E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
minimal residual disease (MRD) in Philadelphia-Chromosome positive acute lymphoblastic leukemia (Ph+ALL) |
minimale Resterkrankung (MRD) einer Philadelphia-Chromosompositiven akuten lymphatischen Leukämie |
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E.1.1.1 | Medical condition in easily understood language |
minimal residual disease (MRD) in Philadelphia-Chromosome positive acute lymphoblastic leukemia (Ph+ALL) |
minimale Resterkrankung (MRD) einer Philadelphia-Chromosompositiven akuten lymphatischen Leukämie |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10080018 |
E.1.2 | Term | Philadelphia positive acute lymphocytic leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of ponatinib to induce molecular remission in patients |
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E.2.2 | Secondary objectives of the trial |
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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 or after consolidation II 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) |
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E.4 | Principal 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 <1%). Women of childbearing potential are defined as mature women without hysterectomie or surgical sterilization or women without menopause. Menopause means without menstruation for natural reasons for one year 11. Male who has a female partner of childbearing potential, and is not willing to use highly effective forms (as defined in the protocol) of contraception while receiving study treatment and for at least an additional 3 months after the last dose of study treatment (Pearl-Index <1%) 12. Tyrosine kinase inhibitor (TKI) treatment within 3 days prior to receiving the first dose of ponatinib 13. Treatment with medications that are known to be associated with torsades de pointes 14. Prior treatment with ponatinib 15. History or presence of clinically significant bleeding or coagulation disorder unrelated to completed ALL treatment elements, e.g asparaginase treatment 16. History of pancreatitis within 1 year of study start or history of chronic pancreatitis, serum lipase and amylase ≥1.5 x ULN 17. Known impaired cardiac function, including any of the following: a. LVEF < 40% b. Complete left bundle branch block c. Right bundle branch block plus left anterior hemiblock, bifascicular block d. History of or presence of clinically significant ventricular or atrial tachyarrhythmias e. Clinically significant resting bradycardia (< 50 beats per minute) f. Congenital long QT syndrome or QTcF >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 ischemic stroke or transient ischemic attacks (TIAs) 18. Inadequate hepatic functions defined as ASAT or ALAT > 2.5 times the institutional upper limit of normal (ULN) or > 5 times ULN if considered due to leukemia 19. Total bilirubin >1.5 fold the institutional ULN unless considered to be due to organ involvement by the leukemia or to M. Gilbert / M. Meulengracht 20. Concurrent severe diseases which exclude the administra-tion of therapy 21. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL) 22. Major surgery within 14 days prior to first dose of ponatinib 23. Ongoing or active infection 24. Malabsorption syndrome or other gastrointestinal illness that could affect absorption of ponatinib 25. Any other condition or illness that would compromise safety
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of patients who achieve molecular remission after one cycle of treatment with ponatinib |
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E.5.1.1 | 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 |
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E.5.2 | 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. |
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E.5.2.1 | 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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |