Efficacy of Ponatinib vs. Imatinib with Low-Intensity Chemotherapy in Adults with De Novo Ph+ Acute Lymphoblastic Leukemia
- Trial ID
- 2024-517966-40-00
- Sponsor
- Goethe University Frankfurt
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this multicentre, randomized trial is to demonstrate the non-inferiority in overall survival of patients with **Philadelphia-Chromosome positive acute lymphoblastic leukemia** (Ph+ ALL) who achieve molecular complete remission (CR) when treated with a regimen of tyrosine kinase inhibitor (TKI), chemotherapy alternating with **blinatumomab** (TKI-Chemo-Blina), compared to the end of therapy with an indication for stem cell transplantation (SCT). This objective is clinically relevant as it seeks to establish an effective treatment protocol that may reduce the need for SCT, which is associated with significant morbidity and mortality.
Secondary objectives include comparing the rate of molecular complete remission after induction and first consolidation with chemotherapy and **ponatinib** versus **imatinib**. This comparison is crucial for determining the most effective TKI in achieving early molecular remission, which is a predictor of long-term outcomes in Ph+ ALL patients.
Participants
The clinical trial involves participants diagnosed with **acute lymphoblastic leukemia (ALL)**, specifically de novo, Ph/BCR::ABL1 positive (Ph+). The study population includes both male and female subjects aged between 18 and 65 years. Participants are required to have a Philadelphia chromosome or BCR::ABL1 positive ALL and must not have been previously treated, except with corticosteroids for a duration of 7 days or less. The trial does not include a vulnerable population. Participants are expected to have a good general health status, with an ECOG performance status of 2 or less. The trial population was selected based on specific inclusion criteria, including the requirement for a molecular evaluation for BCR::ABL1 and a negative pregnancy test for women of childbearing potential. Additionally, participants must be willing to use two highly effective methods of contraception during the study and for three months after the last dose of study treatment. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed as a **randomized**, controlled study to evaluate the efficacy of **ponatinib** versus **imatinib** in combination with low-intensity chemotherapy in adults with de novo Philadelphia-Chromosome positive **acute lymphoblastic leukemia** (Ph+ ALL). The trial will also assess the use of **blinatumomab** in both optimal and suboptimal responders. The study is expected to run until July 14, 2030, with recruitment having commenced on July 14, 2023. Participants will be involved in the study for a maximum treatment period of 130 days for **imatinib** and 77 days for **ponatinib**, with **blinatumomab** administered for up to 4 days.
Study visits are structured to include an initial screening visit to confirm eligibility based on criteria such as age, diagnosis, and prior treatment history. Following randomization, participants will undergo regular follow-up visits to monitor treatment response and manage any adverse effects. The primary endpoint is the probability of overall survival at 2, 3, and 4 years from randomization in patients achieving molecular remission. Secondary endpoints include the rate of molecular complete remission at week 11 post-consolidation with chemotherapy. The end-of-study visit will evaluate the long-term outcomes and overall survival of participants.
Participant involvement is expected to last until the end of the treatment period, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with study protocols. The trial is conducted under a double-blind methodology to ensure unbiased results, with neither participants nor investigators aware of the treatment allocations. This study aims to provide critical insights into the comparative effectiveness of these therapeutic regimens in managing Ph+ ALL.
Treatment
The clinical trial involves the administration of **Imatinib**, a **film-coated tablet** containing the active substance imatinib, which is of chemical origin. The pharmaceutical form is designed for **oral use**. The maximum daily dose of imatinib is 600 mg, with a total maximum dose of 546,000 mg over a treatment period of up to 130 days. Imatinib is utilized as a comparator treatment in this study, serving as a standard-of-care therapy for patients with Philadelphia-Chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
**Ponatinib**, marketed as Iclusig 45 mg film-coated tablets, is another experimental medication used in this trial. It is also of chemical origin and is administered orally. The maximum daily dose for ponatinib is 45 mg, with a total maximum dose of 3,465 mg over a treatment period of up to 77 days. Ponatinib is employed as a test treatment in the study, aiming to assess its efficacy in comparison to imatinib when combined with low-intensity chemotherapy.
Additionally, the trial includes the use of **Blinatumomab**, marketed as BLINCYTO 38.5 micrograms powder for concentrate and solution for infusion. Blinatumomab is a protein-based medication administered via **intravenous infusion**. The maximum daily dose is 28 micrograms, with a total maximum dose of 336 micrograms over a treatment period of up to 4 days. Blinatumomab is evaluated in both optimal and suboptimal responders to the initial treatment regimen, providing an alternative therapeutic approach in the study.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The study aims to evaluate the non-inferiority of the overall survival of patients treated with a tyrosine kinase inhibitor (TKI) and chemotherapy alternating with blinatumomab, compared to the end of therapy with an indication for stem cell transplantation (SCT).
Efficacy
The efficacy of the clinical trial will be assessed through several key endpoints. The primary endpoint is the probability of overall survival at 2, 3, and 4 years from randomization in patients with **molecular remission** after consolidation 1. This will compare a combination treatment of tyrosine kinase inhibitor (TKI), blinatumomab, and chemotherapy versus end of therapy with indication for stem cell transplantation (SCT). Secondary endpoints include the rate of molecular complete remission at week 11 after consolidation with chemotherapy in combination with ponatinib versus imatinib.
