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, sunitinib malate, sorafenib tosylate, ponatinib hydrochloride, pacritinib, ruxolitinib, and idelalisib 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:

Terminated

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: R21CA159265
  • NCT ID: NCT01620216

Conditions

  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Chronic Myelomonocytic Leukemia
  • Recurrent Acute Lymphoblastic Leukemia
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Lymphoblastic Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
DasatinibBMS-354825, Dasatinib Hydrate, Dasatinib Monohydrate, SprycelGroup I (dasatinib)
IdelalisibCAL-101, GS 1101, GS-1101, Phosphoinositide-3 Kinase Delta Inhibitor CAL-101, ZydeligGroup VII (idelalisib)
PacritinibOral JAK2 Inhibitor SB1518, SB 1518, SB-1518, SB1518Group V (pacritinib)
PonatinibAP-24534, AP24534Group IV (ponatinib hydrochloride)
Ponatinib HydrochlorideAP24534 HCl, IclusigGroup IV (ponatinib hydrochloride)
RuxolitinibINCB-18424, INCB18424, Jakafi, Oral JAK Inhibitor INCB18424Group VI (ruxolitinib)
SorafenibBA4 43 9006, BAY 43-9006, Bay-439006Group III (sorafenib tosylate)
Sorafenib TosylateBAY 43-9006 Tosylate, BAY 54-9085, Nexavar, sorafenibGroup III (sorafenib tosylate)
SunitinibGroup II (sutinib malate)
Sunitinib MalateSU011248, SU11248, sunitinib, SutentGroup II (sutinib 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, sunitinib malate, sorafenib tosylate, ponatinib hydrochloride, pacritinib, ruxolitinib, and idelalisib 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 OBJECTIVE:

      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).

      EXPLORATORY/CORRELATIVE 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 7 treatment groups based on pre-clinical kinase
      inhibitor activity.

      GROUP I: Patients receive dasatinib orally (PO) once daily (QD) on days 1-28. Cycles repeat
      every 28 days in the absence of disease progression or unacceptable toxicity.

      GROUP II: Patients receive sutinib malate PO QD on days 1-28. Cycles repeat every 28 days in
      the absence of disease progression or unacceptable toxicity.

      GROUP III: Patients receive sorafenib tosylate PO twice daily (BID) on days 1-28. Cycles
      repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      GROUP IV: Patients receive ponatinib hydrochloride PO QD on days 1-28. Cycles repeat every 28
      days in the absence of disease progression or unacceptable toxicity.

      GROUP V: Patients receive pacritinib PO BID on days 1-28. Cycles repeat every 28 days in the
      absence of disease progression or unacceptable toxicity.

      GROUP VI: Patients receive ruxolitinib PO BID on days 1-28. Cycles repeat every 28 days in
      the absence of disease progression or unacceptable toxicity.

      GROUP VII: Patients receive idelalisib PO BID on days 1-28. Cycles 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. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Dasatinib
Group II (sutinib malate)ExperimentalPatients receive sutinib malate PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Sunitinib
  • Sunitinib Malate
Group III (sorafenib tosylate)ExperimentalPatients receive sorafenib tosylate PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Sorafenib
  • Sorafenib Tosylate
Group IV (ponatinib hydrochloride)ExperimentalPatients receive ponatinib hydrochloride PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity
  • Ponatinib
  • Ponatinib Hydrochloride
Group V (pacritinib)ExperimentalPatients receive pacritinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Pacritinib
Group VI (ruxolitinib)ExperimentalPatients receive ruxolitinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Ruxolitinib
Group VII (idelalisib)ExperimentalPatients receive idelalisib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Idelalisib

Eligibility Criteria

        Inclusion Criteria:

          -  Participants >= 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:

               -  Individuals aged 18-64 years with salvage treatment failures only - defined as
                  relapsed or refractory to after least 1 cycle of salvage therapy

                    -  Given the clinical activity and use of hypomethylating agents in AML
                       patients, initial and salvage therapy may include hypomethylating agents

               -  Age >= 65 years: Refractory to induction chemotherapy - defined as no response to
                  initial therapy or have relapsed after initial therapy

                    -  Individuals aged >= 65 years, with chronic myelomonocytic leukemia (CMML) or
                       myelodysplasia (MDS) that transform to acute leukemia while actively
                       receiving hypomethylating agents (i.e., decitabine or azacytidine) will be
                       considered induction failures and are thus eligible for this trial; for
                       Philadelphia positive (Ph+) ALL, initial therapy and salvage therapy may
                       include steroids and imatinib or dasatinib

          -  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 on study drug treatment

          -  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 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 clinically significant 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

          -  Serum sodium (Na), potassium (K), magnesium (Mg), and total serum calcium (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 corrected serum Ca and/or ionized Ca
             must be replete for protocol entry

          -  Dasatinib

               -  Discontinuation of any medications known to contribute significantly to the risk
                  of QT prolongation at least 48 hours prior to start of study drug; Levaquin and
                  Zofran are an exception; of note, certain agents that prolong the corrected QT
                  (QTc) may be allowed but only after discussion with the chemotherapy pharmacist;
                  should the investigator believe that therapy with a potentially QT prolonging
                  medication is vital to an individual subject's care, then additional
                  electrocardiogram (ECG)s should be done at the investigator's discretion to
                  ensure the subject's safety

