Alternating or Combined Therapy With Axitinib and Bosutinib for Patients With Chronic Myeloid Leukemia in Chronic, Accelerated, or Blastic Phases
Phase: PHASE1
Conditions: Accelerated Phase Chronic Myelogenous Leukemia (CML), Blast Phase Chronic Myelogenous Leukemia (CML), Chronic Phase Phase Chronic Myelogenous Leukemia (CML), Philadelphia Chromosome Positive (Ph+) Phase Chronic Myelogenous Leukemia (CML)
Sponsor: M.D. Anderson Cancer Center

Protocol Page
Alternating or Combined Therapy with Axitinib and Bosutinib for Patients with 
Chronic Myeloid Leukemia in Chronic, Accelerated or Blastic Phases
2015-0787
Core Protocol Information
Short Title 
Axitinib and Bosutinib in CML
Study Chair: 
Prithviraj Bose
Additional Contact:
Andrea L. Booker
Vicky H. Zoeller
Leukemia Protocol Review Group
Additional Memo Recipients:
Recipients List
OPR Recipients (for OPR use only)
None
Study Staff Recipients
None
Department:
Leukemia
Phone:
713-792-7747
Unit:
428
Study Manager:
Carissa G. Jurisprudencia
Full Title: 
Alternating or Combined Therapy with Axitinib and 
Bosutinib for Patients with Chronic Myeloid Leukemia in 
Chronic, Accelerated or Blastic Phases
Public Description:
N/A
Protocol Type:
Standard Protocol
Protocol Phase:
Phase I/Phase II
Version Status:
Activated -- Closed to new patient entry as of 09/23/2019
Version:
11
Document Status:
Saved as "Final"
Submitted by:
Andrea L. Booker--9/16/2019 12:25:43 PM
OPR Action:
Accepted by:  Rosheta McCray -- 9/23/2019 11:51:49 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)

Protocol Body
 
  
Hidden Fields=====================

2015-0787 
January 18, 2018 
Page 1 of 53 
 
1 
 
 
 
Alternating or Combined Therapy with Axitinib and Bosutinib for Patients with Chronic 
Myeloid Leukemia in Chronic, Accelerated or Blastic Phases 
 
 
 
 
 
 
 
 
PI: Prithviraj Bose, M.D. 
Co-PI: Jorge Cortes, M.D. 
 
 
 
 
Department of Leukemia 
 
The University of Texas, MD Anderson Cancer Center 
 
 

2015-0787 
January 18, 2018 
Page 2 of 53 
 
2 
 
 
TABLE OF CONTENTS 
1.0  Objectives and endpoints ................................................................ 3 
1.1 
Objectives ....................................................................................................................... 3 
1.2 
Endpoints ........................................................................................................................ 4 
2.0 Background ....................................................................................... 45 
3.0  Background Drug Information ................................................... 1211 
3.1  
Axitinib (INLYTA®) ................................................................................................ 1211 
3.2  
Bosutinib (BOSULIF®) ................................................................................................ 19 
4.0 Patient Eligibility ............................................................................... 25 
4.1 
Inclusions: ..................................................................................................................... 25 
4.2 
Exclusions: .................................................................................................................... 26 
5.0  Treatment Plan ................................................................................ 27 
5.1 
General .......................................................................................................................... 27 
5.2 
Treatment Plan .............................................................................................................. 27 
5.3       Dose Modifications: ...................................................................................................... 3029 
5.4       Missed Doses .................................................................................................................... 33 
5.5       Duration of Therapy ...................................................................................................... 3433 
5.6 
Prohibited and Restricted Therapies During the Study ............................................. 3433 
6.0  Pretreatment Evaluation ............................................................. 3534 
7.0  Evaluation During Study ............................................................ 3635 
8.0  Criteria for Response ................................................................. 4039 
9.0  Criteria for Removal from the Study ......................................... 4241 
10.0 
Statistical Considerations ....................................................... 4241 
10.1 Sample Size and Estimation of Efficacy. .......................................................................... 4241 
10.2 Safety Monitoring. ............................................................................................................ 4544 
10.3  Data Analyses. ................................................................................................................. 4645 
10.4  
Statistical Considerations for MDASI and QoL ....................................................... 4645 
11.0 
Reporting Requirements ............................................................. 46 
12.0 
Confidentiality Plan ..................................................................... 48 
13.0   References ................................................................................... 49 
 

2015-0787 
January 18, 2018 
Page 3 of 53 
 
3 
 
1.0 
Objectives and endpoints 
 
1.1 
Objectives 
 
1.1.1 Primary: 
 Chronic phase cohort: To assess the rate of major cytogenetic response (MCyR) of an 
alternating schedule of axitinib and bosutinib in patients with chronic myeloid 
leukemia – chronic phase (CML-CP) after failure of/intolerance to ≥3 tyrosine kinase 
inhibitors (TKIs) using standard response criteria1. 
 
 Advanced phase cohort – phase I portion: To determine the recommended phase II 
doses (RPTDs) of axitinib and bosutinib in combination in patients with CML in 
accelerated phase (CML-AP) or blast phase (CML-BP). (AP patients must have 
received ≥1 prior TKI). 
 
 Advanced phase cohort - phase II portion: To evaluate the rate of major hematologic 
response (MaHR) of combined treatment with axitinib and bosutinib in patients with 
CML-AP or CML-BP using standard response criteria1. (AP patients must have 
received ≥1 prior TKI). 
 
1.1.2 Secondary: 
 Chronic phase cohort:  
o To determine the rate of complete cytogenetic response (CCyR), BCR-ABL/ABL 
≤10% and ≤1%, major molecular response (MMR), molecular response 4-log 
(MR4), molecular response 4.5-log (MR4.5), and complete molecular response 
(CMR), overall and at different time points. 
 
o To determine the duration of response (DOR), event-free survival (EFS), 
transformation-free survival (TFS), failure-free survival (FFS) and overall 
survival (OS) for patients with CML-CP treated with alternating axitinib and 
bosutinib after failure of/intolerance to ≥3  TKIs. 
 
o To determine the safety and tolerability of alternating therapy with axitinib and 
bosutinib after failure of/intolerance to ≥3 TKIs. 
 
 Advanced phase cohort – phase I portion: To establish the response rate of concurrent 
administration of axitinib and bosutinib to patients with CML-AP or CML-BP. (AP 
patients must have received ≥1 prior TKI). 
 
 Advanced phase cohort - phase II portion:  
o To determine the rate of complete hematologic response (CHR), complete 
cytogenetic response (CCyR), BCR-ABL/ABL ≤10% and ≤1%, major molecular 
response (MMR), molecular response 4-log (MR4), molecular response 4.5-log 
(MR4.5), and complete molecular response (CMR), overall and at different time 
points of combined treatment with axitinib and bosutinib in patients with CML-
AP or CML-BP. (AP patients must have received ≥1 prior TKI). 

2015-0787 
January 18, 2018 
Page 4 of 53 
 
4 
 
o To determine the DOR, EFS, TFS, FFS and OS for patients with CML-AP or –BP 
treated with combined axitinib and bosutinib. (AP patients must have received ≥1 
prior TKI).   
o To analyze differences in response rates, duration and survival according to pre-
treatment mutations and patient characteristics in both the CP and AP/BP cohorts.   
o To evaluate symptom burden in patients with CML receiving axitinib and 
bosutinib, whether alternating (CP) or in combination (AP/BP). 
 
1.2 Endpoints 
 
1.2.1 Primary: 
 Chronic phase cohort: The rate of major cytogenetic response (MCyR) among 
patients with CML-CP s/p failure of/intolerance to ≥3 TKIs treated with alternating 
axitinib and bosutinib. 
 
 Advanced phase cohort – phase I portion: The maximum tolerated doses (MTDs, up 
to the target doses) of the combination of axitinib and bosutinib among patients with 
CML-AP or –BP. (AP patients must have received ≥1 prior TKI). 
 
 Advanced phase cohort - phase II portion: The major hematologic response (MaHR) 
rate to the combination of axitinib and bosutinib among patients with CML-AP or –
BP. (AP patients must have received ≥1 prior TKI).  
 
1.2.2 Secondary: 
 Chronic phase cohort: The rates of CHR, CCyR, MMR, MR4, MR4.5, CMR, BCR-
ABL/ABL ≤10% and ≤1%, DOR, EFS, TFS, FFS and OS among patients with CML-
CP after resistance and/or intolerance to ≥3 TKIs treated with alternating axitinib and 
bosutinib.  
 Advanced phase cohort – phase I portion: The nature, incidence and severity of 
adverse events (AEs), as determined by history and physical examination and 
laboratory assessment, seen with the combination of axitinib and bosutinib among 
patients with CML-AP or –BP. (AP patients must have received ≥1 prior TKI). 
 Advanced phase cohort - phase II portion: The rates of CHR, CCyR, MMR, MR4, 
MR4.5, CMR, BCR-ABL/ABL ≤10% and ≤1%, DOR, EFS, TFS, FFS and OS 
among patients with CML-AP or –BP receiving combined therapy with axitinib and 
bosutinib. (AP patients must have received ≥1 prior TKI). 
 Characterization of somatic mutations in BCR-ABL at baseline and throughout the 
study in all patients receiving study drugs.MDASI-CML scores in all patients 
receiving study drugs.  
 
2.0 Background 
 
   2.1 Purpose 

2015-0787 
January 18, 2018 
Page 5 of 53 
 
5 
 
 
The basic hypothesis underlying our therapeutic programs in CML is to be able to 
achieve meaningful and sustained suppression of the Philadelphia chromosome and the 
resultant fusion protein, BCR-ABL.  CCyRs have been associated with improved overall 
survival (OS) in CML, while MMRs are associated with improved event-free survival 
(EFS) and possibly more durable CCyRs2. Deeper molecular responses, e.g., MR4, 
MR4.5, or undetectable levels of BCR-ABL do not appear to further improve survival3.   
 
   2.2 Overview of the disease 
 
CML has an incidence of 1-2 cases per 100,000 people and accounts for 15% of 
leukemias in adults. The median age at presentation is 45-55 years, and most cases (85%) 
are diagnosed in CP. Untreated, CML-CP progresses to the accelerated and blastic phases 
(AP and BP) within 3-5 years4. The diagnostic and pathogenetic hallmark of CML is the 
Philadelphia chromosome (Ph, present in 95% of patients), a shortened chromosome 22 
resulting from the t(9;22)(q34;q11) translocation, the molecular consequence of which is 
the creation of the BCR-ABL fusion protein, a constitutively active cytoplasmic tyrosine 
kinase (TK). Nearly all patients with typical CML-CP express a 210-kd-BCR-ABL 
protein5.  
 
CML-BP is defined by the presence of ≥30% leukemic cells in peripheral blood or 
marrow or the presence of extramedullary infiltrates of blast cells, apart from in the 
spleen4. In one-third of cases, the blasts have a lymphoid morphology, express lymphoid 
markers and respond to acute lymphoblastic leukemia (ALL)-like regimens, and in the 
remaining two-thirds of cases, express myeloid markers; the latter comprise a 
heterogeneous group. Criteria derived from multivariate analyses to define CML-AP 
include 15-29% circulating or marrow blasts, or blasts plus promyelocytes in blood or 
marrow >30%, with blasts <30%1, peripheral basophilia (≥20%), thrombocytopenia 
unrelated to therapy (<100,000/µL) and cytogenetic clonal evolution4.   
 
BCR-ABL signaling is causative in CML, activating numerous downstream signaling 
pathways, e.g., JAK-STAT, Ras/Raf/MAPK, JUN, MYC and PI3K/Akt, among others4, 5. 
Disease progression in CML and transformation to BP are accompanied by increased 
BCR-ABL levels, differentiation arrest, genomic instability, inhibition of DNA repair, 
inactivation of tumor suppressor genes and acquisition of additional chromosomal 
abnormalities, e.g., +8, i(17q) and duplicate Ph6.    
 
2.3    First and second generation tyrosine kinase inhibitor (TKI) therapy of CML 
 
            The development of small molecule inhibitors of the oncogenic kinase activity of BCR-
ABL has revolutionized the treatment of CML7, so much so that the rate of OS in newly 
diagnosed patients in CP in all age groups in the TKI era is only slightly lower than, and 
that in patients who achieve CCyR or better within 1 year of treatment is similar to that of 
the general population8. In marked contrast, however, median survival after diagnosis of 
CML-BP currently ranges between 7 and 11 months, compared with 3-4 months in the 
pre-TKI era9. 

2015-0787 
January 18, 2018 
Page 6 of 53 
 
6 
 
 
 
Imatinib 
 
            Imatinib was the first small molecule BCR-ABL TKI to be widely used, being approved 
by the FDA for the treatment of CML in 2001. In addition to ABL and BCR-ABL, it also 
inhibits c-kit and platelet derived growth factor receptor (PDGFR) TKs10. In a large phase 
II study in late CP patients who had failed interferon alfa (IFN-α), it induced MCyRs in 
60% and CHRs in 95%; 89% had not progressed and 95% were alive after a median 
follow-up of 18 months11. These promising findings led to the landmark International 
Randomized Study of Interferon (plus cytarabine) vs. STI571 (IRIS), a phase III, open-
label trial in previously untreated CML-CP patients. The 6-year update of IRIS reported a 
cumulative best CCyR rate of 82%, an estimated EFS at 6 years of 83%, and an estimated 
rate of freedom from progression (FFP) to AP/BP of 93%. The estimated OS rate was 
88% (95% when considering only CML-related deaths)12.     
 
            In a phase II study in patients with CML-AP, imatinib led to sustained hematologic 
responses in 69% (34% CHRs) and MCyRs in 24% (17% CCyRs), with estimated 12-
month progression-free survival (PFS) and OS rates of 59% and 74%, respectively13. 
Among patients with CML in myeloid BP, imatinib induced sustained hematologic 
responses (8% CHRs) in 31%, with a median duration of response (DOR) of 10 months, 
and MCyRs in 16% (7% CCyRs)14. Finally, in a smaller phase II trial in patients with 
relapsed/refractory Ph+ ALL or CML in lymphoid BP, imatinib induced sustained CHRs 
and marrow CRs in 6%, with median estimated time to progression (TTP) and OS for the 
ALL patients being 2.2 and 4.9 months, respectively, while one of eight CML-BP 
patients had a sustained CHR15. 
 
 
Dasatinib   
 
 
Dasatinib is a 2nd generation TKI with a two-log increased potency relative to imatinib 
against BCR-ABL that retains activity against many imatinib-resistant BCR-ABL 
mutants, but not T315I16. Additionally, dasatinib inhibits SRC-family kinases. It was 
approved by the FDA in 2006 for patients with CML or Ph+ ALL resistant to or intolerant 
of prior therapy including imatinib, and in newly diagnosed CML-CP patients in 2010. In 
a large, phase 3 trial, 670 patients with CML-CP resistant/intolerant to imatinib were 
randomized to 4 different dose cohorts of dasatinib17. Estimated 6-year PFS and OS rates 
ranged from 40-51% and 70-77% across the 4 dose cohorts, respectively, and rates of 
survival without transformation ranged from 74-83%. MMR was achieved in 43% of 
patients in the approved 100 mg once daily cohort and 40% of the rest by 6 years17. 
Approval for newly diagnosed CML-CP patients was based on the DASISION trial, that 
compared dasatinib 100 mg/d to imatinib 400 mg/d18. At the final, 5-year analysis of this 
trial, the rates of CCyR (83% vs. 78%), MMR (76% vs. 64%), MR4.5 (42% vs. 33%) and 
transformation to AP/BP (4.6% vs. 7.3%) all significantly favored dasatinib, as did time 
to CCyR and MMR, although PFS and OS were not significantly different19.    
 
 
In a phase II trial in 174 imatinib resistant/intolerant patients with CML-AP receiving 
dasatinib 70 mg bid, CHRs were attained by 45%, and MCyRs and CCyRs by 39% and 

2015-0787 
January 18, 2018 
Page 7 of 53 
 
7 
 
32% of patients, respectively, at a median follow-up of 14.1 months. 12-month PFS and 
OS rates were 66% and 82%, respectively20. In another phase II trial in 157 CML-BP 
patients (109 myeloid, 48 lymphoid), major hematologic responses were achieved in 34% 
and 35% of myeloid and lymphoid BP patients, respectively, MCyRs in 33% and 52%, 
respectively, and CCyRs in 26% and 46%, respectively. Median PFS and OS were 6.7 
and 3 months, and 11.8 and 5.3 months, respectively, in myeloid and lymphoid BP 
patients21. A phase III study in patients with imatinib-resistant/intolerant CML-BP that 
compared dasatinib 140 mg once daily to 70 mg bid found improved tolerability (with 
similar efficacy) for the once-daily regimen22.  
 
 
Nilotinib 
 
 
Nilotinib is a 2nd generation, selective inhibitor of BCR-ABL which is significantly more 
potent than imatinib, and active against a number of imatinib-resistant Bcr-Abl mutants, 
with the exception of T315I23. It was initially FDA-approved in 2007 for the treatment of 
patients with CML-CP and –AP resistant to or intolerant of prior therapy including 
imatinib, and subsequently in 2010 for newly diagnosed patients with CML-CP. 48-
month follow-up of a phase II study of nilotinib in CML-CP patients resistant to or 
intolerant of imatinib yielded a 59% MCyR rate with 45% CCyRs. The estimated rates of 
PFS and OS at 48 months were 57% and 78%, respectively24. The phase III ENESTnd 
trial compared nilotinib 300 or 400 mg bid to imatinib 400 mg/d and served as the basis 
for the approval of nilotinib for frontline use in CML-CP patients. After 1 and 2 years of 
treatment, nilotinib demonstrated significantly faster and higher rates of CCyR, MMR, 
MR4 and MR4.5, as well as significantly lower rates of progression to AP/BP and fewer 
CML-related deaths compared to imatinib25, 26. Estimated 3-year rates of EFS, PFS and 
OS were all higher for both nilotinib arms compared with imatinib27. Long-term 
(minimum 5 years) follow-up of this trial has continued to show significantly higher 
cumulative rates of MMR and MR4.5 in the nilotinib groups, as well as significantly 
fewer progressions to AP/BP28.   
 
Among 137 imatinib-resistant/intolerant patients with CML-AP, 31% attained CHR on nilotinib 
400 mg bid, and 32% achieved MCyRs, with most being CCyRs. Responses were 
durable, with 66% of patients maintaining MCyR at 24 months. The estimated OS and 
PFS rates at 24 months were 70% and 33%, respectively29. Among 136 CML-BP patients 
(105 myeloid, 31 lymphoid), major hematologic responses were achieved in 60% and 
59% of myeloid and lymphoid BP patients, respectively, MCyRs in 38% and 52%, 
respectively, and CCyRs in 30% and 32%, respectively. Median DOR (MCyR) and OS 
were 10.8 and 3.2 months, and 10.1 and 7.9 months, respectively, in myeloid and 
lymphoid BP patients30. 
 
Bosutinib  
 
Bosutinib is a dual Src/Abl inhibitor that potently inhibits BCR-ABL TK activity in CML cells 
and blocks their proliferation, causing complete regression of tumor xenografts in nude 
mice upon once-daily administration31. It was approved by the FDA in 2012 for the 
treatment of patients with CML with resistance or intolerance to prior therapy. 2-year 

2015-0787 
January 18, 2018 
Page 8 of 53 
 
8 
 
(minimum) follow-up of a phase I/II trial of bosutinib as 2nd line therapy for 288 patients 
with imatinib-resistant/intolerant CML-CP showed 85% CHRs, 59% MCyRs and 35% 
MMRs. 2-year estimates of retaining response were >70%, and of PFS and OS were 81% 
and 91%, respectively32. Among 118 patients with CML-CP previously treated with 
imatinib followed by dasatinib and/or nilotinib in another phase I/II study, bosutinib 
produced/maintained MCyRs in 40% and CCyRs in 32% at 4 years of follow-up33, while 
CHR was achieved/maintained in 73% at 2 years. At 2 years, estimated PFS was 73% 
and OS 83%34. Responses to bosutinib were seen across BCR-ABL mutants, with the 
exception of T315I32, 34. 
 
Bosutinib 500 mg/d was compared to imatinib 400 mg/d in 502 newly diagnosed CML-CP 
patients in the phase III BELA trial. The 12-month CCyR rate was not significantly 
different (70% for bosutinib vs. 68% for imatinib); however, the rate of MMR was 
significantly higher with bosutinib (41% vs. 27%). Both CCyR and MMR were reached 
significantly faster with bosutinib, and fewer patients had transformed to AP/BP (2% vs. 
4%) or died (3 vs. 8) compared to imatinib35. Cumulative CCyR rates remained similar 
(79% vs. 80%) at the 24-month time point, while cumulative MMR rates were 59% for 
bosutinib and 49% for imatinib. No new disease progressions occurred between the 12- 
and 24-month analyses with bosutinib; 4 occurred with imatinib36.    
 
The safety of bosutinib has been assessed in both the frontline setting (BELA) and in the context 
of previous therapy. Among patients with 2nd line CML-CP (n=286),  3rd/4th line CML-
CP (n=118) or advanced Ph+ leukemia (n=166) who received bosutinib for a median of 
11.1 months, treatment-emergent adverse events (TEAEs) were primarily GI – diarrhea 
(74-86%), nausea (46-48%) and vomiting (37-43%). Diarrhea was grade 3 or 4 in 8%, 
and 6% required a dose reduction because of diarrhea. Grade 3/4 myelosuppression 
occurred in 41%, and was mostly manageable with treatment interruption (46%) or dose 
reduction (32%). ALT elevation occurred in 17% (grade 3/4 in 7%). Bosutinib re-
challenge was successful in 74% of dose-interrupted patients37. In the BELA trial, the 
toxicity profiles of bosutinib and imatinib were distinct. Diarrhea (70% vs. 26%), 
vomiting (33% vs. 16%), ALT (33% vs. 9%) and AST (28% vs. 10%) elevations and 
pyrexia (19% vs. 12%) were significantly more common with bosutinib, while edema, 
musculoskeletal pain, increased CPK and neutropenia/leukopenia were significantly more 
common with imatinib38.      
 
2.4 
Bcr-Abl kinase domain mutations and resistance to TKI therapy in CML 
 
           Mutations in the kinase domain (KD) of BCR-ABL are the most prevalent mechanism of 
acquired TKI resistance in patients with CML39, 40, and their detection is strongly 
suggestive of the development of clinical resistance41. Amino acid substitutions at seven 
residues (M244V, G250E, Y253F/H, E255K/V, T315I, M351T, and F359V) account for 
85% of all resistance-associated mutations, which are more common in patients with 
advanced phases of CML or Ph+ ALL40. KD mutations are associated with a greater 
likelihood of progression to AP/BP and shorter survival, at least in imatinib-treated 
CML-CP patients40, 42. The T315I “gatekeeper” mutation43 uniformly confers resistance 
to all first and second generation TKIs44. Although primary resistance to imatinib is very 

2015-0787 
January 18, 2018 
Page 9 of 53 
 
9 
 
uncommon45, KD mutations are associated in 30% of cases40 and the T315I mutation has 
been described at diagnosis of CML46. Mutations in the ATP-binding “P-loop” confer 
high level resistance to imatinib and a poor prognosis in imatinib-treated patients40-42. 
 
Both preclinical and clinical studies suggest that the spectra of mutations that confer 
resistance to imatinib, dasatinib and nilotinib are distinct, with cross-resistance being 
limited to T315I44, 47, 48. In one series, 43% of imatinib-treated patients had mutations 
predicting for reduced sensitivity to nilotinib/dasatinib at imatinib cessation or 
commencement of dasatinib/nilotinib, including 14% with T315I48. In another series, the 
prevalence of T315I at the start of 2nd line TKI therapy was 15%, and response rates to 
2nd or 3rd line TKI were similar for patients with and without mutations, regardless of 
mutation site, except for T315I. In this cohort, 26% developed new KD mutations after 
2nd or 3rd line TKI therapy, but only 4% developed T315I49. In general, analyses of the 2nd 
line nilotinib/dasatinib trials in CML-CP patients have shown that the Y253H, E255V/K, 
and F359V/C mutants may respond slightly less favorably to nilotinib50, while high 
response rates and durable efficacy have been reported with dasatinib regardless of BCR-
ABL mutation status, except T315I51. In these and other studies, the frequency of 
mutations among imatinib-resistant patients at initiation of nilotinib/dasatinib was 43-
55%40, 42, 50, 51. Some studies have suggested reduced activity of dasatinib against the 
F317L and V299L mutants48. In the CA180-034 phase III trial that compared 4 
doses/schedules of dasatinib in 670 imatinib resistant/intolerant CML-CP patients, the 3 
mutations that persisted or developed in patients who discontinued dasatinib 100 mg/d 
due to loss of response were V299L, T315I and F317L52.      
 
Ponatinib is a rationally designed, multi-targeted TKI that potently inhibits the BCR-ABL 
T315I mutant, as well as retains activity against other mutants and wild type BCR-ABL 
(pan-BCR-ABL inhibitor)53. However, emergence of compound mutations in a BCR-
ABL allele may confer ponatinib resistance54. 449 heavily pretreated patients with CML 
or Ph+ ALL with resistance or intolerance to dasatinib or nilotinib or who had the T315I 
mutation received ponatinib, initially at 45 mg/d in a phase II trial (PACE)55.  Among 
267 patients with CML-CP, 56%, 46% and 34% achieved MCyR, CCyR and MMR, 
respectively; rates were higher among those with the T315I  mutation (70%, 66% and 
56%, respectively). The estimated rate of a sustained (≥12 months) MCyR was 91%. 
Major hematologic response and MCyR rates among patients with CML-AP (n=83), 
CML-BP (n=62) and Ph+ ALL (n=32) were 55% and 39%, 31% and 23%, and 41% and 
47%, respectively55. At a median follow-up of 27.9 months, 2-year rates of MCyR 
duration, estimated PFS and OS among CML-CP patients were 87%, 67% and 86%, 
respectively. For patients with CML-AP, CML-BP, and Ph+ ALL, estimated OS and PFS 
at 2 years were 72% and 39%, 18% and 11%, and 18% and not available, respectively56.    
 
64% of patients in the PACE trial had ≥1 dose reduction within the first year to manage 
adverse events (AEs). Frequent (≥20%) TEAEs were thrombocytopenia (44%), 
abdominal pain (41%), rash (41%), constipation (37%), headache (37%), dry skin (35%), 
fatigue (29%), pyrexia (29%), nausea (28%), arthralgia (28%), hypertension (26%), 
neutropenia (25%), anemia (22%), myalgia (21%), diarrhea (21%), vomiting (21%), 
increased lipase (21%). The most common serious adverse events (SAEs) were 

2015-0787 
January 18, 2018 
Page 10 of 53 
 
10 
 
pneumonia (7%) and pancreatitis (6%). Arterial thrombotic events were observed in 19% 
(14% serious) patients and included 10% cardiovascular  (7% serious), 7% 
cerebrovascular  (5% serious) and 7% peripheral vascular  (4% serious) events. Venous 
thromboembolic events were observed in 5% (3% serious) of patients56. Because of 
serious safety concerns, ponatinib is currently indicated for the treatment of patients with 
CML or Ph+ ALL with T315I, and for those for whom no other TKI is indicated. The 
drug label carries a black box warning for arterial/venous thrombosis and occlusions 
(≥27%), heart failure (8%) and hepatotoxicity.  
 
Omacetaxine mepesuccinate, a semi-synthetic derivative of homoharringtonine, is a 
protein synthesis inhibitor that is active in CML patients with the T315I mutation after 
TKI failure57. In a phase 2 trial, 77% of 62 CML-CP patients achieved CHR for a median 
of 9.1 months, and 23% MCyR (16% CCyR). Median PFS was 7.7 months. Grade 3/4 
thrombocytopenia, neutropenia and anemia occurred in 76%, 44% and 39%, 
respectively57. The drug was approved by the FDA in 2012 for the treatment of patients 
with CML-CP or –AP after failure of or intolerance to ≥2 TKIs. In the phase II open-
label registration trial, among 46 CML-CP patients who had all received imatinib + 
dasatinib and/or nilotinib, 67% achieved or maintained a hematologic response for a 
median of 7 months. 22% achieved MCyR (4% CCyRs) and median PFS was 7 months. 
Grade 3/4 thrombocytopenia, neutropenia and anemia occurred in 54%, 48% and 33%, 
respectively58. In the final analysis of this study, with 24 months of follow-up, the MCyR 
rate had come down to 18% with a median duration of 12.5 months; responses were 
maintained for at least a year in 3 of 14 responders, and median OS was 40.3 months59. 
MCyR was not achieved in AP patients, whose median OS was 14.3 months59. 
 
2.5 
Rationale for alternating or concurrent therapy with axitinib and bosutinib 
 
Options for the treatment of patients with CML bearing the T315I mutation remain 
unsatisfactory, given the high toxicity of ponatinib and the modest efficacy of 
omacetaxine. Additionally, omacetaxine is highly myelosupressive and requires twice 
daily administration by subcutaneous injection in a healthcare setting. The temporary 
withdrawal of ponatinib by the FDA in view of the high rate of vascular 
thrombotic/occlusive and other adverse events reported in the clinical trials of this agent 
have substantially reduced enthusiasm for its use. As noted above, outcomes for patients 
in CML-BP remain dismal9. Therapeutic options also remain limited for patients in 
CML-AP who exhibit resistance to TKI therapy, as well as for patients with CP disease 
who fail or are intolerant to ≥2 TKIs60. 
 
           Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 
(VEGFRs) that is FDA-approved for the 2nd line therapy of advanced renal cell 
carcinoma at a dose of 5 mg bid. In a large, head-to-head phase III trial vs. sorafenib, it 
demonstrated a highly significant PFS benefit and was better tolerated, with diarrhea, 
hypertension and fatigue being the major AEs61. Very recently, axitinib has been found to 
be a selective and effective inhibitor of BCR-ABL T315I62. The T315I mutation shifts 
the conformational equilibrium of the kinase in favor of an active (DFG-in) A-loop 
conformation, which has more optimal binding interactions with axitinib. Furthermore, 
axitinib fills a different binding space than the 5 commercially available BCR-ABL TKIs. 

2015-0787 
January 18, 2018 
Page 11 of 53 
 
11 
 
Axitinib potently inhibited BCR-ABL T315I, at both biochemical and cellular levels 
(both in cell lines and in primary patient-derived cells), and treatment of a T315I-bearing 
CML patient with axitinib resulted in a rapid reduction of T315I-positive cells from the 
bone marrow. However, axitinib appears to be a selective gatekeeper-mutant inhibitor 
that is less active against BCR-ABL without T315I62. 
 
There has been considerable interest in using rational, noncross-resistant TKI 
combinations in the treatment of CML, particularly in advanced phases of the disease, 
given that the spectrum of resistance-conferring BCR-ABL KD mutations differs 
between individual TKIs, and because novel yet viable ones are unlikely to emerge 
(many mutations would not be viable due to kinase inactivation)45. Indeed, preclinical 
studies have demonstrated both the feasibility and high efficacy of TKI combinations47, 
63. Finally, particularly in chronic phase disease, intermittent therapy with a potent TKI 
could be sufficient to induce apoptosis64, 65. 
 
In light of these considerations, we propose a clinical trial of axitinib and bosutinib in 
patients with CML in 2 cohorts: a phase II study in CP patients who have failed or are 
intolerant to ≥2 other TKIs employing the 2 drugs on an alternating schedule; and a phase 
I/II study in AP/BP patients of the 2 agents in combination. For BP patients, prior therapy 
will not be required, whereas AP patients must have failed or been intolerant to ≥1 TKI in 
order to be eligible. Apart from the mechanistic rationale discussed above, the 
combination of axitinib and bosutinib is a particularly appealing one because of their 
largely non-overlapping toxicity profiles, their excellent safety profiles when used alone, 
and because these 2 agents do not inhibit their own metabolism via CYP3A462. 
     
2.6    MD Anderson Symptom inventory (MDASI) 
 
Symptoms are subjective phenomena reported by patients that indicate a change in 
normal functioning, sensation, or appearance due to disease. Symptom burden is the 
combined impact of disease- and therapy-related symptoms on the ability of persons to 
function as they did prior to onset of their disease and/or therapy. The MDASI is a valid 
and reliable measure of symptom burden66. Recently a CML-specific version of the 
MDASI, the MDASI-CML, that assesses 7 CML-specific symptoms, i.e., diarrhea, 
swelling, rash/skin changes, muscle soreness/cramping, easy bruising/bleeding, malaise 
and headache, in addition to the 13 symptom items and 6 interference items of the core 
MDASI, has been validated67. Common symptoms of chronic myeloid leukemia (CML) 
and its treatment can significantly impair the daily functioning of patients. Symptoms 
such as fatigue, drowsiness, sleep disturbance, memory loss, nausea and vomiting, 
diarrhea, muscle cramps, skin changes, and headache add to the burden of CML67. 
Patients with serious illnesses often report that they would like to “return to a normal 
life”. Decreasing the symptom burden of CML and its treatments will allow patients to 
function as normally as possible. Currently, there is little research on symptoms and their 
impact on daily functioning experienced by patients with CML to direct interventions that 
may assist patients in returning to normal.  
 

2015-0787 
January 18, 2018 
Page 12 of 53 
 
12 
 
We have successfully developed IVR technology for the assessment of multiple 
symptoms using the MDASI in patients with cancer undergoing chemotherapy, radiation 
therapy, and surgery. We currently have one active study in a sample of patients with 
CML, many of whom are receiving kinase inhibitor therapies, using the MDASI-CML. 
Initial evaluation has shown this to be a feasible option for patient-reported symptom 
burden assessment in this group of patients and further evaluation is ongoing. The patient 
chooses the day and the time to receive the IVR system call; the system calls the patient 
three times if necessary to complete the assessment. 
 
3.0 
Background Drug Information 
 
3.1  
Axitinib (INLYTA®) 
 
3.1.1 Product description 
Axitinib is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma 
(RCC) after failure of one prior systemic therapy. Axitinib has the chemical name N-
methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide. The 
molecular formula is C22H18N4OS and the molecular weight is 386.47 Daltons. The 
chemical structure is: 
 
Axitinib is a white to light-yellow powder with a pKa of 4.8. The solubility of axitinib in 
aqueous media over the range pH 1.1 to pH 7.8 is in excess of 0.2 µg/mL. The partition 
coefficient (n-octanol/water) is 3.5. 
Axitinib is supplied as red, film-coated tablets containing either 1 mg or 5 mg of axitinib 
together with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, 
magnesium stearate, and Opadry® II red 32K15441 as inactive ingredients. The Opadry 
II red 32K15441 film coating contains lactose monohydrate, HPMC 2910/Hypromellose 
15cP, titanium dioxide, triacetin (glycerol triacetate), and red iron oxide. 
3.1.2 Storage and handling 
 

2015-0787 
January 18, 2018 
Page 13 of 53 
 
13 
 
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 
86°F). 
 
3.1.3 How supplied 
Axitinib tablets are supplied as follows: 
1 mg tablets are red film-coated, oval tablets debossed with "Pfizer" on one side and "1 
XNB" on the other; available in bottles of 180: NDC 0069-0145-01. 
5 mg tablets are red film-coated, triangular tablets debossed with "Pfizer" on one side and 
"5 XNB" on the other; available in bottles of 60: NDC 0069-0151-11. 
3.1.4 Route of administration and pharmacokinetics 
 
Oral. 
Absorption and Distribution: Following single oral 5-mg dose administration, the median 
Tmax ranges from 2.5 to 4.1 hours. Based on the plasma half-life, steady state is expected 
within 2 to 3 days of dosing. Dosing of axitinib at 5 mg twice daily results in 
approximately 1.4-fold accumulation compared to administration of a single dose. At 
steady state, axitinib exhibits approximately linear pharmacokinetics within the 1-mg to 
20-mg dose range. The mean absolute bioavailability of axitinib after an oral 5 mg dose is 
58%. 
Axitinib can be administered with or without food. 
Axitinib is highly bound (>99%) to human plasma proteins with preferential binding to 
albumin and moderate binding to α1-acid glycoprotein.  
Metabolism and Elimination: The plasma half-life of axitinib ranges from 2.5 to 6.1 
hours. Axitinib is metabolized primarily in the liver by CYP3A4/5 and to a lesser extent 
by CYP1A2, CYP2C19, and UGT1A1 to carboxylic acid, N-glucuronide and sulfoxide 
metabolites. Unchanged axitinib is not detected in urine but is the major component 
identified in feces.  
3.1.5 Availability 
 
Axitinib tablets for this study will provided by Pfizer. 
 
3.1.6 Agent Destruction and Return 
 
Unused/expired drug will be disposed of onsite according to institutional guidelines. 
 
3.1.7 Contraindications 
 

2015-0787 
January 18, 2018 
Page 14 of 53 
 
14 
 
None. 
 
3.1.8 Drug Interactions 
In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser 
extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 
1A1. 
CYP3A4/5 Inhibitors 
Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma 
exposure of axitinib in healthy volunteers. Co-administration of axitinib with strong 
CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase 
axitinib plasma concentrations and should be avoided. Selection of concomitant 
medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a 
strong CYP3A4/5 inhibitor must be co-administered, the axitinib dose should be reduced. 
CYP3A4/5 Inducers 
Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma 
exposure of axitinib in healthy volunteers. Co-administration of axitinib with strong 
CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, 
rifapentin, phenobarbital, and St. John's wort) should be avoided. Selection of 
concomitant medication with no or minimal CYP3A4/5 induction potential is 
recommended. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, 
modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be 
avoided if possible. 
3.1.9 Warnings and Precautions 
Hypertension and Hypertensive Crisis 
In a controlled clinical study with axitinib for the treatment of patients with RCC, 
hypertension was reported in 145/359 patients (40%) receiving axitinib and 103/355 
patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 
patients (16%) receiving axitinib and 39/355 patients (11%) receiving sorafenib. 
Hypertensive crisis was reported in 2/359 patients (<1%) receiving axitinib and none of 
the patients receiving sorafenib. The median onset time for hypertension (systolic blood 
pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month 
of the start of axitinib treatment and blood pressure increases have been observed as early 
as 4 days after starting axitinib. Hypertension was managed with standard 
antihypertensive therapy. Discontinuation of axitinib treatment due to hypertension 
occurred in 1/359 patients (<1%) receiving axitinib and none of the patients receiving 
sorafenib. 

2015-0787 
January 18, 2018 
Page 15 of 53 
 
15 
 
Blood pressure should be well-controlled prior to initiating axitinib. Patients should be 
monitored for hypertension and treated as needed with standard anti-hypertensive 
therapy. In the case of persistent hypertension despite use of anti-hypertensive 
medications, reduce the axitinib dose. Discontinue axitinib if hypertension is severe and 
persistent despite anti-hypertensive therapy and dose reduction of axitinib, and 
discontinuation should be considered if there is evidence of hypertensive crisis. If axitinib 
is interrupted, patients receiving antihypertensive medications should be monitored for 
hypotension. 
Arterial Thromboembolic Events  
In clinical trials, arterial thromboembolic events have been reported, including deaths. In 
a controlled clinical study with axitinib for the treatment of patients with RCC, Grade 3/4 
arterial thromboembolic events were reported in 4/359 patients (1%) receiving axitinib 
and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported 
in 1/359 patients (<1%) receiving axitinib and none of the patients receiving sorafenib. 
In clinical trials with axitinib, arterial thromboembolic events (including transient 
ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery 
occlusion) were reported in 17/715 patients (2%), with two deaths secondary to 
cerebrovascular accident. 
Venous Thromboembolic Events 
In clinical trials, venous thromboembolic events have been reported, including deaths. In 
a controlled clinical study with axitinib for the treatment of patients with RCC, venous 
thromboembolic events were reported in 11/359 patients (3%) receiving axitinib and 
2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were 
reported in 9/359 patients (3%) receiving axitinib (including pulmonary embolism, deep 
vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients 
(1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients 
(<1%) receiving axitinib and none of the patients receiving sorafenib. In clinical trials 
with axitinib, venous thromboembolic events were reported in 22/715 patients (3%), with 
two deaths secondary to pulmonary embolism. 
Hemorrhage 
In a controlled clinical study with axitinib for the treatment of patients with RCC, 
hemorrhagic events were reported in 58/359 patients (16%) receiving axitinib and 64/355 
patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 
(1%) patients receiving axitinib (including cerebral hemorrhage, hematuria, hemoptysis, 
lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving 
sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving axitinib 
(gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib. 
Cardiac Failure 

2015-0787 
January 18, 2018 
Page 16 of 53 
 
16 
 
In a controlled clinical study with axitinib for the treatment of patients with RCC, cardiac 
failure was reported in 6/359 patients (2%) receiving axitinib and 3/355 patients (1%) 
receiving sorafenib. Grade 3/4 cardiac failure was observed in 2/359 patients (1%) 
receiving axitinib and 1/355 patients (<1%) receiving sorafenib. Fatal cardiac failure was 
reported in 2/359 patients (1%) receiving axitinib and 1/355 patients (<1%) receiving 
sorafenib. Monitor for signs or symptoms of cardiac failure throughout treatment with 
axitinib. Management of cardiac failure may require permanent discontinuation of 
axitinib. 
Gastrointestinal Perforation and Fistula Formation 
In a controlled clinical study with axitinib for the treatment of patients with RCC, 
gastrointestinal perforation was reported in 1/359 patients (<1%) receiving axitinib and 
none of the patients receiving sorafenib. In clinical trials with axitinib, gastrointestinal 
perforation was reported in 5/715 patients (1%), including one death. In addition to cases 
of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%). 
Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout 
treatment with axitinib. 
Thyroid Dysfunction 
In a controlled clinical study with axitinib for the treatment of patients with RCC, 
hypothyroidism was reported in 69/359 patients (19%) receiving axitinib and 29/355 
patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) 
receiving axitinib and 4/355 patients (1%) receiving sorafenib. In patients who had 
thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to 
≥10 μU/mL occurred in 79/245 patients (32%) receiving axitinib and 25/232 patients 
(11%) receiving sorafenib. 
Monitor thyroid function before initiation of, and periodically throughout, treatment with 
axitinib. Treat hypothyroidism and hyperthyroidism according to standard medical 
practice to maintain euthyroid state. 
Wound Healing Complications 
No formal studies of the effect of axitinib on wound healing have been conducted. 
Stop treatment with axitinib at least 24 hours prior to scheduled surgery. The decision to 
resume axitinib therapy after surgery should be based on clinical judgment of adequate 
wound healing. 
Reversible Posterior Leukoencephalopathy Syndrome 
In a controlled clinical study with axitinib for the treatment of patients with RCC, 
reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 

2015-0787 
January 18, 2018 
Page 17 of 53 
 
17 
 
patients (<1%) receiving axitinib and none of the patients receiving sorafenib. There were 
two additional reports of RPLS in other clinical trials with axitinib. 
RPLS is a neurological disorder which can present with headache, seizure, lethargy, 
confusion, blindness and other visual and neurologic disturbances. Mild to severe 
hypertension may be present. Magnetic resonance imaging is necessary to confirm the 
diagnosis of RPLS. Discontinue axitinib in patients developing RPLS. The safety of 
reinitiating axitinib therapy in patients previously experiencing RPLS is not known. 
Proteinuria  
In a controlled clinical study with axitinib for the treatment of patients with RCC, 
proteinuria was reported in 39/359 patients (11%) receiving axitinib and 26/355 patients 
(7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) 
receiving axitinib and 6/355 patients (2%) receiving sorafenib. 
Monitoring for proteinuria before initiation of, and periodically throughout, treatment 
with axitinib is recommended. For patients who develop moderate to severe proteinuria, 
reduce the dose or temporarily interrupt axitinib treatment. 
Elevation of Liver Enzymes 
In a controlled clinical study with axitinib for the treatment of patients with RCC, alanine 
aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both 
arms, with Grade 3/4 events in <1% of patients on the axitinib arm and 2% of patients on 
the sorafenib arm. 
Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and 
periodically throughout treatment with axitinib. 
Hepatic Impairment 
The systemic exposure to axitinib was higher in subjects with moderate hepatic 
impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A 
dose decrease is recommended when administering axitinib to patients with moderate 
hepatic impairment (Child-Pugh class B). Axitinib has not been studied in patients with 
severe hepatic impairment (Child-Pugh class C). 
Pregnancy 
Axitinib can cause fetal harm when administered to a pregnant woman based on its 
mechanism of action. There are no adequate and well-controlled studies in pregnant 
women using axitinib. In developmental toxicity studies in mice, axitinib was teratogenic, 
embryotoxic and fetotoxic at maternal exposures that were lower than human exposures 
at the recommended clinical dose. 

2015-0787 
January 18, 2018 
Page 18 of 53 
 
18 
 
3.1.10 Adverse Events (using NCI CTCAE version 3.0)  
 
Adverse Reaction 
Axitinib  
Sorafenib 
(N=359) 
(N=355) 
All Grades Grade 3/4 All Grades Grade 3/4 
% 
% 
% 
% 
Diarrhea 
55 
11 
53 
7 
Hypertension 
40 
16 
29 
11 
Fatigue 
39 
11 
32 
5 
Decreased appetite 
34 
5 
29 
4 
Nausea 
32 
3 
22 
1 
Dysphonia 
31 
0 
14 
0 
Palmar-plantar 
erythrodysesthesia syndrome 
27 
5 
51 
16 
Weight decreased 
25 
2 
21 
1 
Vomiting 
24 
3 
17 
1 
Asthenia 
21 
5 
14 
3 
Constipation 
20 
1 
20 
1 
Hypothyroidism 
19 
<1 
8 
0 
Cough 
15 
1 
17 
1 
Mucosal inflammation 
15 
1 
12 
1 
Arthralgia 
15 
2 
11 
1 
Stomatitis 
15 
1 
12 
<1 
Dyspnea 
15 
3 
12 
3 
Abdominal pain 
14 
2 
11 
1 
Headache 
14 
1 
11 
0 
Pain in extremity 
13 
1 
14 
1 
Rash 
13 
<1 
32 
4 
Proteinuria 
11 
3 
7 
2 
Dysgeusia 
11 
0 
8 
0 
Dry skin 
10 
0 
11 
0 
Dyspepsia 
10 
0 
2 
0 
Pruritus 
7 
0 
12 
0 
Alopecia 
4 
0 
32 
0 
Erythema 
2 
0 
10 
<1 
 
 
 

2015-0787 
January 18, 2018 
Page 19 of 53 
 
19 
 
 
Laboratory Abnormality 
N 
Axitinib 
N 
Sorafenib  
All Grades Grade 3/4 
All Grades Grade 3/4 
% 
% 
% 
% 
Hematology 
Hemoglobin decreased 
320 
35 
<1 
316 
52 
4 
Lymphocytes (absolute) decreased 317 
33 
3 
309 
36 
4 
Platelets decreased 
312 
15 
<1 
310 
14 
0 
White blood cells decreased 
320 
11 
0 
315 
16 
<1 
Chemistry 
Creatinine increased 
336 
55 
0 
318 
41 
<1 
Bicarbonate decreased 
314 
44 
<1 
291 
43 
0 
Hypocalcemia 
336 
39 
1 
319 
59 
2 
ALP increased 
336 
30 
1 
319 
34 
1 
Hyperglycemia 
336 
28 
2 
319 
23 
2 
Lipase increased 
338 
27 
5 
319 
46 
15 
Amylase increased 
338 
25 
2 
319 
33 
2 
ALT increased 
331 
22 
<1 
313 
22 
2 
AST increased 
331 
20 
<1 
311 
25 
1 
Hypernatremia 
338 
17 
1 
319 
13 
1 
Hypoalbuminemia 
337 
15 
<1 
319 
18 
1 
Hyperkalemia 
333 
15 
3 
314 
10 
3 
Hypoglycemia 
336 
11 
<1 
319 
8 
<1 
Hyponatremia 
338 
13 
4 
319 
11 
2 
Hypophosphatemia 
336 
13 
2 
318 
49 
16 
 
3.2 
Bosutinib (BOSULIF®) 
 
3.2.1 Product Description 
Bosutinib is a kinase inhibitor indicated for the treatment of adult patients with CP, AP or 
BP Ph+ CML with resistance or intolerance to prior therapy.. The chemical name for 
bosutinib monohydrate is 3-Quinolinecarbonitrile, 4-[(2,4-dichloro-5-
methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl) propoxy]-, hydrate 
(1:1). Its chemical formula is C26H29Cl2N5O3∙H2O (monohydrate); its molecular 
weight is 548.46 (monohydrate), equivalent to 530.46 (anhydrous). Bosutinib 
monohydrate has the following chemical structure:  

2015-0787 
January 18, 2018 
Page 20 of 53 
 
20 
 
 
Bosutinib monohydrate is a white to yellowish-tan powder. Bosutinib monohydrate has a 
pH dependent solubility across the physiological pH range. At or below pH 5, bosutinib 
monohydrate behaves as a highly soluble compound. Above pH 5, the solubility of 
bosutinib monohydrate reduces rapidly. 
Bosutinib tablets are supplied for oral administration in two strengths: a 100 mg yellow, 
oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "100" on the 
other; and a 500 mg red, oval, biconvex, film-coated tablet debossed with "Pfizer" on one 
side and "500" on the other.  
Each 100 mg bosutinib tablet contains 103.40 mg of bosutinib monohydrate, equivalent 
to 100 mg of bosutinib; each 500 mg bosutinib tablet contains 516.98 mg of bosutinib 
monohydrate, equivalent to 500 mg of bosutinib. The following inactive ingredients are 
included in the tablets: microcrystalline cellulose, croscarmellose sodium, poloxamer, 
povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, 
talc, and iron oxide yellow (for 100 mg tablet) and iron oxide red (for 500 mg tablet).  
3.2.2 Storage and handling 
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 
86°F). 
3.2.3 How supplied 
Bosutinib tablets are supplied for oral administration in two strengths: a 100 mg yellow, 
oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "100" on the 
other; and a 500 mg red, oval, biconvex, film-coated tablet debossed with "Pfizer" on one 
side and "500" on the other. 
 
3.2.4 Route of administration and pharmacokinetics 
 
Oral. 
Absorption 
Following administration of a single dose of bosutinib 500 mg with food in patients with 
cancer, the median time-to-peak concentration (Tmax) was 4–6 hours. Bosutinib exhibits 

2015-0787 
January 18, 2018 
Page 21 of 53 
 
21 
 
dose proportional increases in AUC and Cmax, over the dose range of 200 to 800 mg. 
After 15 daily doses of bosutinib (500 mg) with food in patients with CML, the mean 
(SD) Cmax value was 200 (12) ng/mL, and the mean (SD) AUC was 3650 (425) 
ng∙h/mL. When given with a high fat meal, the Cmax and AUC of bosutinib increased 
1.8- and 1.7-fold, respectively. 
Distribution 
Bosutinib is highly bound to human plasma proteins in vitro (94%) and ex vivo in healthy 
subjects (96%), and binding was not concentration-dependent. Bosutinib is a P-gp 
substrate and inhibitor in vitro. No studies have been conducted with other transporters.  
Metabolism 
Bosutinib is primarily metabolized by CYP3A4 to oxydechlorinated (M2) and N-
desmethylated (M5) bosutinib (major metabolites) and bosutinib N-oxide (M6) - minor 
metabolite. All the metabolites are inactive.  
Elimination 
In patients with CML given single oral doses of bosutinib 500 mg with food, the mean 
terminal phase elimination half-life (t1/2) was 22.5 (1.7) hours, and the mean (SD) 
clearance (Cl/F) was 189 (48) L/h. The vast majority is eliminated in the feces, and a very 
small amount in the urine.  
Hepatic Impairment 
In a dedicated hepatic impairment trial, a single dose of bosutinib 200 mg was 
administered with food to 18 volunteers with hepatic impairment (Child-Pugh classes A, 
B, and C) and 9 matched healthy volunteers. Cmax of bosutinib increased 2.4-fold, 2-
fold, and 1.5-fold, respectively, in Child-Pugh classes A, B, and C, and bosutinib AUC 
increased 2.3-fold, 2-fold, and 1.9-fold, respectively. 
Renal Impairment 
In a dedicated renal impairment trial, a single dose of bosutinib 200 mg was administered 
with food to 26 subjects with mild (CLcr: 51 to 80 mL/min), moderate (CLcr: 30 to 50 
mL/min) or severe renal impairment (CLcr less than 30 mL/min) and to 8 subjects with 
normal renal function. Creatinine Clearance for category classification was calculated by 
the Cockcroft-Gault formula. Subjects with moderate and severe renal impairment had a 
35% and 60% increase in AUC compared to subjects with normal renal function, 
respectively. Bosutinib exposure was not changed in subjects with mild renal impairment. 
The bosutinib dose should be reduced in patients with severe (CLcr less than 30 mL/min) 
or moderate (CLcr between 30 to 50 mL/min) renal impairment. 
3.2.5 Availability 

2015-0787 
January 18, 2018 
Page 22 of 53 
 
22 
 
Bosutinib tablets for this study will be provided by Pfizer. 
 
3.2.6 Agent Destruction and Return  
Unused/expired drug will be disposed of onsite according to institutional guidelines. 
 
3.2.7 Contraindications 
Hypersensitivity to bosutinib. In clinical trials, anaphylactic shock occurred in less than 
0.2% of treated patients. 
 
3.2.8 Drug Interactions 
Drugs That May Increase Bosutinib Plasma Concentrations 
CYP3A or P-glycoprotein (P-gp) inhibitors: Avoid the concomitant use of strong or 
moderate CYP3A and/or P-gp inhibitors with bosutinib as an increase in bosutinib 
plasma concentration is expected. In a dedicated cross-over drug-interaction trial in 
healthy volunteers (N=24), concomitant ketoconazole (strong CYP3A inhibitor) 
increased bosutinib Cmax 5.2-fold and AUC 8.6-fold compared to bosutinib alone. 
Drugs That May Decrease Bosutinib Plasma Concentrations 
CYP3A Inducers: Avoid the concomitant use of strong or moderate CYP3A inducers 
with bosutinib as a large reduction in exposure is expected. In a dedicated cross-over 
drug-interaction trial in healthy volunteers (N=24), concomitant rifampin (strong CYP3A 
inducer) decreased bosutinib Cmax by 86% and AUC by 94% compared to bosutinib 
alone. 
Proton Pump Inhibitors: In a dedicated cross-over drug-interaction trial in healthy 
volunteers (N=24), concomitant lansoprazole (PPI) decreased bosutinib Cmax by 46% 
and AUC by 26% compared to bosutinib alone. 
Consider using short-acting antacids or H2 blockers instead of PPIs to avoid a reduction 
in bosutinib exposure. Separate antacid or H2 blocker dosing and bosutinib dosing by 
more than 2 hours. 
Drugs That May Have Their Plasma Concentrations Altered By Bosutinib 
Substrates of P-glycoprotein: An in vitro study suggests that bosutinib may have the 
potential to increase the plasma concentrations of drugs that are P-gp substrates, such as 
digoxin. 
3.2.9 Warnings and Precautions 
Gastrointestinal Toxicity 
Diarrhea, nausea, vomiting, and abdominal pain occur with bosutinib treatment. Monitor 
and manage patients using standards of care, including antidiarrheals, antiemetics, and 
fluid replacement. In the single-arm Phase 1/2 clinical trial, the median time to onset for 
diarrhea (all grades) was 2 days and the median duration per event was 1 day. Among the 

2015-0787 
January 18, 2018 
Page 23 of 53 
 
23 
 
patients who experienced diarrhea, the median number of episodes of diarrhea per patient 
during treatment with bosutinib was 3 (range 1–221).  
Myelosuppression 
Thrombocytopenia, anemia and neutropenia occur with BOSULIF treatment. Perform 
complete blood counts weekly for the first month of therapy and then monthly thereafter, 
or as clinically indicated.  
Hepatic Toxicity  
One case consistent with drug induced liver injury (defined as concurrent elevations in 
ALT or AST greater than or equal to 3×ULN with total bilirubin greater than 2×ULN and 
alkaline phosphatase less than 2×ULN) occurred in a trial of bosutinib in combination 
with letrozole. The patient recovered fully following discontinuation of bosutinib. This 
case represented 1 out of 1209 patients in bosutinib clinical trials.  
In the 546 patients from the safety population, the incidence of ALT elevation was 17% 
and AST elevation was 14%. Twenty percent of the patients experienced an increase in 
either ALT or AST. Most cases of transaminase elevations occurred early in treatment; of 
patients who experienced transaminase elevations of any grade, more than 80% 
experienced their first event within the first 3 months. The median time to onset of 
increased ALT and AST was 30 and 33 days, respectively, and the median duration for 
each was 21 days. 
Perform hepatic enzyme tests monthly for the first three months of bosutinib treatment 
and as clinically indicated. In patients with transaminase elevations, monitor liver 
enzymes more frequently.  
Fluid Retention 
Fluid retention occurs with bosutinib and may manifest as pericardial effusion, pleural 
effusion, pulmonary edema, and/or peripheral edema. 
In the single-arm Phase 1/2 clinical trial in 546 patients with CML treated with prior 
therapy, severe fluid retention was reported in 14 patients (3%). Specifically, 9 patients 
had a Grade 3 or 4 pleural effusion, 3 patients experienced both Grade 3 or Grade 4 
pleural and pericardial effusions, 1 patient experienced Grade 3 peripheral and pulmonary 
edema, and 1 patient had a Grade 3 edema.  
Renal Toxicity 
An on-treatment decline in estimated glomerular filtration rate (eGFR) has occurred in 
patients treated with bosutinib. Table 2 identifies the shift from baseline to lowest 
observed estimated glomerular filtration rate (eGFR) during bosutinib therapy for patients 

2015-0787 
January 18, 2018 
Page 24 of 53 
 
24 
 
in the global Ph+ Leukemia studies. The median duration of therapy with bosutinib was 
approximately 17 months (range, 0.03 to 95) for patients in these studies. 
Embryofetal Toxicity 
There are no adequate and well controlled studies of bosutinib in pregnant women. 
Bosutinib can cause fetal harm when administered to a pregnant woman. Bosutinib 
caused embryofetal toxicities in rabbits at maternal exposures that were greater than the 
clinical exposure at the recommended bosutinib dose of 500 mg/day. 
3.2.10 Adverse Events 
Chronic Phase CML 
N=406 
Advanced Phase CML 
N=140 
 
All Grades  
(%) 
Grade 3/4 
(%) 
All Grades  
(%) 
Grade 3/4  
(%) 
Diarrhea 
84 
9 
76 
5 
Nausea 
46 
1 
47 
2 
Abdominal Pain 
40 
1 
29 
5 
Thrombocytopenia 
40 
26 
42 
37 
Vomiting 
37 
3 
42 
4 
Rash 
34 
8 
35 
4 
Fatigue 
26 
1 
20 
4 
Anemia 
23 
9 
37 
26 
Pyrexia 
22 
<1 
36 
3 
Increased alanine 
aminotransferase  
20 
7 
10 
5 
Headache 
20 
1 
18 
4 
Cough 
20 
0 
21 
0 
Increased aspartate 
aminotransferase  
16 
4 
11 
3 
Neutropenia 
16 
11 
19 
18 
Edema 
14 
<1 
14 
1 
Arthralgia 
14 
<1 
13 
0 
Decreased appetite 
13 
1 
14 
0 
Respiratory tract infection 
12 
<1 
10 
0 
Nasopharyngitis 
12 
0 
5 
0 
Back pain 
12 
1 
7 
1 
Asthenia 
11 
1 
10 
1 
Pruritus 
11 
1 
8 
0 
Dizziness 
10 
0 
13 
1 
Dyspnea 
10 
1 
19 
6 

