Clinical Trials /

Blinatumomab, Methotrexate, Cytarabine, and Ponatinib in Treating Patients With Philadelphia Chromosome-Positive, or BCR-ABL Positive, or Relapsed/Refractory, Acute Lymphoblastic Leukemia

NCT03263572

Description:

This phase II trial studies how well blinatumomab, methotrexate, cytarabine, and ponatinib work in treating patients with Philadelphia chromosome (Ph)-positive, or BCR-ABL positive, or acute lymphoblastic leukemia that has come back or does not respond to treatment. Immunotherapy with monoclonal antibodies, such as blinatumomab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as methotrexate and cytarabine, 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. Ponatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving blinatumomab, methotrexate, cytarabine, and ponatinib may work better in treating patients with acute lymphoblastic leukemia.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Blinatumomab and Ponatinib in Patients With Philadelphia Chromosome (Ph)-Positive and/or BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL)
  • Official Title: Phase II Study of the Combination of Blinatumomab and Ponatinib in Patients With Philadelphia Chromosome (Ph)-Positive and/or BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL)

Clinical Trial IDs

  • ORG STUDY ID: 2016-0792
  • SECONDARY ID: NCI-2018-01078
  • NCT ID: NCT03263572

Conditions

  • Malignant Neoplasms Stated as Primary Lymphoid Haematopoietic
  • Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
MethotrexateNewly Diagnosed Ph-Positive and/or BCR-ABL-Positive ALL
CytarabineAra-C, Cytosar, DepoCyt, Cytosine Arabinosine HydrochlorideNewly Diagnosed Ph-Positive and/or BCR-ABL-Positive ALL
BlinatumomabNewly Diagnosed Ph-Positive and/or BCR-ABL-Positive ALL
DexamethasoneDecadronNewly Diagnosed Ph-Positive and/or BCR-ABL-Positive ALL
PonatinibIclusig, AP24534Newly Diagnosed Ph-Positive and/or BCR-ABL-Positive ALL

Purpose

The goal of this clinical research study is to learn if the combination of blinatumomab and ponatinib can help to control Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL); BCR-ABL-positive ALL; or ALL that has come back (relapsed) or has not responded to treatment (refractory). Ph+ and BCR-ABL positive are types of genetic mutations (changes). The safety of this drug combination will also be studied. This is an investigational study. Blinatumomab is FDA approved and commercially available for the treatment of other types of ALL. Ponatinib is FDA approved and commercially available for the treatment of several types of leukemia, including some types of Ph+ ALL. It is investigational to use the study drugs in combination with each other. The study doctor can describe how the study drugs are designed to work. Up to 60 participants will be enrolled in this study. All will take part at MD Anderson.

Trial Arms

NameTypeDescriptionInterventions
Newly Diagnosed Ph-Positive and/or BCR-ABL-Positive ALLExperimentalFirst cycle is Induction Cycle, Cycles 2-5 are Consolidation Cycles, and Cycles 6 and beyond are Maintenance Cycles. Each cycle is 6 weeks. Blinatumomab by vein non-stop on Days 1-28 of Cycles 1-5. Dexamethasone by vein given within 1 hour before the start of each treatment cycle and at the time of any increase in dose to prevent side effects associated with Blinatumomab treatment. If side effects do occur, Dexamethasone given by mouth or orally or by vein for 3 to 7 days. Methotrexate and Cytarabine given intrathecally on Days 1, 15, and 29 of Cycles 1-4. Ponatinib by mouth each day during Weeks 1-4 of Cycle 1, followed by 2 weeks of no Ponatinib. Beginning with Cycle 2, Ponatinib given by mouth every day while on study.
  • Methotrexate
  • Cytarabine
  • Blinatumomab
  • Dexamethasone
  • Ponatinib
Relapsed/Refractory ALL DiseaseExperimentalFirst cycle is Induction Cycle, Cycles 2-5 are Consolidation Cycles, and Cycles 6 and beyond are Maintenance Cycles. Each cycle is 6 weeks. Blinatumomab by vein non-stop on Days 1-28 of Cycles 1-5. Dexamethasone by vein given within 1 hour before the start of each treatment cycle and at the time of any increase in dose to prevent side effects associated with Blinatumomab treatment. If side effects do occur, Dexamethasone given by mouth or orally or by vein for 3 to 7 days. Ponatinib by mouth each day during Weeks 1-4 of Cycle 1, followed by 2 weeks of no Ponatinib. Beginning with Cycle 2, Ponatinib given by mouth every day while on study.
  • Blinatumomab
  • Dexamethasone
  • Ponatinib

Eligibility Criteria

        Inclusion Criteria:

          1. Diagnosis of one of the following: a) Patients >/= 60 years of age with previously
             untreated Ph-positive ALL [either t(9;22) and/or BCR-ABL positive] (includes patients
             initiated on first course of therapy before cytogenetics known) or with lymphoid
             accelerated or blast phase CML. These patients could have received one or two courses
             of chemotherapy with or without other TKIs and still eligible. Patients < 60 years of
             age may be enrolled if they are considered unfit for intensive chemotherapy: i) If
             they achieved CR, they are assessable only for event-free and overall survival; OR ii)
             If they failed to achieve CR, they are assessable for CR, event-free, and overall
             survival;

          2. Continued from #1: Diagnosis of one of the following: b) Patients >/= 18 years of age
             with relapsed / refractory Ph-positive ALL or with previously treated lymphoid
             accelerated or blast phase CML

          3. Performance status </=2 (ECOG Scale)

          4. Adequate liver function as defined by the following criteria: a) Total serum bilirubin
             </= 2 x upper limit of normal (ULN), unless due to Gilbert's syndrome, b) Alanine
             aminotransferase (ALT) </= 3 x ULN, c) Aspartate aminotransferase (AST) </= 3 x ULN

          5. Adequate pancreatic function as defined by the following criteria: a) Serum lipase and
             amylase </= 1.5 x ULN

          6. For females of childbearing potential, a negative urine pregnancy test must be
             documented

          7. Female patients who: Are postmenopausal for at least 1 year before the screening
             visit, OR Are surgically sterile, OR If they are of childbearing potential, agree to
             practice 2 effective methods of contraception, at the same time, from the time of
             signing the informed consent through 4 months after the last dose of study drug, OR
             agree to completely abstain from heterosexual intercourse

          8. Male patients, even if surgically sterilized (i.e., status post-vasectomy), who: Agree
             to practice effective barrier contraception during the entire study treatment period
             and through 4 months after the last dose of study drug, OR Agree to completely abstain
             from heterosexual intercourse

          9. Adequate cardiac function as assessed clinically by history and physical examination

         10. Signed informed consent

        Exclusion Criteria:

          1. Active serious infection not controlled by oral or intravenous antibiotics.

          2. History of acute pancreatitis within 1 year of study or history of chronic
             pancreatitis

          3. History of alcohol abuse

          4. Uncontrolled hypertriglyceridemia (triglycerides > 450mg/dL)

          5. Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or
             squamous cell carcinoma) that in the investigator's opinion will shorten survival to
             less than 1 year.

          6. Active Grade III-V cardiac failure as defined by the New York Heart Association
             Criteria.

          7. Uncontrolled, or active cardiovascular disease, specifically including, but not
             restricted to: Myocardial infarction (MI), stroke, or revascularization within 3
             months; Unstable angina or transient ischemic attack; Congestive heart failure prior
             to enrollment, or left ventricular ejection fraction (LVEF) less than lower limit of
             normal per local institutional standards prior to enrollment; Diagnosed or suspected
             congenital long QT syndrome; Clinically significant atrial or ventricular arrhythmias
             (such as atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or
             Torsades de pointes) as determined by the treating physician; Prolonged QTc interval
             on pre-entry electrocardiogram (> 470 msec) unless corrected after electrolyte
             replacement;

          8. Continued from #7 Uncontrolled, or active cardiovascular disease, specifically
             including, but not restricted to: Significant venous or arterial thromboembolism
             including deep venous thrombosis or pulmonary embolism. Patients with a history of
             treated prior superficial or catheter associated will not be considered as significant
             embolism and after discussion with PI will not be excluded from eligibility;
             Uncontrolled hypertension (diastolic blood pressure >90mmHg; systolic >140mmHg).
             Patients with hypertension should be under treatment on study entry to effect blood
             pressure control

          9. Taking any medications or herbal supplements that are known to be strong inhibitors of
             CYP3A4 within at least 14 days or 5 half-lives before the first dose of ponatinib in
             patients with newly diagnosed only.

         10. History or presence of clinically relevant CNS pathology such as epilepsy, childhood
             or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia,
             Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
             Patients with active CNS leukemia will NOT be excluded

         11. Current autoimmune disease or history of autoimmune disease with potential CNS
             involvement

         12. Treatment with any investigational antileukemic agents or chemotherapy agents in the
             last 7 days before study entry, unless full recovery from side effects has occurred or
             patient has rapidly progressive disease judged to be life-threatening by the
             investigator.

         13. Pregnant and lactating women will not be eligible; women of childbearing potential
             should have a negative pregnancy test prior to entering on the study and be willing to
             practice methods of contraception. Women do not have childbearing potential if they
             have had a hysterectomy or are postmenopausal without menses for 12 months. In
             addition, men enrolled on this study should understand the risks to any sexual partner
             of childbearing potential and should practice an effective method of birth control.

         14. History of significant bleeding disorder unrelated to cancer, including: Diagnosed
             congenital bleeding disorders (e.g., von Willebrand's disease); Diagnosed acquired
             bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)

         15. Patients with documented significant pleural or pericardial effusions unless they are
             thought to be secondary to their leukemia
      
Maximum Eligible Age:N/A
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Molecular Response (CMR) Rate in Newly Diagnosed Ph-Positive and/or BCR-ABL-Positive ALL
Time Frame:18 weeks
Safety Issue:
Description:CMR defined as normalization of the peripheral blood and bone marrow with less than 5% blasts in normocellular or hypercellular marrow with a granulocyte count of 1 x 109/L or above, and platelet count of 100 x 109/L, and CR with RT-PCR negativity for BCR-ABL.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Malignant neoplasms stated as primary lymphoid haematopoietic
  • Acute Lymphoblastic Leukemia
  • ALL
  • Philadelphia chromosome-positive acute lymphoblastic leukemia
  • Ph+ ALL
  • BCR-ABL-positive ALL
  • ALL relapsed or refractory
  • Methotrexate
  • Cytarabine
  • Ara-C
  • Cytosar
  • DepoCyt
  • Cytosine arabinosine hydrochloride
  • Blinatumomab
  • Dexamethasone
  • Decadron
  • Ponatinib
  • Iclusig
  • AP24534

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