There are 5 clinical trials
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.
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 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. --- T315I --- --- T315A ---
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 Leukemia Leukemia Leukemia, Myelogenous, Chronic, BCR-ABL Positive null --- T315I --- --- T315A ---
Description: 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.
Measure: Recommended Phase 2 Dose (RP2D) of BMS-833923 Plus Dasatinib in Chronic Myeloid Leukemia-Chronic Phase Time: Day 1 to Week 80, with observation for DLT in Weeks 5-8Description: 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.
Measure: 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: Day 1 to Week 80Description: 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.
Measure: 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: Day 1 to Week 80Description: 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.
Measure: 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: Day 1 to Week 80, continuously, with observation for dose-limiting toxicities (DLTs) in Weeks 5-8Description: 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.
Measure: Number of Participants With Grade 3-4 Abnormalities on Laboratory Test Results Time: Day 1 to Week 80The purpose of the study is to compare response rates in newly diagnosed Chronic Phase (CP) CML subjects treated with dasatinib plus BMS-833923 versus dasatinib alone.
- Eastern Co-Operative Group (ECOG) Performance Status (PS) Score 0 - 2 Exclusion Criteria: - Known Abl-kinase T315I or T315A mutation - Serious or uncontrolled medical disorder (including infection or cardiovascular disease) or dementia or other serious psychiatric condition - Prior chemotherapy. --- T315I --- --- T315A ---
Description: Major molecular response (MMR) was assessed using BCR-ABL transcript levels measured by real-time quantitative polymerase chain reaction (qPCR). MMR was defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value). Number of participants with MMR by timepoint are cumulative.
Measure: Number of Participants With Major Molecular Response Time: Baseline up to 12 monthsDescription: AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a 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.
Measure: Number of Participants Experiencing Serious Adverse Events (SAE), Drug-Related Adverse Event (AE), AE Leading to Discontinuation, and Death Time: From date of first dose of study treatment up to the date of the last dose plus 30 days (approximately 49 months)This is the study to test combination regimen of Nilotinib and Ruxolitinib therapy for the treatment of patients with Philadelphia positive chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who is resistant to multiple tyrosine kinase inhibitor therapies with BCR-ABL kinase inhibition activity. Ruxolitinib is a tyrosine kinase inhibitor blocking alternative pathway independent of BCR-ABL mediated pathway, thus having a potential to overcome tyrosine kinase inhibitor resistance in Philadelphia positive CML or ALL patients. Phase I study will be conducted to define a recommended phase II dose (RPTD) and phase II study will examine the hypothesis that combinational approach will increase response rate of resistant CML/ALL patients, thus evaluating efficacy of the combination regimen.
Developed the T315I, T315A Y253H, E255K/V or F359C/V mutation after any TKI therapy. --- T315I --- --- T315A ---
Description: Maximum Tolerated Dose (MTD) of Ruxolitinib with fixed dose of Nilotinib. Dose escalation will follow a 3+3 study design. The CTCAE v4.03 criteria will be used. Grade 4 toxicity will be accounted as dose limiting toxicity (DLT).
Measure: Phase I: Maximum Tolerated Dose (MTD) Time: Average of 6 monthsDescription: Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow from CML and ALL patients
Measure: Phase II: Major cytogenetic response Time: Average of 6 monthsDescription: Complete hematologic response defined by CBC differential without any evidence of leukemia. It will be evaluated in CML patients in AP or BP, and patients with Ph+ ALL.
Measure: Phase I: complete hematologic response Time: Average of 3 monthsDescription: Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow taken at 6 months.
Measure: Phase I: major cytogenetic response Time: Average of 6 monthsDescription: It will be defined by NCI Common Terminology Criteria for Adverse Events (CTCAE)version 4.03 for adverse event reporting.
Measure: Phase I: Safety and tolerability Time: Average of 6 monthsDescription: Complete hematologic response defined by CBC differential without any evidence of leukemia. It will be evaluated in the CML patients in AP or BP and in patients with Ph+ ALL.
