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

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.

Time frame: Day 1 to Week 80, with observation for DLT in Weeks 5-8

Population: Participants who were dose-limiting toxicity (DLT)-evaluable (DLT-evaluable=received combination therapy on \>21 of 28 days in Weeks 5 through 8 or interrupted treatment for drug-related AEs)

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.

Time frame: Day 1 to Week 80, continuously, with observation for dose-limiting toxicities (DLTs) in Weeks 5-8

Population: All participants who received at least 1 dose of study drug

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.

Time frame: Day 1 to Week 80

Population: All participants who received at least 1 dose of study drug.

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.

Time frame: Day 1 to Week 80

Population: All patients without CCyR at dosing start date who received at least 4 weeks of dasatinib and had at least 1 on-treatment cytogenetic evaluation of the bone marrow data after at least 4 weeks on treatment

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.

Time frame: Day 1 to Week 80

Population: Patients without complete hematologic response at dosing start date who received at least 4 weeks of dasatinib and who had at least 1 on-treatment evaluation of both peripheral blood counts and bone marrow cytogenetic response after at least 4 weeks on treatment.