E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult patients (age ≥ 18) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) who have proven to be resistant or intolerant to prior first line Tyrosine Kinase Inhibitor Treatment |
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E.1.1.1 | Medical condition in easily understood language |
Adult patients (age ≥ 18) suffering from Chronic Myeloid Leukemia in Chronic Phase and who are resistant or intolerant to earlier treatment with another Tyrosine Kinase Inhibitor |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054352 |
E.1.2 | Term | Chronic phase chronic myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Major molecular response (MMR) by 12 months of treatment with second line Ponatinib treatment |
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E.2.2 | Secondary objectives of the trial |
- Rate, time and dose to first clinical manifestation of vascular toxicity related to 2nd line therapy with Ponatinib - Rate of MCyR, CCyR and MR4 by 3, 6, 12, 18, 24 months - Rate of MMR by 3, 6, 18, 24 months - Time to CCyR, MMR, MCyR, MR4 - Durations of hematologic, cytogenetic, molecular response - Occurrence of bar-abl mutations in Ponatinib-resistant CP-CML patients - Time to progression and overall survival - Cardiovascular safety |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients ≥18 years old 2. Diagnosis of Ph-positive (by cytogenetics) or BCR-ABL-positive (by PCR) CP-CML 3. Patients should have demonstrated to have • a failure of a prior 1st line TKI treatment with either imatinib, dasatinib or nilotinib. A failure is defined as per European LeukemiaNet (ELN) recommendations: o Less than CHR and/or Ph+ > 95% at or beyond 3 months o No cytogenetic response (Ph+>35%) and/or BCR-ABL1 >10% at or beyond 6 months o BCR-ABL (on international scale) >1% and/or Ph+ >0% o Less than MMR at or beyond 18 months o Loss of response or development of mutations or other clonal chromosomal abnormalities at any time during the first line TKI treatment • or intolerance to prior TKI treatment defined as grade 3 or 4 toxicity, or persistent grade 2 toxicity despite optimal management including dose adjustment, or in a patient where dose reductions are considered to be not in the patient’s best interest to obtain an adequate response. Intolerant patients should not have achieved or have lost major molecular response at the time of enrollment 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 5. Adequate hepatic function as defined by the following criteria: • Total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert’s syndrome, in which case it should be ≤ 3.0xULN) 6. Adequate renal function as defined by the following criterion: • Creatinine clearance of ≥ 50 mL/min 7. Adequate pancreatic function as defined by the following criterion: • Serum lipase and amylase ≤1.5×ULN 8. For patients of childbearing potential, a negative pregnancy test must be documented prior to enrollment. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential 9. Female and male patients who are fertile must agree to use effective forms of contraception with their sexual partners from signing off the informed consent form for this study until 3 months after the end of treatment 10. Provision of written informed consent and specifically the consent to the collection and processing of health-related data 11. Willingness and ability to comply with scheduled visits and study procedures 12. Patients should have discontinued therapy with prior TKI (except hydroxyurea), at least 48 hours prior to start of study therapy 13. Fully recovered from the acute effects of prior cancer therapy before initiation of study drug 14. Patients must have had an eye examination confirming no objectives towards study participation by the ophthalmologist within 8 weeks prior to first treatment. . It is recommended to use Ophthalmoscopy to perform the eye examination (additional tests may be used as clinically indicated or as per physician discretion).The eye examinations should test the retinal vasculature |
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E.4 | Principal exclusion criteria |
1. Any 1st line anti-CML treatment other than TK (apart from therapy with hydroxyurea) 2. Any 2nd line therapy with a tyrosine kinase inhibitor (>1 EMA approved TKI for CML, or any investigational non EMA-approved TKI) 3. Concurrent participation in any other clinical trial involving another investigational drug within 4 weeks prior to enrollment and throughout participation in PONS-Study 4. NYHA cardiac class 3-4 heart disease 5. Cardiac Symptoms within the past 12 months prior recruitment: Patients meeting the following criteria are not eligible: • History of unstable angina, myocardial infarction, TIA, stroke, peripheral arterial occlusive disease or pulmonary embolism • Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) • Prolonged QTc interval on pre-entry electrocardiogram (> 450 ms in men, > 470 ms in women) on the Fridericia correction formula • Congestive heart failure (NYHA Class III or IV) within 3 months prior to first dose of ponatinib 6. Patients with active, uncontrolled psychiatric disorders including: psychosis, major depression, and bipolar disorders 7. Patients with uncontrolled hypertension (defined as sustained systolic blood pressure > 140 mmHg or diastolic > 90 mmHg) 8. Pregnant or breast-feeding women are excluded 9. Patients with history of pancreatitis 10. Patients in accelerated or blast phase, or patients who have ever been documented to be in blast phase CML, are excluded. The definitions of excluded CML phases are as follows: • Blastic phase: presence of 30% blasts or more in the peripheral blood or bone marrow • Accelerated phase CML: presence of any of the following features: o Peripheral or marrow blasts 15% or more o Peripheral or marrow basophils 20% or more o Thrombocytopenia < 100 x 10^9/L unrelated to therapy o Documented extramedullary blastic disease outside liver or spleen • Clonal evolution defined as the presence of additional chromosomal abnormalities other than the Ph chromosome has historically been included as a criterion for accelerated phase. However, patients with clonal evolution as the only criterion of accelerated phase have a significantly better prognosis. Thus, patients with clonal evolution and no other criteria for accelerated phase will be eligible for this study, but analyzed separately 11. Patients showing an intolerance to the active substance or to any of the other ingredients of the test drug 12. Patients who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities 13. Patients who may be dependent on the sponsor, trial site or investigator |
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E.5 End points |
E.5.1 | Primary end point(s) |
MMR by 12 months of treatment with 2nd line Ponatinib treatment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Rate, time and dose to first clinical manifestation of vascular toxicity related to 2nd line therapy with Ponatinib - Rate of MCyR, CCyR and MR4 by 3, 6, 12, 18, 24 months - Rate of MMR by 3, 6, 18, 24 months - Time to CCyR, MMR, MCyR, MR4 - Durations of hematologic, cytogenetic, molecular response - Occurrence of bar-abl mutations in Ponatinib-resistant CP-CML patients - Time to progression and overall survival - Cardiovascular safety |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 7 |
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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Last visit of last patient / LVLS |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |