Nordic sites Sweden Uppsala University Hospital PI: Ulla Olsson-Strömberg Norway Haukeland University Hospital PI: Bjørn Tore Gjertsen Finland Jyväskylä University Hospital PI: Dr Marita Nurmi Denmark Aarhus Universitetshospital PI: Professor Jesper Stentoft

OPTIC - Background In PACE, a phase two pivotal trial of ponatinib in heavily pretreated patients with CML or Ph+ ALL, a starting dose of 45 mg daily was used. Longer follow-up in PACE demonstrated a cumulative incidence of vascular events. Current data suggest that a dose-side effect relationship exists and that a lower daily dose may reduce the incidence of vascular events while maintaining a good efficacy. OPTIC will test 2 methods for assessing the relationships between exposure, efficacy, and safety: patients will receive a range of initial doses at defined time points, patients in response will undergo a dose reduction .

OPTIC study design

Key Inclusion Criteria Chronic Phase CML Previously treated and resistant to at least 2 TKIs Resistance criteria (at least 1 required, mostly according to Baccarani et al, 2009): 3 months: No cytogenetic response (> 95 % Ph+) or failure to achieve CHR 6 months: Less than a minor cytogenetic response (> 65 % Ph+) 12 months: Less than a PCyR (> 35 % Ph+) At any time, the development of new BCR-ABL KD mutations in absence of MCyR At any time, the development of new clonal evolution in absence of MCyR At any time, the loss of any cytogenetic response (confirmed in at least 2 consecutive analyses separated by at least 4 weeks) Normal QTcF at entry

Key Exclusion Criteria Autologous or allogeneic stem cell transplant < 2 months prior to the first dose Immunosuppressive therapy within 14 days prior to the first dose Active CNS disease Clinically significant, uncontrolled, or active cardiovascular disease, including but not restricted to: Any history of MI, unstable angina, cerebrovascular accident or TIA Any history of peripheral vascular infarction Congestive heart failure (NYHA class III or IV) or left ventricular ejection fraction (LVEF) < lower limit of normal, within 6 months of enrollment History of clinically significant atrial or ventricular arrhythmia Venous thromboembolism DVT or pulmonary embolism, within 6 months of enrollment Uncontrolled hypertension or poorly controlled diabetes