Ponatinib in Participants With Resistant Chronic Phase Chronic Myeloid Leukemia (CP-CML) to Characterize the Efficacy and Safety of a Range of Doses
Condition: Myeloid Leukemia, Chronic, Chronic Phase
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase
Intervention: Ponatinib
Intervention description: Tablet, taken orally once daily.
Intervention MeSH terms: Ponatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 283.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Chronic Phase Chronic Myeloid Leukemia; Molecular Response; CML; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; CP-CML

Summary:

      The purpose of this study is to characterize the efficacy of ponatinib administered in 3
      starting doses (45 mg, 30 mg, and 15 mg daily) in participants with CP-CML who are resistant
      to prior tyrosine-kinase inhibitor (TKI) therapy or have T315I mutation, as measured by <=1 %
      Breakpoint Cluster Region-Abelson Transcript Level using International Scale (BCR-ABL1IS) at
      12 months.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Have chronic phase-chronic myelogenous leukemia/chronic myeloid leukemia (CP-CML) and
             have received at least two prior tyrosine kinase inhibitor (TKI) therapies and have
             demonstrated resistance to treatment OR have documented history of presence of T315I
             mutation after receiving any number of prior TKI.

             o] The diagnosis of chronic myeloid leukemia (CML) will be made using standard
             hematopathologic and cytogenetic criteria; CP-CML will be defined by all of the
             following: i <15% blasts in bone marrow ii <30% blasts plus promyelocytes in bone
             marrow iii <20% basophils in peripheral blood. iv >= 100*10^9/liter (L) platelets
             (>=100,000/mm^3). v No evidence of extramedullary disease except hepatosplenomegaly vi
             No prior diagnosis of AP-CML, and BP-CML o] Cytogenetic assessment at screening must
             demonstrate the BCR-ABL1 fusion by presence of the t(9;22) Philadelphia chromosome.

             i Variant translocations are only allowed provided they meet inclusion criterion 1d.

             o] Resistance to prior TKI therapy is defined as follows (participants must meet at
             least 1 criterion): i Three months after the initiation of prior TKI therapy: No
             cytogenetic response (>95% Ph+) or failure to achieve CHR or new mutation ii Six
             months after the initiation of prior TKI therapy: BCR-ABL1IS >10% and/or Ph+ >65% or
             new mutation iii Twelve months after the initiation of prior TKI therapy: BCR ABL1IS
             >10% and/or Ph+ >35% or new mutation iv At any time after the initiation of prior TKI
             therapy, the development of a new BCR-ABL1 kinase domain mutation(s) v At any time
             after the initiation of prior TKI therapy, the development of new clonal evolution vi
             At any time after the initiation of prior TKI therapy, the loss of CHR, or CCyR, or
             the confirmed loss of MMR in 2 consecutive tests, one of which has a BCR-ABL1IS
             transcript level of >=1% or new mutation o] >1% of BCR-ABL1IS as shown by real-time
             polymerase chain reaction

          2. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

          3. Have adequate renal function as defined by the following criterion:

             o] Serum creatinine <=1.5*ULN for institution o] Estimated creatinine clearance >=30
             milliliter per minute (mL/min) (Cockcroft-Gault formula)

          4. Have adequate hepatic function as defined by the following criteria:

             o] Total serum bilirubin <=1.5*ULN, unless due to Gilbert's syndrome o] Alanine
             transaminase (ALT) <=2.5*ULN, or <=5*ULN if leukemic infiltration of the liver is
             present o] Aspartate transaminase (AST) <=2.5*ULN, or <=5*ULN if leukemic infiltration
             of the liver is present

          5. Have normal pancreatic status as defined by the following criterion:

             o] Serum lipase and amylase <=1.5*ULN

          6. Have normal QT interval corrected (Frederica) (QTcF) interval on screening
             electrocardiogram (ECG) evaluation, defined as QTcF of <=450 milliseconds (ms) in
             males or <=470 ms in females.

