E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with AML in need of new treatment principles |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001941 |
E.1.2 | Term | AML |
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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 trial for the two schedules of PXD101 and idarubicin combination treatment is to determine the safety and tolerance (Maximum Tolerated Dose, Dose Limiting Toxicity) and explore the efficacy (Response rate (CR or PR), using the response criteria of the International Working Group (Cheson et al 2003)).(CR will in this protocol include CRi, CRc, CRm – see section 9.0 in the protocol). |
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E.2.2 | Secondary objectives of the trial |
The secondary objective of the trial is • To examine the time to response, response duration, overall survival, relapse-free survival, event-free survival and remission duration following PXD101 combination therapy. • To examine aspects of PK and PHDY of PXD101 in combination with idarubicin in the two PXD101 schedules.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria 1. Signed consent of an IEC-approved informed consent form. 2. AML patients evaluable for efficacy: a. patients above 60 years in first relapse or refractory. b. patients 18-60 years 2nd relapse or refractory to at least two intensive chemotherapy cycles. c. patients above 60 years with high risk features (cytogenetics, secondary or treatment related AML). d) myelodysplastic syndrome with > 10% blasts in bone marrow (WHO RAEB-2). 3. Performance status (ECOG) ≤ 2. 4. Age >18 years. 5. Acceptable liver, renal and bone marrow function including the following: a. Bilirubin ≤ 1.5 times upper limit of normal (ULN) b. AST (SGOT) or ALT (SGPT) and Alkaline Phosphatase ≤ 3 times upper limit of normal (if liver metastases are present, then ≤ 5 x ULN is allowed). c. Serum creatinine ≤ 1.5 times upper limit of normal (ULN). 6. Serum potassium within normal range. 7. Acceptable coagulation status: APTT, PT or INR within £ 1.5 times upper limit of normal or in the therapeutic range if on anticoagulation. 8. Female patients with reproductive potential with a negative pregnancy test within the last 7 days before trial enrollment and must use a safe contraceptive during and for a period of 60 days after the trial. Fertile female partners to male participants must likewise use contraceptive for the same period.
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E.4 | Principal exclusion criteria |
1. Treatment with investigational agents within the last 4 weeks 2. Prior treatment with HDAC inhibitors including valproic acid 3. Prior anti-leukemic therapy within the last 3 weeks of trial dosing including chemotherapy, radiotherapy, endocrine therapy or immunotherapy. Cytoreduction with hydroxyurea for high blood counts is allowed during the pre-trial investigation phase but the treatment should be discontinued at least 3 days before the PXD101 treatment. 4. Co-existing active infection (including HIV) or any co-existing medical condition likely to interfere with trial procedures, including significant cardiovascular disease (New York Heart Association Class III or IV cardiac disease), myocardial infarction within the past 6 months, unstable angina, congestive heart failure requiring therapy, unstable arrhythmia or a need for anti-arrhythmic therapy, or evidence of ischemia on ECG, marked baseline prolongation of QT/QTcF interval, e.g., repeated demonstration of a QTcF interval > 500 msec; long QT Syndrome; the required use of concomitant medication on PXD101 infusion days that may cause Torsade de Pointes. (See Appendix A). 5. Altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures. 6. Concurrent second malignancy. 7. History of hypersensitivity to idarubicin 8. Cumulative idarubicin dose exceeding 100 mg/m2, or a (with respect cardiotoxicity) corresponding dose of other anthracyclines 9. LVEF below normal range ( < 45% by MUGA) 10. Known CNS leukemia
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E.5 End points |
E.5.1 | Primary end point(s) |
Response Endpoints: The number of subjects per schedule and dose in which PXD101 and idarubicin treatment shows anti-leukemic activity according to the International Working Group criteria will be the primary exploratory response endpoint at Cycle 2. At the MTD expansion a response rate exceeding 10% would be of interest and a response rate of 30% would indicate activity and that further study is warranted.
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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 | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 8 |
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 | Information not present in EudraCT |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |