Sequential Treatment With Ponatinib and Blinatumomab vs Chemotherapy and Imatinib in Newly Diagnosed Adult Ph+ ALL

February 6, 2024 updated by: Gruppo Italiano Malattie EMatologiche dell'Adulto

Newly Diagnosed Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL). Sequential Treatment With Ponatinib and the Bispecific Monoclonal Antibody Blinatumomab vs Chemotherapy and Imatinib

This is a randomised, open-label, multicenter, phase III study for adult de novo Ph+ ALL patients based on the combination of Ponatinib with Blinatumomab. The control arm will be represented by a chemotherapeutic scheme combined with Imatinib for patients aged 18-65 and by Imatinib plus age-adjusted chemotherapy for elderly patients (>65 years old).

Patients will be randomized 2:1 to receive the experimental or control arm. If patients in the control arm do not achieve a CHR and/or MRD negativity, after the sixth consolidation cycle (week 20), a crossover to receive Blinatumomab is planned. Likewise, if patients in the control arm develop an ABL1 mutation at any time of treatment, they will switch to experimental arm. HLA typing will be performed immediately after diagnosis in both arms for patients aged up to 65 years.

After the 2 cycles of Blinatumomab in the experimental arm and after consolidation in the control arm, patients aged 18-65 will be stratified for transplant allocation.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This is a randomised, open-label, multicenter, phase III study for adult de novo Ph+ ALL patients (≥18 years, no upper age-limit) based on the combination of the pan-TKI Ponatinib, with the bispecific monoclonal antibody Blinatumomab. The control arm will be represented by a chemotherapeutic scheme combined with Imatinib for patients aged 18-65 and by Imatinib plus age-adjusted chemotherapy for elderly patients (>65 years old).

Patients (≥18 years, no upper age limit) will be randomized 2:1 to receive the experimental or control arm. If patients in the control arm do not achieve a CHR and/or MRD negativity, after the sixth consolidation cycle (week 20), a crossover to receive Blinatumomab is planned. Likewise, if patients in the control arm develop an ABL1 mutation at any time of treatment, they will switch to experimental arm. HLA typing will be performed immediately after diagnosis in both arms for patients aged up to 65 years.

After the 2 cycles of Blinatumomab in the experimental arm and after consolidation in the control arm, patients aged 18-65 will be stratified for transplant allocation.

Study Type

Interventional

Enrollment (Estimated)

236

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Ascoli Piceno, Italy
        • Recruiting
        • Area Vasta N. 5 Ascoli Piceno - S. Benedetto Del Tronto, Presidio Ospedaliero Av5 Osp. Gen. Prov.Le "C.G.Mazzoni" - Uoc Ematologia
        • Contact:
      • Bari, Italy
        • Recruiting
        • Irccs Oncologico Istituto Tumori Giovanni Paolo Ii - Bari - Uo Ematologia
        • Contact:
      • Bergamo, Italy
        • Recruiting
        • Asst Papa Giovanni Xxiii - Ospedale Di Bergamo - Sc Ematologia
        • Contact:
      • Bolzano, Italy
        • Recruiting
        • As Dell'Alto Adige, Ospedale Centrale Di Bolzano - Ematologia E Centro Trapianto Midollo Osseo
        • Contact:
      • Brescia, Italy
        • Recruiting
        • Asst Degli Spedali Civili Di Brescia - Uo Ematologia
        • Contact:
      • Mestre, Italy
        • Recruiting
        • Aulss 3 Serenissima, Ospedale Dell'Angelo - Mestre - Uo Ematologia
        • Contact:
      • Modena, Italy
      • Pagani, Italy
        • Recruiting
        • Asl Salerno, Presidio Ospedaliero Tortora Pagani - Ematologia
        • Contact:
      • Perugia, Italy
        • Recruiting
        • Ao Di Perugia, Ospedale S. Maria Della Misericordia - Ematologia E Trapianto Midollo Osseo
        • Contact:
      • Pesaro, Italy
        • Recruiting
        • Ao Ospedali Riuniti Marche Nord - Ospedale San Salvatore - Pesaro - Uoc Ematologia E Centro Trapianti
        • Contact:
      • Piacenza, Italy
        • Recruiting
        • Asl Di Piacenza, Ospedale "Guglielmo Da Saliceto" - Ematologia E Centro Trapianti
        • Contact:
      • Roma, Italy
        • Recruiting
        • Università Degli Studi Di Roma "Sapienza" - Dipartimento Di Medicina Traslazionale E Di Precisione - U.O.C. Ematologia
        • Contact:
      • San Giovanni Rotondo, Italy
        • Recruiting
        • Ente Ecclesiastico Casa Sollievo Della Sofferenza - San Giovanni Rotondo - Ematologia
        • Contact:
      • Siena, Italy
        • Recruiting
        • Aou Senese - Uoc Ematologia E Trapianti
        • Contact:
      • Udine, Italy
        • Recruiting
        • Asui Di Udine - Presidio Ospedaliero "Santa Maria Della Misericordia" - Clinica Ematologica
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Signed written informed consent according to ICH/EU/GCP and national local laws.
  2. Newly diagnosed adult B-precursor Ph+ ALL patients.
  3. WHO performance status less or equal to 2.
  4. Age greater or equal to18 years, with no upper age limit.

