A Phase 4 Safety and Efficacy Study of Bosutinib (Bosulif®) in Patients with Philadelphia Chromosome Positive Chronic Myeloid Leukemia Previously Treated with One or More Tyrosine Kinase Inhibitors

Bosutinib (Bosulif®) is an orally bioavailable, potent, multi-targeted, dual
Src-Abl tyrosine kinase inhibitor (TKI) that has been approved for the
treatment of adult patients with Philadelphia chromosome positive (Ph+) chronic
phase chronic myelogenous leukemia previously treated with other TKI therapy.
Chronic myelogenous leukemia (CML) is the fourth most commonly occurring adult
leukemia. CML traditionally follows a triphasic course with most patients being
diagnosed in an initial oligosymptomatic chronic phase (CP) which eventually
progresses into a more advanced accelerated phase (AP) and culminates in a
blastic phase (BP), which resembles a highly treatment-refractory form of acute
leukemia that generally shows either a myeloid or a lymphoid phenotype. The
transformation of CML from a deadly cancer to a chronic illness that took place
over the last decade has been due to the development of TKIs, small-molecule
inhibitors of the kinase activity of BCR-ABL1, including imatinib, bosutinib,
dasatinib, nilotinib, and ponatinib. The transition of patients with CML from
CP to BP with an intermediate AP is becoming less standard with the chief
determinants of survival being
disease stage and TKI responsiveness.
On September 4, 2012, bosutinib was approved by the US Food and Drug
Administration (FDA) for the treatment of adult patients with chronic,
accelerated, or blast phase Ph+ CML with resistance or intolerance to prior
therapy (United States Prescribing Information BOSULIF®). More recently, on
March 27, 2013, the European Medicines Agency (EMA) granted conditional
marketing authorization in the European Union (EU), for the treatment of
adult patients with CP, AP and BP Ph+ CML previously treated with one or more
TKIs and for whom imatinib, nilotinib and dasatinib are not considered
appropriate treatment options (EMA Summary of Product Characteristics).
The FDA and EMA approvals were granted based on the results obtained from the
singlearm, Phase 1/2 study (3160A4-200-WW, *Study-200*) in adult patients with
Ph+ leukemias who had failed prior TKI therapy, and with the support of the
safety results obtained from the Phase 3 study (3160A4-3000-WW) comparing
bosutinib with imatinib in newly diagnosed CP Ph+ CML patients. In addition,
the EMA was provided with descriptive narrative information from the bosutinib
compassionate use program in patients with Ph+CML who had received at least one
prior TKI treatment and had progressed or were intolerant, and otherwise not
considered suitable for other TKI therapy, as well as efficacy and safety
analyses from a subset of Study-200 patients whose disease had failed prior
imatinib and/or dasatinib or nilotinib and were contraindicated for treatment
with dasatinib or nilotinib, as
well as 4th-line CML patients on the study.
The purpose of this phase 4 study is to fulfill the post-authorization
commitment made by Pfizer to the EMA in providing additional safety and
efficacy data in approximately 150 Ph+ CML patients with high unmet medical
need, including 75 CP, AP or BP patients in the 4th or later line treatment
setting (i.e., after treatment with at least 3 other TKIs). The EMA conditional
approval requires completion of this post-authorization study in order to
convert the conditional approval to a full marketing authorization approval.

The purpose of this study is to fulfill the post-authorization commitment made
by Pfizer to the EMA in providing additional safety and efficacy data in
approximately 150 patients with Ph+ CML whose disease had failed or who are
otherwise not appropriate for treatment with dasatinib, nilotinib or imatinib
TKI, including 75 patients in the 4th line treatment setting (i.e., after
treatment with at least 3 other TKIs). The EMA conditional approval requires
completion of this post-authorization study in order to convert the conditional
approval to a full marketing approval.

This is a single-arm, open-label, non-randomized, multi-center Phase 4 study to
evaluate bosutinib (Bosulif ®) in patients with CP/AP/BP Ph+ CML whose disease
has failed prior treatment with commercially available TKIs due to drug
resistance or intolerance, or are otherwise contraindicated for treatment with
commercially available TKIs such as imatinib, dasatinib, or nilotinib (i.e.,
presence of a BCR-ABL mutation or medical condition making commercially
available TKIs unsuitable for a patient). Patients will receive bosutinib for
at least 4 years from the time of first dose, unless disease progression,
unacceptable toxicity, patient withdrawal of consent, death or Sponsor
discontinuation of study. Patients discontinuing bosutinib prior to completing
at least 4 years of therapy will be followed for survival until they complete
at least 4 years on study. Patients completing at least 4 years of bosutinib
with continued benefit may be switched to commercially available therapy at that
time.
During the first 3 months of study, disease assessments will be performed
weekly during the first month, then approximately every 4 weeks until Week 13.
Assessments will then be performed every 3 months until Week 52, then at 6
month intervals during year 2, 3, and 4 of
treatment. Complete blood counts should be performed weekly for the first month
and then monthly thereafter, and as clinically indicated. Hematologic,
cytogenetic and extramedullary disease assessments will be done locally, while
molecular and mutation analysis will be
carried out by independent central analysis. Copies of the cytogenetic
assessment (karyotype photograph or other relevant image) will be submitted and
stored centrally for independent analysis. Patient participation will conclude
not more than 4 years after the first dose.

Patients will receive bosutinib 500 mg orally once daily, preferably in the
morning with food. Bosutinib commercial formulation of 100 mg and 500 mg
tablets will be provided.

See section E9 of this form.