LeukemiaPhase 1/2NCT01218477
Dasatinib Combination Therapy With the Smoothened (SMO) Inhibitor BMS-833923 in Chronic Myeloid Leukemia (CML)
A Phase 1/2 study testing Dasatinib and BMS-833923 in people with Leukemia, run by Bristol-Myers Squibb at 12 sites in 7 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Leukemia
- What is being tested?
- Dasatinib and BMS-833923
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 33 participants
- Where
- 12 sitesin 7 countries
- Study dates
- Jan 2011to Apr 2013
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 15Show fewer
- 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 locations and contacts
12 sites in 7 countries.
12 sites in 7 countries
United States3 sites
Sidney Kimmel Cancer Center At Johns Hopkins
Baltimore, Maryland, 21287
Ut M.D. Anderson Cancer Center
Houston, Texas, 77030
University Of California Medical Center
San Francisco, California, 94143
Canada2 sites
Local Institution
Hamilton, Ontario, L8N 3Z5
Local Institution
Toronto, Ontario, M5G 2M9
France2 sites
Local Institution
Bordeaux, 33076
Local Institution
Poitiers, 86021
Italy2 sites
Local Institution
Bologna, 40138
Local Institution
Orbassano(To), 10043
About this study
Official title: 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.
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DasatinibDrug
Also called Sprycel
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)
BMS-833923Drug
Oral capsules, 50-200 mg, depending on cohort (100 mg for those with CML-chronic phase; 140 mg for those with CML-advanced phase)
| Study group | Role | What they receive |
|---|---|---|
| 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) Receives: 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 Receives: 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) Receives: 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) Receives: Drug: Dasatinib; Drug: BMS-833923 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Day 1 to Week 80
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Oct 2010 (estimated)
- Study startJan 2011
- Primary completionApr 2013
- Study completionApr 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for LeukemiaStudies of the same condition, open and under way.
- More trials run by Bristol-Myers SquibbThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 33 participants (actual)
Sponsor and investigators
- Lead sponsor
- Bristol-Myers Squibb
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Bristol-Myers Squibb, Study director, Bristol-Myers Squibb
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01218477
- Sponsor's protocol ID
- CA180-323
- Other IDs
- 2010-019480-11
- Status last verified
- May 2016
- First submitted
- 8 Oct 2010
- Last updated
- 17 Jun 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 17 Jun 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Dasatinib (BMS-354825) Combined With SMO Inhibitor (BMS-833923; XL139) in CML With Resistance or Suboptimal Response to a Prior TKI
- ClinicalTrials.gov ID
- NCT01218477
- Acronym / sponsor ID
- CA180-323
- Conditions
- Leukemia
- Keywords
- Leukemia, (Chronic Myeloid Leukemia-Chronic Phase and Advanced)
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 33 participants (actual)
- Lead sponsor
- Bristol-Myers SquibbIndustry (pharma, biotech, devices)
- Study start
- Jan 2011
- Primary completion
- Apr 2013 (actual)
- Study completion
- Apr 2013 (actual)
- First posted
- 11 Oct 2010 (estimated)
- Results
- Posted 20 May 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Dasatinib, 100/140 mg QD | Experimental | Drug: DasatinibParticipants 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) |
| Dasatinib, 100/140 mg QD + BMS-833923, 50 mg QD | Experimental | Drug: Dasatinib, Drug: BMS-833923Participants 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 |
| Dasatinib, 100/140 mg QD + BMS-833923, 100 mg BID/QD | Experimental | Drug: Dasatinib, Drug: BMS-833923Participants 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) |
| Dasatinib, 100 /140 mg QD+ BMS-833923, 200 mg BID/QD | Experimental | Drug: Dasatinib, Drug: BMS-833923Participants 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) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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 (15 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DasatinibAlso: SprycelOral 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) | Drug | 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-833923Oral capsules, 50-200 mg, depending on cohort (100 mg for those with CML-chronic phase; 140 mg for those with CML-advanced phase) | Drug | 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 |
Primary outcome
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
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.
4 secondary outcomes
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
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
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
Number of Participants With Grade 3-4 Abnormalities on Laboratory Test Results
Time frame: Day 1 to Week 80
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jun 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bristol-Myers Squibb study director
Bristol-Myers Squibb
12 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Dasatinib and BMS-833923 in people with Leukemia, run by Bristol-Myers Squibb at 12 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Jun 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 12 sites in United States, Canada, France, Italy, Finland and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 May 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jun 2016.