  5. Renal and hepatic function as defined below:

    • AST (GOT), ALT (GPT), and AP <2 x upper limit of normal (ULN).
    • Total bilirubin <1.5 x ULN.
    • Creatinine clearance equal or greater than 50 mL/min.

  6. Pancreatic function as defined below:

    • Serum amylase less or equal to 1.5 x ULN and serum lipase less or equal to1.5 x ULN.
  7. Normal cardiac function.
  8. No evidence of CNS leukemia at blinatumomab start.
  9. Negative HIV test, negative hepatitis B (HBsAg) and hepatitis C virus (anti-HCV) test.
  10. Negative pregnancy test in women of childbearing potential.
  11. Bone marrow specimen from primary diagnosis available.

Exclusion Criteria:

  1. History of or current relevant CNS pathology (ongoing grade ≥2 epilepsy, seizure, paresis, aphasia, clinically relevant apoplexia, severe brain injuries, dementia, Parkinson's disease, organic brain syndrome, psychosis).

  2. Impaired cardiac function, including any one of the following:

    • LVEF <45% as determined by MUGA scan or echocardiogram.
    • Complete left bundle branch block.
    • Use of a cardiac pacemaker.
    • ST depression of >1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads.
    • Congenital long QT syndrome.
    • History of or presence of significant ventricular or atrial arrhythmia.
    • Clinically significant resting bradycardia (<50 beats per minute).
    • QTc >450 msec on screening ECG (using the QTcF formula).
    • Right bundle branch block plus left anterior hemiblock, bifascicular block.
    • Myocardial infarction within 3 months prior to starting Ponatinib.
    • Angina pectoris.
  3. Other clinically significant vascular and heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen).
  4. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of Ponatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
  5. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
  6. Taking medications that are known to be associated with Torsades de Pointes and medications or herbal supplements that are known to be strong inhibitors of CYP3A4 within at least 14 days before the first dose of ponatinib.
  7. History of or current autoimmune disease.
  8. Systemic cancer chemotherapy within 2 weeks prior to study.
  9. Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation.
  10. Active malignancy other than ALL with the exception of basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix.
  11. Active infection, any other concurrent disease or medical condition that are deemed to interfere with the conduct of the study as judged by the investigator.
  12. Nursing women or women of childbearing potential not willing to use an effective form of contraception during participation in the study and at least 3 months thereafter or male patients not willing to ensure effective contraception during participation in the study and at least three months thereafter.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ponatinib+Blinatumomab
patients will receive induction with ponatinib followed by at least 2 cycles of blinatumomab
Drug: Ponatinib + Blinatumomab

Patients aged 18-65 will receive Ponatinib at the dose of 45 mg/day for the first 22 days and then will reduce the dose to 30 mg (depending on the morphologic and molecular response), whereas patients older than 65 years will start Ponatinib at 30 mg/day, in order to avoid TAEs. Patients will continue treatment with Ponatinib up to day 70 (10 weeks of treatment), except for disease progression, intolerable toxicity, or withdrawal from study. Thereafter:

  • Patients will receive Blinatumomab (minimum 2 cycles, up to a maximum of 5).
  • Patients not achieving a CHR after 2 cycles of Blinatumomab will go off-study. After the 2 cycles of Blinatumomab patients aged 18-65 will be stratified for transplant allocation
Active Comparator: Chemotherapy+Imatinib
patients will receive a combination of imatinib and chemotherapy.
Drug: Chemotherapy + Imatinib
patients aged 18-65 will receive chemotherapeutic scheme combined with Imatinib. Elderly patients will receive Imatinib plus mild chemotherapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients who are event-free
Time Frame: at 5 months
event-free survival rate
at 5 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Gruppo Italiano Malattie EMatologiche dell'Adulto

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 8, 2021

Primary Completion (Estimated)

September 1, 2027

Study Completion (Estimated)

September 1, 2027

Study Registration Dates

First Submitted

January 20, 2021

First Submitted That Met QC Criteria

January 20, 2021

First Posted (Actual)

January 25, 2021

Study Record Updates

Last Update Posted (Actual)

February 7, 2024

Last Update Submitted That Met QC Criteria

February 6, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ALL2820

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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