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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT01218477
First received: October 8, 2010
Last updated: April 22, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Leukemia
Drug: Dasatinib
Drug: BMS-833923
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Dasatinib (BMS-354825) Combined With SMO Inhibitor (BMS-833923; XL139) in CML With Resistance or Suboptimal Response to a Prior TKI

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Recommended Phase 2 Dose (RP2D) of BMS-833923 Plus Dasatinib in Chronic Myeloid Leukemia-Chronic Phase [ Time Frame: Day 1 to Week 80, with observation for DLT in Weeks 5-8 ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • 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) [ Time Frame: Day 1 to Week 80 ] [ Designated as safety issue: No ]
    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.

  • 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) [ Time Frame: Day 1 to Week 80 ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Day 1 to Week 80, continuously, with observation for dose-limiting toxicities (DLTs) in Weeks 5-8 ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Grade 3-4 Abnormalities on Laboratory Test Results [ Time Frame: Day 1 to Week 80 ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 33
Study Start Date: January 2011
Study Completion Date: April 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: 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 Name: 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 Name: 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)

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01218477

Locations
United States, California
University Of California Medical Center
San Francisco, California, United States, 94143
United States, Maryland
Sidney Kimmel Cancer Center At Johns Hopkins
Baltimore, Maryland, United States, 21287
United States, Texas
Ut M.D. Anderson Cancer Center
Houston, Texas, United States, 77030
Canada, Ontario
Local Institution
Hamilton, Ontario, Canada, L8N 3Z5
Local Institution
Toronto, Ontario, Canada, M5G 2M9
Finland
Local Institution
Helsinki, Finland, 00290
France
Local Institution
Bordeaux, France, 33076
Local Institution
Poitiers Cedex, France, 86021
Germany
Local Institution
Frankfurt/main, Germany, 60590
Italy
Local Institution
Bologna, Italy, 40138
Local Institution
Orbassano(To), Italy, 10043
United Kingdom
Local Institution
Glasgow, United Kingdom, G12 0YN
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01218477     History of Changes
Other Study ID Numbers: CA180-323, 2010-019480-11
Study First Received: October 8, 2010
Results First Received: April 22, 2014
Last Updated: April 22, 2014
Health Authority: United States: Food and Drug Administration
United Kingdom: Medicines and Healthcare Products Regulatory Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Italy: Ministry of Health
Finland: Finnish Medicines Agency
Germany: Federal Institute for Drugs and Medical Devices
Canada: Health Canada

Keywords provided by Bristol-Myers Squibb:
Leukemia
(Chronic Myeloid Leukemia-Chronic Phase and Advanced)

Additional relevant MeSH terms:
Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Dasatinib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014