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

NCT ID: NCT04722848

Last Updated: 2025-01-23

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 236 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-09-08
• Study Completion Date: 2027-09-30

Brief 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.

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.

Conditions

Acute Lymphoblastic Leukemia (Philadelphia Chromosome Positive); ALL, Adult; Philadelphia-Positive ALL

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Ponatinib+Blinatumomab

patients will receive induction with ponatinib followed by at least 2 cycles of blinatumomab

Group Type: EXPERIMENTAL

Ponatinib + Blinatumomab

Intervention Type: DRUG

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

Chemotherapy+Imatinib

patients will receive a combination of imatinib and chemotherapy.

Group Type: ACTIVE_COMPARATOR

Chemotherapy + Imatinib

Intervention Type: DRUG

patients aged 18-65 will receive chemotherapeutic scheme combined with Imatinib. Elderly patients will receive Imatinib plus mild chemotherapy.

Interventions

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

Intervention Type: DRUG

Chemotherapy + Imatinib

patients aged 18-65 will receive chemotherapeutic scheme combined with Imatinib. Elderly patients will receive Imatinib plus mild chemotherapy.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gruppo Italiano Malattie EMatologiche dell'Adulto

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Area Vasta N. 5 Ascoli Piceno - S. Benedetto Del Tronto, Presidio Ospedaliero Av5 Osp. Gen. Prov.Le "C.G.Mazzoni" - Uoc Ematologia

Ascoli Piceno, , Italy

Irccs Oncologico Istituto Tumori Giovanni Paolo Ii - Bari - Uo Ematologia

Bari, , Italy

Asst Papa Giovanni Xxiii - Ospedale Di Bergamo - Sc Ematologia

Bergamo, , Italy

As Dell'Alto Adige, Ospedale Centrale Di Bolzano - Ematologia E Centro Trapianto Midollo Osseo

Bolzano, , Italy

Asst Degli Spedali Civili Di Brescia - Uo Ematologia

Brescia, , Italy

Aulss 3 Serenissima, Ospedale Dell'Angelo - Mestre - Uo Ematologia

Mestre, , Italy

Aou Di Modena - Sc Ematologia

Modena, , Italy

Asl Salerno, Presidio Ospedaliero Tortora Pagani - Ematologia

Pagani, , Italy

Ao Di Perugia, Ospedale S. Maria Della Misericordia - Ematologia E Trapianto Midollo Osseo

Perugia, , Italy

Ao Ospedali Riuniti Marche Nord - Ospedale San Salvatore - Pesaro - Uoc Ematologia E Centro Trapianti

Pesaro, , Italy

Asl Di Piacenza, Ospedale "Guglielmo Da Saliceto" - Ematologia E Centro Trapianti

Piacenza, , Italy

Università Degli Studi Di Roma "Sapienza" - Dipartimento Di Medicina Traslazionale E Di Precisione - U.O.C. Ematologia

Roma, , Italy

Ente Ecclesiastico Casa Sollievo Della Sofferenza - San Giovanni Rotondo - Ematologia

San Giovanni Rotondo, , Italy

Aou Senese - Uoc Ematologia E Trapianti

Siena, , Italy

Asui Di Udine - Presidio Ospedaliero "Santa Maria Della Misericordia" - Clinica Ematologica

Udine, , Italy

Countries

Italy

Other Identifiers

ALL2820

Identifier Type: -

Identifier Source: org_study_id