2015-0787 
January 18, 2018 
Page 25 of 53 
 
25 
 
 
Chronic Phase CML 
Advanced Phase 
CML 
All CP and 
AdvP CML 
N=406 
N=140 
N=546 
n (%) 
n (%) 
n (%) 
Hematology Parameters 
  Platelet Count (Low) less than 50×109/L 
102 (25) 
80 (57) 
182 (33) 
  Absolute Neutrophil Count less than 1×109/L 
74 (18) 
52 (37) 
126 (23) 
  Hemoglobin (Low) less than 80 g/L 
53 (13) 
49 (35) 
102 (19) 
Biochemistry Parameters 
  SGPT/ALT greater than 5.0×ULN 
39 (10) 
8 (6) 
47 (9) 
  SGOT/AST greater than 5.0×ULN 
17 (4) 
4 (3) 
21 (4) 
  Lipase greater than 2×ULN 
33 (8) 
4 (3) 
37 (7) 
  Phosphorus (Low) less than 0.6 mmol/L 
30 (7) 
10 (7) 
40 (7) 
  Total Bilirubin greater than 3.0×ULN 
3 (1) 
2 (1) 
5 (1) 
 
4.0 Patient Eligibility 
 
4.1 Inclusions: 
 
4.1.1 Diagnosis of Ph+ (by cytogenetics or FISH) or BCR-ABL+ (by PCR) CML in CP (cohort 
1), AP (cohort 2) or BP (cohort 2). 
4.1.2 Patients should have failed (demonstrated resistance, intolerance or treatment 
discontinuation for any other reason of) at least 3 FDA-approved TKIs  if in CP (cohort 
1), or at least 1 FDA-approved TKI  if in AP (cohort 2). Resistance will be defined as 
meeting the criteria for failure or warning by the European LeukemiaNet (ELN, 
Appendix)1. No prior therapy is necessary for patients in BP (cohort 2). Patients in CP 
who have failed <3 TKIs, but are ineligible to receive other FDA-approved TKIs, may 
also be enrolled in cohort 1. At least 10 CP patients with the T315I mutation affecting the 
kinase domain of Bcr-Abl will be enrolled in cohort 1, as well as in the phase II portion 
of cohort 2. 
4.1.3 Age >18 years.  
4.1.4 Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 
4.1.5 Adequate end organ function, defined as the following: total bilirubin ≤1.5 x ULN 
(unless due to Gilbert syndrome, in which case it should be ≤3.0 x ULN), ALT and AST 
≤2.5 x ULN, serum creatinine ≤1.5 x ULN. 
4.1.6 Patients must sign the IRB-approved informed consent document for this trial. 
4.1.7 Reliable telephone access so as to be able to receive calls from an IVR system (only 
applicable to patients participating in the optional symptom burden assessment portion). 
4.1.8 Women of childbearing potential (WOCBP) must practice 2 effective methods of birth 
control during the course of the study. Male patients who are partners of WOCBP should 
also practice an effective method of contraception. Effective methods of birth control 

2015-0787 
January 18, 2018 
Page 26 of 53 
 
26 
 
include diaphragm or condoms with spermicidal foam or jelly, birth control pills (BCPs), 
injections or patches, intra-uterine devices (IUDs) and surgical sterilization. 
 
 Postmenopausal women must be amenorrheic for ≥12 months to be considered of 
non-childbearing potential. 
 Women and men must continue birth control for the duration of the trial and ≥3 
months after the last dose of study drug.  
 All WOCBP MUST have a negative pregnancy test prior to first receiving study 
medication(s).   
 
4.1.9 Patients should have discontinued therapy with imatinib, dasatinib, nilotinib, ponatinib, 
omacetaxine or other anti-leukemia therapy (except hydroxyurea) ≥48 hours prior to start 
of study therapy and recovered from any toxicity due to these therapies to grade ≤1. 
Hydroxyurea may be received up to the time of enrollment and for the first 6 weeks of 
study treatment if necessary.   
 
4.2 
Exclusions: 
 
4.2.1 Prior therapy with axitinib. Prior therapy with bosutinib is allowed, except in the 
following circumstances:  
4.2.1.1 the subject is currently on bosutinib  
4.2.1.2 bosutinib is the subject’s most recent TKI for CML  
4.2.1.3 the subject has a history of intolerance to bosutinib. 
 
4.2.2 Active gastrointestinal conditions that are expected to impair absorption of orally 
administered medications. 
 
4.2.3 Patients who currently have or have a history of the following within 6 months preceding 
study entry are not eligible:  
 
Unstable angina (UA), myocardial infarction (MI), transient ischemic attack 
(TIA), stroke, deep vein thrombosis (DVT), acute peripheral or pulmonary arterial 
thromboembolism (PE).  
 
Clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, 
ventricular fibrillation, or torsades de pointes).  
 
New York Heart Association class III or IV heart failure.  
 
4.2.4 Patients with active, uncontrolled psychiatric disorders including:  psychosis, major 
depressive, and bipolar disorders. 
 
4.2.5 Patients with uncontrolled hypertension (defined as sustained systolic blood pressure 
>160 mmHg or diastolic blood pressure >100 mmHg). 
 

2015-0787 
January 18, 2018 
Page 27 of 53 
 
27 
 
4.2.6 Pregnant or breast-feeding women are excluded. 
 
4.2.7 Inability to understand a written informed consent document. 
 
4.2.8 Patients receiving anticoagulants that are unable to be discontinued. 
 
4.2.9 Patients with active, uncontrolled infection. 
 
4.2.10 Patients with a history of hypersensitivity to bosutinib or axitinib.   
 
4.2.11 Patients on proton pump inhibitors, potent CYP3A or P-glycoprotein substrates, 
inhibitors or inducers – minimum 7 day period washout required unless 
discontinuation or substitution is not in the best interests of the patient as 
determined by the investigator. In instances where use of these agents is felt to be 
required for optimal management, inclusion of such patients should be discussed 
with the PI and the rationale documented. These patients, if enrolled on study, 
may require dose modifications for both axitinib and bosutinib (see further below 
in section 5.6). 
 
The list of drugs that interact with cytochrome P450 enzymes can be found online 
at: 
http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.aspx 
 
5.0 
Treatment Plan 
 
5.1 
General 
All patients should be registered with the Data Management Office PDMS/CORE 
system.  
 
5.2 
Treatment Plan 
Patients will be enrolled in one of two cohorts. Patients in CP will be enrolled in cohort 1, 
and will receive axitinib and bosutinib in alternating, 3-month cycles. Those with BCR-
ABL T315I or with a history of treatment with bosutinib will begin therapy with axitinib, 
whereas those without this KD mutation and no history of having received bosutinib will 
begin therapy with bosutinib. Patients in AP or BP will be enrolled in cohort 2. These 
patients will receive the 2 agents in combination in monthly cycles. As data are not 
available on the tolerability of axitinib and bosutinib in combination, cohort 2 patients 
will initially be dosed according to a “3+3” dose escalation schema (phase I portion) until 
a RPTD is identified. Once the RPTD is defined, all subsequent patients in cohort 2 will 
be treated at this dose (phase II portion).  
  
5.2.1 CML Debulking: patients may receive hydroxyurea for debulking before and during the 
first 6 weeks of therapy.  
 
5.2.2 Therapy:  Patients in cohort 1 will receive axitinib and bosutinib at the FDA-approved 
doses of 5 mg bid and 500 mg/d, respectively, in alternating 3-month cycles. Patients in 

2015-0787 
January 18, 2018 
Page 28 of 53 
 
28 
 
cohort 2 will receive axitinib and bosutinib in combination according to the dose levels 
described below (phase I portion) continuously in monthly cycles. Once the RPTDs are 
determined, subsequent patients in cohort 2 (phase II portion) will be treated at these 
doses. If no MTD is defined up to the target doses (see below) of the two agents in 
combination, then the latter will constitute the RPTDs and the phase II portion of the 
study will begin at this dose. If the MTDs of the two agents in combination are exceeded 
at dose level 0, dose levels -1, -2 and -3 will be explored. Dose levels 3, 4 and 5 are 
provided only for the purposes of dose escalation, at the discretion of the principal or co-
principal investigator, during the phase II portion of the study for cohort 2 patients in 
order to optimize anti-leukemic efficacy as long as there is no grade ≥3 toxicity (see 
section 5.3 (d), Dose escalations). Doses of axitinib and bosutinib may also be escalated 
at the discretion of the principal or co-principal investigator for optimization of anti-
leukemic efficacy in appropriate cohort 1 patients as defined in section 5.3 (d).  
 
Dose Level 
Axitinib  
(mg) orally twice daily 
Bosutinib 
(mg) orally once daily 
 -3 
1 
300 
-2 
2 
300 
-1 
3 
300 
0 (starting 
dose) 
3 
400 
1 
5 
400 
2 (target dose) 
5 
500 
3 
7 
500 
4 
7 
600 
5 
10 
600 
  
5.2.3 Dose escalation schema and definition of dose limiting toxicity (DLT) 
 
Definition of DLT (cohort 2, phase I portion) (in cohort 1 and phase 2 portion of 
cohort 2, this DLT definition will be used for purpose of toxicity monitoring per 
statistical section): DLT will be defined by adverse events occurring during the first 
cycle of therapy that are clinically significant and are not related to CML, concomitant 
medications or comorbidities. 
 
Adverse events will be reported on a scale of 1-4 according to the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 
4.0. 
 
Non-hematologic DLT is defined as any grade ≥3 toxicity that is clinically significant and 
not related to CML, concomitant medications or comorbidities, with the following 
exceptions: 
 Grade 3 or 4 nausea, vomiting and diarrhea will be considered DLT only if not 
controlled by optimal therapy. 
 Grade ≥3 biochemical abnormalities (e.g., lipase or bilirubin elevation) will only be 
considered DLT if accompanied by clinical consequences.  

2015-0787 
January 18, 2018 
Page 29 of 53 
 
29 
 
 Grade ≥3 electrolyte abnormalities will only be considered DLT if not corrected by 
optimal replacement therapy. 
 Grade 3 ALT or AST abnormalities that resolve within 7 days. 
 
Hematologic DLT is defined as follows: 
 Grade ≥3 neutropenia and/or thrombocytopenia with a hypocellular bone marrow 
with <5% bone marrow blasts lasting for ≥6 weeks. Hypocellular bone marrow with 
<5% blasts needs to be confirmed with another bone marrow aspiration and/or biopsy 
within 7 -14 days (1-2 weeks) to be counted as DLT. Once one bone marrow study is 
obtained that meets this criterion, study drugs should be stopped and a repeat bone 
marrow aspiration and/or biopsy done within 7-14 days. If this bone marrow is 
confirmed hypocellular and with <5% blasts, a DLT is defined. The confirmation 
bone marrow aspiration and/or biopsy might occur after the 6 week timepoint. (In 
case of a normocellular bone marrow with <5% blasts, ≥8 weeks of grade ≥3 
neutropenia and/or thrombocytopenia will be considered DLT). Anemia will not be 
considered for the definition of DLT. 
 Cohort 1 (CP) (to be used for purpose of toxicity monitoring per statistical section): 
neutropenia and/or thrombocytopenia grade 4 lasting more than 7 days. 
 
Definition of maximally tolerated dose (MTD): The MTD will be defined as the 
highest dose level at which ≤1 of 6 patients experience a first cycle (i.e., the first month) 
DLT. If no MTD is identified at dose level 2 (i.e., the target dose) , this dose will be 
explored further in the phase II portion of the study and no further dose escalation for the 
purpose of defining an MTD will be pursued. 
 
Patients in cohort 2 will be enrolled on the phase I portion to the above dose levels (see 
5.2.2) according to the following “3+3” schema. DLT is defined above. DLTs will be 
defined only during the first cycle (i.e., the first month) of therapy. Subjects will not be 
enrolled onto a higher dose level until all subjects in the current cohort have completed 
the first cycle of treatment.  
 
Number of Patients with 
DLT at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be entered at 
the next lowest dose level if only 3 patients were treated 
previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
 If 0 of these 3 patients experience DLT, proceed to the next 
dose level. 

2015-0787 
January 18, 2018 
Page 30 of 53 
 
30 
 
 If 1 or more of this group suffer DLT, then dose escalation is 
stopped, and this dose is declared the maximally 
administered dose.  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients were 
treated previously at that dose. 
≤1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is generally the recommended phase 2 dose. At least 6 
patients must be entered at the recommended phase 2 dose. 
  
5.3 
Dose Modifications:  
Dose adjustments for toxicity for one or both drugs will be made, based on attribution, by 
dropping the daily dose to the next lower level (see below). For patients receiving 
combination therapy, the dose of only one drug may be adjusted when the adverse event 
is considered to be related to one of the study drugs. For example, GI toxicities (e.g., 
diarrhea), myelosuppression, hepatotoxicity, fluid retention and nephrotoxicity are more 
likely a result of bosutinib, while hypertension, vascular events, bleeding, CHF, GI 
perforation/fistula formation, thyroid dysfunction, wound healing complications, 
reversible posterior leucoencephalopathy and proteinuria are more likely to be a result of 
axitinib. In instances where it is considered appropriate to stop or delay therapy with one 
agent, administration of the other agent may continue as planned. Doses may be re-
escalated upon resolution of the toxicity to grade ≤1, but not above the starting dose for a 
given patient except as specifically noted under “dose escalations”. 
 
Dose modifications for bosutinib and axitinib 
 
Bosutinib dose 
Axitinib dose 
500 mg/d 
5 mg bid 
400 mg/d 
3 mg bid 
300 mg/d 
2 mg bid 
200 mg/d  
1 mg bid  
 
Dose reductions will be based on the nearest available strength of the pill. Dose 
escalations/reductions different from those described in this table (e.g., dose reductions 
by more than one dose level at a time) should be discussed with the PI or co-PI.  
 
a) Non-Hematologic Toxicity 
 Grade 2: Patients with persistent grade 2 toxicity that is considered clinically 
significant and unresponsive to appropriate therapy may have treatment held until 
the toxicity has resolved to grade <1. Study drug(s) may then be resumed at the 
same dose the patient was receiving at the time treatment was interrupted. If the 
grade 2 toxicity recurs, study drug(s) may be held until the toxicity has resolved 

2015-0787 
January 18, 2018 
Page 31 of 53 
 
31 
 
to grade ≤1. Treatment may then be resumed with a one dose level reduction. 
 
