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About
This phase IB trial studies the feasibility of using a functional laboratory based study to determine how well the test can be used to select personalized kinase inhibitor therapy in combination with standard chemotherapy in treating patients with newly diagnosed acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). It also evaluates safety and potential efficacy. Kinase inhibitor is a type of substance that blocks an enzyme called a kinase. Human cells have many different kinase enzymes, and they help control important cell functions. Certain kinases are more active in some types of cancer cells and blocking them may help keep the cancer cells from growing. Testing samples of blood from patients with AML and ALL in the laboratory with kinase inhibitors may help determine which kinase inhibitor has more activity against cancer cells and which one should be combined with standard of care chemotherapy. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving a personalized kinase inhibitor therapy combined with standard chemotherapy may be a better treatment for AML and ALL.
Full description
PRIMARY OBJECTIVES:
I. Determine feasibility of using an in vitro small molecule inhibitor screen to select kinase inhibitors to add to standard chemotherapy induction in AML or ALL.
SECONDARY OBJECTIVES:
I. Determine the safety and tolerability of the addition of the kinase inhibitors when added to standard chemotherapy induction.
II. Evaluate overall objective response rates at completion of induction therapy.
III. Evaluate need for re-induction at day 14 (+/- 3 days) for AML. IV. Evaluate sensitivity to kinase inhibitors using our in vitro small molecule inhibitor screen in newly diagnosed AML/ALL.
V. Determine twelve-month overall survival.
TERTIARY OBJECTIVES:
I. Perform next-generation mutational analysis in primary leukemia samples from study subjects at baseline to establish a panel of known mutations for each subject and at the time of bone marrow recovery after induction chemotherapy to measure residual disease and evaluate utility of next-generation sequencing as a method compared to flow cytometry for minimal residual disease (MRD).
II. Evaluate pharmacokinetics for each individual kinase inhibitor. III. Determine if there is a cytogenetic or other risk group that has a higher rate of treatment failure or inability to obtain results from the small molecule inhibitor screen.
OUTLINE: Patients are assigned to 1 of 2 arms.
ARM I (AML): Patients receive cytarabine intravenously (IV) continuously over 24 hours on days 1-7, and idarubicin IV over 30 minutes on days 1-3.
ARM II (ALL) CYCLE A: Patients receive cyclophosphamide IV over 3 hours twice daily (BID) on days 1-3, vincristine sulfate IV on days 4 and 11, doxorubicin hydrochloride IV on day 4, dexamethasone PO on days 1-4 and 11-14, and rituximab IV on day 1 and 11 (day 11 only of course 1). Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
ARM II (ALL) CYCLE B: Patients receive cytarabine IV over 2 hours BID on days 2-3, methotrexate IV over 2-22 hours on day 1, methylprednisolone sodium succinate IV BID on days 1-3, leucovorin calcium IV every 6 hours until methotrexate level is < 0.05 uM and rituximab IV on days 1 and 8. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
In all arms, based on the results of the kinase inhibitor assay, patients receive either sorafenib tosylate PO BID, sunitinib malate PO daily, dasatinib PO daily, ponatinib hydrochloride PO daily, ruxolitinib phosphate or idelalisib PO BID on days 8-28 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 4-6 weeks, and then for a minimum of 1 year.
Enrollment
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Inclusion criteria
Patients must have histologically confirmed AML or ALL, excluding acute promyelocytic leukemia (APL); for histological confirmation, a bone marrow biopsy and aspirate must be reviewed at Oregon Health & Science University (OHSU)
Patients must have newly diagnosed AML or ALL without previous treatment; hydroxyurea will be allowed to control peripheral blast count as clinically indicated but would need to be stopped prior to initiation of tyrosine kinase inhibitor [TKI]); all-trans retinoic acid (ATRA) is permitted during the period prior to ruling out a diagnosis of APL; previous radiation treatment is allowable; patients must be deemed eligible for treatment with cytotoxic induction chemotherapy with cytarabine and idarubicin for AML or hyper-cyclophosphamide, dexamethasone, doxorubicin, vincristine sulfate (CVAD) for ALL; patients newly diagnosed with ALL must have received no prior treatment for their ALL with the exception of steroids (i.e. prednisone, dexamethasone); intrathecal methotrexate or cytarabine, allowed prior to and throughout the enrollment period for AML and ALL
Subjects must be aged between >= 18 years and =< 64 for AML and > 40 and =< 64 for ALL
Eastern Cooperative Oncology Group (ECOG) performance status =< 2
Total bilirubin < 2.0 x institutional upper limit of normal (ULN)
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN and thought to be due to hepatocellular dysfunction
Potassium > lower limit of normal (LLN) or correctable with supplements prior to first dose of study medication
Magnesium > LLN or correctable with supplements prior to first dose of study medication
Total calcium (corrected for serum albumin) >= LLN or correctable with supplements prior to first dose of study medication
Serum amylase and lipase =< 1.5 x institutional ULN
International normalized ratio (INR) =< 2.0 or correctable to 2.0 with vitamin K therapy
Corrected QT (QTc) =< 450 msec. for men or QTc =< 470 msec. for women
Creatinine < 2.0 x ULN
No clinically significant uncontrolled infections as determined by investigator
Patients must be able to take oral medications
Persons of reproductive potential must agree to an adequate method of contraception throughout treatment and for at least 4 weeks after study drug is stopped
Patients must be willing to accept blood product transfusions
Ability to understand and the willingness to sign a written informed consent document and Health Insurance Portability and Accountability Act (HIPAA) documentation
DRUG-SPECIFIC INCLUSION CRITERIA
DASATINIB
Exclusion criteria
Newly diagnosed AML patients who are identified with FLT3-ITD or tyrosine kinase domain (TKD) point mutation in the codon for an aspartate (D835) or an isoleucine (I836) residue
Patients with a diagnosis of Philadelphia chromosome (Ph)+ ALL are not eligible
Subjects who are currently receiving any other investigational agents
History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent or other agents used in the study
Drugs that affect the cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) systems are allowed but should be used with caution depending on specific kinase inhibitor used
All outside study medications and supplements will be reviewed and monitored by the inpatient pharmacy team; patients will be discouraged from taking herbals and additional supplements
Patients should not be prescribed concomitant medications that may contribute to prolonged QTc without consultation with the chemotherapy pharmacist; additional ECGs should be done at the investigator?s discretion to ensure the subject?s safety; drugs that are generally accepted to increase the risk of Torsades de Pointes, include (but not limited to):
Left ventricular ejection fraction < 50%
Uncontrolled intercurrent illness including but not limited to, symptomatic New York Heart Association (NYHA) class III congestive heart failure, uncontrolled angina pectoris, myocardial infarction or stroke within 6 months prior to enrollment, or psychiatric illness/social situations that would limit compliance with study requirements
Patients with a known human immunodeficiency virus (HIV) diagnosis are excluded from the study
History of hypersensitivity to any of the kinase inhibitors included in this study
Pregnant or lactating women are excluded from the study
Diagnosed congenital long QT syndrome
Any history of significant bleeding disorder unrelated to cancer, including any congenital bleeding disorder or any acquired bleeding disorder within one year of start of study
Any history of clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation or torsade de pointes)
Patients must not have clinically significant malabsorption syndrome or history
All patients must discontinue anti-platelet agents or anticoagulants 7 days prior to initiation of study drug
All patients with unhealed wounds or fistulas should not be given vascular endothelial growth factor (VEGF) inhibiting TKIs
DRUG-SPECIFIC EXCLUSION CRITERIA
PONATINIB
Patients with cytogenetically ?favorable risk' AML (core-binding factor leukemias) will not be enrolled on the ponatinib arm; testing with cytogenetics and fluorescence in situ hybridization (FISH) can establish this subtype within 7 days of the diagnostic bone marrow biopsy
History of acute pancreatitis within 1 year of study or history of chronic pancreatitis
Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)
Any history of myocardial infarction, stroke, or revascularization
Uncontrolled hypertension (diastolic blood pressure > 90 mm Hg; systolic > 140 mm Hg); patients with hypertension should be under treatment on study entry to effect blood pressure control
DASATINIB
SORAFENIB
Idelalisib
Ruxolitinib
Primary purpose
Allocation
Interventional model
Masking
7 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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