Safety and Tolerability Open Label Dose Escalation Study of Acadesine in B-CLL Patients

This is a Phase I/II, open-label, escalating dose and number of doses study that will involve up to 30-40 patients with B-CLL. A patient who fails to reach their final assessment visit due to reasons other than the occurrence of a dose limiting toxicity (DLT) may be replaced. Eligible patients will be enrolled into Part I or Part II of the study in cohorts of three patients. There will be a requirement to stagger Day 1 dosing between all patients in each cohort by a minimum of 48 hours. In the first part of the study (Part I) patients will receive a single dose of acadesine on Day 1. In the second part of the study (Part II), patients will receive up to 5 doses of treatment over a period of up to 20 days starting on Day 1.

In Part I of the study, the starting dose will be 50 mg/kg given as a 4 hour iv infusion on Day 1 only. Patients will continue to be assessed for safety, pharmacokinetics (PK) and pharmacodynamics for up to three weeks after dosing (to Day 22). The decision to escalate to the next dose in a separate cohort of patients will be based on the assessment of safety, including any DLTs, pharmacokinetic modelling (PKM) of exposure to ZMP and pharmacodynamic response data, where available, by an independent Data Monitoring Board (DMB). A DLT is defined as a Grade 3 or 4 toxicity, which may be local to the injection site or systemic, which is observed within 21 days of dosing and is considered to be related to study drug. The dose will not be escalated if PKM indicates that the exposure to ZMP has reached a plateau.

Dose escalation will continue with each new cohort in accordance with the rules described in the following table. The dose below that at which dose escalation is stopped will be considered the Optimal Biological Dose (OBD) and this dose will be the starting dose used in Part II of the study which will assess repeat dosing with acadesine. The OBD will be reviewed by the DMB prior to the start of Part II of the study.

If a DLT is noted in a given cohort in Part I, the following dose escalation rules will be followed to ascertain the maximum administered dose (MAD). In the unlikely event that a DLT is seen in ≥ 2 patients at the starting dose used in Part I, the study may be resumed with a lower dose if there is adequate evidence of the desired pharmacodynamic effect, ie a reduction in B-cell count, at the starting dose.

Dose escalation in Part I of the study shall follow a modified Fibonacci dose escalation design, with 100% dose escalations allowed until a Grade 2 toxicity that is considered related to treatment is confirmed (as defined by the NCI CTCAE v3.0). If this occurs, future escalations shall then be incremental (67%, 50%, 40%, 33%, etc), until the MAD is confirmed. Intermediate dose levels may be evaluated if indicated by the acquired safety or PK data.

In Part I of the study, blood samples for PK analysis (for both acadesine and its metabolite ZMP) will be taken pre-dose and 0, 30, 60 minutes, 2, 6, 20, 72, 96, and 168 hours, 14 and 21 days post-dose in all cohorts. Predictive modelling of repeat dose pharmacokinetics will be carried out and used in conjunction with the safety and pharmacodynamic data to predict a suitable multiple dose regimen in Part II of the clinical study, where up to 5 doses will be administered at regular intervals over a period of up to 20 days. The Part II dosing decision will be based on a review of the data by the DMB.

In Part II one additional acadesine dose will be administered for each successive new cohort enrolled. The decision to add an additional dose in a separate cohort of patients will be based on assessment of safety, including any DLTs, PKM of exposure to ZMP, and pharmacodynamic response data, where available, by the DMB. Blood samples for PK analysis in Part II of the study will be taken pre-dose and at 0, 30, 60 minutes, 2, 6, 20, 72, 96, and 168 hours post-dose on the first and last day of dosing and also at pre-dose and 0 minutes post-dose for any interim doses. Samples will also be taken 14 and 21 days after completion of the last dose for each patient.

As in Part I, patients in Part II will continue to be followed up for 21 days after their last dose of acadesine. If 1 out of the 3 patients experiences a DLT, a further 3 patients will be recruited to the cohort. If ≥ 2 patients out of the 6 experience a DLT, dosing will be stopped for this cohort and further cohorts of patients may be enrolled to receive up to 5 administrations of acadesine at a lower dose (or intermediate dose) over a 20 day period, based on safety, pharmacodynamic and pharmacokinetic data. The decision to continue at a lower dose will be based on a review by the DMB.

Sampling times for pharmacokinetic assessments may be altered during the study based on the data collected in order to fully define the pharmacokinetic profile of acadesine and ZMP. The total volume of blood required for these assessments will not increase.