 Patients with sustained grade 2 hypertension (systolic BP 140-159 mmHg or 
diastolic BP 90-99 mmHg) unresponsive to optimal therapy may have treatment 
with axitinib held until hypertension resolved to grade ≤1.  Axitinib may then be 
resumed at the same dose the patient was receiving at the time treatment was 
interrupted.  If sustained grade 2 toxicity recurs, axitinib may be held until the 
toxicity has resolved to grade ≤1.  Treatment may then be resumed with a 1 dose 
level reduction. 
 
 Grade 3-4: If a patient experiences Grade 3-4 toxicity that is considered clinically 
significant and related to study drug(s), therapy must be withheld until the toxicity 
has resolved to Grade < 1. Study drug(s) may then be resumed with a one dose 
level reduction. In the case of elevated liver transaminases not related to 
leukemia, concomitant medications or comorbidities, discontinue bosutinib if 
recovery takes longer than 4 weeks or if grade 4. 
 
 Patients who develop confirmed myocardial infarction, stroke, TIA, peripheral 
arterial occlusive disease, pulmonary thromboembolism, reversible posterior 
leucoencephalopathy, GI perforation or fistula formation or become pregnant on 
study should have axitinib stopped and should be removed from the study. 
 
 If transaminase elevations greater than or equal to 3×ULN occur concurrently 
with bilirubin elevations greater than 2×ULN and alkaline phosphatase less than 
2×ULN, discontinue bosutinib and remove the patient from the study. 
 
b) Hematologic Toxicity – cohort 1 
If granulocytes are <1 x 109/L or platelets are <50 x 109/L, hold therapy until 
granulocytes  ≥1 x 10
9/L and platelets ≥ 50 x 109/l, then resume therapy. 
 
If recovery takes 2 weeks or more, resume study drug(s) at 1 dose level reduction 
from the dose the patient was receiving at the time therapy was interrupted. 
 
If recovery takes less than 2 weeks, resume study drug(s) at the same dose the patient 
was receiving at the time treatment was interrupted. If myelosuppression recurs, 
resume study drug(s) at one dose level reduction from the dose the patient was 
receiving at the time the treatment was interrupted. 
 
If a similar degree of toxicity returns, a further dose reduction by one dose level can 
be performed, using the above procedures.  
 
Hematologic toxicity – cohort 2 
Patients with neutropenia or thrombocytopenia as a consequence of the disease prior 
to the start of therapy do not require treatment interruptions for myelosuppression. 
Dose-reductions and treatment interruptions in these patients should be considered on 
a case by case basis and discussed with the PI or co-PI. No dose-reductions or 

2015-0787 
January 18, 2018 
Page 32 of 53 
 
32 
 
treatment interruptions for myelosuppression are planned during the first month of 
therapy for patients with CML-BP, or for thrombocytopenia for patients with CML-
AP who are classified into CML-AP because of thrombocytopenia. The following 
guidelines can be used for these patients: 
 
Patients with a MaHR and pre-cycle counts of ANC >1 x 109/L and platelets >50 x 
109/L who have sustained low counts of ANC <0.5 x 109/L or platelets <25 x 109/L 
for ≥2 consecutive  
weeks in the current cycle, with <5% blasts in the bone marrow, may receive a 
subsequent course at a one dose level reduction. A reduction of two dose levels may 
be considered if the myelosuppression was deemed severe and life threatening by the 
treating physician, and if it is in the patient's best interest. 
 
If WBC >10 x 109/L and/or absolute blast count >2 x 109/L, may continue treatment 
regardless of neutrophil and platelet count and give transfusions and other support as 
needed. 
 
If WBC is 5 to 10 x 109/L or absolute blast count 0.5 to 2 x 109/L and platelet count 
≥20 x 109/L, may continue treatment at same doses unless drop in platelet count 
represents a decrease of ≥50%, in which case may decrease dose(s) by one level. If 
platelets <20 x 109/L and <50% drop from baseline, also may decrease dose(s) by one 
dose level. 
 
If WBC is <5 x 109/L and absolute blast count <0.5 x 109/L and platelet count ≤20 x 
109/L, may interrupt therapy until platelets ≥50 x 109/L. Then re-start therapy with a 
dose reduction of one dose-level. If WBC increases to >10 x 109/L or blasts to ≥5 x 
109/L before platelets recover, may re-start therapy with a one dose level reduction. 
 
c) Modifications of dose schedules other than the above will be allowed within the 
following guidelines: 
 
 Further dose reductions can be made to keep toxicity grade ≤2. However, the 
lowest acceptable dose of axitinib is 1 mg bid and the lowest acceptable dose of 
bosutinib is 200 mg daily. 
 
 Dose adjustments by more than 1 dose level at a time (e.g., from 5 mg bid to 2 mg 
bid for axitinib or from 500 mg/d to 300 mg/d for bosutinib) can be considered 
when judged to be in the best interests of the patient (e.g., neutropenia with sepsis, 
bleeding requiring platelet transfusions) when toxicity has resolved. The reason 
for this reduction will be discussed with the PI or Co PI and documented in the 
medical record. 
 
 A patient who has had a dose reduction because of any of the reasons mentioned 
above may have their dose escalated provided the patient has remained free of 
toxicity requiring dose adjustments as defined above for at least 1 month. 
Escalation will be made by 1 dose level increments only, and not more frequently 

2015-0787 
January 18, 2018 
Page 33 of 53 
 
33 
 
than every month.  
 
 The maximum allowable daily dose of axitinib is 10 mg bid, and that of bosutinib 
is 600 mg/d, to be possibly used in patients resistant to lower levels, as discussed 
above. 
 
d) Dose escalations  
 
Cohort 1 patients who tolerate axitinib for at least 1 month with no grade ≥3 adverse 
reactions attributable to axitinib (with the same exceptions as noted at the beginning 
of this section under definition of DLT), are normotensive, and are not receiving anti-
hypertensive medications may have their doses escalated if required to optimize 
efficacy from 5 mg bid to 7 mg bid, and then from 7 mg bid to 10 mg bid at the 
discretion of the principal investigator or co-principal investigator.  
 
Cohort 1 patients on 500 mg of bosutinib daily who do not reach CHR by 2 months or 
CCyR by 3 months and do not have grade ≥3 adverse reactions attributable to 
bosutinib (with the same exceptions as noted at the beginning of this section under 
definition of DLT) may have their dose escalated to 600 mg daily at the discretion of 
the principal investigator or co-principal investigator. 
 
As the above dose escalations are within the range approved by the FDA and included 
in the prescribing information for each drug, and as cohort 1 patients will receive the 
drugs as single agents, no formal “3+3” dose escalation is necessary to determine 
safety. 
 
For cohort 2 patients: If no significant anti-leukemic effect is observed after the first 
cycle of therapy and in the absence of grade ≥3 clinically significant non-hematologic 
toxicity that is related to the study drug(s), with the same exceptions as noted at the 
beginning of this section under definition of DLT, patients may be dose-escalated to 
the next dose level, provided the latter has already been deemed safe according to the 
phase I dose escalation rules. Dose levels 3, 4 and 5 are provided only for the 
purposes of dose escalation during the phase II portion of the study. As there is no 
precedent for using these two agents in combination, any dose escalation beyond the 
target doses of the study drugs (5 mg bid of axitinib and 500 mg/d of bosutinib) will 
be conducted only in the context of a rigorous “3+3” schema to assess safety and 
tolerability, following the same dose escalation rules as in the phase I portion. For the 
phase II portion of the study, if patients need to be escalated to dose levels 3, 4 or 5, if 
at any time ≥33% of patients experience DLT at a given dose level during the first 
cycle they receive at that dose, the dose level would be considered to have exceeded 
MTD and should not be used any further.  
5.4 
Missed Doses 
Occasional missed doses will not be considered a deviation.  Missed doses for  ≥2 weeks 
with no proper justification will be considered a protocol deviation. Missed doses will not 
be made up. 

2015-0787 
January 18, 2018 
Page 34 of 53 
 
34 
 
5.5 
Duration of Therapy 
Study treatments will continue as long as patients continue to derive clinical benefit 
without unacceptable toxicity, and the study drugs are available from Pfizer. CP patients 
(cohort 1) who do not reach a CHR (unless there is evidence of improvement in 
cytogenetic or molecular response) by 3 months (1 cycle) will come off study due to lack 
of efficacy. Similarly, AP/BP patients (cohort 2) who exhibit no significant anti-leukemic 
effect (e.g., failure to decrease the WBC count by ≥50% if initial WBC >10 x 109/L, or 
failure to decrease peripheral blood blasts by ≥50% if initial WBC ≤10 x 109/L) after 6 
cycles of therapy (unless there is evidence of improvement in cytogenetic or molecular 
response) will be taken off study.   
 
5.5.1  Consider holding therapy if BCR-ABL is undetectable continuously for ≥2 years and 
patient is aware of the potential risks of treatment discontinuation. 
 
5.5.2   A minimum of 2 full cycles will be required for a patient to be considered as having 
received an adequate trial of the study drugs to evaluate for efficacy unless they 
discontinue therapy because of progressive disease. Patients who fail to complete 2 full 
cycles of therapy will be replaced to reach the planned patient accrual. All patients 
receiving at least one dose of axitinib will be considered evaluable for toxicity. Patients 
achieving a PR or with SD may continue on therapy until definite evidence of disease 
progression.  
 
5.6 
Prohibited and Restricted Therapies During the Study 
 
5.6.1  Prohibited Therapies  
 
No other therapy for the treatment of CML, with the exception of anagrelide 
hydrochloride and/or hydroxyurea, will be permitted while the patient is on study. 
Hydroxyurea use should be limited to the first 6 weeks of therapy. Use of anagrelide, 
WBC colony-stimulating factors (e.g., G-CSF, GM-CSF, etc.), and TPO-mimetics 
(romiplostim, eltrombopag) and erythropoietin, is permitted at the discretion of the 
investigator.  
 
Medications that prolong the QT interval should be avoided, but are not prohibited.  If 
such medications are necessary, and used while a patient is on study, then additional ECG 
monitoring should be performed as clinically indicated.   
 
The list of drugs that can be associated with torsades de pointes or prolonged QT interval 
can be found online at:   
http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm. 
 
The concomitant use of proton pump inhibitors with bosutinib should be avoided 
whenever possible. Instead, the use of short-acting antacids or H2 blockers is 
recommended. Antacid or H2 blocker dosing should be separated from bosutinib dosing 
by ≥2 hours. There is no restriction for use of PPIs in cohort 1 while patients are on 
axitinib therapy. 

2015-0787 
January 18, 2018 
Page 35 of 53 
 
35 
 
 
5.6.2 Restricted Therapies  
 
Ideally, subjects enrolled in this study should not be taking or begin taking medications 
known to prolong the QT interval.  However, should the investigator believe that 
beginning therapy with a potentially QT prolonging medication (other than the ones 
explicitly prohibited) is vital to an individual subject’s care, additional ECG(s) will be 
done as clinically indicated.  
 
Similarly, subjects enrolled in this study should avoid, whenever possible, medications 
that are strong or moderate CYP3A inhibitors or inducers. However, should the 
investigator believe that beginning therapy with a strong or moderate CYP3A inhibitor is 
vital to an individual subject’s care, the dose of axitinib is recommended to be reduced by 
one dose level. Such cases must be discussed with the PI or the co-PI.   
 
6.0 
Pretreatment Evaluation 
 
6.1 
A complete history and physical examination including blood pressure, performance 
status and concomitant medications within 2 weeks prior to start of study treatment. 
 
6.2 
CBC and differential (differential not required if WBC <0.5 x 109/L), coagulation tests 
(PT, PTT, INR), serum sodium, potassium, bicarbonate, calcium, chloride, glucose, 
phosphate, total protein, serum albumin, total bilirubin, SGPT (ALT), SGOT (AST), 
alkaline phosphatase, amylase, lipase, LDH, BUN, creatinine and urinalysis within 1 
week prior to start of study treatment. 
 
6.3 
Bone marrow aspirate for morphology and cytogenetics or FISH within 3 months of 
study enrollment for CP patients (cohort 1), 2 weeks for AP/BP patients (cohort 2). 
 
6.4 
EKG within 2 weeks and echocardiogram within 1 month prior to start of study 
treatment. 
 
6.5 
Pregnancy test (blood or urine) for female patients of childbearing potential within 7 
days (1 week) prior to initiation of study treatment. 
 
6.6 
Peripheral blood or bone marrow for quantitative PCR (QPCR) for BCR-ABL and ABL 
sequencing within 1 month of study enrollment for CP patients (cohort 1), 2 weeks for 
AP/BP patients (cohort 2).  
 
6.7 
MDASI-CML and single item quality of life (QOL) rating completed by patient 
(optional*). 
 
* Missed collection of an optional procedure will not be considered a protocol deviation or 
violation.  
 

2015-0787 
January 18, 2018 
Page 36 of 53 
 
36 
 
7.0 
Evaluation During Study  
   
7.1 
For CP patients (cohort 1): Physical exam (including heart rate, respiratory rate, blood 
pressure and urinalysis with quantification of urinary protein) and evaluation of 
performance status, adverse events and concomitant medications (clinic visit or telephone 
interview) every 3 months (±1 month) for the first year, then every 6-12 months (±1 
month).  If the evaluation for toxicity is done by telephone, a report of the physical exam 
from the home physician is acceptable provided there is a physical exam at MDACC at 
least every 6 months (± 1 month) for the first year and every 12 months (± 1 month) 
thereafter. For AP/BP patients (cohort 2): every month (±1 week) for the first 3 months, 
then every 3 months (±1 month) until the end of the first year, then every 6 months (±1 
month). 
 
7.2 
For CP patients (cohort 1): CBC and differential every 1-2 weeks for 1 month, then every 
4-6 weeks until 1 year from the start of therapy, then every 3 months until 2 years (±1 
month), then every 4 to 6 months thereafter (1 month). For AP/BP patients (cohort 2): 
weekly for the first 3 months, then every 2-4 weeks for the next 3 months, then every 3 
months until 2 years (±1 month), then every 4 to 6 months thereafter (1 month). 
Differential not required if WBC ≤0.5 x 10
9/L.  
 
7.3 
For CP patients (cohort 1): Bone marrow aspirate with cytogenetics or FISH every 3 
months in year 1 (±1 month), then every 4-6 months until 3 years, then as clinically 
indicated. For AP/BP patients (cohort 2): after 1 month (±1 week), then after 3 months 
(±2 weeks), then every 3 months (±1 month) until the end of the first year, then every 6 
months (±1 month) until the end of the second year, then as clinically indicated. 
 
