Ponatinib Hydrochloride as Second Line Therapy in Treating Patients With Chronic Myeloid Leukemia in Chronic Phase Resistant or Intolerant to Imatinib Mesylate, Dasatinib, or Nilotinib

Study Overview
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Brief Summary
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This phase II trial studies how well ponatinib hydrochloride works as second line therapy in treating patients with chronic myeloid leukemia in chronic phase that has not responded to initial treatment (first line) with imatinib mesylate, dasatinib, or nilotinib or cannot tolerate imatinib mesylate, dasatinib, or nilotinib. Ponatinib hydrochloride may stop or control the growth of cancer cells by blocking a protein needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the proportion of patients with tyrosine kinase inhibitor (TKI)-resistant or intolerant, chronic phase chronic myeloid leukemia (CML) (chronic phase [CP]-CML) attaining major cytogenetic response (MCyR) at 6 months of treatment with second line ponatinib (ponatinib hydrochloride) therapy. II. To estimate the time to toxicity related to ponatinib for patients with TKI-intolerant or TKI-resistant CP-CML. SECONDARY OBJECTIVES: I. To estimate the proportion of patients achieving a MCyR, complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR) at 3, 6, 12, 18 and 24 months of treatment with ponatinib after one TKI failure (by resistance or intolerance). II. To estimate the time to CCyR, MMR, MCyR and CMR for patients treated with ponatinib as second line therapy for CP-CML. III. To evaluate the durations of hematologic, cytogenetic and molecular response to ponatinib after one TKI failure. IV. To define the time to progression and overall survival for patients with CML in chronic phase treated with ponatinib after one TKI failure. V. To evaluate the toxicity profile of ponatinib in patients with CML in chronic phase after one TKI failure. VI. To evaluate the probability of developing v-abl Abelson murine leukemia viral oncogene homolog 1 (ABL) mutations for patients with CML in chronic phase treated with ponatinib after one TKI failure. VII. To analyze differences in response rates and in prognosis according to pre-treatment mutations and patient characteristics. VIII. To investigate mechanisms of resistance in patients who develop resistance to ponatinib used as second line therapy for CP-CML. IX. To evaluate symptom burden in patients with CP-CML receiving ponatinib. TERTIARY OBJECTIVES: I. To investigate the presence of micro-ribonucleic acid (miRNA) that may be predictive of outcome. OUTLINE: Patients receive ponatinib hydrochloride orally (PO) once daily (QD). Treatment continues for up to 5 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up within 30 days.

Official Title
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Ponatinib as Second Line Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase Resistant or Intolerant to Imatinib, Dasatinib or Nilotinib

Conditions
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Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Philadelphia Chromosome Positive, BCR-ABL1 Positive Chronic Myelogenous Leukemia, Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Ponatinib Hydrochloride
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Philadelphia chromosome (Ph)-positive (by cytogenetics or fluorescent in situ hybridization [FISH]) or breakpoint cluster region (BCR)-ABL-positive (by polymerase chain reaction [PCR]) CML in chronic phase Patients should have demonstrated to have failure to therapy to one Food and Drug Administration (FDA)-approved TKI (currently imatinib [imatinib mesylate], dasatinib, and nilotinib are approved as frontline therapy), defined as per European LeukemiaNet (ELN) recommendations: 1) less than complete hematologic response (CHR) at or beyond 3 months; 2) no cytogenetic response at or beyond 6 months; 3) less than PCyR (Ph+ > 35%) at or beyond 12 months; 4) less than CCyR at or beyond 18 months; 5) loss of response or development of mutations or other clonal chromosomal abnormalities at any time during TKI treatment; 6) intolerance to imatinib, dasatinib or nilotinib defined as grade 3 or 4 toxicity, or persistent grade 2 toxicity despite optimal management including dose adjustment, or in a patient where dose reductions are considered to be not in the patients best interest to obtain or maintain an adequate response; intolerant patients should not have achieved or have lost major cytogenetic response at the time of enrollment Eastern Cooperative Oncology Group (ECOG) performance of 0-2 Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless due to Gilbert syndrome, in which case it should be =< 3.0 x ULN) Serum glutamate pyruvate transaminase (SGPT) =< 2.5 x ULN Creatinine =< 1.5 x ULN Patients must sign an informed consent indicating they are aware of the investigational nature of this study, in keeping with the policies of the hospital Reliable telephone access to receive calls from an interactive voice response system (IVR) (only applicable to patients who will participate in optional symptom burden assessment) Women of pregnancy potential must practice an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized: 1) prior to study enrollment, women of childbearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation & the potential risk factors for an unintentional pregnancy; 2) postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential; 3) in addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential & should practice an effective method of birth control; 4) women & men must continue birth control for the duration of the trial & at least 3 months after the last dose of study drug; 5) all WOCBP MUST have a negative pregnancy test prior to first receiving investigational product Patients should have discontinued therapy with imatinib, dasatinib or nilotinib or other anti-leukemia therapy (except hydroxyurea), at least 48 hours prior to start of study therapy and recovered from any toxicity due to these therapies to at least grade 1; the use of hydroxyurea is allowed immediately prior to study entry Exclusion Criteria: Prior therapy with other BCR-ABL-targeted TKIs except imatinib, dasatinib or nilotinib (e.g., bosutinib) New York Heart Association (NYHA) cardiac class 3-4 heart disease Patients meeting the following criteria are not eligible: history of unstable angina, myocardial infarction, transient ischemic attack (TIA), stroke, peripheral arterial occlusive disease, venous thromboembolism or pulmonary embolism; any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes); prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 470 msec) on both the Fridericia and Bazett's correction; congestive heart failure (NYHA class III or IV) within 3 months prior to first dose of ponatinib Patients with active, uncontrolled psychiatric disorders including: psychosis, major depression, and bipolar disorders Patients with uncontrolled hypertension (defined as sustained systolic blood pressure > 160 mmHg or diastolic > 100 mmHg) Pregnant or breast-feeding women are excluded Patients with history of pancreatitis Patients in accelerated or blast phase, or patients who have ever been documented to be in blast phase CML, are excluded; the definitions of excluded CML phases are as follows: Blastic phase: Presence of 30% blasts or more in the peripheral blood or bone marrow Accelerated phase CML: Peripheral or marrow blasts 15% or more Peripheral or marrow basophils 20% or more Thrombocytopenia < 100 x 10(9)/L unrelated to therapy Documented extramedullary blastic disease outside liver or spleen Clonal evolution defined as the presence of additional chromosomal abnormalities other than the Ph chromosome has been historically been included as a criterion for accelerated phase; however, patients with clonal evolution as the only criterion of accelerated phase have a significantly better prognosis; thus, patients with clonal evolution and no other criteria for accelerated phase will be eligible for this study, but analyzed separately Patients who have received more than one FDA-approved TKI for CML, or any investigational, non-FDA approved TKI

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ponatinib hydrochloride<br>Patients receive ponatinib hydrochloride PO QD. Treatment continues for up to 5 years in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Blood draws.<br>Drug: Ponatinib Hydrochloride<br>* Starting dose: 30 mg by mouth once a day.<br>* Other names: Iclusig;Other: Quality-of-Life Assessment<br>* Surveys completed.<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MCyR at 6 months (MCyR6) | The method of Kaplan and Meier will be used to estimate the unadjusted distribution of duration of MCyR. An appropriate time-to-event regression model will be fit to the event time data to assess the effects of patient covariates on the event time variable, with the particular model determined by preliminary goodness-of-fit analyses. The distribution of MCyR6 will be tabulated and effects of baseline patient covariates on this variable will be assessed by logistic regression. | At 6 months | 
| Time-to-toxicity defined as any grade 3 or 4 drug-related adverse event that is not responsive to standard therapeutic management and requires permanent treatment discontinuation | Time-to-toxicity will be monitored using the Bayesian method of Thall, et al. The method of Kaplan and Meier will be used to estimate the unadjusted distribution of time to toxicity. An appropriate time-to-event regression model will be fit to the event time data to assess the effects of patient covariates on the event time variable, with the particular model determined by preliminary goodness-of-fit analyses. | Up to 30 days post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of MCyR | The method of Kaplan and Meier will be used to estimate the unadjusted distribution of the duration of MCyR. An appropriate time-to-event regression model will be fit to the event time data to assess the effects of patient covariates on the event time variable, with the particular model determined by preliminary goodness-of-fit analyses. | Up to 24 months | 
| Time to transformation to accelerated phase CML | The method of Kaplan and Meier will be used to estimate the unadjusted distribution of the time to transformation to accelerated phase CML. An appropriate time-to-event regression model will be fit to the event time data to assess the effects of patient covariates on the event time variable, with the particular model determined by preliminary goodness-of-fit analyses. | Up to 5 years | 
| Time to transformation to blastic phase CML | The method of Kaplan and Meier will be used to estimate the unadjusted distribution of the time to transformation to blastic phase CML. An appropriate time-to-event regression model will be fit to the event time data to assess the effects of patient covariates on the event time variable, with the particular model determined by preliminary goodness-of-fit analyses. | Up to 5 years | 
| MMR | An appropriate time-to-event regression model will be fit to the event time data to assess the effects of patient covariates on the event time variable, with the particular model determined by preliminary goodness-of-fit analyses. The distribution of MMR will be tabulated and effects of baseline patient covariates on this variable will be assessed by logistic regression. | Up to 24 months |