               -  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

          -  Sorafenib

               -  Creatinine < 1.5 X ULN

          -  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; Levaquin and
                  Zofran are an exception; of note, certain agents that prolong the QTc may be
                  allowed but only after discussion with the chemotherapy pharmacist; should the
                  investigator believe that therapy with a potentially QT prolonging medication is
                  vital to an individual subject's care, then additional ECGs should be done at the
                  investigator's discretion to ensure the subject's safety

               -  Serum lipase =< 1.5 x ULN

               -  Serum amylase =< 1.5 x ULN

          -  Pacritinib

               -  Discontinuation of any medications known to contribute significantly to the risk
                  of QT prolongation at least 48 hours prior to start of study drug; Levaquin and
                  Zofran are an exception; of note, certain agents that prolong the QTc may be
                  allowed but only after discussion with the chemotherapy pharmacist; should the
                  investigator believe that therapy with a potentially QT prolonging medication is
                  vital to an individual subject's care, then additional ECGs should be done at the
                  investigator's discretion to ensure the subject's safety

        Exclusion Criteria:

          -  Any leukemia treatment within 1 week (for cytotoxic therapy) and/or 5 half lives (for
             targeted agents) prior to starting study drug; corticosteroids are allowable
             throughout the study to treat concomitant medical disorders per provider discretion;
             hydroxyurea is allowed prior to enrollment and after the start of the study drug for
             the control of peripheral leukemic blasts in subjects with leukocytosis per physician
             discretion

          -  Recent uncontrolled angina, recent > New York Heart Association (NYHA) class II
             congestive heart failure, or recent myocardial infarction (MI) within 6 months prior
             to start of study treatment

          -  Diagnosed congenital long QT syndrome

          -  Any recent history of clinically significant ventricular arrhythmias (such as
             ventricular tachycardia, ventricular fibrillation, or torsades de pointes)

          -  History of clinically 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 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

          -  History of hypersensitivity to any of the kinase inhibitors included in this study

          -  Dasatinib

               -  Known pulmonary arterial hypertension

               -  Patients may not have a clinically significant pleural or pericardial effusion

               -  Uncontrolled hypertension: inability to maintain blood pressure below the limit
                  of 140/90 mmHg

               -  Any history of second or third degree heart block (may be eligible if the subject
                  currently has a pacemaker)

               -  Prolonged QTc interval (> 450 msec for men and > 470 msec for women) on pre-entry
                  electrocardiogram

          -  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

                    -  Line associated deep vein thrombosis (DVTs) which are adequately treated
                       (line removed and/or patient anticoagulated) are permitted

               -  Uncontrolled hypertension

               -  Active bleeding during screening

          -  Ponatinib

               -  History of acute pancreatitis within 1 year of study or history of chronic
                  pancreatitis

               -  QTC > 450 msec for men and > 470 msec for women

               -  Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)

               -  Any history of myocardial infarction, stroke, or revascularization

               -  Any history of venous thromboembolism including deep venous thrombosis or
                  pulmonary embolism

               -  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

               -  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

               -  History of ongoing alcohol abuse

               -  Ocular toxicity present as measure during a comprehensive eye exam

          -  Pacritinib

               -  Major surgery, open biopsy, or significant traumatic injury within 30 days

               -  Active bleeding during screening

               -  QTC > 450 mSec for men and > 470 msec for women

               -  NYHA class II congestive heart failure (a history of CHF is allowed as long as
                  this has resolved to < NYHA class II within 30 days of initiation of pacritinib

          -  Ruxolitinib

               -  Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or risk
                  of reactivation: HBV deoxyribonucleic acid (DNA) and HCV ribonucleic acid (RNA)
                  must be undetectable; subjects cannot be positive for hepatitis B surface antigen
                  (HBsAg) or anti-hepatitis B core antibody; subjects who have positive
                  anti-hepatitis B surface antibdy (HBs) as the only evidence of prior exposure may
                  participate in the study provided that there is both 1) no known history of HBV
                  infection, and 2) verified receipt of hepatitis B vaccine

          -  Idelalisib

               -  Ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic
                  active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis,
                  primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis,
                  cirrhosis of the liver, portal hypertension, or history of autoimmune hepatitis

               -  Ongoing symptomatic pneumonitis.

               -  Ongoing inflammatory bowel disease or autoimmune colitis.

               -  Ongoing cytomegalovirus (CMV) infection, treatment, or prophylaxis within the
                  past 28 days prior to the screening test for active CMV

               -  History of serious allergic reaction including anaphylaxis and epidermal
                  necrolysis
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:Overall objective response rates (complete and partial)
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:Progression-free survival
Time Frame:From the start of study drug treatment to death, regardless of cause of death, or date of disease progression defined as a >= 50% increase 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 survival
Time Frame:From the date of subject registration to death, regardless of causes of death, assessed up to 3 years
Safety Issue:
Description:Kaplan-Meier method will be used to estimate the survival curve.
Measure:Clinical activity
Time Frame:Up to 28 days
Safety Issue:
Description:Will be defined as a decrease of at least 25% in bone marrow blast counts or in peripheral blood blasts in subjects who have failed the initial inhibitor but are then treated with another inhibitor identified on repeat pre-clinical activity testing. The proportion of patients achieving the endpoint along with its 95% exact binomial confidence interval will be presented.

Details

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

Last Updated

December 3, 2020