Newly Diagnosed Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia (Ph+ ALL) MedDRA version: 24.0 Level: LLT Classification code 10080018 Term: Philadelphia positive acute lymphocytic leukemia System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Iclusig
Product Name: ponatinib
Pharmaceutical Form: Tablet
INN or Proposed INN: ponatinib
CAS Number: 943319-70-8
Current Sponsor code: Ponatinib
Other descriptive name: PONATINIB
Concent
Sponsors
Takeda Development Center Americas, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female patients aged 18 years or older. 2. Newly diagnosed Ph+ or BCR-ABL1 positive ALL, as defined by the 2017 National Comprehensive Cancer Network guidelines. 3. Eastern Cooperative Oncology Group performance status of =2. 4. Clinical laboratory values as follows, within 30 days before randomization: a) Total serum bilirubin =1.5× the upper limit of normal (ULN), unless due to Gilbert´s syndrome. b) Alanine aminotransferase or aspartate aminotransferase =2.5× the ULN. c) Serum creatinine =1.5× the ULN and estimated creatinine clearance = 30 mL/minute (Cockcroft-Gault formula). d) Serum lipase and amylase =65 years) yes F.1.3.1 Number of subjects for this age range 34
Exclusion criteria
Exclusion criteria: 1. Patients with a history or current diagnosis of chronic phase, accelerated phase, or blast phase chronic myeloid leukemia 2. Prior/current treatment with any systemic anticancer therapy and/or radiotherapy for ALL with the exception of an optional prephase therapy or chemotherapy induction (no more than 1 cycle), which should be discussed with the sponsor’s medical monitor/designee 3. Treatment with any investigational products within 30 days before randomization or 6 half-lives of the agent, whichever is longer 4. Currently taking drugs that are known to have a risk of causing prolonged QTc or TDP (unless these can be changed to acceptable alternatives or discontinued) 5. Taking any medications or herbal supplements that are known to be strong inhibitors or strong inducers of cytochrome P450 3A4 within at least 14 days before the first dose of study drug 6. Uncontrolled active serious infections that could in the investigator´s opinion potentially interfere with the completion of treatment according to this protocol 7. Major surgery within 28 days before randomization (minor surgical procedures such as catheter placement or BM biopsy are not exclusionary criteria) 8. Known seropositive HIV, known active hepatitis B or C infection 9. History of acute pancreatitis within 1 year of study screening or history of chronic pancreatitis 10. Uncontrolled hypertriglyceridemia (tg >450 mg/dL) 11. Diagnosed and treated for another malignancy within 5 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection 12. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome or psychosis 13. Clinical manifestations of CNS or extramedullary involvement with ALL other than lymphadenopathy or depatosplenomegaly 14. Autoimmune disease with potential CNS involvement 15. Known significant neuropathy of Grade =2 severity 16. Clinically significant, uncontrolled, or active cardiovascular, cerebrovascular, or peripheral vascular disease, or history of or active VTE disease, including, but not restricted to: a) Complete left bundle branch block b) Right bundle branch block plus left anterior hemiblock, or bifascicular block c) History of or presence of clinically significant ventricular or atrial tachyarrhythmias d) Clinically significant resting bradycardia (<50 beats per min) e) Uncontrolled HTN (systolic blood pressure [BP] =150 mmHg and/or diastolic BP =90 mmHg). Patients with Stage 2 HTN (systolic BP =140 mmHg and/or diastolic BP =90 mmHg) should be under treatment at study entry per the current AHA guidelines to ensure BP control. Patients requiring 3 or more antihypertensive medications should have controlled HTN for the past 6 months. Isolated elevation(s) of systolic and/or diastolic BP during screening are not exluded f) Any history of myocardial infarction, unstable angina, coronary artery disease, cerebrovascular accident, ischemic stroke, or transient ischemic attack. Note: patients with any history of these events, whether considered clinically significant or not, are excluded g) History of congestive heart failure (NYHA class III or IV) or left ventricular ejection fraction <40%, within 6 month
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To compare the efficacy of ponatinib versus imatinib, administered as first-line therapy in combination with reduced-intensity chemotherapy, in patients with newly diagnosed Ph+ ALL, as measured by the MRD-negative CR rate at the end of induction.;Secondary Objective: Key Secondary Objectives: To compare EFS between the 2 cohorts Other Secondary Objectives: Please refer to the study protocol Exploratory Objective: To explore biomarkers of disease sensitivity and resistance to ponatinib and Imatinib and/or biomarkers affecting ponatinib efficacy or safety. ;Primary end point(s): Primary efficacy endpoint: MRD-negative CR (BCR-ABL/ABL1 =0.01% and meeting criteria for CR) ;Timepoint(s) of evaluation of this end point: End of 3 cycle induction | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): EFS is defined as the dates of randomization until death due to any cause or failure to achieve CR by end of induction or relapse from CR. CR is defined as meeting all of the following for at least 4 weeks (ie, no recurrence): 1. No circulating blasts and 1000/µl (or >1.0*10^9/L). 5. Platelets >100,000/µl (or >100*10^9/L). CRi is defined as hematologic complete remission with incomplete hematologic recovery and meeting all criteria for CR except platelet count and/or ANC. ORR is defined as CR + CRi. Duration of MRD-negative CR is defined as the interval between the first assessment at which the criteria for MRD-negative CR are met until the earliest date at which loss of MRD negativity or relapse from CR occurs. Duration of CR is defined as the interval between the first assessment at which the criteria for CR are met until the earliest date at which relapse from CR occurs. Time to treatment failure is defined as time to being off study randomized treatment (except for hematopoietic stem cell transplantation [HSCT] without loss of MRD-negative CR) due to safety and/or efficacy reasons. Molecule response is assessed by 3-Log Reduction (MR3), Molecular Response 4-Log Reduction (MR4) and Molecular Response 4.5-Log Reduction (MR4.5). PIF is defined as participants who received treatment for chromosomepositive acute lymphoblastic leukemia (ALL) but never achieved CR or CRi by the end of induction. PIF is not limited by the number of unsuccessful treatments; this disease status only applies to recipients who have never been in CR or CRi. MR4.5 is molecular response 4.5-log reduction (=0.0032% BCRABL1/ ABL1), or undetectable BCR-ABL1 transcripts in cDNA with = 32,000 ABL1 transcripts. On-study participants with or without HSCT will be evaluated. OS is defined as the interval between randomization and death due to any cause, censored at the last contact date when the participant was alive. On-study participants with or without HSCT will be | — |
Countries
Argentina, Australia, Austria, Belarus, Brazil, Bulgaria, Canada, China, Finland, France, Greece, Italy, Japan, Korea, Republic of, Mexico, Poland, Romania, Russian Federation, Spain, Taiwan, Turkey, United States
Contacts
Public ContactVijay Maharaj
Takeda Development Center Americas, Inc.
Outcome results
None listed