| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| refractory or relapsed acute myeloid leukemia |
|
| 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 | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
|
| 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 |
To determine the maximum-tolerated dose (MTD) in terms of the incidence of
dose-limiting toxicity (DLT) of panobinostat in combination with ara-C and
mitoxantrone at a fixed dose in adult patients with relapsed or is primary
refractory acute myeloid leukemia (AML). |
|
| E.2.2 | Secondary objectives of the trial |
Dose escalation and expansion part:
To assess the safety profile of panobinostat in combination with ara-C and
mitoxantrone in this patient population during the escalation and expansion
phase (at MTD) of the study.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients with cytopathologically confirmed diagnosis of AML according to
WHO criteria
Relapsed after receiving up to 1 prior induction regimens (first relapse) or
patients who are refractory (no CR) to not more than one prior combination
chemotherapy induction regimen.
Age more than 18 years
ECOG performance status ≤ 2
Patients must have the following laboratory values unless considered due to
leukemia: AST/SGOT and/or ALT/SGPT ≤ 2.5 x ULN; Serum creatinine ≤ 1.5
x ULN or GFR ≥ 60 mL/min; Total and direct serum bilirubin ≤ 1.5 x ULN;
electrolyte panel within normal ranges for the institution unless attributed to
the underlying disease.
Eligible for ara-C and mitoxantrone chemotherapy
Written informed consent obtained prior to any screening procedures |
|
| E.4 | Principal exclusion criteria |
Subjects with Acute Promyelocytic Leukemia (APL)
Concurrent therapy with any other investigational agent
Patients who received more than maximal two chemotherapy induction cycles
and four chemotherapy consolidation cycles for their AML disease
CNS involvement
Female patients who are pregnant or breast feeding or patients of
childbearing potential (WOCBP) not willing to use a double barrier method of
contraception during the study and for 3 months following the last dose of
study drug.
Male patients whose sexual partner(s) are women of childbearing potential
who are not willing to 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.
Prior treatment with deacetylase inhibitors
Patients who have received cumulative doses of ≥ 360 mg/m2 of doxorubicin
(or its equivalent to other anthracyclines, e.g. 225 mg/m2 of idarubicin, 900
mg/m2 of daunorubicin, 140 mg/m2 of mitoxantrone, 450 mg/m2 of pegylated
liposomal doxorubicin hydrochloride).
Any of concurrent severe and/or uncontrolled medical conditions which could
compromise participation in the study. For example:
Complete left bundle branch block or use of a permanent cardiac pacemaker, congenital long QT syndrome, history or presence of ventricular
tachyarrhythmia, clinically significant resting bradycardia (<50 beats per
minute), QTcF > 460 ms on screening ECG, or right bundle branch block +
left anterior hemiblock (bifascicular block)
Presence of unstable atrial fibrillation (ventricular response rate >100 bpm).
Patients with stable atrial fibrillation are eligible provided they do not meet the
other cardiac exclusion criteria
Previous history of angina pectoris or acute MI within 6 months
Baseline LVEF <45% by echocardiography
Other clinically significant heart disease (e.g. uncontrolled hypertension or
history of poor compliance with an antihypertensive regimen)
Uncontrolled diabetes
Active or uncontrolled infection
Uncontrolled hypothyroidism
Acute or chronic liver or renal disease
Impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral panobinostat (e.g., ulcerative
diseases, diarrhea, malabsorption syndrome, or small bowel resection)
Time windows for prior therapies:
All acute toxic effects of any prior therapy of leukemic disease must have
resolved to National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Events (CTCAE, Version 3.0) Grade <2 (with exception of
chemotherapy-induced alopecia)
Last dose of prior chemotherapy, immunotherapy or investigational agent no
less than 14 days prior to receipt of study medication and have recovered at
least CTCAE Grade <2, except for hydroxyurea which must be finished 48
hours before first administration.
Wide field radiotherapy ≤ 4 weeks or limited radiation for palliation ≤ 2 weeks
prior to starting the study treatment or who have not recovered from side
effects of such therapy
Drugs which may cause QT prolongation and the treatment cannot be
discontinued or switched to a different medication prior to starting study drug.
HIV, Hepatitis B/C infection according to the medical history (testing will not
be performed)
Unwilling or unable to comply with the protocol
Inability to swallow capsules |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose escalation part:
Incidence of DLT |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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) | 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 | 6 |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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