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.