A single arm phase II study to individualize dasatinib dosing based on trough levels and molecular response to maintain efficacy whilst minimising toxicity (CML12)

Funding

Commercial sector/Industry,Bristol Myers Squibb

Scientific enquiries

Dr David Yeung

Brief Summary

The primary purpose of this study is to evaluate the efficacy and safety of individualised dosing of dasatinib for elderly patients with chronic myelogenous leukaemia. Who is it for? You may be eligible to participate in this study if you are aged 18 years or over, and have been diagnosed with chronic myelogenous leukaemia in the chronic phase (CML-CP) in the previous three months. Study details All participants in this study will start taking dasatinib at 100mg per day. At day 7, a blood sample .... The primary purpose of this study is to evaluate the efficacy and safety of individualised dosing of dasatinib for elderly patients with chronic myelogenous leukaemia. Who is it for? You may be eligible to participate in this study if you are aged 18 years or over, and have been diagnosed with chronic myelogenous leukaemia in the chronic phase (CML-CP) in the previous three months. Study details All participants in this study will start taking dasatinib at 100mg per day. At day 7, a blood sample will be taken to measure the levels of dasatinib in the blood just prior to taking that day's dose. If the blood dasatinib level is above a certain point, then the daily dose will be decreased to 70mg per day. If the blood dasatinib level is adequately low, then the participant will continue taking 100mg per day. This process will be repeated on days 28 and 56, with further lower dose levels of 50mg per day and 50mg every other day available if blood dasatinib levels are above the specific concentration. The dose level may also be dropped at any time if signs of drug toxicity are present. Participants may also be escalated back up a dose level (up to a maximum of 100mg per day), if further blood tests every 3-6 months show that the drug has not sufficiently decreased markers of the leukaemia, i.e. treatment has not been adequately effective. Participants will continue taking the drug for the two year study period, followed by a further three years if it has proven to be safe and effective in these patients. It is hoped that the findings of this study will provide information on whether an individualised dose of dasatinib can be used in elderly CML-CP patients to minimise toxicity whilst maintaining the therapeutic effect to treat the disease.
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Key Inclusion Criteria

1. Newly diagnosed CML-CP who have had either no prior exposure or less than 1 month of exposure to alternative TKI therapy a) Must demonstrate a quantifiable BCR-ABL1 fusion transcript on molecular studies, reported on the international scale; and b) Must have morphological appearance consistent with CML-CP, as defined by the European Leukaemia Net criteria.1 Additional cytogenetic abnormalities at baseline or diagnosis do not classify a patient as accelerated phase for the purpose of this stud .... 1. Newly diagnosed CML-CP who have had either no prior exposure or less than 1 month of exposure to alternative TKI therapy a) Must demonstrate a quantifiable BCR-ABL1 fusion transcript on molecular studies, reported on the international scale; and b) Must have morphological appearance consistent with CML-CP, as defined by the European Leukaemia Net criteria.1 Additional cytogenetic abnormalities at baseline or diagnosis do not classify a patient as accelerated phase for the purpose of this study. Extramedullary leukaemia would automatically classify a patient as having blastic phase disease; and c) Must be less than or equal to 3 months from diagnosis to screening 2. Aged 18 years or older 3. Willingly provide informed consent and agree to comply with study protocol 4. ECOG performance status 0-2. 5. No prior anti-CML therapy, except for short term (less than 12 weeks) treatment with hydroxyurea, anagrelide or leukapheresis. Less than 1 month of prior non-dasatinib TKI therapy permitted prior to screening. 6. Adequate liver and renal function. a) ALP, ALT and AST less than or equal to 2.5 x ULN; or = 5.0 if tumour related; and b) Bilirubin less than or equal to 2 x ULN unless secondary to Gilbert’s syndrome; and c) Creatinine Clearance of greater than or qqual to 20mL/min, calculated using the Cockroft-Gault formula. Idealised body weight should be used for patients at the extremes of body weight. 7. Serum Na, K, Mg, and total serum Ca or ionized Ca levels must be greater than or equal to the institutional lower limit of normal. Subjects with low K or Mg levels, total serum Ca and/or ionized Ca must be replete for protocol entry. 8. Subjects are expected to have a life expectancy of greater than or equal to 12 months in the opinion of the investigator, in the context of the patient’s general condition and comorbidities. 9. Eligible for a reimbursed treatment with dasatinib under the PBS complex drug program in Australia, the Pharmac system in New Zealand, or through other arrangements with regulatory and funding authorities.
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Key Exclusion Criteria

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 ven .... 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)
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