AN OPEN-LABEL BOSUTINIB TREATMENT EXTENSION STUDY FOR SUBJECTS WITH CHRONIC MYELOID LEUKEMIA (CML) WHO HAVE PREVIOUSLY PARTICIPATED IN BOSUTINIB STUDIES B1871006 OR B1871008

Bosutinib (Bosulif®) is an orally bioavailable, potent, selective, dual Src-Abl
tyrosine kinase inhibitor (TKI) that has been developed as a tablet formulation
for the treatment of adult patients with Philadephia positive (Ph+) chronic
phase chronic myelogenous leukemia (CML) previously treated with other tyrosine
kinase therapy.

CML is the fourth most commonly occurring adult leukemia and accounts for
nearly 5,000 new cases annually in the United States.1 CML classically follows
a tri-phasic course with most patients being diagnosed in an initial, chronic
phase (CP) which eventually progresses into a more advanced accelerated phase
(AP) and culminates in a blast phase (BP), a highly treatment-refractory form
of acute leukemia that shows either a myeloid or a lymphoid phenotype. The
transformation of CML from a fatal disease 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(2).

Bosutinib is being developed for the treatment of Philadelphia chromosome
positive (Ph+) chronic myelogenous leukemia (CML) and to delay disease
progression in patients with autosomal dominant polycystic kidney disease
(ADPKD). Human experience with bosutinib is based on preliminary information
obtained from subjects in clinical studies, including subjects with Ph+
leukemias; subjects with solid tumors, including advanced or metastatic breast
cancer; subjects with autosomal dominant polycystic kidney disease; and healthy
subjects. As presented in the May 2016 Bosutinib Investigator Brochure,
approximately 2478 patients, including 2141 patients with cancer, have received
at least 1 dose of bosutinib in 24 clinical studies.

Bosutinib has shown an acceptable safety profile in the phase 1, phase 2, and
phase 3 studies to date. In general, AEs with bosutinib have included
predominantly low-grade GI toxicities and general symptoms such as fatigue and
asthenia. Other frequent AEs include rash and increases in plasma levels of
hepatic transaminase (alanine aminotransferase [ALT] and aspartate
aminotransferase [AST]). Following continuous daily dose administration in
cancer subjects, most GI AEs resolved with therapy, treatment interruption,
and/or dose reduction and less frequently discontinuation of bosutinib in the
case of dose-limiting toxicities (DLTs).

On 04 September 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. More recently, on 17 January 2013, the CHMP issued a positive opinion
recommending that bosutinib be 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 tyrosine kinase inhibitor(s) and
for whom imatinib, nilotinib and dasatinib are not considered appropriate
treatment options. Those approvals have been granted mainly based on the
results obtained from the phase 1/2 study (B1871006) in adult patients with Ph+
leukemias who had failed prior TKI therapy, with the support of the results
obtained as part of the phase 3 study (B1871008) comparing bosutinib with
imatinib in newly diagnosed chronic phase Ph+ CML patients

This study is a treatment extension protocol aimed to allow long term bosutinib
treatment in patients with chronic or advanced phases Ph+ CML who received
bosutinib in a previous Pfizer sponsored CML study (i.e., Studies B1871006 and
B1871008) and who are thought to have the potential, as judged by the
investigator, to derive clinical benefit from continued treatment with
bosutinib. It will also enable the collection of subsequent TKI therapy and
long-term survival data for these patients, including those who have already
discontinued treatment and are in the long term follow-up phase or who have
completed the parent study. Finally, this study will fulfill the European
Medicines Agency (EMA) post approval requirement for the collection and
analysis of safety data about diarrhea incidence after switch from clinical
study to commercial bosutinib formulation. Every effort should be made to
enroll qualified patients into this extension study. The patients enrolled in
China, due to a lack of local resources, are excluded from the requirements for
pharmacokinetic (PK) and mutational analyses of the BCR ABL kinase domain
testing.

The objectives of the current study are:

1. To allow long term bosutinib treatment in patients with chronic or advanced
phases of Ph+ CML who received bosutinib in a previous Pfizer sponsored CML
study (i.e., studies B1871006 and B1871008) and who have the potential, as
judged by the investigator, to derive clinical benefit from continued reatment
with bosutinib;
2. To collect long term safety and efficacy data for bosutinib;
3. To assess the duration of clinical benefit for Ph+ CML patients treated with
bosutinib;
4. To fulfill the EMA post-approval requirement for the collection and analysis
of safety data about diarrhea incidence after switch from clinical study to
commercial bosutinib formulation.

This is an open-label bosutinib treatment extension protocol. This protocol
will be offered to those bosutinib patients who were previously enrolled in one
of the two parent CML bosutinib studies (B1871006 or B1871008).

Patients to be enrolled will include those who at the time of this protocol
amendment approval, are still receiving bosutinib in either one of the parent
studies and are benefiting from bosutinib treatment as judged by the
investigator, as well as those patients who have already discontinued bosutinib
as part of the parent studies and are in follow up for survival. The former
group will continue to receive bosutinib as part of the extension study; the
latter group will only enter into the long term survival follow up part of the
extension study.

In order to have the most accurate and unbiased statistical analysis of long
term survival, the maximum number of patients who have received bosutinib
should be enrolled in the extension study including those who have completed
the 2 years of follow-up as planned in the study B1871006 and then discontinued
the study. For this purpose every effort should be made to re-contact the
patients who have completed the parent study B1871006 and offer themthe
opportunity to participate in the extension study.

Each patient will remain in the extension study, either on bosutinib treatment
or in long term survival follow-up phase, until the last patient has reached 10
years of follow-up, as calculated from the date of his/her first dose of
bosutinib administered in the parent study. When this milestone is reached, the
present study will be closed. At that time, patients still benefiting from
bosutinib will switch to the most appropriate therapy available at that time.

This is an open-label bosutinib treatment extension protocol. This protocol
will be offered to those bosutinib patients who were previously enrolled in one
of the two parent CML bosutinib studies (B1871006 or B1871008).

In this extension study, patients who are still on treatment will receive
open-label bosutinib. The commercial formulation of bosutinib will be used in
this study. Dosing will be continuous and at the dose currently administered in
the respective parent study. Each patient will receive daily bosutinib until
such time as the last patient reaches 10 years of follow-up, unless disease
progression, unacceptable toxicity, death, withdrawal of consent or Sponsor
study discontinuation occurs.

For a list of the associated side effects and risks, please see section E9 of
this form.

Benefits:
It is possible that the patient's condition or health may improve because of
taking part in this study. However, there is no guarantee that the patient
will benefit in any way. Information from this study may help other people in
the future.