1. 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

2. 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 .

3. OPTIC study design

4. 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

5. 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