7.4 
For CP patients (cohort 1): Total bilirubin, total protein, serum albumin, SGPT (ALT) or 
SGOT (AST), alkaline phosphatase, amylase, lipase and serum sodium, potassium, 
bicarbonate, chloride, calcium, phosphate, glucose, LDH, BUN and creatinine every 2-4 
weeks for 1 month, then every 4-6 weeks until 1 year from the start of therapy, then every 
3 months until 2 years (±1 month), then every 4 to 6 months thereafter (1 month). For 
AP/BP patients (cohort 2): every 1-2 weeks for the first 3 months, then every 4-6 weeks 
until 1 year from the start of therapy, then every 3 months until 2 years (±1 month), then 
every 4 to 6 months thereafter (1 month). 
 
7.5 
Coagulation tests (PT, PTT, INR) to be conducted approximately every month for the 
first 3 months, then approximately every 3 months. 
 
7.6 
EKGs to be done approximately every 3 months until 1 year from the start of therapy. 
 
7.7 
Echocardiogram after approximately 3 months and 1 year from the start of therapy. 
 
7.8 
Peripheral blood or bone marrow for quantitative PCR (QPCR) every 3 months (± 1 
month). 
 
7.9 
Abl sequencing after 3 months of therapy and at the end of study.  

2015-0787 
January 18, 2018 
Page 37 of 53 
 
37 
 
 
7.10 
MDASI–CML weekly during the first 3 months of treatment, then every other week for 
the remainder of the study. MDASI-CML will be collected on paper, on the computer, or 
by the IVR system. Patients will be instructed during the first visit on the use of the 
Interactive Voice Response (IVR) system (optional*). 
 
7.11 
Single item QOL at each clinic visit during study (optional*). 
 
* Every effort will be made to collect data on optional procedures at all time points for all 
patients; however, missing collection at one or more of these time points in occasional 
consenting patients will not be considered a protocol deviation/violation.  
 
7.12 
Standard tests such as CBC, blood chemistries, EKGs and echocardiograms may be done 
at outside facilities.  Under exceptional circumstances other tests might be done at outside 
facilities after discussion with PI. 
 
7.13 
Patients that come off therapy will continue follow-up for toxicity (clinic visit or 
telephone interview) for 30 days (+/- 5 days) after end of therapy. At the end-of-study 
visit, patients will have a physical exam, including recording of vital signs, weight and 
assessment of performance status, a CBC, urinalysis and serum chemistries, 
PT/PTT/INR, adverse event evaluation, a bone marrow aspiration with cytogenetics or 
FISH, Q-PCR for BCR-ABL, Abl sequencing and all optional tests they may have 
consented for (MDASI-CML and/or other QOL assessments). 
 
7.14 
All study participants will be given study drug diaries to keep a log of each dose of study 
drug(s) taken, the time the dose was taken, and any missed doses along with the reason 
for missing the dose, as well as doses that may be vomited up.  
 
 
 

2015-0787 
January 18, 2018 
Page 38 of 53 
 
38 
 
Study calendar for cohort 1 patients (CML-CP) – 1 cycle = 3 months 
 
Pre- 
Study 
M 
3 
M 
6 
M 
9 
M 
12 
M 
15 
M 
18 
M 
21 
M 
24 
M 
27 
M 
30 
M 
33 
M 
36 
Off Study 
(30±5 days 
after last 
dose)  
Axitinib (A)/Bosutinib (B) 
 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
 
Bosutinib (B)/Axitinib (A) 
 
B 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
A 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
 
ePhysical exam 
X 
Xd 
Xd 
Xd 
Xd 
Every 6-12 months (±1 month) 
X 
eVital signs 
X 
Xd 
Xd 
Xd 
Xd 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
eWeight 
X 
Xd 
Xd 
Xd 
Xd 
Every 4-6  months (±1 month) 
X 
ePerformance status 
X 
Xd 
Xd 
Xd 
Xd 
X 
CBC w/diff (diff not 
required if WBC <0.5 x 
109/l) 
X 
q1-2 weeks for 1 month, 
then q4-6 weeks 
Xd 
Xd 
Xd 
Xd 
q4-6 months (±1 month) 
X 
Serum chemistrya 
X 
q2-4 weeks for 1 month, 
then q4-6 weeks 
Xd 
Xd 
Xd 
Xd 
q4-6 months (±1 month) 
X 
eUrinalysis 
X 
Xd 
Xd 
Xd 
Xd 
Every 4-6 months (±1 month) 
X 
PT, PTT, INR 
X 
Xf 
Xf 
Xf 
Xf 
Every 3 months (±1 month) 
X 
EKG 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Echocardiogram 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Bone marrow aspiration 
X 
Xd 
Xd 
Xd 
Xd 
Every 4-6 months until 3 years, then as clinically 
indicated 
X 
Q-PCR for BCR-ABL 
X 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
X 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------X 
X 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
ABL sequencing 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
MDASI-CML and/or other 
QOL assessmentsc 
X 
MDASI-CML weekly during the first 3 months, then every other week; single-item 
QOL assessment at each clinic visit during study (both optional) 
X 
Axitinib (A):  Dose as assigned; orally twice daily. Patients with the T315I mutation or with a history of prior bosutinib treatment will start 
with axitinib. 
Bosutinib (B):  Dose as assigned; orally once daily. Patients without the T315I mutation and no history of prior bosutinib treatment will start 
with bosutinib.  
aAlbumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium, amylase, lipase. 
bSerum or urine pregnancy test (women of childbearing potential) within 7 days (1 week) prior to initiation of study treatment. 
cOptional.   
   d±1 month.  
   eIf the evaluation for toxicity is done by telephone, a report of the physical exam from the home physician is acceptable provided there is a 
physical exam at MDACC at least every 6 months (±1 month) for the first year and every 12 months (±1 month) thereafter.  
  fEvery month (±1 week) for the first 3 months, then every 3 months (±1 month). 
Patients who receive cycle 1 of study treatment at home will receive a phone call from the designated MDACC research nurse on day 14 (±5 
days) of cycle 1 for assessment of toxicity.  
Please see text (section 7) for details. Standard tests may be done at outside facilities. 
 
 

2015-0787 
January 18, 2018 
Page 39 of 53 
 
39 
 
Study calendar for cohort 2 patients (CML-AP/BP) – 1 cycle = 1 month 
 
Pre- 
Study 
M   
3 
M 
6 
M 
9 
M 
12 
M 
15 
M 
18 
M 
21 
M 
24 
M 
27 
W 
30 
M 
33 
M 
36 
Off Study 
(30±5 days 
after last 
dose) 
Axitinib (A) 
 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
 
Bosutinib (B) 
 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
 
Physical exam 
X 
q1 month (±1 week) for 
the first 3 months, then 
q3months (±1 month) 
 
 
Xe 
 
Xe 
 
Xe 
 
Xe 
X 
Vital signs 
X 
X 
Weight 
X 
 
Xe 
 
Xe 
 
Xe 
 
Xe 
X 
Performance status 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
CBC w/diff (diff not 
required if WBC <0.5 x 
109/L) 
X 
Weekly for 
the first 3 
months, 
then q2-
4weeks  
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
q4-6 months (±1 month) 
X 
Serum chemistrya 
X 
q1-2weeks for the first 3 
months, then q4-6 weeks 
Xe 
Xe 
Xe 
Xe 
q4-6 months (±1 month) 
X 
Urinalysis 
X 
q1month (±1 week) for the 
first 3 months, then 
q3months (±1 month) 
 
Xe 
 
Xe 
 
Xe 
 
Xe 
X 
PT, PTT, INR 
X 
q1month (±1 week) for the first 3 months, then q3months (±1 month) 
X 
EKG 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Echocardiogram 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Bone marrow aspirationd 
X 
Xf 
Xe 
Xe 
Xe 
 
Xe 
 
Xe 
As clinically indicated 
X 
Q-PCR for BCR-ABL 
X 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
X 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------X 
X 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
ABL sequencing 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
MDASI-CML and/or other 
QOL assessmentsc 
X 
MDASI-CML weekly during the first 3 months, then every other week; single-item 
QOL assessment at each clinic visit during study (both optional) 
X 
Axitinib (A):  Dose as assigned; orally twice daily. 
Bosutinib (B):  Dose as assigned; orally once daily. 
aAlbumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium, amylase, lipase. 
bSerum or urine pregnancy test (women of childbearing potential) within 7 days (1 week) prior to initiation of study treatment. 
cOptional.   
    dCohort 2 patients also need a bone marrow aspiration after 1 month (±1 week) of study treatment initiation. 
      e±1 month. 
   f±2 weeks. 
  Patients who receive cycle 1 of study treatment at home will receive a phone call from the designated MDACC research nurse on day 14 (±5  
days) of cycle 1 for assessment of toxicity.  
Please see text (section 7) for details. Standard tests may be done at outside facilities. 
 

2015-0787 
January 18, 2018 
Page 40 of 53 
 
40 
 
 
 
Outside Physician Participation During Treatment 
 
1. 
MDACC Physician communication with the outside physician is required prior to the 
patient returning to the local physician. This will be documented in the patient record. 
2. 
A letter to the local physician outlining the patient's participation in a clinical trial will 
request local physician agreement to participate in the patient's care. 
3. 
Protocol required evaluations outside MDACC will be documented by telephone, fax or 
e-mail.  Fax and/or e-mail will be dated and signed by the MDACC physician, indicating 
that they have reviewed it. 
4. 
Changes in drug dose and/or schedule must be discussed with and approved by the 
MDACC physician investigator, or their representative prior to initiation, and will be 
documented in the patient record. 
5. 
All decisions regarding dose adjustments and treatment interruptions or re-initiation of 
treatment, grading and attribution of adverse events and assessment of efficacy will be 
done by MDACC investigators. The home physician will not make any decisions 
regarding dose adjustments and/or treatment interruptions or resumption of treatment, 
grading and/or attribution of adverse events, or assessment of efficacy. These will all be 
done by the MDACC investigators.  
6. 
Only routine, standard-of-care laboratory assessments will be done by the home 
physician. All protocol-specific tests will be done at MDACC.  
7. 
A copy of the informed consent, protocol abstract, treatment schema and evaluation 
during treatment will be provided to the local physician. 
8. 
Documentation to be provided by the local physician will include drug administration 
records, progress notes, reports of protocol required laboratory and diagnostic studies, 
and documentation of any hospitalizations. 
9. 
The home physician will be requested to report to the MDACC physician investigator all 
life threatening events within 24 hours of documented occurrence. 
10. 
Cohort 1 (CP) patients will return to MDACC every 3-6 months during the first year and 
every 4-6 months thereafter for evaluation. Cohort 2 (AP/BP) patients will return to 
MDACC for evaluation every cycle (1 month) for the first 3 months, then every 2-4 
cycles for the first year, and every 6 (±1) cycles thereafter. 
11. 
Patients who receive cycle 1 of study treatment at home will receive a phone call from 
the designated MDACC research nurse on day 14 (±5 days) of cycle 1 for assessment of 
toxicity.  
 
8.0 
Criteria for Response 
 
8.1 
Complete Hematologic Remission (CHR) – non-palpable spleen and normalization of 
the bone marrow (≤5% blasts) and peripheral blood with WBC <10 x 109/L and ANC ≥1 
x 109/L, <5% basophils, no peripheral myeloblasts or promyelocytes, <5% myelocytes 
plus metamyelocytes, and platelet count 100-450 x 109/L.  This is in addition to 
disappearance of all signs and symptoms of the disease. 
 
8.2 
Morphologic Leukemia-free state (MLFS) – All CHR criteria met except for ≥1 of the 

2015-0787 
January 18, 2018 
Page 41 of 53 
 
41 
 
following:  
a.  20 x 109/L ≤ Platelets <100 x 109/L  
b. 0.5 x 109/L ≤ ANC <1 x 109/L 
 
8.3 
Partial Hematologic Response (PHR) - CHR except for persistence of immature cells 
(myelocytes, metamyelocytes), or splenomegaly < 50% of pretreatment, or 
thrombocytosis >450 x 109/L but <50% of pretreatment. 
 
8.4 
Minor Hematologic Response (MiHR) - <15% bone marrow and peripheral blood 
blasts, <30% blasts + promyelocytes in bone marrow and peripheral blood, <20%  
peripheral 
blood 
basophils 
and 
no 
extra-medullary 
disease 
apart 
from 
hepatosplenomegaly. 
 
8.5 
Major Hematologic Response (MaHR) – Either CHR or MLFS qualifies as a MaHR. 
Thus, the sum of the CHR rate and the rate of MLFS is the MaHR rate.   
 
8.6 
A confirmed HR is obtained when all HR criteria are fulfilled at least 28 days after they 
are first met. 
 
8.7 
Cytogenetic response is classified according to suppression of the Philadelphia 
chromosome (Ph) by conventional karyotyping (FISH if cytogenetic analysis not 
informative, e.g., insufficient metaphases) 
 
8.7.1 No cytogenetic response - Ph positive >95% of pretreatment value 
 
8.7.2 Minimal cytogenetic response – Ph positive 66-95% 
 
8.7.3 Minor cytogenetic response - Ph positive 36-95% of pretreatment value 
 
8.7.4 Partial cytogenetic response - Ph positive 1-35% of pretreatment value 
 
8.7.5 Complete cytogenetic response - Ph positive 0% 
 
* Major cytogenetic response = complete + partial (Ph positive <35%) 
 
8.8 
 Molecular Response  
 
8.8.1 Major (MMR): BCR-ABL/ABL ratio ≤0.1% (IS). Currently, results from the MDACC 
laboratory can be converted to the IS by multiplying the BCR-ABL/ABL ratio by 0.35. 
 
8.8.2 MR4: BCR-ABL/ABL ratio ≤0.01% (IS). 
 
8.8.3 MR4.5: BCR-ABL/ABL ratio ≤0.0035% (IS) 
 
8.8.4 CMR: Undetectable BCR-ABL. 

2015-0787 
January 18, 2018 
Page 42 of 53 
 
42 
 
 
9.0 
Criteria for Removal from the Study 
 
9.1 
Patients with clinically significant progressive disease (excludes patients in CP who 
develop clonal evolution but no other criterion for progression to AP). 
 
9.2 
Poor compliance with study treatments or protocol-mandated study procedures. 
 
9.3 
Unacceptable severe (grade 3-4) toxicity despite dose optimization and optimal 
management of toxicity in the absence of significant anti-leukemic effect. 
 
9.4 
Patient request. 
 
9.5     Lack of appreciable benefit in the presence of better therapeutic options in the opinion of 
the investigator.  
 
10.0 Statistical Considerations 
 
10.1 Sample Size and Estimation of Efficacy.  
 
This is a 2-cohort study of axitinib and bosutinib in CML patients. Cohort 1 will enroll 
CP patients who will receive alternating axitinib and bosutinib. Cohort 2 will enroll 
patients in AP or BP who will receive the two drugs in combination. In cohort 2, it will 
be initially in a phase I dose-finding portion and then in the phase II portion once the 
RPTDs are determined.  
 
A maximum of 52 patients will be enrolled in this study.   
 
