CML12 DIRECT: This phase II trial is evaluating oral dosing of the drug dasatinib in elderly patients with Chronic Myelogenous Leukaemia (CML)A single arm phase II study to individualize dasatinib dosing based on trough levels and molecular response to maintain efficacy whilst minimising toxicity in elderly patients with chronic myelogenous leukaemia.

Exclusion

1. Patients who have undergone major surgery within the 4 weeks prior to study entry or have not recovered from earlier surgery.
2. Impaired cardiac function, uncontrolled or significant cardiovascular disease, including any of the following:
a) A myocardial infarction within 6 months
b) Uncontrolled angina within 3 months
c) Congestive heart failure within 3 months
d) Diagnosed or suspected congenital long QT syndrome
e) Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointe, or third degree heart block without pace maker insertion)
f) Prolonged QTcF interval greater than 450 msec on baseline ECG (rescreening allowed after correction of rectifiable factors, eg electrolytes management, or rationalisation of medications)
g) Patient receiving medications associated with QT interval prolongation
3. Impaired pulmonary function including any of the following:
a) Previously diagnosed with pulmonary hypertension
b) Severe pre-existing pulmonary disease that
i) Imposes limits on activities of daily living
ii) FEV1, FVC or DLCO less than or equal to 50% of the predicted value (formal pulmonary function testing is not required for patients without antecedent diagnosis of pulmonary disease) or
iii) Impaired pulmonary function as defined using any other relevant clinical measure by the investigator
c) Current and unresolved pleural effusion(s), or previous history of pleural effusions (excluding those infective in aetiology)
4. Treatment with agents that prolong QT interval or inhibit CYP3A4, as listed under prohibited concomitant medications (Consult Appendix 1 for CYP3A4 inducers, inhibitors and substrates, as well as prohibited medications).
5. Another primary malignant disease, except for such conditions that do not currently require treatment, lesions that can be or had been completely excised (e.g. Skin Cancers) and neoplasms that does not significantly affect long term survival of the patient
6. Other concurrent uncontrolled medical conditions (e.g. uncontrolled diabetes, active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol.
7. Cytopathologically confirmed CNS infiltration. [In the absence of suspicion of CNS involvement, lumbar puncture is not required.]
8. Patients unwilling or unable to comply with protocol and patients with a history of noncompliance or inability to grant informed consent.
9. Prior stem cell transplantation.
10. Reproductive status
h) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
i) Women must not be breastfeeding.
j) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug, plus 30 days (duration of ovulatory cycle) for a total of 30 days post-treatment completion.
k) Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 90 days (duration of sperm turnover) for a total of 90 days post-treatment completion.
l) Azoospermic males and WOCBP, who are not heterosexually active, are exempt from contraceptive requirements. However, WOCBP must still under pregnancy testing as described in this section.
m) Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of unexpected pregnancy. Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective contraception. Highly effective methods of contraception have a failure rate of <1% when used consistently and correctly.
n) At a minimum, subjects must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective as listed below.11. Current participation in another therapeutic clinical trial (participation in clinical trials that do not involve active interventions is not an exclusion for the study).
12. Congenital or acquired platelet disorders with increased risk of clinically significant bleeding.
c) Diagnosed congenital bleeding disorders (e.g. von Willebrand’s disease)
d) Diagnosed acquired bleeding disorder within one year (e.g. acquired anti-factor VIII antibodies)