minimal residual disease (MRD) in Philadelphia-Chromosome positive acute lymphoblastic leukemia (Ph+ALL) MedDRA version: 20.1 Level: LLT Classification code 10080018 Term: Philadelphia positive acute lymphocytic leukemia System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Iclusig®
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: INN-ponatinib
CAS Number: 943319-70-8
Other descriptive name: PONATINIB
Concentration unit: mg milligram(s)
Concentrat
Sponsors
Universitätsklinikum Frankfurt
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients with Philadelphia-Chromosome/BCR-ABL1 positive ALL in complete hematological remission defined as less than 5% blasts in bone marrow after at least three intense chemotherapy blocks (e.g., GMALL induction I-II/consolidation I for patients 55 years) who received treatment with at least one tyrosine kinase inhibitor 2. Presence of minimal residual disease (MRD) in molecular failure or with molecular relapse documented after an interval of at least 2 weeks from last systemic chemotherapy (Definition of Molecular failure/Mo-lecular Relapse: BCR-ABL1/ABL1>10E-04 and BCR-ABL1 copies > 10) 3. Molecular evaluation for BCR-ABL1 performed 4. Bone marrow function as defined below: ANC (Neutrophils) = 1,000/µL Platelets = 50,000/µL (transfusion permitted) HB level = 9g/dl (transfusion permitted) 5. ECOG performance status =2 6. Normal QTcF interval =450 ms for males and =470 ms for females 7. 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 8. Adequate renal, hepatic and pancreatic function 9. Minimum life expectancy of =3 months 10. Negative pregnancy test and agree to use effective form of contraception (as applicable) 11. Age =18 years 12. Ability to understand and willingness to sign a written informed consent 13. Signed and dated written informed consent is available 14. Participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 15 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 5
Exclusion criteria
Exclusion criteria: 1. Ph-negative ALL 2. Presence of circulating blasts or current extramedullary involvement by ALL 3. Current detection of ALL blast cells in cerebro-spinal fluid 4. Any cancer chemotherapy or immunotherapy after sampling for the MRD test which leads to study inclu-sion (except for intrathecal prophylaxis and continued tyrosine kinase inhibitor) 5. Autologous hematopoietic stem cell transplantation (SCT) or allogeneic SCT 6. Treatment with any investigational product within four weeks prior to study treatment or within five terminal elimination half-lives of a preceding investigational medicinal product or of its relevant me-tabolite. The longer period of time will apply 7. History of malignancy other than ALL diagnosed within 5 years prior to start of protocol-specified ther-apy with the exception of: a. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease b. Adequately treated cervical carcinoma in situ without evidence of disease c. Adequately treated breast ductal carcinoma in situ without evidence of disease d. Prostatic intraepithelial neoplasia without evidence of prostate cancer 8. 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 9. Pregnant and nursing women 10. Woman of childbearing potential and is not willing to use highly effective methods (as defined in the pro-tocol) of contraception while receiving study treatment and for an additional 3 months after the last dose of study treatment (Pearl-Index 470 msec on screening ECG. If QTc > 470 msec and electrolytes are not within normal ranges before ponatinib dosing, electrolytes should be cor-rected and then the patient rescreened for QTcF criterion. g. Previous myocardial infarction h. Other clinically significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension) i. History of or presence of clinically relevant peripheral vascular disease or other vascular ste-nosis or occlusion, j. Any history of ische
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of ponatinib to induce molecular remission in patients;Secondary Objective: Other secondary objectives: To evaluate - Remission duration, relapse-free survival and overall survival - Relapse localisation and relapse characteristics - Efficacy of ponatinib in patients - Safety and tolerability of ponatinib in patients - Effect of ponatinib on duration of MRD response and molecular remission - Effect of ponatinib on the kinetics on MRD response - Outcome of SCT after ponatinib including mortality rate - Outcome of patients without SCT after ponatinib - Patient’s quality of life during and after therapy Exploratory objectives - Effect of pre-defined dose reductions, recommendations and local handling practices on safety, tolerability and treatment realisation of ponatinib - Resource utilization and practical treatment organisation - To assess potential biologic predictors of response to ponatinib, toxicity and relapse risk after ponatinib - To analyse the spectrum and kinetics in MRD-positive patients receiving ponatinib;Primary end point(s): Proportion of patients who achieve molecular remission after one cycle of treatment with ponatinib;Timepoint(s) of evaluation of this end point: at the end of each treatment cycle (day 29) and during the efficacy follow-up visits at least 3-monthly (calculated from cycle 1 day 1) within the first year and 6-monthly within the second year until completion of a 18 months period after treatment start with ponatinib | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Endpoints - Probability of continuous molecular remission (remission duration) at 18 months follow-ing initiation of ponatinib - Probability of hematological relapse-free survival rate at 18 months following initiation of ponatinib - Probability of overall survival at 18 months following initiation of ponatinib - Frequency of different relapse localisations in proportion to total hematological relapses - Biological evaluation of hematological and extramedullary relapses including ABL-TKD mutation status - Overall incidence and severity of adverse events in patients (CTC-AE 4.0) - Proportion of patients who achieve molecular remission after one cycle of treatment with ponatinib - Probability of continuous MRD response and molecular remission and duration of mo-lecular remission at 18 months following initiation of ponatinib - Time to molecular remission measured by time-point of first achievement Evaluation of overall survival, remission duration, relapse-free survival and treatment re-lated mortality (at day 100 and later) in patients with SCT in complete remission after ponatinib - Evaluation of overall survival, remission duration, relapse-free survival and treatment re-lated mortality in patients without SCT in complete remission after ponatinib - Measurement of Quality of Life with EORTC instruments (EORTC QLQ C30 and EQ 5D) at different time points during treatment Exploratory endpoints - Incidence of dose reductions, incidence of treatment interruptions, days of interruption, withdrawals, total days of treatment and realisation rate calculated as delivered total dose/scheduled total dose - Hospitalisation days - Evaluation of ABL1-TKD mutations at different time-points during first treatment cycle, in primary materials and in comparison of primary materials and relapse material.;Timepoint(s) of evaluation of this end point: at the end of each treatment cycle (day 29) and during the efficacy follow-up visits at least 3-monthly | — |
Countries
Germany
Contacts
Public ContactStudienzentrale Hämatologie
Universitätsklinikum Frankfurt
Outcome results
None listed