Ponatinib in Adult Ph+ ALL Patients With MRD Positivity or Hematological Relapse

Study Overview
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Brief Summary
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This is a phase II interventional trial to evaluate if the use of ponatinib, with or without chemotherapy, can induce a molecular remission in MRD-positive patients, in patients in hematologic and extra-hematologic relapse and in the few patients who never achieved an hematologic remission after whatever prior treatment.

Detailed Description
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This is a phase II interventional multicenter study for adult patients with Ph+ALL who: Are MRD+ (i.e. BCR-ABL1/ABL1 >0.01) (or loose their molecular response) after whichever kind of previous treatment. MRD positivity is indeed regarded as a relapse/resistance, since it represents the early recognition of cases who will eventually experience an hematologic recurrence of disease. Are in hematologic relapse after whichever kind of previous treatment. Have never achieved an hematologic remission at least after one month of treatment. Patients will be treated with Ponatinib at a dose of 45 mg/die per os for 28 days for 3 cycles and - if in hematologic and extra-hematologic relapse/refractoriness, clinically fit and according to medical decision - with concurrent systemic chemotherapy. In case of CMR achievement, dosing will be reduced to 30 mg. In case of toxicity, Ponatinib will be reduced to 30 (or 15) mg daily.

Official Title
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Ponatinib for the Management of Minimal Residual Disease (MRD) and Hematologic Relapse in Adult Ph+ Acute Lymphoblastic Leukemia (Ph+ ALL) Patients

Conditions
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Philadelphia-Positive ALL, Acute Lymphoblastic Leukemia, in Relapse

Intervention / Treatment
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* Drug: Ponatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ph+ ALL patients with evidence of MRD disease or in hematologic and extra-hematologic relapse/refractoriness after any previous treatment, will be considered eligible to enter the study. Age ≥18 years old with no upper age limit. Adequate hepatic function as defined by the following criteria: total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome alanine aminotransferase (ALT) ≤2.5 × ULN aspartate aminotransferase (AST) ≤2.5 × ULN. Adequate pancreatic function as defined by the following criterion: - serum lipase and amylase ≤1.5 × ULN. For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment. Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from enrollment through 4 months after the end of treatment. Signed written informed consent according to ICH/EU/GCP and national local laws. Exclusion Criteria: WHO performance status ≤ 50% (Karnofsky) or ≥ 3 (ECOG). Uncontrolled active HBV or HCV hepatitis, or AST/ALT ≥ 2.5 x ULN and bilirubine ≥ 1.5 x ULN not due to the disease. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis. History of alcohol abuse. Ongoing or active uncontrolled infections. 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 enrollment 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. Creatinine level >2.5mg/dl or glomerular filtration rate (GFR) <20 ml/min or proteinuria >3.5 g/day. Patients who are currently receiving treatment with any of the medications listed in Appendix E if the medications cannot be either discontinued or switched to a different medication prior to starting study drug. The medications listed in Appendix E have the potential to prolong QT.

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: Experimental arm<br>MRD+ Ph+ ALL adult patients will receive Ponatinib x 4 weeks x 3 courses; +/-Concomitant chemotherapy (according to hematologic status). Patients will receive the study drug until disease relapse or progression. | Drug: Ponatinib<br>* Ponatinib 45 mg/day x 4 weeks x 3 courses. +/- chemotherapy: vincristine or L-VAMP (leucovorin, vincristine, aracytin, methotrexate, prednisone)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRD negativity/reduction rate | Rate of patients who achieve a MRD negativity/MRD reduction following treatment with either Ponatinib alone or in combination with systemic chemotherapy | After 3 months of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of CMR | Duration of the CMR status after 3 months of ponatinib treatment | at 24 months | 
| Hematologic remission rate | The achievement of an hematologic remission in patients treated for an hematologic and extra-hematoloigc relapse and for a refractory disease. | at 24 months | 
| Best molecular response | Best molecular response achieved during the follow-up | at 24 months | 
| Rate of AE/SAEs | Safety profile in terms of incidence of grade >3 CTC-NCI side effects and toxicities (AE/SAEs). | at 24 months | 
| Mutational analysis | Mutational analysis in terms of occurrence, type and number of BCR-ABL1 kinase domain mutations. | at 24 months | 
| Correlation between biological and MRD parameters | Correlation between the achievement and duration of CMR (or MRD reduction) with the type of fusion protein (e.g. p190 or p210) and the potential occurrence of mutations, as well as with additional genomic lesions. | at 24 months | 
| Disease free survival | Time interval between the achievement of CHR after three months of ponatinib and hematologic relapse of the disease or death in CHR; patients still alive, in CHR. | 24 months | 
| Overall survival | Time interval between treatment start and death for any cause. | 24 months | 
| Cumulative incidence of relapse | Time interval between achievement of CHR after three months of ponatinib until the date of first hematologic relapse of the disease. | 24 months | 
| Role of hematological profile on survival outcome | Identification of hematological profile on survival outcome | at 24 months |