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A Phase I/II Multicenter, National, Open-Label Study of Panobinostat in Combination With Idarubicin and Cytarabine in Patients Aged 65 Years or Older With Newly Diagnosed Acute Myeloblastic Leukaemia (AML)

Phase 1/Phase 2
65 Years
Open (Enrolling)
Acute Myeloblastic Leukaemia

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Trial Information

A Phase I/II Multicenter, National, Open-Label Study of Panobinostat in Combination With Idarubicin and Cytarabine in Patients Aged 65 Years or Older With Newly Diagnosed Acute Myeloblastic Leukaemia (AML)

A phase Ib will be initially performed to establish the MTD of panobinostat that can be
administered in combination with the classic regimen of idarubicin and cytarabine in
patients aged 65 years or older. This MTD will be established in the induction cycle. For
this purpose, the first patients enrolled in the trial will be successively distributed into
three cohorts of patients for each dose level of panobinostat (20 mg, 30 mg, 40 mg) in
combination with idarubicin and cytarabine, according to the classical 3+3 schedule (vid
section 5.2). In case of an unacceptable toxicity in the first dose step (20 mg), a dose
reduction to a -1 step will be considered (10 mg). Patients included in the phase Ib part of
the study will continue throughout the treatment with the starting dose of panobinostat
corresponding to the step to which they were initially assigned (except for those patients
receiving a dose higher than the MTD which will be deescalated to the MTD). 9 additional
patients will be included at the MTD dose level to confirm the safety of this dose.

Once the MTD of panobinostat is determined, during the phase II of the study, up to a total
of 46 patients will be recruited (40 of them at the MTD dose) and the scheduled assessments
and visits will be carried out in three periods: Pre-treatment, Treatment, and Follow-up.

The pre-treatment period includes the screening visit where the written informed consent for
participating in the study is obtained. Then, during the screening visit that is completed
14 days before the baseline visit (Days -14 to -1), patients are assessed for eligibility.
The patients eligible for inclusion in the study will start the treatment period where they
will receive two or three cycles of cytarabine and idarubicin in combination with
panobinostat (induction and consolidation, or induction, re-induction and consolidation)
followed by treatment with panobinostat as monotherapy (vid. schema in appendix 4). The
induction cycle will comprise of cytarabine 100 mg/m2 (Day 1 to 7) and idarubicin 8 mg/m2
(Days 1 to 3) followed by panobinostat administered three times a week for three weeks (Days
8, 10, 12, 15, 17, 19, 22, 24, 26) (Table 4 ). The patients will be assessed by bone marrow
aspiration on day +14 and at the moment of the recovery from aplasia.

If the patient experiences an unsatisfactory response, i.e. partial remission or resistant
disease after the first cycle, a second induction cycle, identical to the first one
(re-induction cycle), will be administered not sooner than seven days after receiving the
last dose of panobinostat (in the induction cycle).

If the patient reaches a complete morphological remission (or CRi) after the induction or
the re-induction cycles, then, in the absence of unacceptable toxicity, a consolidation
cycle, identical to the induction cycle, will be administered once recovered from aplasia
and always leaving the seven days of Panobinostat treatment free interval. If a patient does
not reach a CR or CRi after the re-induction, she/he will be removed from the protocol.

Then, after the recovery from the aplasia caused by the last consolidation, all patients
will be assessed for efficacy and safety, and, in the absence of relapse (i.e. patients in
CR or CRi) or unacceptable toxicity will turn to the maintenance phase, during which they
will receive single agent panobinostat at a dose of 40 mg with the following treatment
regimen: three times a week for a total duration of three weeks (Days 1, 3, 5, 8, 10, 12,
15, 17 and 19), followed by a rest period of 9 days (Table 5). This cycle will be repeated
every 28 days and a total of six cycles will be administered in the absence of relapse or
unacceptable toxicity. During this period, patients will be assessed monthly for efficacy
based on the hematimetric values (bone marrow aspirate will be performed every three months
and when relapse is suspected) and toxicity/vital signs until the end of treatment.

Finally, during the follow-up period that starts once the patient completes the treatment,
patients will be assessed for efficacy based on the hematimetric values (bone marrow
aspirate will be performed every six months and when relapse is suspected) and toxicity
every 3 months for one additional year.

Safety will be assessed by monitoring all adverse events, physical examination, vital signs,
cardiological examinations, and blood and biochemical tests. The left ventricular ejection
fraction (LVEF) will be assessed by echocardiography. The response to treatment will be
assessed according to the standard Cheson response criteria. Furthermore, the impact of MRD
in the prognosis of these patients will be assessed. For this purpose, MRD changes at
different treatment time points will be tested by multiparametric flow cytometry: at Day +14
post-induction, before starting the first consolidation cycle (this is to say at the moment
of achieving CR), at the start of maintenance therapy, every three months during this phase
and every six months during the follow-up period.

Inclusion Criteria:

- The patient should, in the investigator's opinion, be able to meet all clinical trial

- The patient should have voluntarily give the informed consent before performing any
study test that is not part of the regular care of the patients.

- Age > 65 years.

- The patient should be diagnosed with AML according to the standard criteria of the
World Health Organisation (WHO) (see Appendix 8).

- The patient should not have received any prior treatment for AML.

- The patient should have a performance status measured by the ECOG scale <= 2 .

- The patient should have the following laboratory values prior to the start of the

- Aspartate transaminase (AST): ≤ 2.5 x the upper normal ranges.

- Alanine transaminase (ALT): ≤ 2.5 x the upper normal ranges.

- Total bilirubin: ≤ 1.5 x the upper normal ranges.

- Alkaline phosphatase: ≤ 2.5 x the upper normal ranges.

- Serum creatinine ≤ 2 mg/dl.

- Serum potassium, magnesium, phosphorus, sodium, total calcium (corrected for
serum albumin) or ionized calcium within normal limits (WNL) for the
institution. Note: Electrolytes (supplemental therapy) should be given to
correct values that are clinically significant abnormality prior to patients being dosed.

- Left ventricular ejection fraction measured by echocardiography ≥ 50%

Exclusion Criteria:

- Patients previously receiving treatment with histone deacetylase inhibitors (HDACi).

- Patient will need valproic acid for any medical condition during the study or within
5 days prior to the first panobinostat dose.

- Promyelocytic AML (M3).

- Secondary AML or previous history of MDS.

- Male patients whose sexual partners are women of a fertile age and do not use

- Known brain or leptomeningeal involvement.

- Presence of any limitation affecting the ability of the patient to comply with the

- Patients receiving any investigational agent in the 30 days prior to inclusion.

- Patient carrier of human immunodeficiency virus (HIV), hepatitis B virus surface
antigen or active infection by hepatitis C virus.

- Presence of heart disorders or clinically significant heart diseases, including any
of the following:

- Congenital QT prolongation "long QT syndrome").

- History or presence of sustained ventricular tachyarrhythmia (patients with a
history of atrial arrhythmia are acceptable, but this must be discussed with the
sponsor prior to inclusion).

- Any history of ventricular fibrillation or "torsade de pointes".

- Bradycardia defined as HR < 50 bpm. Patients with pacemakers are eligible if HR
≥ 50 bpm.

- Screening ECG with QTc > 450 msec.

- Right bundle branch block + left anterior hemiblock (bifascicular block).

- Patients with acute myocardial infarction or unstable angina ≤ 6 months before
the start of the investigational drug.

- Any clinically significant heart disease (e.g., NYHA grades III or IV, or
baseline LVEF <45%, uncontrolled hypertension, or history of poor compliance of
antihypertensive treatment).

- Gastrointestinal disease making panobinostat absorption significantly difficult.

- Diarrhea > grade 1 according to CTCAE criteria, version 3.0.

- Any serious or uncontrolled medical condition (e.g., uncontrolled diabetes, or active
or uncontrolled infection), including laboratory disorders that could involve
unacceptable risks or affect protocol compliance.

- Concomitant administration of drugs with a relative risk of increasing the QT
interval or inducing "torsade de pointes" if this treatment cannot be discontinued or
replaced by another prior to the start of the test drug.

- Patient has active bleeding diathesis or is currently being treated with therapeutic
doses of sodium warfarin (Coumadin®) or other vitamin K active agents Note: mini-dose
of Coumadin® (e.g., 1 mg/day) or anti-coagulants given to maintain intravenous line
patency, as well as unfractionated or low molecular weight heparin therapy is

- Patients undergoing major surgery in the four weeks prior to the start of the study
treatment or not recovering from the treatment adverse events.

- Patients with a history of malignancies in the past five years. Basal cell carcinoma,
skin epithelioma and carcinoma of the cervix in situ are excluded.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To establish the maximum tolerated dose (MTD) of panobinostat in combination with idarubicin and cytarabine after an induction cycle in patients aged 65 years or older with newly diagnosed AML

Outcome Time Frame:

1 year

Safety Issue:



Spain: Ministry of Health

Study ID:




Start Date:

September 2009

Completion Date:

September 2012

Related Keywords:

  • Acute Myeloblastic Leukaemia
  • Acute Myeloblastic Leukaemia (AML)
  • Panobinostat
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid