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 Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
33
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)
Oral capsules, 50-200 mg, depending on cohort (100 mg for those with CML-chronic phase; 140 mg for those with CML-advanced phase)
University Of California Medical Center
San Francisco, California, United States
Sidney Kimmel Cancer Center At Johns Hopkins
Baltimore, Maryland, United States
Ut M.D. Anderson Cancer Center
Houston, Texas, United States
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.
Time frame: Day 1 to Week 80, with observation for DLT in Weeks 5-8
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.
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)
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.
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Local Institution
Hamilton, Ontario, Canada
Local Institution
Toronto, Ontario, Canada
Local Institution
Helsinki, Finland
Local Institution
Bordeaux, France
Local Institution
Poitiers, France
Local Institution
Frankfurt am Main, Germany
Local Institution
Bologna, Italy
...and 2 more locations
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
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
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.
Time frame: Day 1 to Week 80