior treatment with a corticosteroid
* Prior treatment with an anthracycline unless not clinically indicated (eg, cardiac disease)
Demographic
* Age ≥ 18 years
* Life expectancy of at least 1 month
* Eastern Cooperative Oncology Group (ECOG) performance status 0–2
Laboratory
* Adequate hepatic function, with serum alanine aminotransferase (ALT) < 4 times the upper limit of normal and serum bilirubin < 2.5 mg/dL (42.5 µmol/L). Patients with total bilirubin ≥ 2.5 mg/dL may enroll if their serum direct bilirubin is < 2.5 mg/dL
* Total white blood cell (WBC) count ≥ 1.5 x 10(9)/L and absolute neutrophil count (ANC) ≥ 1.0 × 10(9)/L (use of colony-stimulating factors to achieve these counts is allowed)
* Hemoglobin ≥ 7.5 g/dL (75 g/L)
• Use of erythropoietic stimulating factors is allowed:
• For all patients who receive a RBC transfusion within 28 days of obtaining the Screening hemoglobin value. The following information must be provided for the Medical Monitor’s review for assessment for eligibility:
Pre-transfusion Hb
Number of RBC units administered
Use of erythropoeitic stimulating factors
* Platelet count ≥ 30 × 10(9)/L
• There is no restriction on platelet transfusions or thrombopoeitic growth factor before or during the screening period
• For all patients who receive a platelet transfusion within 7 days of obtaining the Screening platelet value, the following information must be provided for the Medical Monitor's review for assessment of eligibility:
Pre-transfusion platelet count
Number of platelet units administered
Use of thrombopoeitic stimulating factors
* Creatinine clearance (CrCl) ≥ 15 mL/minute (either measured or calculated using a standard formula such as Cockcroft and Gault) and dialysis-independent
Ethical/Other
* Written informed consent in accordance with federal, local, and institutional guidelines.
* Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days of the first dose of study treatment and agree to use an effective method of contraception during the study and for 3 months following the last dose of study treatment. Postmenopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from these requirements. Male patients must use an effective barrier method of contraception while on randomized study treatment and for at least 3 months following the last dose if sexually active with a female of childbearing potential.
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E.4 | Principal exclusion criteria |
Disease-related
* Waldenström’s macroglobulinemia or IgM myeloma
* Refractory to all prior therapies
* Disease measurable only by serum free light chain assay (SFLC)
* POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
* Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard differential)
* Prior carfilzomib treatment
Concurrent Treatments
* Chemotherapy (approved or investigational) within 14 days prior to randomization
* Immunotherapy or antibody therapy within 28 days prior to randomization
* Corticosteroid therapy at a dose equivalent to dexamethasone > 4 mg/day within 14 days prior to randomization
* Radiotherapy within 7 days prior to randomization
Concurrent Conditions
* Major surgery within 21 days prior to randomization
* Congestive heart failure (NYHA Class III or IV) or symptomatic cardiac ischemia, conduction system abnormalities uncontrolled by conventional intervention (conduction abnormalities not clinically warranting intervention are allowed)
* Myocardial infarction in the previous 3 months
* Acute active infection requiring systemic treatment (antibiotics, antivirals, or antifungals) within 14 days prior to randomization
* Known human immunodeficiency virus seropositivity
* Active hepatitis A, B, or C infection
* Other 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, vulva, or breast; c) prostate cancer of Gleason Score 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 localized transitional cell carcinoma of the bladder, carcinoma in situ of the breast, or benign tumors of the adrenal or pancreas
* Significant neuropathy (Grades 3–4, or Grade 2 with pain) at the time of randomization
* Any other clinically significant medical disease or condition that, in the Investigator’s opinion, may interfere with protocol adherence or a patient’s ability to give informed consent
*Pregnant or lactating females |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
OS will be evaluated after 253 OS events are reached, which is expected within approximately 39 months of the first randomized patient (Dec 2013). Two interim analyses are planned at 50% and 75% of the total OS events reported, which are anticipated to occur approximately 22 months (June 2012) and 27 months (Nov 2012) after the first patient is randomized. |
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E.5.2 | Secondary end point(s) |
- PFS
- ORR (sCR + CR + VGPR + PR)
- CBR (ORR + MR)
- DCR (CBR + stable disease lasting for at least 8 weeks)
- DOR (calculated separately for overall response, clinical benefit, and disease control)
- Safety |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary end points are to be evaluated at the time of the final OS analysis |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
BSC regimen (corticosteroid+cyclophosphamide) |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Belgium |
Czech Republic |
France |
Germany |
Greece |
Hungary |
Israel |
Italy |
Poland |
Russian Federation |
Serbia |
Slovakia |
Spain |
Sweden |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
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 | 4 |
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 |