          7. Have a negative pregnancy test documented prior to enrollment (for females of
             childbearing potential).

          8. Agree to use a highly effective form of contraception with sexual partners from
             randomization through at least 4 months after the end of treatment (for female and
             male participants who are fertile).

          9. Provide written informed consent.

         10. Be willing and able to comply with scheduled visits and study procedures.

         11. Have recovered from toxicities related to prior anticancer therapy to National Cancer
             Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 grade
             <=1.

        Exclusion Criteria:

          1. Have used any approved TKIs or investigational agents within 2 weeks or 6 half-lives
             of the agent, whichever is longer, prior to receiving study drug.

          2. Received interferon, cytarabine, or immunotherapy within 14 days, or any other
             cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior
             to receiving the first dose of ponatinib, or have not recovered (>grade 1 by NCI
             CTCAE, version 4.0) from AEs (except alopecia), due to agents previously administered.

          3. Have undergone autologous or allogeneic stem cell transplant <60 days prior to
             receiving the first dose of ponatinib; have any evidence of ongoing graft-versus-host
             disease (GVHD) or GVHD requiring immunosuppressive therapy.

          4. Are being considered for hematopoietic stem cell transplant (HSCT) within 6-12 months
             of enrollment (note: ponatinib is not to be used as a bridge to HSCT in this trial).

          5. Are taking medications with a known risk of Torsades de Pointes.

          6. Have previously been treated with ponatinib.

          7. Have active CNS disease as evidenced by cytology or pathology; in the absence of
             clinical CNS disease, lumbar puncture is not required. History itself of CNS
             involvement is not exclusionary if CNS has been cleared with a documented negative
             lumbar puncture.

          8. Have clinically significant, uncontrolled, or active cardiovascular disease,
             specifically including, but not restricted to:

             o] Any history of myocardial infarction (MI), unstable angina, cerebrovascular
             accident, or Transient Ischemic Attack (TIA) o] Any history of peripheral vascular
             infarction, including visceral infarction o] Any revascularization procedure,
             including the placement of a stent o] Congestive heart failure (CHF) (New York Heart
             Association [NYHA] class III or IV) 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 o] History of clinically
             significant (as determined by the treating physician) atrial arrhythmia or any history
             of ventricular arrhythmia o] Venous thromboembolism, including deep venous thrombosis
             or pulmonary embolism, within 6 months prior to enrollment

          9. Have uncontrolled hypertension (that is, >150 and >90 for systolic blood pressure
             (SBP) and diastolic blood pressure (DBP) respectively). Participants with hypertension
             should be under treatment at study entry to ensure blood pressure control. Those
             requiring 3 or more antihypertensive medications should be discussed with the medical
             monitor.

         10. Have poorly controlled diabetes defined as HbA1c values of >7.5%. Participants with
             preexisting, well-controlled diabetes are not excluded.

         11. Have a significant bleeding disorder unrelated to CML.

         12. Have a history of alcohol abuse.

         13. Have a history of either acute pancreatitis within 1 year of study enrollment or of
             chronic pancreatitis.

         14. Have malabsorption syndrome or other gastrointestinal illness that could affect oral
             absorption of study drug.

         15. Have a history of another malignancy, other than cervical cancer in situ or basal cell
             or squamous cell carcinoma of the skin; the exception is if participants have been
             disease-free for at least 5 years, and are deemed by the investigator to be at low
             risk for recurrence of that malignancy.

         16. Are pregnant or lactating.

         17. Have undergone major surgery (with the exception of minor surgical procedures, such as
             catheter placement or BM biopsy) within 14 days prior to first dose of ponatinib.

         18. Have an active infection which requires intravenous antibiotics.

         19. Have a known history of human immunodeficiency virus infection; testing is not
             required in the absence of prior documentation or known history.

         20. Have any condition or illness that, in the opinion of the investigator, would
             compromise participant safety or interfere with the evaluation of the drug.

         21. Have hypersensitivity to the ponatinib active substance or to any of its inactive
             ingredients.