Measure: Phase II: complete hematologic response Time: Average of 3 monthsDescription: Cmax will be measured for the maximum plasma concentration of nilotinib after oral administration.
Measure: Phase II (exploratory): pharmacokinetic profile of combination of Nilotinib with Ruxolitinib Time: During first 24 hours of first doseThe purpose of this study is to find a dose of Nivolumab that can be safely added to Dasatinib in patients with Chronic Myeloid Leukemia.
T315I or T315A) For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com. --- T315I --- --- T315A ---
T315I or T315A) Chronic Myeloid Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive null --- T315I --- --- T315A ---
Description: Measured by the Dose limiting Toxicities determined based on the incidence and intensity of selected drug related adverse events, Incidences of Adverse events, Incidences of Serious adverse events, and Frequencies of abnormal Laboratory tests (summarized by worst toxicity grade)
Measure: Safety and Tolerability for the combination of Dasatinib and Nivolumab Time: Up to 2 years (approximately)Description: Based on MMR is defined as >= 3-log reduction in BCR-ABL transcripts or a ratio of <= 0.1% on the International Scale (IS) MR is defined as 4.5-log reduction in BCR-ABL transcripts or a ratio of 0.00316% on the IS
Measure: Major Molecular Response (MMR) and Molecular Response (MR) rates Time: 6, 12, 24, and 36 monthThe purpose of this study is to test the safety of a new combination of three oral drugs in Ph+ ALL. These drugs are dexamethasone, dasatinib, and ruxolitinib. All three drugs have been studied before in humans. This is a phase I study in which ruxolitinib dose will start low for the first patient together with dexamethasone plus dasatinib. If this dose does not cause a bad side effect, the ruxolitinib dose will slowly be made higher as new patients take part in the study. This will help the investigators find the right dose of ruxolitinib to give together with dexamethasone and dasatinib that will be used in future studies
L248R, L248V, Q252H, E255K, V299L, T315A, T315I, F317C, F317L, F317S, F317V) - Relapsed or refractory Ph-like ALL without prior exposure to dasatibin and with mutations or rearrangements of genes conferring sensitivity to dasatibin (ABL, CSF1R, PDGFRB) or ruxolitinib (CRLF2, JAK3, EPOR, TSLP) - Newly diagnosed or relapsed CML in lymphoid blast crisis - Confirmation of Philadelphia chromosome positivity by cytogenetics (karyotype/FISH) and/or molecular tests (BCR-ABL1 transcripts) - Acceptable end-organ function, except for documented exclusions for organ function compromise due to ALL itself - ECOG performance status ≤ 2 - Men and women of childbearing potential must be willing to practice an effective method of birth control during treatment and for at least 4 months following treatment on study Exclusion Criteria: - Ph-negative ALL - Patients with dominant leukemic clone bearing documented bcr-abl mutations enabling bcr-abl TKI resistance at diagnosis - Mature B-cell (Burkitt's) ALL - Serum creatinine > 1.5x ULN and calculated creatinine clearance, based on a 24-hour urine collection, < 30 mL/min--unless related to ALL/tumor lysis syndrome and able to be corrected - Direct Bilirubin > 2x ULN; AST/ALT > 10x ULN, unless related to ALL liver infiltration. --- L248R --- --- L248V --- --- Q252H --- --- E255K --- --- V299L --- --- T315A ---
Description: is to be evaluated by using a combination of criteria. Molecular remissions will be defined by standard criteria for BCR-ABL1 and IGH qRT-PCR. Flow cytometric assessment of MRD will be defined by standard flow cytometry criteria
Measure: Clinical response Time: 2 yearsDescription: Molecular remission status will be defined by undetectable BCR-ABL1 transcripts and/or IGH clonal gene rearrangement in bone marrow aspirate (BMA) examination as determined by qRT-PCR in CLIA laboratory.
Measure: Complete Molecular Remission (CMR) rate Time: 2 years