A phase I, multicenter, open-label study of oral ABL001 in patients with chronic myelogenous leukemia or Philadelphia Chromosome-positive acute lymphoblastic Leukemia (CABL001X2101)

Despite the dramatic progress made over the past decade with TKIs in the
treatment of Chronic Myeloid Leukemia (CML), allogeneic stem cell transplant
remains the only proven curative therapy. To achieve cure or benefit from
treatment-free remissions with pharmacologically-based therapies, it is
estimated that patients will likely need to achieve a sustained reduction in
tumor burden of at least 4 logs, often referred to as a complete molecular
response (CMR). Currently, only 32% and 11% of patients achieve CMR after 12
months of treatment with single agent nilotinib or imatinib, respectively.
The development of the novel and potent BCR-ABL (Breakpoint Cluster
Region-Abelson oncogene) allosteric inhibitor, ABL001, presents an opportunity
to assess the effect of a different mechanism of inhibition of BCR-ABL in the
treatment of CML and Ph+ ALL (Philadelphia Chromosome-positive acute
lymphoblastic Leukemia).
This first-in-human trial with ABL001 is a dose escalation study whose primary
purpose is to estimate the maximum tolerated dose (MTD) and/or recommended dose
for expansion of ABL001 administered orally as a single agent to adult patients
with CML or Ph+ ALL.
By virtue of its distinct pharmacological profile and by preclinical
pharmacological studies demonstrating an additive effect, a combination of
ABL001 and a Tyrosine Kinase Inhibitor (TKI) has the potential to achieve a
deeper molecular response in a higher proportion of CML patients as compared to
single agent TKI therapy. Such a combination has the added theoretical
advantage of preventing treatment resistance. The prediction is that a
TKI/ABL001 combination will increase the percentage of patients who achieve a
CMR and decrease the time to CMR. In addition, some patients may be intolerant
of therapy with TKIs or may develop mutations that promote resistance to TKI
therapy. In these patients, ABL001 may provide a novel therapeutic option.

Primary:Determine the MTD and/or RDE(s) of ABL001:
* As a single agent for CML CP and AP patients
* In combination with either nilotinib or imatinib or dasatinib in CML CP and
AP patients
* As a single agent for CML BP patients and Ph+ ALL patients
Secondary: Characterize the safety and tolerability of oral ABL001 as a single
agent and in combination
with either nilotinib or imatinib or dasatinib
* To assess the pharmacokinetic profile of all study drugs in single agent and
combination
arms in plasma
* To assess preliminary anti-CML activity associated with ABL001 as a single
agent and in
combination with either nilotinib or imatinib or dasatinib and preliminary anti
Ph+ ALL activity
associated with ABL001 as a single agent

There will be 5 arms in this study:
* Arm 1: ABL001 as single agent in CP and AP CML patients
including an expansioncohort with approx. 65 patienten with a
T315I mutation
* Arm 2: ABL001 in combination with nilotinib in CP and AP CML patients

* Arm 3: ABL001 in combination with imatinib in CP and AP CML patients
* Arm 4: ABL001 in combination with dasatinib in CP and AP CML patients
* Arm 5: ABL001 as single agent in CML blast phase and Ph+ ALL patients
Each arm will begin with a dose escalation part and then have an expansion
part. After
determination of each MTD/RDE(s), further safety and tolerability will be
evaluated in the
expansion part.

Treatment with ABL001 as single agent and in combination with nilotinib,
dasatinib en imatinib.

Risk: Adverse effects of study medication.
Burden: Cycle 1: 6 visits, cycle 2; 5 visits, thereafter: 2 visits per cycle.
Visit duration 3-4 h (2-3 PK visits of 8 h).
Physical examination 2-3 times per cycle.
Blood draws every visit (10-30 ml); during 2-3 serial PK visits 8 samples.
Bone marrow sample at screening. To be repeated if needed.
ECG 1-2 times per cycle (up to cycle 6).
MRI-scan abdomen screening, cycle 2, every 3rd cycle thereafter.