E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Flt3-ITD positive AML in complete hematological remission (CHR) after allogenic stem cell transplantation (allo-SCT) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
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 |
Primary objective: Relapse free survival (RFS) of Flt3-ITD+ AML patients in complete hematological remission after allo-SCT receiving Sorafenib maintenance therapy versus placebo
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E.2.2 | Secondary objectives of the trial |
Secondary objective: 1. To compare the median overall survival (OS) of Flt3-ITD+AML patients in CHR after allo-SCT receiving Sorafenib maintenance treatment versus placebo 2. To compare the median RFS and OS of Flt3-ITD+ AML patients with and without NPM mutations receiving Sorafenib versus placebo 3. To compare the median RFS and OS of Flt3-ITD+AML patients in CHR after allo-SCT receiving Sorafenib maintenance treatment versus placebo depending on the baseline expression level of Flt3-ITD at diagnosis 4. To compare the toxicity of Sorafenib maintenance versus placebo 5. To longitudinally evaluate biomarkers associated with Sorafenib treatment response and Sorafenib resistance and correlation with RFS and OS 6. To assess safety with type, severity graded by NCI CTC criteria version 4.02.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Written informed consent • Age 18 y. • ECOG performance ≤ 1 • FLT3-ITD-positive AML • Complete hematological remission (CHR) after allo-SCT CHR must be confirmed by bone marrow analysis within 14 days before randomization (CHR criteria are: ≤ 5% marrow blasts, no peripheral blasts, blood platelet count > 100/nl, WBC count > 3 G/L, ANC > 1000 G/l). • Allo-SCT with a HLA-identical allo-family donor (FAM) or a matched unrelated donor (MUD) with up to 1 antigen mismatch acceptable (9/10) • Time point of study treatment start of patients in CHR: between d+60 up to d+100 after allo-SCT • Adequate organ function: Serum creatinine 1.5 x upper normal value ALT, AST, AP 2.5 x upper normal value Total bilirubin 1.5 x upper limit of normal PT-INR/PTT 1.5 x upper limit of normal • Patients who are being therapeutically anticoagulated with an agent such as Coumadin or Heparin will be allowed to participate in the trial provided that the medical need for anticoagulation is evidence-based (level I evidence) and PT-INR and PTT values are closely monitored to maintain the therapeutic window. • Negative serum pregnancy test within seven days prior to first dose in women of child-bearing potential (WOCBP) • WOCBP must use a double barrier method of contraception during the study and for 3 months following the last dose of study drug. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or surgical sterilization or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). • Male subjects whose sexual partners are WOCBP must use a double barrier method of contraception, one of which includes a condom, during the study and for 3 months after the end of treatment.
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E.4 | Principal exclusion criteria |
• Any severe concomitant conditions which make it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol (such as substance abuse, uncontrolled infection, known HIV, HBV, HCV infection • Psychiatric disorder that interferes with ability to understand the study and give informed consent, and/or impacts study participation or follow-up. • Cardiac disease: heart failure NYHA III/IV, unstable coronary artery disease (MI more than 6 months prior to study entry is permitted), serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted) • Resting blood pressure consistently higher than systolic 150 mmHg and/or diastolic 90 mmHg despite antihypertensive therapy • Patients undergoing renal dialysis • Evidence or history of severe non-leukemia associated bleeding diathesis or coagulopathy • Patients with uncontrolled seizure disorder despite medication • History of organ allograft (except for allogenic SCTX) • Patients with major surgery, open biopsy, or significant traumatic injury within 4 weeks prior to start of first dose of study drug • Serious non-healing wound, ulcer or bone fracture • Known Flt3-kinase inhibitor resistance • Previous Sorafenib therapy • Active (uncontrolled) graft versus host disease GvHD (> grade I) at time of randomization despite the use of adequate therapeutic measures • Investigational drug therapy outside of this trial during or within 4 weeks of study entry • Pregnancy or breast feeding • Allergy to study medication or compositions of excipients in study medication • Secondary allo-SCT • Previous or concurrent cancer curatively treated ≤ 3 years prior to study entry
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E.5 End points |
E.5.1 | Primary end point(s) |
Relapse free survival (RFS), 50 events (relapse) RFS is defined as time interval from randomization until relapse of AML or death from any cause, which ever occurs first. Relapse is defined as any blast appearance in the peripheral blood, in the bone marrow (> 5%) or extramedullary blasts (chloroma). For a patient with no relapse before the end of study follow-up, observation of RFS will be censored at the date of his or her last follow-up examination.
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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 | Yes |
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 | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 | 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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study ends with last vist of the last patient |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |