Patient case: 4-year-old female with leukemia; genetic feature: ABL1

Clinical trial: Targeted Therapy in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia or Acute Myelogenous Leukemia

Summary: This phase II trial studies how well targeted therapy works in treating patients with acute lymphoblastic leukemia or acute myelogenous leukemia that has come back after a period of improvement or does not respond to treatment. Testing patients' blood or bone marrow to find out if their type of cancer may be sensitive to a specific drug may help doctors choose more effective treatments. Dasatinib, nilotinib, sunitinib malate, sorafenib tosylate, and ponatinib hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving targeted therapy based on cancer type may be an effective treatment for acute lymphoblastic leukemia or acute myelogenous leukemia.

Detailed description: PRIMARY OBJECTIVES:
  I. To determine the clinical activity of kinase inhibitors using pre-clinical (in-vitro) activity to select individual therapy.
  SECONDARY OBJECTIVES:
  I. To evaluate overall objective response rates (complete response plus partial response).
  II. Determine overall survival (OS) and progression-free survival (PFS). III. Any changes in transfusion requirements.
  TERTIARY OBJECTIVES:
  I. Prioritize active/aberrant kinase pathways using an in vitro inhibitor screen using individual primary leukemia samples.
  II. Measure "on target" in vivo kinase inhibition and signal transducer and activator of transcription (STAT)-5 phosphorylation and correlate with response to treatment.
  III. Perform next generation sequencing (whole exome sequencing) for complete mutational analysis.
  IV. Identify aberrant gene expression in primary leukemia samples from study subjects.
  V. Evaluate pharmacokinetics for each individual kinase inhibitor during therapy.
  OUTLINE: Patients are assigned to 1 of 5 treatment groups based on pre-clinical kinase inhibitor activity.
  GROUP I: Patients receive dasatinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  GROUP II: Patients receive nilotinib PO twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  GROUP III: Patients receive sunitinib malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  GROUP IV: Patients receive sorafenib tosylate PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  GROUP V: Patients receive ponatinib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  After completion of study treatment, patients are followed up periodically.

