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

Study Overview
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Brief Summary
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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.

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

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Dasatinib
* Drug: BMS-833923


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dasatinib, 100/140 mg QD<br>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<br>* 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)<br>* Other names: Sprycel;|
| Experimental: Dasatinib, 100/140 mg QD + BMS-833923, 50 mg QD<br>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<br>* 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)<br>* Other names: Sprycel;Drug: BMS-833923<br>* Oral capsules, 50-200 mg, depending on cohort (100 mg for those with CML-chronic phase; 140 mg for those with CML-advanced phase)<br>|
| Experimental: Dasatinib, 100/140 mg QD + BMS-833923, 100 mg BID/QD<br>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<br>* 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)<br>* Other names: Sprycel;Drug: BMS-833923<br>* Oral capsules, 50-200 mg, depending on cohort (100 mg for those with CML-chronic phase; 140 mg for those with CML-advanced phase)<br>|
| Experimental: Dasatinib, 100 /140 mg QD+ BMS-833923, 200 mg BID/QD<br>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<br>* 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)<br>* Other names: Sprycel;Drug: BMS-833923<br>* Oral capsules, 50-200 mg, depending on cohort (100 mg for those with CML-chronic phase; 140 mg for those with CML-advanced phase)<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, (Chronic Myeloid Leukemia-Chronic Phase and Advanced)