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

Leukemia Clinical Trial

Official title:

Dasatinib (BMS-354825) Combined With SMO Inhibitor (BMS-833923; XL139) in CML With Resistance or Suboptimal Response to a Prior TKI

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01218477
• Other study ID #: CA180-323
• Secondary ID: 2010-019480-11
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: October 8, 2010
• Last updated: April 22, 2014
• Start date: January 2011
• Est. completion date: April 2013

Study information

• Verified date: April 2014
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Italy: Ministry of HealthFinland: Finnish Medicines AgencyGermany: Federal Institute for Drugs and Medical DevicesCanada: Health Canada
• Study type: Interventional

Clinical 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 33
• Est. completion date: April 2013
• Est. primary completion date: April 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Intervention

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)
• 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)

Locations

Country	Name	City	State
Canada	Local Institution	Hamilton	Ontario
Canada	Local Institution	Toronto	Ontario
Finland	Local Institution	Helsinki
France	Local Institution	Bordeaux
France	Local Institution	Poitiers Cedex
Germany	Local Institution	Frankfurt/main
Italy	Local Institution	Bologna
Italy	Local Institution	Orbassano(To)
United Kingdom	Local Institution	Glasgow
United States	Sidney Kimmel Cancer Center At Johns Hopkins	Baltimore	Maryland
United States	Ut M.D. Anderson Cancer Center	Houston	Texas
United States	University Of California Medical Center	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Canada,  Finland,  France,  Germany,  Italy,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	Yes

External Links

•   BMS clinical trial educational resource
•   BMS Clinical Trial Information
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