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.

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Drug: Dasatinib; Drug: BMS-833923

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Local Institution
    • Toronto, Ontario, Canada, M5G 2M9
      • Local Institution
• Finland
  • Helsinki, Finland, 00290
    • Local Institution
• France
  • Bordeaux, France, 33076
    • Local Institution
  • Poitiers Cedex, France, 86021
    • Local Institution
• Germany
  • Frankfurt/main, Germany, 60590
    • Local Institution
• Italy
  • Bologna, Italy, 40138
    • Local Institution
  • Orbassano(To), Italy, 10043
    • Local Institution
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Local Institution
• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Sidney Kimmel Cancer Center at Johns Hopkins
  • Texas
    • Houston, Texas, United States, 77030
      • UT M.D. Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dasatinib, 100/140 mg QD; 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)	Drug: Dasatinib; Oral tablets, 100-140 mg once daily, depending on cohort (100 mg for those with chronic myeloid leukemia [CML]-chronic phase; 140 mg for those with CML-advanced phase); Other Names: Sprycel
Experimental: Dasatinib, 100/140 mg QD + BMS-833923, 50 mg QD; 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	Drug: Dasatinib; Oral tablets, 100-140 mg once daily, depending on cohort (100 mg for those with chronic myeloid leukemia [CML]-chronic phase; 140 mg for those with CML-advanced phase); Other Names: Sprycel; Drug: BMS-833923; Oral capsules, 50-200 mg, depending on cohort (100 mg for those with CML-chronic phase; 140 mg for those with CML-advanced phase)
Experimental: Dasatinib, 100/140 mg QD + BMS-833923, 100 mg BID/QD; 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)	Drug: Dasatinib; Oral tablets, 100-140 mg once daily, depending on cohort (100 mg for those with chronic myeloid leukemia [CML]-chronic phase; 140 mg for those with CML-advanced phase); Other Names: Sprycel; Drug: BMS-833923; Oral capsules, 50-200 mg, depending on cohort (100 mg for those with CML-chronic phase; 140 mg for those with CML-advanced phase)
Experimental: Dasatinib, 100 /140 mg QD+ BMS-833923, 200 mg BID/QD; 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)	Drug: Dasatinib; Oral tablets, 100-140 mg once daily, depending on cohort (100 mg for those with chronic myeloid leukemia [CML]-chronic phase; 140 mg for those with CML-advanced phase); Other Names: Sprycel; Drug: BMS-833923; Oral capsules, 50-200 mg, depending on cohort (100 mg for those with CML-chronic phase; 140 mg for those with CML-advanced phase)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended Phase 2 Dose (RP2D) of BMS-833923 Plus Dasatinib in Chronic Myeloid Leukemia-Chronic Phase	The following drug-related adverse events (AEs) occurring in the first 28 days of treatment were considered dose-limiting toxicities (DLT): Grade 4 hematologic AE lasting >7 days; ≥Grade 3 nonhematologic AE, despite medical intervention; ≥Grade 2 AE uncontrolled by medical intervention and requiring treatment interruption for >7 days. RP2D was that dose at which ≤1 of 6 patients had a DLT in the first 4 weeks of treatment. If <3 patients were DLT-evaluable, up to 6 additional patients entered the same dose level. Accrual to a dose level closed if 6 patients were enrolled and <3 were DLT-evaluable. If ≥3 patients at a dose level had no DLTs when a new patient enrolled, the dose was escalated to next level. If 1 DLT was observed in <6 patients, ≥6 patients were required; if no additional DLT was observed, the dose was escalated to the next highest level. If ≥2 DLTs were observed in <6 patients, that level exceeded the RP2D, and the dose was deescalated to the next lowest level.	Day 1 to Week 80, with observation for DLT in Weeks 5-8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With a Major Cytogenetic Response (MCyR) in Chronic Myeloid Leukemia-Advanced Phase (CML-Adv) and Chronic Myeloid Leukemia-Chronic Phase (CML-CP)	Cytogenetic response (CyR) was based on the proportion of Philadelphia chromosome-positive (Ph+) cells in metaphase analysis of bone marrow. Complete cytogenetic response (CCyR)=0 Ph+ cells; Partial CyR (PCyR)=1 to 35 Ph+ cells; Minor CyCR= 36-65 Ph+ cells; Minimal CyCR= 66-95 Ph+ cells; No response= >96 Ph+ cells. MCyR=CCyR + PCyR. Nilo=nilotinib; SOR=suboptimal response.	Day 1 to Week 80
