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A Phase I/II Open Label Dose Escalation Study to Investigate the Safety and Tolerability of Acadesine in Patients With B-cell Chronic Lymphocytic Leukemia

Phase 1/Phase 2
18 Years
Not Enrolling
Leukemia, B-Cell, Chronic

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Trial Information

A Phase I/II Open Label Dose Escalation Study to Investigate the Safety and Tolerability of Acadesine in Patients With B-cell Chronic Lymphocytic Leukemia

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

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.

Inclusion Criteria:

- B-CLL patients with refractory or relapsed disease who have received one or more (≥
1) prior lines of treatment which must have included either a fludarabine based
regimen or an alkylator based regimen. Refractoriness is defined as any patient who
has failed to achieve a CR, nPR or PR according to the National Cancer Institute
(NCI) working group guidelines for CLL. Fludarabine refractoriness will also include
patients who achieved a CR, nPR or PR of ≤ 6 months duration.

- Diagnosis of B-CLL according to NCI Working Group Criteria.

- Have an elevated B-cell count of ≥ 5000/mm3.

- Have a T-cell count ≥ 200/mm3.

- ECOG Performance Status ≤ 2.

- Have a life expectancy of at least 3 months.

- Age ≥ 18 years, of either gender.

- Have given written informed consent, prior to any study related procedure not part
of the patient's normal medical care

- Receive allopurinol prophylaxis for hyperuricaemia.

Exclusion Criteria:

- Patients who, in the opinion of the Investigator, need immediate treatment with
proven chemotherapy and/or immunotherapy, and/or transplantation.

- Have B-CLL with central nervous system involvement.

- Have participated in any other investigational drug study or have undergone an
experimental therapeutic procedure considered to potentially interfere with the study
in the 30 days preceding Day 1.

- Have received chemotherapy or radiotherapy treatment in the 30 days preceding Day 1.

- Require oral or parenteral steroids with the exception of inhaled steroids or
low-dose oral steroids (<10mg prednisolone per day or equivalent) for an indication
other than B-CLL.

- Have a serious medical or psychiatric condition that could, in the Investigator's
opinion, potentially interfere with their treatment and/or participation in the

- Have uncontrolled diabetes mellitus

- Have a history of gout.

- Have a serious concomitant disease including:

- Significant cardiac disease - New York Heart Association Classes III or IV or
have suffered a myocardial infarction in the last 6 months.

- Chronic pulmonary obstructive disease with hypoxemia.

- Clinically active auto-immune disease.

- Active infection such as tuberculosis, CMV (Cytomegalovirus).

- Any secondary malignancy requiring active treatment (except hormonal therapy).

- Have inadequate bone marrow reserve: neutrophils < 1.0 x 109/L, platelet count < 50
x 109/L (unsupported by transfusion), or coagulation abnormalities.

- Have inadequate liver function: total bilirubin > 1.5 x upper limit of normal values
(ULN), AST, ALT, or alkaline phosphatase > 2.5 x ULN.

- Have inadequate renal function, defined by serum creatinine ≥ 1.5 x ULN, unless
creatinine clearance is measured and found to be at least 60 mL/min.

- Have serum uric acid levels outside the normal range.

- Females of childbearing potential who are unwilling to employ adequate means of
contraception (hormonal contraceptive, intrauterine device, diaphragm with spermicide
or condom with spermicide) for the duration of the study and 30 days after the last
acadesine administration.

- Pregnant or lactating females.

- Male patients who are not surgically sterile and who are unwilling to use a condom
with spermicide for the duration of the study and for 3 months after the last
acadesine administration.

- Abuse of alcohol or other recreational drugs.

- Known HIV or Hepatitis B (unless clearly due to vaccination) or C positive.

- Known allergy to acadesine or any of its excipients.

- Have undergone previous allogeneic stem cell transplant.

- Transformation to Richter's syndrome or other aggressive B-cell malignancy

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

adverse event and serious adverse events(incidence, causality, severity), local tolerability (including liver enzymes, blood glucose and uric acid) and vital signs.

Outcome Time Frame:

up to and including Day 22 follow up visit

Safety Issue:


Principal Investigator

Eric Van Den Neste, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cliniques universitaires Saint-Luc


Belgium: Federal Agency for Medicinal Products and Health Products

Study ID:




Start Date:

December 2007

Completion Date:

December 2010

Related Keywords:

  • Leukemia, B-Cell, Chronic
  • safety
  • tolerability
  • dose-escalation
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Leukemia, B-Cell