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

Bristol-Myers Squibb (BMS)

Status and phase: Completed; Phase 2; Phase 1

Conditions: Leukemia

Treatments: Drug: BMS-833923; Drug: Dasatinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT01218477

2010-019480-11 (EudraCT Number)

CA180-323

Details and patient eligibility

About

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.

Enrollment: 33 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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33 participants in 4 patient groups

Dasatinib, 100/140 mg QD

Experimental group

Description:

Participants received dasatinib, 100/140 mg once daily (QD), depending on cohort (100 mg for those with chronic myeloid leukemia \[CML\]-chronic phase; 140 mg for those with CML-advanced phase)

Treatment:

Drug: Dasatinib

Dasatinib, 100/140 mg QD + BMS-833923, 50 mg QD

Experimental group

Description:

Participants received dasatinib, 100/140 mg once daily (QD), depending on cohort (100 mg for those with CML-chronic phase; 140 mg for those with CML-advanced phase) plus BMS-833923, 50 mg, QD

Treatment:

Drug: Dasatinib

Drug: BMS-833923

Dasatinib, 100/140 mg QD + BMS-833923, 100 mg BID/QD

Experimental group

Description:

Participants received BMS-833923, 100 mg twice daily (BID) for 7 days then once daily (QD) + dasatinib, 100/140 mg QD, depending on cohort (100 mg for those with CML-chronic phase; 140 mg for those with CML-advanced phase)

Treatment:

Drug: Dasatinib

Drug: BMS-833923

Dasatinib, 100 /140 mg QD+ BMS-833923, 200 mg BID/QD

Experimental group

Description:

Participants received BMS-833923, 200 mg twice daily (BID) for 7 days then 200 mg once daily (QD) plus dasatinib, 100 /140 mg QD), depending on cohort (100 mg for those with CML-chronic phase; 140 mg for those with CML-advanced phase)

Treatment:

Drug: Dasatinib

Drug: BMS-833923