| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with refractory de novo or secondary acute myelogenous leukemia (AML) |
|
| 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 | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 complete remission rate (CRR, defined as CR or CRi) |
|
| E.2.2 | Secondary objectives of the trial |
• to assess partial response
• to assess time to and duration of remission
• to assess event-free and overall survival
• to assess safety and tolerability |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Stratum A Specific Inclusion Criterion:
Refractory AML with confirmed initial diagnosis of de novo AML (excluding
APL)
OR
Stratum B Specific Inclusion Criterion:
Refractory AML with confirmed initial diagnosis of AML (excluding APL)
secondary to precedent AHD or MDS with either condition being diagnosed
at least three months before confirmed diagnosis of AML . [Patients may
have received no prior treatment or treatment with conventional care
regimens, including best supportive care , low dose cytarabine, intensive
chemotherapy, hypomethylating agents (azacitidine, decitabine), or other
therapies (e.g. lenalidomide)] for precedent MDS/AHD.
Stratum A or B General Inclusion Criteria:
1. Written informed consent prior to study-specific screening procedures.
2. Age ≥ 18 years old
3. Patients with refractory AML (according to Estey 1996b)], whose
disease:
• is primary refractory (= no complete remission following initial
induction therapy), OR
• has relapsed within 12 months after CR1 and for whom salvage (reinduction)
chemotherapy is not indicated for documented clinical
reasons OR documented patient refusal OR
• has relapsed within 12 months after CR1 and patient has failed
one salvage (re-induction) (Failure or relapse after CR2)
4. Eastern Cooperative Group (ECOG) performance status ≤ 2
5. Laboratory values defined as follows:
• Electrolyte panel WNL for the institution (potassium and magnesium
values < lower limit of normal must be corrected to WNL prior to
dosing)
• Total calcium (corrected for serum albumin) or ionized calcium WNL
for the institution
• AST/SGOT and ALT/SGPT ≤ 2.5 x ULN (NCI CTCAE Gr 1)
• Serum creatinine ≤ 1.5 x ULN (NCI CTCAE Gr 1)
• Serum bilirubin ≤ 1.5 x ULN (NCI CTCAE Gr 1) unless attributed to
underlying disease
• INR ≤ 1.5 and PTT WNL. Patients receiving anticoagulation therapy
(e.g. coumadin, heparin) are eligible provided anticoagulation
therapy can be discontinued or changed to parenteral medications
while the platelet count is less than 50,000/mm3
• Negative serum pregnancy test (within 7 days of first dose)
• Negative urine pregnancy test immediately prior to first dose
• Clinically euthyroid (hypothyroidism corrected with supplementation
is permitted)
6. Patient has received a minimum of one and a maximum of three
administrations of conventional remission induction therapy (this may
include consolidation and/or HSCT) for newly diagnosed AML.
7. Previous therapy for AML has stopped at least 2 weeks or at least five half lives, whichever is longer, before the first dose of study drug
8. Patient has recovered from toxicity of previous AML treatment, including
≤ Gr 1 non-hematologic toxicity prior to the first dose of study drug |
|
| E.4 | Principal exclusion criteria |
Stratum A or B General Exclusion Criteria:
1. Patients with initial diagnosis of AML secondary to ionizing
radiation/cytotoxic therapy (e.g. alkylating agents) for precedent
malignancy
2. Patients requiring valproic acid for any medical condition during the
study or within 5 days prior to the first dose of study drug
3. Clinical symptoms suggesting CNS leukemia (patients with neurologic
symptoms must undergo lumbar puncture and a CT scan or MRI of the
brain to exclude CNS involvement)
4. Patients receiving supportive therapy related to complications of
allogeneic transplantation, including infections or graft versus host
(GVH) directed therapy
5. Patients who have received either hydroxyurea or glucocorticosteroids
for prevention of leukostasis less than 24 hours before the first dose of
study drug
6. Patients with another malignancy (with the exception of prior MDS for
secondary AML patients in Stratum B) unless disease-free for at least 3
years following the completion of curative intent therapy. Patients with
treated non-melanoma skin cancer, in situ carcinoma, or cervical
intraepithelial neoplasm regardless of the disease-free duration, are
eligible if definitive treatment for the condition has been completed
7. Patients with impaired cardiac function including any of the following:
• Complete left bundle branch block or use of a permanent cardiac
pacemaker, congenital long QT syndrome, history or presence of
ventricular tachyarrhythmias, clinically significant resting bradycardia
(<50 bpm), QTcF ≥ 450 ms on screening ECG, or right bundle
branch block + left anterior hemiblock (bifascicular block)
• LVEF < lower limit of institutional normal, as assessed by ECHO or
MUGA
• 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
• Angina pectoris or acute myocardial infarction (MI) within 6 months
• Other clinically significant heart disease (e.g. uncontrolled
hypertension or history of poor compliance with a antihypertensive
regimen)
8. Other concurrent severe and/or uncontrolled medical conditions (e.g.,
uncontrolled diabetes mellitus, chronic obstructive or chronic restrictive
pulmonary disease including dyspnea at rest from any cause) or history
of serious organ dysfunction or disease involving the heart, kidney or
liver and/or known seropositive HIV (HIV screening testing is not
required)
9. Patient has an impairment of gastrointestinal (GI) function or GI disease
that may significantly alter the absorption of oral panobinostat (e.g.,
ulcerative disease, uncontrolled vomiting, grade > 1 diarrhea,
malabsorption syndrome, obstruction, or stomach and/or small bowel
resection)
10. Psychiatric disorder that interferes with ability to understand the study
and give informed consent, and/or would impact study participation or
follow-up
11. Concurrent use of medications that have a relative risk of prolonging the
QT interval or of inducing Torsade de Pointes, if such treatment cannot
be discontinued or switched to a different medication prior to the first
dose of study drug
12. 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. WOCBP are defined as sexually mature women
who have not undergone a hysterectomy or surgical sterilization or who
have not been postmenopausal for at least 12 consecutive months (i.e.
has had menses any time in the preceding 12 consecutive months)
13. Male patients whose sexual partner(s) are women of childbearing
potential (WOCBP) who are not willing to use a double method of
contraception, one of which includes a condom, during the study and for
3 months after the end of treatment
14. Patient is receiving concurrent immuno, gene, or biologic therapy
15. Patient is unable to swallow capsules |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Complete remission rate (CRR), defined as the number of CR/CRi in patients with
refractory de novo AML (Stratum A) or refractory secondary AML (Stratum B). CR and
CRi will be assessed by the Investigator according to the response criteria for AML
(Cheson, et al 2003) as implemented in the Post-test supplement 1. |
|
| 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) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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