Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs

Inclusion Criteria:

Male or female patients with a diagnosis of CML-CP ≥ 18 years of age

Patients must meet all of the following laboratory values at the screening visit:

- < 15% blasts in peripheral blood and bone marrow

- < 30% blasts plus promyelocytes in peripheral blood and bone marrow

- < 20% basophils in the peripheral blood

- ≥ 50 x 109/L (≥ 50,000/mm3) platelets

- Transient prior therapy related thrombocytopenia (< 50,000/mm3 for ≤ 30 days prior to
screening) is acceptable

- No evidence of extramedullary leukemic involvement, with the exception of
hepatosplenomegaly

BCR-ABL1 ratio ≥ 1% IS according to central laboratory at the screening examination

Prior treatment with a minimum of 2 prior ATP-binding site TKIs (i.e. imatinib, nilotinib,
dasatinib, radotinib or ponatinib)

Failure (adapted from the 2013 ELN Guidelines Bacarrani 2013) or intolerance to the most
recent TKI therapy at the time of screening

- Failure is defined for CML-CP patients (CP at the time of initiation of last therapy)
as follows. Patients must meet at least 1 of the following criteria.

- Three months after the initiation of therapy: No CHR or > 95% Ph+ metaphases

- Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 65% Ph+
metaphases

- Twelve months after initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 35% Ph+
metaphases

- At any time after the initiation of therapy, loss of CHR, CCyR or PCyR

- At any time after the initiation of therapy, the development of new BCR-ABL1 mutations
which potentially cause resistance to study treatment

- At any time after the initiation of therapy, confirmed loss of MMR in 2 consecutive
tests, of which one must have a BCR-ABL1 ratio ≥ 1% IS

- At any time after the initiation of therapy, new clonal chromosome abnormalities in
Ph+ cells: CCA/Ph+

- Intolerance is defined as:

- Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or
with persistent grade 2 toxicity, unresponsive to optimal management, including dose
adjustments (unless dose reduction is not considered in the best interest of the
patient if response is already suboptimal)

- Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil
count [ANC] or platelets) while on therapy that is recurrent after dose reduction to
the lowest doses recommended by manufacturer

Exclusion Criteria:

Known presence of the T315I or V299L mutation at any time prior to study entry Known second
chronic phase of CML after previous progression to AP/BC Previous treatment with a
hematopoietic stem-cell transplantation Patient planning to undergo allogeneic
hematopoietic stem cell transplantation

Cardiac or cardiac repolarization abnormality, including any of the following:

- History within 6 months prior to starting study treatment of myocardial infarction
(MI), angina pectoris, coronary artery bypass graft (CABG)

- Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete
left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type
II and third degree AV block)

- QTcF at screening ≥450 msec (male patients), ≥460 msec (female patients)

- Long QT syndrome, family history of idiopathic sudden death or congenital long QT
syndrome, or any of the following:

- Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or
hypomagnesemia, history of cardiac failure, or history of clinically
significant/symptomatic bradycardia

- Concomitant medication(s) with a known risk of Torsades de Pointes per www.qtdrugs.org
that cannot be discontinued or replaced 7 days prior to starting study drug by safe
alternative medication.

- Inability to determine the QTcF interval

- Severe and/or uncontrolled concurrent medical disease that in the opinion of the
investigator could cause unacceptable safety risks or compromise compliance with the
protocol (e.g. uncontrolled diabetes, active or uncontrolled infection, pulmonary
hypertension)

- History of acute pancreatitis within 1 year of study entry or past medical history of
chronic pancreatitis

- History of acute or chronic liver disease

- Treatment with medications that meet one of the following criteria and that cannot be
discontinued at least one week prior to the start of treatment with study treatment

- Moderate or strong inducers of CYP3A

- Moderate or strong inhibitors of CYP3A and/or P-gp

- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 3 days after last dose of ABL001. Highly effective contraception
methods include:

- Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception

- Female sterilization (have had surgical bilateral oophorectomy (with or without
hysterectomy) total hysterectomy or bilateral tubal ligation at least six weeks before
taking study treatment). In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment

- Male sterilization (at least 6 months prior to screening). The vasectomized male
partner should be the sole partner for that subject.

- Use of oral, injected or implanted hormonal methods of contraception or placement of
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal
contraception that have comparable efficacy (failure rate <1%), for example hormone
vaginal ring or transdermal hormone contraception.

- In case of use of oral contraception women should have been stable on the same pill
for a minimum of 3 months before taking study treatment.

- Women are considered post-menopausal and not of child bearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal
ligation at least six weeks before taking study medication. In the case of
oophorectomy alone, women are considered post-menopausal and not of child bearing
potential only when the reproductive status of the woman has been confirmed by follow
up hormone level assessment.

- Sexually active males unless they use a condom during intercourse while taking the
drug during treatment and for 3 days after stopping treatment and should not father a
child in this period. A condom is required to be used also by vasectomized men as well
as during intercourse with a male partner in order to prevent delivery of the drug via
semen.