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

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2016 by OHSU Knight Cancer Institute
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier:
NCT01620216
First received: June 13, 2012
Last updated: December 1, 2016
Last verified: December 2016
  Purpose
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.

Condition Intervention Phase
Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Myelodysplastic Syndrome
Recurrent Adult Acute Lymphoblastic Leukemia
Recurrent Adult Acute Myeloid Leukemia
Refractory Adult Acute Lymphoblastic Leukemia
Other: Antitumor Drug Screening Assay
Drug: Dasatinib
Other: Laboratory Biomarker Analysis
Drug: Nilotinib
Other: Pharmacological Study
Drug: Ponatinib Hydrochloride
Drug: Sorafenib Tosylate
Drug: Sunitinib Malate
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Proof-of-Concept Trial to Study Kinase Inhibition in Relapsed/Refractory Acute Leukemias: Using a Comprehensive In Vitro Kinase Inhibitor Panel to Select Individualized, Targeted Therapies

Resource links provided by NLM:


Further study details as provided by OHSU Knight Cancer Institute:

Primary Outcome Measures:
  • Clinical activity, defined as a decrease of at least 25% in bone marrow blast counts [ Time Frame: Up to 28 days ] [ Designated as safety issue: No ]
    The proportion of patients achieving the endpoint along with its 95% exact binomial confidence interval will be presented.


Secondary Outcome Measures:
  • Changes in transfusion requirements [ Time Frame: Baseline to 3 years ] [ Designated as safety issue: No ]
  • Clinical activity (defined as a decrease of at least 25% in bone marrow blast counts) in subjects who have failed the initial inhibitor but are then treated with another inhibitor identified on repeat pre-clinical activity testing [ Time Frame: Up to 28 days ] [ Designated as safety issue: No ]
    The proportion of patients achieving the endpoint along with its 95% exact binomial confidence interval will be presented.

  • Disease-free survival [ Time Frame: From the date of registration to date of death or disease progression defined as a an increase of at least 50% in leukemic bone marrow blasts, whichever occurs first, assessed up to 3 years ] [ Designated as safety issue: No ]
    Kaplan-Meier method will be used to estimate the survival curve.

  • Overall objective response rates (complete and partial), determined using formal AML and ALL response criteria [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    The proportion of patients achieving the endpoint along with its 95% exact binomial confidence interval will be presented.

  • Overall survival [ Time Frame: From the date of registration to death, assessed up to 3 years ] [ Designated as safety issue: No ]
    Kaplan-Meier method will be used to estimate the survival curve.


Other Outcome Measures:
  • Presence of active/aberrant kinase pathways [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Will be correlated with treatment response, mutational analysis using next generation sequencing, and characterization of aberrant gene expression in primary leukemia samples.


Estimated Enrollment: 24
Study Start Date: May 2012
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: March 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group I (dasatinib)
Patients receive dasatinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Antitumor Drug Screening Assay
Undergo pre clinical kinase inhibitor activity screening
Other Name: Drug Screening Assays, Antitumor
Drug: Dasatinib
Given PO
Other Names:
  • BMS-354825
  • Sprycel
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Experimental: Group II (nilotinib)
Patients receive nilotinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Antitumor Drug Screening Assay
Undergo pre clinical kinase inhibitor activity screening
Other Name: Drug Screening Assays, Antitumor
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Nilotinib
Given PO
Other Names:
  • AMN 107
  • Tasigna
Other: Pharmacological Study
Correlative studies
Experimental: Group III (sunitinib malate)
Patients receive sunitinib malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Antitumor Drug Screening Assay
Undergo pre clinical kinase inhibitor activity screening
Other Name: Drug Screening Assays, Antitumor
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Drug: Sunitinib Malate
Given PO
Other Names:
  • SU011248
  • SU11248
  • sunitinib
  • Sutent
Experimental: Group IV (sorafenib tosylate)
Patients receive sorafenib tosylate PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Antitumor Drug Screening Assay
Undergo pre clinical kinase inhibitor activity screening
Other Name: Drug Screening Assays, Antitumor
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Drug: Sorafenib Tosylate
Given PO
Other Names:
  • BAY 43-9006 Tosylate
  • BAY 54-9085
  • Nexavar
  • sorafenib
Experimental: Group V (ponatinib hydrochloride)
Patients receive ponatinib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Antitumor Drug Screening Assay
Undergo pre clinical kinase inhibitor activity screening
Other Name: Drug Screening Assays, Antitumor
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Drug: Ponatinib Hydrochloride
Given PO
Other Names:
  • AP24534 HCl
  • Iclusig

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

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01620216

Locations
United States, Maryland
National Heart Lung and Blood Institute Not yet recruiting
Bethesda, Maryland, United States, 20824
Contact: Christopher S. Hourigan    301-803-8029    hourigan@nih.gov   
Principal Investigator: Christopher S. Hourigan         
United States, Oregon
OHSU Knight Cancer Institute Recruiting
Portland, Oregon, United States, 97239
Contact: Marc Loriaux    503-494-9383    loriauxm@ohsu.edu   
Principal Investigator: Marc Loriaux         
United States, Texas
UT Southwestern/Simmons Cancer Center-Dallas Not yet recruiting
Dallas, Texas, United States, 75390
Contact: Robert H. Collins    214-648-4155    robert.collins@utsouthwestern.edu   
Principal Investigator: Robert H. Collins         
United States, Utah
Huntsman Cancer Institute/University of Utah Not yet recruiting
Salt Lake City, Utah, United States, 84112
Contact: Tibor J. Kovacsovics    801-585-3229    tibor.kovacsovics@hci.utah.edu   
Principal Investigator: Tibor J. Kovacsovics         
Sponsors and Collaborators
OHSU Knight Cancer Institute
National Cancer Institute (NCI)
Investigators
Principal Investigator: Marc Loriaux OHSU Knight Cancer Institute
  More Information

Responsible Party: OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT01620216     History of Changes
Other Study ID Numbers: IRB00007195  NCI-2012-01084  CA180-392  IRB00007195  P30CA069533  R21CA159265 
Study First Received: June 13, 2012
Last Updated: December 1, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia
Syndrome
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia, Myelomonocytic, Chronic
Neoplasms by Histologic Type
Neoplasms
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Myelodysplastic-Myeloproliferative Diseases
Sorafenib
Sunitinib
Ponatinib
Dasatinib
Antineoplastic Agents
Niacinamide
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on December 02, 2016