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

NCT01218477 | Completed Phase 1 Results

• 2 other identifiers: CA180-3232010-019480-11
• Study Type: interventional
• Target: 33
• Locations: 7 countries
• Sites: 12

Brief Summary

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.

Conditions

Leukemia

Keywords

Leukemia; (Chronic Myeloid Leukemia-Chronic Phase and Advanced)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• 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)

  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)

  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

  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

  Day 1 to Week 80

Study Arms (4)

Dasatinib, 100/140 mg QD

EXPERIMENTAL

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

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

EXPERIMENTAL

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; Drug: BMS-833923

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

EXPERIMENTAL

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; Drug: BMS-833923

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

EXPERIMENTAL

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; Drug: BMS-833923

Interventions

Dasatinib DRUG

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)

Also known as: Sprycel

Dasatinib, 100 /140 mg QD+ BMS-833923, 200 mg BID/QD; Dasatinib, 100/140 mg QD; Dasatinib, 100/140 mg QD + BMS-833923, 100 mg BID/QD; Dasatinib, 100/140 mg QD + BMS-833923, 50 mg QD

BMS-833923 DRUG

Oral capsules, 50-200 mg, depending on cohort (100 mg for those with CML-chronic phase; 140 mg for those with CML-advanced phase)

Dasatinib, 100 /140 mg QD+ BMS-833923, 200 mg BID/QD; Dasatinib, 100/140 mg QD + BMS-833923, 100 mg BID/QD; Dasatinib, 100/140 mg QD + BMS-833923, 50 mg QD

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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
• months or longer after stem cell transplantation
• days or longer after any investigational agent
• 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

Sponsors & Collaborators

• Bristol-Myers Squibb: lead

Study Sites (12)

University Of California Medical Center

San Francisco, California, 94143, United States

Location

Sidney Kimmel Cancer Center At Johns Hopkins

Baltimore, Maryland, 21287, United States

Location

Ut M.D. Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Local Institution

Hamilton, Ontario, L8N 3Z5, Canada

Location

Local Institution

Toronto, Ontario, M5G 2M9, Canada

Location

Local Institution

Helsinki, 00290, Finland

Location

Local Institution

Bordeaux, 33076, France

Location

Local Institution

Poitiers, 86021, France

Location

Local Institution

Frankfurt am Main, 60590, Germany

Location

Local Institution

Bologna, 40138, Italy

Location

Local Institution

Orbassano(To), 10043, Italy

Location

Local Institution

Glasgow, G12 0YN, United Kingdom

Location

Related Links

• BMS clinical trial educational resource
• Investigator Inquiry form

MeSH Terms

Conditions

Leukemia; Leukemia, Myeloid, Chronic-Phase

Interventions

Dasatinib; BMS-833923

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Myeloproliferative Disorders; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Limitations and Caveats

Bristol-Myers Squibb discontinued research in the area of smoothened inhibitors. This study was completed early and limited efficacy data was published in a synoptic clinical study report .

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 8, 2010
• First Posted: October 11, 2010
• Study Start: January 1, 2011
• Primary Completion: April 1, 2013
• Study Completion: April 1, 2013
• Last Updated: June 17, 2016
• Results First Posted: May 20, 2014

Record last verified: 2016-05

Locations

US (3); FR (2); DE (1); FI (1); GB (1); IT (2); CA (2)