The trial will involve adult patients with de novo Philadelphia-Chromosome positive acute lymphoblastic leukemia. Efficacy parameters will be measured at specified timepoints, including week 11 for secondary endpoints, and at 2, 3, and 4 years for the primary endpoint. The trial aims to prove non-inferiority in overall survival of patients treated with TKI, chemotherapy alternating with blinatumomab, compared to end of therapy with indication for SCT. The assessments will be conducted using validated methods to ensure accuracy and reliability of the data collected.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female patients >= 18 years, <=65 years, Philadelphia chromosome or BCR::ABL1 positive ALL, Not previously treated except with corticosteroids ≤ 7 days, standard GMALL prephase with dexamethasone and cyclophosphamide including intrathecal therapy, hydroxyurea, a single dose vincristine or other cytostatic drugs and start of standard induction for Ph-positive ALL (1 dose vincristine, 1 dose of Rituximab, 2 doses dexamethasone and up to 5 days Imatinib), ECOG performance status ≤2, Signed written inform consent, Molecular evaluation for BCR::ABL1 performed, Negative pregnancy test in women of childbearing potential, Woman of childbearing potential willing to use 2 highly effective methods of contraception while receiving study treatment and for an additional 3 months after the last dose of study treatment (Pearl-Index <1%). Male who has a female partner of childbearing potential willing to use 2 highly effective forms of contraception while receiving study treatment and for at least an additional 3 months after the last dose of study treatment (Pearl-Index <1%). Effective Contraception is defined as: o abstinence o a hormonal contraceptive method (birth control pills, intrauterine spiral, vaginal ring, contraceptive patches, depot implants or injections) in combination with barrier methods (condoms, cervical cap, diaphragm with spermicides) o Vasectomy in patients or male partners Women of childbearing potential are defined as mature women without hysterectomie or surgical sterilization or women without menopause. Menopause means without without menstruation for natural reasons for one year, Normal serum levels > LLN (lower limit of normal) of potassium and magnesium, or corrected to within normal limits with supplements, prior to the first dose of study medication, Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis, Normal QTcF interval ≤450 ms for males and ≤470 ms for females, Signed and dated written informed consent is available, Participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL)
Exclusion Criteria
- History of malignancy other than ALL diagnosed within 5 years (yrs) prior to start of protocol-specified therapy with defined exceptions: o Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease o Adequately treated cervical carcinoma in situ without evidence of disease o Adequately treated breast ductal carcinoma in situ without evidence of disease o Prostatic intraepithelial neoplasia without evidence of prostate cancer, Contraindications against the use of Imatinib, Ponatinib, chemotherapy or Blinatumomab, Patient previously treated with tyrosine kinase inhibitors, Nursing women, Known impaired cardiac function, including any of the following: o LVEF < 40% o Complete left bundle branch block o Right bundle branch block plus left anterior hemiblock, bifascicular block o History of or presence of clinically significant ventricular or atrial tachyarrhythmias o Clinically significant resting bradycardia (< 50 beats per minute) o Congenital long QT syndrome or QTcF >470 msec for females and >450 msec for males on screening ECG. If QTc > 470 msec for females and > 450 msec for males and electrolytes are not within normal ranges before ponatinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF crite- rion. o Myocardial infarction within 12 months prior to starting study treatment o Other clinically significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension), Symptomatic peripheral vascular disease, Any history of ischemic stroke or transient ischemic attacks (TIAs), Uncontrolled hypertriglyceridaemia, History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, cerebrovascular ischemia/haemorrhage, severe brain injuries, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis (with exception of CNS leukemia that is well controlled with intrathecal therapy), History or active relevant autoimmune disease, Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation, Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not man- datory) or active infection with Hepatitis B or C, History of pancreatitis within 6 months previous to start of treatment within the trial, Treatment with any other investigational agent or participating in another trial within 30 days prior to entering this study, Inadequate hepatic functions defined as ASAT or ALAT > 2,5 times the institutional upper limit of noral or > 5 times ULN if considered due to leukemia, Total bilirubin > 1.5-fold the institutional upper limit unless considered to be due to organ involvement by the leukemia or to M. Gilbert / M. Meulengracht, Concurrent severe diseases which exclude the administration of therapy e.g. severe, uncontrolled acute or chronic infections, Inability to understand and/or unwillingness to sign a written informed consent
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 14 Jul 2023 | 208 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Iclusig 45 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 45 | 77 | PRD4563016 |
IMATINIB | Comparator | — | ORAL | 600 | 130 | SUB25387 |
IMATINIB | Comparator | — | ORAL USE | 600 | 130 | SUB25387 |
BLINCYTO 38.5 micrograms powder for concentrate and solution for solution for infusion. | Test | POWDER FOR CONCENTRATE AND SOLUTION FOR SOLUTION FOR INFUSION | INTRAVENOUS | 28 | 4 | PRD3418637 |