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

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ClinicalTrials.gov Identifier: NCT04475731
Recruitment Status : Not yet recruiting
First Posted : July 17, 2020
Last Update Posted : January 5, 2021
Sponsor:
Information provided by (Responsible Party):
Gruppo Italiano Malattie EMatologiche dell'Adulto

Tracking Information
First Submitted Date  ICMJE June 25, 2020
First Posted Date  ICMJE July 17, 2020
Last Update Posted Date January 5, 2021
Estimated Study Start Date  ICMJE February 2021
Estimated Primary Completion Date November 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 14, 2020)
MRD negativity/reduction rate [ Time Frame: After 3 months of treatment ]
Rate of patients who achieve a MRD negativity/MRD reduction following treatment with either Ponatinib alone or in combination with systemic chemotherapy
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 14, 2020)
  • Duration of CMR [ Time Frame: at 24 months ]
    Duration of the CMR status after 3 months of ponatinib treatment
  • Hematologic remission rate [ Time Frame: at 24 months ]
    The achievement of an hematologic remission in patients treated for an hematologic and extra-hematoloigc relapse and for a refractory disease.
  • Best molecular response [ Time Frame: at 24 months ]
    Best molecular response achieved during the follow-up
  • Rate of AE/SAEs [ Time Frame: at 24 months ]
    Safety profile in terms of incidence of grade >3 CTC-NCI side effects and toxicities (AE/SAEs).
  • Mutational analysis [ Time Frame: at 24 months ]
    Mutational analysis in terms of occurrence, type and number of BCR-ABL1 kinase domain mutations.
  • Correlation between biological and MRD parameters [ Time Frame: at 24 months ]
    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.
  • Disease free survival [ Time Frame: 24 months ]
    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.
  • Overall survival [ Time Frame: 24 months ]
    Time interval between treatment start and death for any cause.
  • Cumulative incidence of relapse [ Time Frame: 24 months ]
    Time interval between achievement of CHR after three months of ponatinib until the date of first hematologic relapse of the disease.
  • Role of hematological profile on survival outcome [ Time Frame: at 24 months ]
    Identification of hematological profile on survival outcome
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ponatinib in Adult Ph+ ALL Patients With MRD Positivity or Hematological Relapse
Official Title  ICMJE Ponatinib for the Management of Minimal Residual Disease (MRD) and Hematologic Relapse in Adult Ph+ Acute Lymphoblastic Leukemia (Ph+ ALL) Patients
Brief Summary 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

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Philadelphia-Positive ALL
  • Acute Lymphoblastic Leukemia, in Relapse
Intervention  ICMJE Drug: Ponatinib

Ponatinib 45 mg/day x 4 weeks x 3 courses.

+/- chemotherapy:

  • vincristine or
  • L-VAMP (leucovorin, vincristine, aracytin, methotrexate, prednisone)
Study Arms  ICMJE Experimental: Experimental arm

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.

Intervention: Drug: Ponatinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 14, 2020)
67
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2024
Estimated Primary Completion Date November 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. 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.
  2. Age ≥18 years old with no upper age limit.
  3. 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.
  4. Adequate pancreatic function as defined by the following criterion:

    - serum lipase and amylase ≤1.5 × ULN.

  5. For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment.
  6. 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.
  7. Signed written informed consent according to ICH/EU/GCP and national local laws.

Exclusion Criteria:

  1. WHO performance status ≤ 50% (Karnofsky) or ≥ 3 (ECOG).
  2. Uncontrolled active HBV or HCV hepatitis, or AST/ALT ≥ 2.5 x ULN and bilirubine ≥ 1.5 x ULN not due to the disease.
  3. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis.
  4. History of alcohol abuse.
  5. Ongoing or active uncontrolled infections.
  6. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
  7. 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.
  8. Taking medications that are known to be associated with Torsades de Pointes.
  9. 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.
  10. Creatinine level >2.5mg/dl or glomerular filtration rate (GFR) <20 ml/min or proteinuria >3.5 g/day.
  11. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Paola Fazi 0670390528 p.fazi@gimema.it
Contact: Enrico Crea 0670390514 e.crea@gimema.it
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04475731
Other Study ID Numbers  ICMJE ALL2620
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Gruppo Italiano Malattie EMatologiche dell'Adulto
Study Sponsor  ICMJE Gruppo Italiano Malattie EMatologiche dell'Adulto
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Gruppo Italiano Malattie EMatologiche dell'Adulto
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP