E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary myelofibrosis, post-polycythemia vera myelofibrosis, or post- essential thrombocythemia myelofibrosis |
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E.1.1.1 | Medical condition in easily understood language |
blood disorder in which the bone marrow makes too many red blood
cells, or blood disorder in which the bone marrow makes too many
platelets |
Vérképzési rendellenesség, melynek során a csontvelő túl sok
vörösvértestet, vagy túl sok vérlemezkét termel. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018864 |
E.1.2 | Term | Haematopoietic neoplasm NOS |
E.1.2 | System Organ Class | 100000004864 |
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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 |
To evaluate the efficacy of daily oral doses of 400 mg or 500 mg of SAR302503 (Investigational Medicinal Product, IMP) compared to placebo in the reduction of spleen volume as determined by magnetic resonance imaging (MRI) (or computed tomography scan in patients with contraindications for MRI). |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect on Myelofibrosis (MF)-associated symptoms (key MF symptoms) as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) diary.
To evaluate the Overall Survival of patients treated with either 400 mg/day or 500 mg/day of IMP as compared to placebo.
To evaluate the Progression Free Survival of patients treated with either 400 mg/day or 500 mg/day of IMP as compared to placebo.
To evaluate the durability of splenic response.
To evaluate the safety of IMP.
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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 |
Full title : A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Study of SAR302503 in Patients with Intermediate-2 or High-Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis with Splenomegaly Date : 26 July 2011
Version : 1
Protocol : section 9.5 pharmacogenetics
Objectives : pharmacogenetics explores the effect of genes on the variability of drug responses and/or drug metabolism among people taking the same medicine
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E.3 | Principal inclusion criteria |
Diagnosis of Primary Myelofibrosis (MF) or Post-Polycythemia Vera MF or Post-Essential Thrombocythemia MF, according to the 2008 World Health Organization and International Working Group of Myelofibrosis Research and Treatment (IWG-MRT) criteria.
MF classified as high-risk or intermediate-risk level 2, as defined by modified IWG-MRT criteria.
Enlarged spleen, palpable at least 5 cm below costal margin.
At least 18 years of age.
Eastern Cooperative Oncology Group performance status of 0, 1, or 2 at study entry.
The following laboratory values within 14 days prior to the initiation of IMP or placebo:
Absolute Neutrophil Count (ANC) ≥1.0 x 10exp9/L
Platelet count ≥50 x 10exp9/L
Serum creatinine ≤1.5 x Upper Limit of Normal (ULN)
Serum amylase and lipase ≤1.5 x ULN
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E.4 | Principal exclusion criteria |
Splenectomy.
Any chemotherapy (eg, hydroxyurea), immunomodulatory drug therapy (eg, thalidomide, interferon-alpha), Anagrelide, immunosuppressive therapy, corticosteroids >10 mg/day prednisone or equivalent, or growth factor treatment (eg, erythropoietin), or hormones (eg, androgens, danazol) within 14 days prior to initiation of IMP or placebo; darbepoetin use within 28 days prior to initiation of IMP or placebo. Patients who have had exposure to hydroxyurea (eg, hydrea) in the past may be enrolled into the study as long as it has not been administered within 14 days prior to initiation of IMP or placebo.
Major surgery within 28 days or radiation within 6 months prior to initiation of IMP or placebo.
Prior treatment with a Janus Kinase 2 (JAK2) inhibitor.
Known active (acute or chronic) Hepatitis A, B, or C; and hepatitis B and C carriers
AST or ALT ≥2.5 x ULN
Total Bilirubin: Exclude if ≥3.0 x ULN
Subjects with total bilirubin between 1.5-3.0 x ULN must be excluded if the direct bilirubin fraction is ≥25% of the total
Prior history of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemachromatosis, non-alcoholic steatohepatitis [NASH])
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E.5 End points |
E.5.1 | Primary end point(s) |
Response Rate (RR), defined as the proportion of patients who have a ≥35% reduction in volume of spleen size at the end of Cycle 6, and confirmed 4 weeks thereafter |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Symptom Response Rate (SRR): Proportion of patients with ≥50% reduction from baseline to the end of Cycle 6 in the total symptom score. This assessment will be conducted through the modified MFSAF diary, which will be completed during the week prior to Day 1 of each treatment cycle up to Cycle 6 and during the week prior to the end of Cycle 6.
OS (overall survival) of either 400 mg/day or 500 mg/day of IMP as compared to placebo.
PFS (progression free survival) of either 400 mg/day or 500 mg/day of IMP as compared to placebo.
Proportion of patients who have ≥25% reduction in volume of spleen size at end of Cycle 6, and confirmed 4 weeks thereafter.
Duration of spleen response, measured by MRI (or CT scan in patients with contraindications for MRI.
Safety, as assessed by clinical, laboratory, ECG, and vital sign events; graded by the NCI CTCAE v4.03. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
6 months to approximately 5 year(s) |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 57 |
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 | No |
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 |
Brazil |
Canada |
Israel |
Korea, Republic of |
Mexico |
Russian Federation |
Singapore |
South Africa |
Taiwan |
Turkey |
United States |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 55 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 55 |
E.8.9.2 | In all countries concerned by the trial days | 0 |