Efficacy and Safety of LBH589B in Adult Patients With Refractory Chronic Myeloid Leukemia in Accelerated or Blast Phase

A Phase II, Multicentre Study of Oral LBH589 in Patients With Accelerated Phase or Blast Phase (Blast Crisis) Chronic Myeloid Leukemia With Resistant Disease Following Treatment With at Least Two BCR-ABL Tyrosine Kinase Inhibitors

This study will evaluate the efficacy and safety of LBH589B in adult patients with chronic myeloid leukemia who are in accelerated phase or blast phase (blast crisis) with resistant disease following treatment with at least two BCR-ABL tyrosine kinase inhibitors

study was designed to assess the hematologic response associated with treatment of oral panobinostat. Hematologic response is defined as the overall of complete hematologic response (CHR), and of no evidence of leukemia (NEL) and of the return to chronic phase (RTC). Hematologic responses were to be confirmed after 4 weeks, and all criteria listed below for each type of response were to be concomitantly met to result into a response.

Inclusion criteria:

• Male or female patients aged ≥ 18 years old
• Diagnosis of Philadelphia chromosome positive accelerated or blast phase chronic myeloid leukemia defined as:

Accelerated phase - the presence of at least one of the following:

• ≥15% but <30% blasts in blood or bone marrow
• ≥30% blasts plus promyelocytes in peripheral blood or bone marrow (providing that <30% blasts present in bone marrow)
• ≥ 20% basophiles in the peripheral blood
• Thrombocytopenia <100 X 109 /L unrelated to sole therapy

Blast phase (blast crisis) - the presence of one of the following:

• ≥ 30% blasts in the blood, in bone marrow or both

• Extramedullary infiltrates of leukemic cells other than liver or spleen involvement

• Prior treatment with at least two a fusion gene of the BCR and ABL genes (BCR-ABL) tyrosine kinase inhibitors (i.e., imatinib, nilotinib, or dasatinib) and demonstrated resistance to the most recent kinase inhibitor therapy. Resistance to a BCR-ABL tyrosine kinase inhibitors (TKI) for this study was defined as:

  • Progression from chronic phase to either accelerated phase or blast crisis
  • Progression from accelerated phase to blast crisis
  • No hematologic response (defined as not achieving complete hematologic response (CHR), no evidence of leukemia (NEL) or return to chronic phase (RTC)) within 3 months of starting therapy
  • Increasing blast counts in peripheral blood of increasing marrow leukemic infiltrate (MLI, the percent marrow blasts multiplied by marrow cellularity)

• Patients with a history of intolerance to one BCR-ABL kinase inhibitors (defined as discontinuation of treatment due grade 3 or 4 adverse events related to treatment) will be considered eligible to enter the study if they demonstrate resistance to their most recent BCR-ABL kinase inhibitor. Intolerance was defined as discontinuation of treatment due to either grade 3 or 4 treatment-related Adverse Event (AE) or a grade 2 treatment-related AE persisting for ≥ one month or recurring more than three times despite dose reduction.

• Patients must have adequate laboratory values:

  • Serum albumin ≥ 3g/dL
  • Aspartate Aminotransferase (AST)/Serum Glutamate Oxalacetate Transaminase (SGOT) and Alanine Aminotransferase (ALT)/Serum Glutamate Pyruvate Transaminase (SGPT) ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if the transaminase elevation is due to leukemic involvement
  • Serum bilirubin ≤ 1.5 x ULN
  • Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min
  • Serum potassium, phosphorus, magnesium, and serum total calcium (corrected for serum albumin) or serum ionized calcium ≥ Lower Limit of Normal (LLN). Supplementation was allowed to correct potassium, calcium, and magnesium values prior to enrollment.
  • Thyroid Stimulating Hormone (TSH) and free Thyroxine (T4) within normal limits (WNL) (patients may have been on thyroid hormone replacement)

• Baseline measurement of left ventricular ejection fraction [assessment of the hearts ability to pump effectively]

• Assessment of patients ability to perform every day activities. Assessment by the Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.

Exclusion criteria:

• A candidate for hematopoietic stem cell transplantation

• Prior therapy with certain medications:

  • Therapeutic doses of sodium warfarin or any other anti-vitamin K drug (low doses for line patency were allowed).
  • Candidate for hematopoietic stem cell transplantation (HSCT)
  • Prior histone deacetylase (HDAC) inhibitor treatment of Chronic Myelogenous Leukemia (CML)
  • Concomitant use of drugs with a risk of causing QT complex (QTc) prolongation or torsades de pointes, CYP3A4/5 inhibitors, anti-cancer therapy or radiation therapy, valproic acid (within 5 days prior to study drug treatment or during the study), chemotherapy (within 3 weeks), immunotherapy (within 1 week), BCR-ABL kinase inhibitor ≤ 1 week of first treatment with panobinostat

• Patients who are in chronic phase chronic myeloid leukemia

• Impaired cardiac function or clinically significant cardiac diseases

• Concomitant use of drugs with a risk of possible risk of causing QTc prolongation or torsades de pointes

• Concomitant use of certain medications

• Impairment of Gastrointestinal (GI) function or GI disease

• Patients with unresolved diarrhea

• Women who are pregnant or breast feeding or women of childbearing potential not using an effective method of birth control

• Male patients whose sexual partners are women of child bearing potential not using effective birth control Other protocol-defined inclusion/exclusion criteria may apply