Trial of PXD101 in Combination With Idarubicin to Treat Acute Myeloid Leukemia (AML) Not Suitable for Standard Intensive Therapy

An open-label, non-randomized, multi-centre, Phase I/II trial to assess the efficacy and safety of 2 schedules of PXD101 in combination with idarubicin in patients with AML not suitable for standard intensive therapy.

This trial is an open-label, multi-centre, dose-escalation Phase I/II study to evaluate safety, explore efficacy, pharmacodynamics, and pharmacokinetics of the combination of PXD101 with idarubicin administered in two different schedules in patients with AML. The PXD101 plus idarubicin treatment will be repeated at suitable intervals (target is every 3 weeks for schedule A and every 2 weeks for schedule B) depending upon toxicities or disease progression. Safety and efficacy assessments will be performed at every cycle.

Schedule A uses PXD101 by 30 min infusion daily for 5 days every 3 weeks with escalating doses of idarubicin.

Schedule B uses escalating doses of continuous infusion (48h) of PXD101 alone or in combination with idarubicin.

In both regimens the trial may be expanded at the Maximum Tolerated Dose (MTD).

• Drug: PXD101
  Other Name: Belinostat
• Drug: idarubicin
  Other Name: Zavedos

• Experimental: Arm A

  PXD101 administered as a 30-minute intravenous (IV) infusion of 1000 mg/m²/d for five consecutive days every 3 weeks.

  Idarubicin administered on day 5 (first steps) or days 4 and 5 (later steps). Patients will be treated in a 21-day cycle for a minimum of 2 cycles and a maximum of 6 cycles (depending on cumulated idarubicin dose).

  Interventions:

  • Drug: PXD101
  • Drug: idarubicin
• Experimental: Arm B
  PXD101 administered by continuous intravenous infusion over 24-48 hours and idarubicin (in the later steps) added after the first 24 hours. The second cycle will start on day 15 but under observation of possible toxicity. Further cycles will be administered q 14 d for up to 6 cycles. The first dose steps will be carried out with PXD101 alone for safety reasons.
  Interventions:

  • Drug: PXD101
  • Drug: idarubicin

Inclusion Criteria: (abbreviated)

1. Signed consent

2. AML patients:

   1. above 60 years in first relapse or refractory.
   2. 18-60 years 2nd relapse or refractory to at least two intensive chemotherapy cycles.
   3. above 60 years with high risk features (cytogenetics, secondary or treatment related AML) d) above 60 years with myelodysplastic syndrome with >10% blasts in bone marrow (WHO RAEB-2 (Refractory anemia with excess blasts-2)). For patients below 60 years potential curative treatments should have been exhausted.
3. Performance status (ECOG) ≤ 2
4. Age ≥ 18 years
5. Acceptable liver, renal and bone marrow function as defined
6. Serum potassium within normal range.
7. Acceptable coagulation status as defined
8. Precautions for female patients with reproductive potential as defined

Exclusion Criteria:

1. Treatment with investigational agents within the last 4 weeks
2. Prior treatment with HDAC (Histone deacetylases) inhibitors including valproic acid
3. Prior anti-leukemic therapy (except hydroxyurea) within the last 3 weeks of trial dosing
4. Co-existing active infection (including HIV) or any co-existing medical condition likely to interfere with trial procedures, including significant cardiovascular disease
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 (left ventricular ejection fraction) below normal range (< 45% )
10. Known Central Nervous System (CNS) leukemia