Percentage of Participants With a Major Hematologic Response (MHR) in Chronic Myeloid Leukemia-Advanced Phase (CML-Adv) and Chronic Myeloid Leukemia-Chronic Phase (CML-CP)	MHR was defined as complete hematologic response (CHR) or no evidence of leukemia (NEL). CHR for CML-Adv criteria: white blood cell count (WBC) ≤upper limit normal; absolute neutrophil count (ANC) ≥1,000/mm^3; platelets ≥100,000/mm^3; no blasts or promyelocytes in peripheral blood (PB); basophils <5% in PB; myelocytes + metamyelocytes < 5% in PB; no extramedullary involvement; blasts must be <5%, if bone marrow assessment (BMA) performed. NEL had same criteria, but with lower thresholds for reconstitution of PB counts, as follows: Platelets ≥ 20,000/mm^3 or ANC >500/mm^3. Confirmed MHR obtained if these criteria met and maintained for ≥28 days. CHR for CML-CP criteria WBC ≤10,000/mm^3; platelets <450,000/mm^3; basophils <5% in PB; no blasts or promyelocytes in PB; myelocytes + metamyelocytes <5% in PB; no extramedullary involvement; blasts must be <5% if BMA performed. Confirmed CHR obtained if these criteria met and maintained for ≥28 days. Nilo=nilotinib; SOR=suboptimal response.	Day 1 to Week 80
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, Drug-related AEs Leading to Discontinuation, at Least 1 Drug-related AE, and Dose-limiting Toxicities	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment and may or may not be related to treatment. SAE=an untoward medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related=having certain, probable, possible, or missing relationship to study drug. The following drug-related AEs occurring during the first 28 days of treatment with both agents were considered to be dose-limiting toxicities (DLTs): Grade 4 hematologic AE lasting >7 days; ≥Grade 3 nonhematologic AE, despite adequate medical intervention; ≥Grade 2 AE not controlled by medical intervention and requiring treatment interruption for >7 days.	Day 1 to Week 80, continuously, with observation for dose-limiting toxicities (DLTs) in Weeks 5-8
Number of Participants With Grade 3-4 Abnormalities on Laboratory Test Results	ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal. Abnormalities were graded according to the Common Toxicity Criteria of the National Cancer Institute from 1 (least severe) to 4 (life threatening). ANC (*10^9): Grade 3, <1.0- 0.5; Grade 4, <0.5. Hemoglobin (mmol/L): Grade 3, <4.9-4.0; Grade 4, <4.0. Platelet count (*10^9/L): Grade 3, <50.0-25.0; Grade 4, <25. WBCs (*10^9): Grade 3, <2.0-1.0; Grade 4, <1.0. Hypocalcemia (mmol/L): Grade 3, <1.75-1.5; Grade 4, <1.5. Hyperkalemia (mmol/L): Grade 3, >6.0-7.0; Grade 4, >7.0. Hypokalemia (mmol/L): Grade 3, <3.0-2.5; Grade 4, <2.5. Hyponatremia (mmol/L), Grade 3, <130-120; Grade 4, <120. Hypermagnesemia (mg/dL): Grade 3, >1.23-3.30; Grade 4, >3.30. Phosphorus (mmol/L): Grade 3, <0.6-0.3; Grade 4, <0.3. Lipase (*ULN): Grade 3, >2.0-5.0; Grade 4, >5.0.	Day 1 to Week 80

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: October 8, 2010
• First Submitted That Met QC Criteria: October 8, 2010
• First Posted (Estimate): October 11, 2010

Study Record Updates

• Last Update Posted (Estimate): June 17, 2016
• Last Update Submitted That Met QC Criteria: May 16, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: Leukemia; (Chronic Myeloid Leukemia-Chronic Phase and Advanced)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Dasatinib
• Other Study ID Numbers: CA180-323; 2010-019480-11 (EudraCT Number)