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

  • STATUS
    Recruiting
  • End date
    Sep 24, 2027
  • participants needed
    236
  • sponsor
    Gruppo Italiano Malattie EMatologiche dell'Adulto
Updated on 24 March 2022

Summary

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.

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.

Details
Condition Acute Lymphoblastic Leukemia (Philadelphia Chromosome Positive), ALL, Adult, Philadelphia-Positive ALL
Treatment Ponatinib + Blinatumomab, Chemotherapy + Imatinib
Clinical Study IdentifierNCT04722848
SponsorGruppo Italiano Malattie EMatologiche dell'Adulto
Last Modified on24 March 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Signed written informed consent according to ICH/EU/GCP and national local laws
Newly diagnosed adult B-precursor Ph+ ALL patients
WHO performance status less or equal to 2
Age greater or equal to18 years, with no upper age limit
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
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
Normal cardiac function
No evidence of CNS leukemia at blinatumomab start
Negative HIV test, negative hepatitis B (HBsAg) and hepatitis C virus (anti-HCV) test
Negative pregnancy test in women of childbearing potential
Bone marrow specimen from primary diagnosis available

Exclusion Criteria

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)
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
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)
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)
Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL)
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
History of or current autoimmune disease
Systemic cancer chemotherapy within 2 weeks prior to study
Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation
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
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
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
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