Dasatinib Combination Therapy With the Smoothened (SMO) Inhibitor BMS-833923 in Chronic Myeloid Leukemia (CML)

Dasatinib (BMS-354825) Combined With SMO Inhibitor (BMS-833923; XL139) in CML With Resistance or Suboptimal Response to a Prior TKI

The purpose of the study is to determine the safety and tolerability of the combination of BMS-833923 plus dasatinib in patients with chronic myeloid leukemia.

Key Inclusion Criteria

• Age ≥18 years
• Diagnosis of chronic myeloid leukemia (CML) and cytogenetic positive for the Philadelphia chromosome (Ph+), documented Ph+ cells on bone marrow assessment (BMA) ≤6 weeks prior to treatment
• Either chronic-phase CML, with <15% blasts in peripheral blood and bone marrow, or advanced-phase CML, including Ph+ acute lymphoblastic leukemia (ALL) (> 5% blasts) or hematologic progression with ≥15% blasts not in complete cytogenetic remission
• Resistance or suboptimal response to imatinib, dasatinib, or nilotinib and no known T315I/A Abl-kinase mutation.

Key Exclusion Criteria

• Known Abl-kinase T315I or T315A mutation

• CCyR at baseline

• Any serious or uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy

• Uncontrolled or significant cardiovascular disease

• Grade 3 or higher peripheral blood counts

• Serum calcium or phosphate below the lower limit of normal

• Baseline hypomagnesemia and amylase or lipase at least Grade 1 or higher

• Reduced renal function, defined as serum creatinine level >3*upper limit of normal

• Prior therapies for CML or Ph+ ALL permitted, with the following restriction:

  • Therapy permitted with corticosteroids, hydroxyurea, or anagrelide prior to starting treatment and during the first 4 weeks on study
  • 6 months or longer after stem cell transplantation
  • 28 days or longer after any investigational agent
  • 7 days or longer after any standard chemotherapy agent
  • Concomitant use of medications with a known risk of causing Torsades de Pointes
  • Concomitant use of strong inhibitors of the CYP3A4 isoenzyme