Eligibility: Inclusion Criteria:
  -  Patients with >= 18 years of age with relapsed/refractory leukemia with a confirmed diagnosis of acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL) who meet the following criteria:
  -  Age 18-64: Salvage treatment failures only - defined as relapsed or refractory to after least 1 cycle of salvage therapy
  -  Age > 65: Refractory to or have relapsed after induction chemotherapy defined as no response to initial therapy
  -  Given the clinical activity and use of hypomethylating agents in AML patients, for all AML populations, initial therapy and salvage therapy may include hypomethylating agents; furthermore, patients >= 65 with hematologic malignancies including chronic myelomonocytic leukemia (CMML) or myelodysplasia (MDS) that transform to acute leukemia while actively receiving hypomethylating agents (i.e. decitibine or azacytidine) will be considered induction failures and thus are eligible; for Philadelphia positive (Ph+) ALL, initial therapy and salvage therapy may include steroids and imatinib or dasatinib or nilotinib
  -  Primary patient samples must show in vitro kinase inhibitor sensitivity as determined by the Oregon Health and Science University (OHSU) functional kinase inhibitor screen; for OHSU patients, functional kinase inhibitor screening may be performed as part of this study or through enrollment in eIRB4422 if the identical Food and Drug Administration (FDA)/Clinical Laboratory Improvement Act (CLIA) approved assay is used and a result is available within 2 weeks of starting drug treatment
  -  Have not received any leukemia treatment within 1 week prior to starting study drug; corticosteroids (oral and systemic) can be administered up to 24 hours prior to first administration of study drug; doses of steroids =< 20 mg of prednisone (or equivalent) are permitted; hydroxyurea must be stopped 24 hours prior to initiation of study drug
  -  Patients must have normal organ function as defined below:
  -  Serum creatinine < 2.0 x institutional upper limit of normal (ULN)
  -  International normalized ratio (INR) < 1.5 x institutional ULN
  -  Adequate hepatic function as defined by the following criteria:
  -  Total serum bilirubin =< 1.5 x upper normal limit (ULN), unless due to Gilbert's syndrome
  -  Alanine aminotransferase (ALT) =< 2.5 x ULN
  -  Aspartate aminotransferase (AST) =< 2.5 x ULN
  -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  -  Discontinuation of anti-coagulants and anti-platelet drugs at least 7 days prior to start of study drug; aspirin 81 mg is permitted as long as platelet count is > 50 and there is no evidence of active bleeding or coagulopathy (INR > 1.5, fibrinogen > 150)
  -  No uncontrolled infections as determined by the investigator
  -  No uncontrolled thyroid disease (e.g. hyperthyroid/hypothyroidism)
  -  No active graft versus host disease (GVHD): patients with a history of stem cell transplant are eligible but cannot have evidence of active GVHD as determined by the investigator
  -  Must be able to take oral medication
  -  Women of childbearing potential must have a negative serum or urine pregnancy test (sensitivity < 25 IU human chorionic gonadotropin (HCG)/L) within 72 hours prior to the start of study drug
  -  Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 4 weeks after study drug is stopped; women of childbearing potential and men with a sexual partner of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy
  -  Ability to understand and the willingness to sign a written informed consent and Health Insurance Portability and Accountability Act (HIPPA) document
  -  Ponatinib
  -  Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from randomization through 4 months after the end of treatment
  -  Discontinuation of any medications known to contribute significantly to the risk of QT prolongation at least 48 hours prior to start of study drug
  -  Serum lipase =< 1.5 x ULN
  -  Serum amylase =< 1.5 x ULN
  -  Dasatinib
  -  Normal corrected QT (QTc) interval on screening electrocardiogram (ECG) evaluation, defined as < 450 msec
  -  Discontinuation of any medications known to contribute significantly to the risk of QT prolongation at least 48 hours prior to start of study drug
  -  Serum Na, K, Mg, and total serum Ca or ionized Ca levels must be greater than or equal to the institutional lower limit of normal; subjects with low K or Mg levels, total serum Ca and/or ionized Ca must be replete for protocol entry
  -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug
  -  Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 90 days (duration of sperm turnover) for a total of 90 days post-treatment completion
  -  Azoospermic males and WOCBP, who are not heterosexually active, are exempt from contraceptive requirements; however, WOCBP must still under pregnancy testing as described in this section
  -  Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of unexpected pregnancy; investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective contraception; highly effective methods of contraception have a failure rate of <1% when used consistently and correctly
  -  At a minimum, subjects must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective as listed
  -  Nilotinib
  -  Normal QTc interval on screening ECG evaluation, defined as < 450 msec
  -  Discontinuation of any medications known to contribute significantly to the risk of QT prolongation at least 48 hours prior to start of study drug
  -  Sorafenib
  -  Creatinine (Crt) < 1.5 X ULN
  Exclusion Criteria:
  -  Patients may not receive concurrent chemotherapy, radiotherapy or immunotherapy, nor have received any investigational agents within 7 days prior to drug sensitivity screening
  -  Uncontrolled angina, > New York Heart Association (NYHA) class III congestive heart failure or myocardial infarction (MI) within 6 months prior to start of study treatment
  -  Diagnosed congenital long QT syndrome
  -  Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
  -  History of significant bleeding disorder unrelated to cancer
  -  Drugs that affect the cytochrome P450 family 3 subfamily A polypeptide 4 (CYP3A4) system (inducers/inhibitors/substrates) are allowed but should be used with caution depending on specific kinase inhibitor used; dietary supplements will be discouraged; however, their use may be allowed on a case by case basis per the discretion of the investigator after consultation with an oncology pharmacist
  -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  -  Pregnant or lactating women are excluded from this study
  -  Known human immunodeficiency virus (HIV)-positive patients are excluded from the study because of possible risk of lethal infection hen treated with marrow suppressive therapy
  -  Ponatinib
  -  History of acute pancreatitis within 1 year of study or history of chronic pancreatitis
  -  History of alcohol abuse
  -  Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)
  -  Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
  -  Any history of myocardial infarction, stroke, or revascularization
  -  Unstable angina or transient ischemic attack within 6 months prior to start of study treatment
  -  Congestive heart failure within 6 months prior to enrollment, or left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards within 6 months prior to enrollment
  -  History of clinically significant (as determined by the treating physician) atrial arrhythmia
  -  Any history of ventricular arrhythmia
  -  Any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism
  -  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; taking medications that are known to be associated with torsades de pointes
  -  Taking any medications or herbal supplements that are known to be strong inhibitors of CYP3A4 within at least 14 days before the first dose of ponatinib
  -  Ocular toxicity present as measured during a comprehensive eye exam
  -  Dasatinib
  -  Known pulmonary arterial hypertension
  -  Patients may not have pleural or pericardial effusion of any grade
  -  Patients may not have clinically significant pleural or pericardial effusion per provider discretion
  -  Uncontrolled hypertension: inability to maintain blood pressure below the limit of 140/90 mgHg
  -  Any history of second or third degree heart block (may be eligible of the subject currently has a pacemaker)
  -  Sorafenib
  -  Major surgery, open biopsy, or significant traumatic injury within 30 days
  -  Non-healing wound, ulcer, or bone fracture
  -  Thrombotic or embolic venous or arterial events, such as cerebrovascular
  -  Accident, including transient ischemic attacks, arterial thrombosis, deep vein
  -  Thrombosis and pulmonary embolism within the past 6 months
  -  Uncontrolled hypertension
  -  Active bleeding during screening
  -  Hypersensitivity to sorafenib

Relevance to patient case: not relevant