Clinical Trials /

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

NCT01620216

Description:

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
Recruiting Status:

Unknown status

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Targeted Therapy in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia or Acute Myelogenous Leukemia
  • 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

Clinical Trial IDs

  • ORG STUDY ID: IRB00007195
  • SECONDARY ID: NCI-2012-01084
  • SECONDARY ID: CA180-392
  • SECONDARY ID: IRB00007195
  • SECONDARY ID: P30CA069533
  • SECONDARY ID: R21CA159265
  • NCT ID: NCT01620216

Conditions

  • 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

Interventions

DrugSynonymsArms
DasatinibBMS-354825, SprycelGroup I (dasatinib)
NilotinibAMN 107, TasignaGroup II (nilotinib)
Ponatinib HydrochlorideAP24534 HCl, IclusigGroup V (ponatinib hydrochloride)
Sorafenib TosylateBAY 43-9006 Tosylate, BAY 54-9085, Nexavar, sorafenibGroup IV (sorafenib tosylate)
Sunitinib MalateSU011248, SU11248, sunitinib, SutentGroup III (sunitinib malate)

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Group I (dasatinib)ExperimentalPatients receive dasatinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Dasatinib
Group II (nilotinib)ExperimentalPatients receive nilotinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Nilotinib
Group III (sunitinib malate)ExperimentalPatients receive sunitinib malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Sunitinib Malate
Group IV (sorafenib tosylate)ExperimentalPatients receive sorafenib tosylate PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Sorafenib Tosylate
Group V (ponatinib hydrochloride)ExperimentalPatients receive ponatinib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Ponatinib Hydrochloride

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Clinical activity, defined as a decrease of at least 25% in bone marrow blast counts
Time Frame:Up to 28 days
Safety Issue:
Description:The proportion of patients achieving the endpoint along with its 95% exact binomial confidence interval will be presented.

Secondary Outcome Measures

Measure:Changes in transfusion requirements
Time Frame:Baseline to 3 years
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:The proportion of patients achieving the endpoint along with its 95% exact binomial confidence interval will be presented.
Measure: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
Safety Issue:
Description:Kaplan-Meier method will be used to estimate the survival curve.
Measure:Overall objective response rates (complete and partial), determined using formal AML and ALL response criteria
Time Frame:Up to 3 years
Safety Issue:
Description:The proportion of patients achieving the endpoint along with its 95% exact binomial confidence interval will be presented.
Measure:Overall survival
Time Frame:From the date of registration to death, assessed up to 3 years
Safety Issue:
Description:Kaplan-Meier method will be used to estimate the survival curve.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:OHSU Knight Cancer Institute

Last Updated

December 1, 2016