Cohort 1:  
Cohort 1 will enroll CP patients who will receive alternating axitinib and bosutinib in 3 
month rotation. A total of 20 patients will be enrolled, including at least 10 with the 
T315I mutation. The primary objective is to evaluate major cytogenetic response during 
the first 12 months of therapy. The target response rate is 20%. There is one prior study 
using bosutinib as third line treatment34. In that study, the rate of MCyR was reported as 
32%34. The following considerations went into effect when choosing this rate as a signal 
to consider further studies of this combination in this setting:  
1.   The prior study34 included 115 patients treated with two prior TKIs and only 3 
patients who had received 3 prior TKIs. In our proposed study, patients are required 
to have received at least 3 prior TKIs, unless ineligible to receive other FDA-
approved TKIs.   
2.   The MCyR rate of 32% in the prior study34 represents a cumulative response reported 
after a median follow-up of 28.5 months. Our 20% goal is set at 12 months of 
therapy, reflecting both the more refractory nature of our patient population, and the 
shorter time requirement for response.  

2015-0787 
January 18, 2018 
Page 43 of 53 
 
43 
 
3.   The design of the proposed study requires that at least 10 of the 20 patients in cohort 
1 have the T315I mutation. Bosutinib alone has no in vitro or in vivo activity against 
this mutation. 
  
The Bayesian approach of Thall, Simon, Estey61 will be implemented for the futility 
monitoring. The following futility stopping rule will be applied in cohort size of 5, 
starting from the 10th patient: prob{p(RR)> 0.2) < 0.08, where p(RR) denotes the 
response rate. That is, the trial will be stopped early due to futility, if during the study we 
determine that there is less than 8% chance that the OR is more than 20%.  Assuming that 
the prior distribution of p(RR) is beta (0.4, 1.6), the stopping boundaries corresponding to 
this futility monitoring rule are shown below in Table 10.1. The operating characteristics 
(OCs) for this futility stopping rule are summarized in Table 10.2. Futility summaries in 
cohorts of five for cohort 1 will be submitted to the medical monitor at the IND office. 
 
Table 10.1. Futility stopping boundaries for cohort 1, in cohort size of 5.  
Number of patients  
Stop the trial if there are this 
many or fewer patients 
achieving RR 
10 
0 
15 
1 
 
             Table 10.2. Operating characteristics for the monitoring of response rate in cohort 1.  
True RR Rate 
Early Stopping 
Probability 
Average 
number of 
patients treated 
0.1 
0.58 
15.4 
0.2 
0.2 
18.5 
0.25 
0.1 
19.2 
0.3 
 0.05 
 19.6 
0.4 
 0.01 
 19.9 
0.5 
0.001 
20.0 
 
Cohort 2:  
 
Cohort 2 will enroll patients in AP or BP who will receive the two drugs in combination, 
initially in a phase I dose-finding portion and then in the phase II portion once the RPTDs 
are determined.  
 
Phase I 
 
First, phase I study is performed to assess the safety of different dosing regimens. Three 
combination dose levels (dose level 0, 1, 2) are defined. A 3+3 design will be used to for 

2015-0787 
January 18, 2018 
Page 44 of 53 
 
44 
 
dose escalation. Detailed dose escalation rules are described in the following section. A 
maximum of 18 patients will enroll in the phase I study.  
 
Dose Escalation Procedures  
 
The dose of treatment agent will be escalated in successive cohorts of patients.    
Patients will be entered sequentially to each dose level.  If none of the first 3 patients at a 
dose level experience first cycle dose-limiting toxicity (DLT), new patients may be 
entered at the next higher dose level. If 1 of 3 patients experience first cycle DLT, up to 3 
more patients are started at that same dose level. If 1of 6 experience DLT, then new 
patients may be entered at the next higher dose level.  If 2 or more experience first cycle 
DLT, no further patients are started at that dose. The MTD is the highest dose level in 
which <2 patients of 6 develop first cycle DLT.  
A cohort summary will be submitted to the medical monitor at the IND office before 
moving to the next dose level for the phase I portion of Cohort 2. 
Phase II 
A total of 20 patients will be enrolled in phase II of cohort 2, including at least 10 with 
the T315I mutation. The 6 patient in the phase I of MTD will be included in phase II part. 
The primary objective is to evaluate hematologic response during the first 3 cycles (1 
month per cycle) of therapy. The target response rate is 30%. The Bayesian approach of 
Thall, Simon, Estey61 will be implemented for the futility monitoring. The following 
futility stopping rule will be applied in cohort size of 5, starting from the 10th patient: 
prob{p(RR)> 0.3) < 0.08, where p(RR) denotes the response rate. That is, the trial will be 
stopped early due to futility, if during the study we determine that there is less than 8% 
chance that the OR is more than 30%.  Assuming that the prior distribution of p(RR) is 
beta (0.6, 1.4), the stopping boundaries corresponding to this futility monitoring rule are 
shown below in Table 10.3. The operating characteristics (OCs) for this futility stopping 
rule are summarized in Table 10.4. Futility summaries in cohorts of five for cohort 2 will 
be submitted to the medical monitor at the IND office. 
 
Table 10.3. Futility stopping boundaries for cohort 2, in cohort size of 5.  
Number of patients  
Stop the trial if there are this 
many or fewer patients 
achieving RR 
10 
1 
15 
2 
 
            Table 10.4. Operating characteristics for the monitoring of response rate in cohort 2.  

2015-0787 
January 18, 2018 
Page 45 of 53 
 
45 
 
True RR Rate 
Early Stopping Probability 
Average number of patients treated 
0.1 
0.74 
 12.1 
0.2 
0.47 
15.7 
0.3 
0.19 
18.3 
0.4 
0.06 
19.5 
0.5 
0.01 
19.9 
 
10.2 Safety Monitoring.  
The Bayesian approach of Thall, Simon, Estey61 will be implemented for toxicity 
monitoring for patients enrolled in cohorts 1 and 2 separately, where toxicity is defined as 
any event meeting the definition of DLT as per section 5.2.3. The toxicity, denoted as 
TOX will be monitored by the Bayesian stopping boundaries calculated based on beta-
binomial distributions. We assume as a priori, p(TOX) ~ beta (0.6, 1.4).  The study will 
be stopped for toxicity if Pr(p(TOX)> 0.30 | data)  >0.85. That is, we will stop the trial 
for new patient enrollment if at any time during the study we determine that there is more 
than 85% chance that the toxicity rate is more than 30%. The toxicity monitoring rule 
will be applied starting from the 5th patient, and then in cohort size of 5. The toxicity will 
be considered continuously throughout the study treatment duration.  Stopping 
boundaries corresponding to this toxicity monitoring rule are shown in Table 10.5 below. 
The operating characteristics for toxicity monitoring are summarized in Table 10.6. 
Toxicity summaries will be submitted to the Medical Monitor at the IND office after 5, 
10, and 15 participants for cohorts 1 and 2. 
 
Table 10.5. Toxicity stopping boundaries in cohort size of 5 for patients enrolled in 
cohorts 1 or 2.   
Number of patients  
Stop the trial if there are this many or 
more patients having toxicity 
5 
3 
10 
5 
15 
7 
 
            Table 10.6. Operating characteristics for toxicity monitoring.  
True Toxicity 
Rate 
Early Stopping 
Probability 
Average 
number of 
patients treated 
0.1 
0.01 
19.9 
0.2 
0.08 
19.0 
0.3 
0.26 
16.8 
0.4 
0.53 
13.5 
0.5 
0.78 
10.1 

2015-0787 
January 18, 2018 
Page 46 of 53 
 
46 
 
10.3  Data Analyses.   
Summary statistics will be provided for continuous variables.  Frequency tables will be  
used to summarize categorical variables.  The response rate will be estimated along with  
the 95% credible interval.  For the time-to event variables, like duration of response,  
overall survival will be estimated by Kaplan-Meier estimates. Data from all subjects who  
receive any study drug will be included in the safety analyses. Subjects who entered the  
study and did not take any of the  study drug and had this confirmed, will not be 
evaluated  for safety. The severity of the toxicities will be graded according to the NCI 
CTCAE v4.0 whenever possible. We will follow standard reporting guidelines for 
adverse events. Concomitant medications will be documented on the case report forms at 
baseline only. All other concomitant medications will be documented in the medical 
record. 
 
10.4  Statistical Considerations for MDASI and QoL   
Continuous variables (e.g., age, hematology values) will be summarized using the mean 
(s.d.) or median (range).  Frequency tables will be used to summarize categorical 
variables.  The t-tests and chi-square tests (or Fisher’s exact tests when sample sizes for 
some categories are smaller than 5) will be used to evaluate the statistical significance 
levels of observed differences.  
 
11.0 Reporting Requirements  
These guidelines will be followed for the recording and reporting of adverse and serious 
adverse events.  
1. Baseline events will be recorded in the medical history section of the case report 
form and will include the terminology event name, grade and start date of the 
event. The medical history section of the case report form will serve as the source 
document for baseline events once signed and dated by the principal investigator. 
a. Baseline events are any medical condition, symptom, or clinically significant 
lab abnormality present before the informed consent is signed. 
i. 
Hematologic laboratory abnormalities will not be recorded as baseline 
events for patients with chronic myeloid leukemia in blast phase. 
ii. 
If exact start date is unknown, month and year or year may be used as 
the start date of the baseline event. 
2. The maximum grade of the adverse event will be captured per course of protocol 
defined visit date. 
3. These adverse events will be recorded in the case report form: 
a. Any grade adverse event that is possibly, probably or definitely related to the 
study drugs(s). 
b. All serious adverse events regardless of attribution to the study drug(s). 
c. Any grade adverse event regardless of attribution to the study drug(s) that 
results in any dose modification. 
4. Hematologic adverse events will not be recorded or reported for studies in 
patients with chronic myeloid leukemia in blast phase except for: 
a. Prolonged myelosuppression as defined by the NCI-CTCAE criteria specific  
for leukemia, e.g., marrow hypocellularity on day 42 or later (6 weeks) from 

2015-0787 
January 18, 2018 
Page 47 of 53 
 
47 
 
start of therapy without evidence of leukemia (<5% blasts), or that results in 
dose modifications, interruptions or meets the protocol definition of DLT or 
SAE. 
5. Serious adverse events will be reported according to institutional policy. 
6. Protocol specific language regarding the recording and reporting of adverse and 
serious adverse events will be followed in the event of discordance between the 
protocol and Leukemic-specific adverse event recording and reporting guidelines. 
 
Serious Adverse Event Reporting (SAE) for M. D. Anderson-Sponsored IND 
Protocols  
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
 Death 
 A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
  A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse 
(21 CFR 312.32). 
 
 Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 
 All events occurring during the conduct of a protocol and meeting the definition of a 
SAE must be reported to the IRB in accordance with the timeframes and procedures 
outlined in “The University of Texas M. D. Anderson Cancer Center Institutional 
Review Board Policy for Investigators on Reporting Unanticipated Adverse Events 
for Drugs and Devices”. Unless stated otherwise in the protocol, all SAEs, expected 
or unexpected, must be reported to the IND Office, regardless of attribution (within 5 
working days of knowledge of the event). 

2015-0787 
January 18, 2018 
Page 48 of 53 
 
48 
 
 
 All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office.  
 
 Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB. 
 
 Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete 
and laboratory tests have returned to baseline, progression of the event has stabilized, 
or there has been acceptable resolution of the event.  
 
 Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
Reporting to FDA: 
 Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional Review 
Board policy. 
 
Investigator Communication with Supporting Companies: 
 
These reports will also be submitted to Pfizer safety (fax number 1-866-997-8322). 
 
Reporting of External SAEs 
 The MDACC institutional policy for reporting of external SAEs will be followed. 
 
 
12.0 Confidentiality Plan 
 
All data will be entered in PDMS/CORE. 
 

2015-0787 
January 18, 2018 
Page 49 of 53 
 
49 
 
 
13.0  References 
 
References  
1. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the 
management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-884.  
2. Cortes J and Kantarjian H. How I treat newly diagnosed chronic phase CML. Blood. 
2012;120(7):1390-1397.  
3. Falchi L, Kantarjian HM, Wang X, et al. Significance of deeper molecular responses in 
patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase 
inhibitors. Am J Hematol. 2013;88(12):1024-1029.  
4. Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM. The biology of chronic 
myeloid leukemia. N Engl J Med. 1999;341(3):164-172.  
5. Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;340(17):1330-1340.  
6. Quintas-Cardama A and Cortes J. Molecular biology of bcr-abl1-positive chronic myeloid 
leukemia. Blood. 2009;113(8):1619-1630.  
7. Druker BJ. Translation of the Philadelphia chromosome into therapy for CML. Blood. 
2008;112(13):4808-4817.  
8. Sasaki K, Strom SS, O'Brien S, et al. Relative survival in patients with chronic-phase chronic 
myeloid leukaemia in the tyrosine-kinase inhibitor era: analysis of patient data from six 
prospective clinical trials. The Lancet Haematology. 2015;2:e186-e193.  
9. Hehlmann R. How I treat CML blast crisis. Blood. 2012;120(4):737-747.  
10. Schiffer CA. BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N 
Engl J Med. 2007;357(3):258-265.  
11. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to 
imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346(9):645-652.  
12. Hochhaus A, O'Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib 
for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009;23(6):1054-1061.  
13. Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic 
responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 
study. Blood. 2002;99(6):1928-1937.  
14. Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic 
responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a 
phase II study. Blood. 2002;99(10):3530-3539.  
15. Ottmann OG, Druker BJ, Sawyers CL, et al. A phase 2 study of imatinib in patients with 
relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood. 
2002;100(6):1965-1971.  
16. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance 
with a novel ABL kinase inhibitor. Science. 2004;305(5682):399-401.  

2015-0787 
January 18, 2018 
Page 50 of 53 
 
50 
 
17. Shah NP, Guilhot F, Cortes JE, et al. Long-term outcome with dasatinib after imatinib failure 
in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood. 
2014;123(15):2317-2324.  
18. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed 
chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260-2270.  
19. Cortes JE, Saglio G, Baccarani M, et al. Final Study Results of the Phase 3 Dasatinib Versus 
Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Trial 
(DASISION, CA180-056). Blood. 2014;124(21):152-152.  
20. Apperley JF, Cortes JE, Kim DW, et al. Dasatinib in the treatment of chronic myeloid 
leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol. 
2009;27(21):3472-3479.  
21. Cortes J, Kim DW, Raffoux E, et al. Efficacy and safety of dasatinib in imatinib-resistant or -
intolerant patients with chronic myeloid leukemia in blast phase. Leukemia. 2008;22(12):2176-
2183.  
22. Saglio G, Hochhaus A, Goh YT, et al. Dasatinib in imatinib-resistant or imatinib-intolerant 
chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy 
and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer. 
2010;116(16):3852-3861.  
23. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective 
inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7(2):129-141.  
24. Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or imatinib-
intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results 
of a phase II study. Leukemia. 2013;27(1):107-112.  
25. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed 
chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251-2259.  
26. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of 
patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic 
myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. 
Lancet Oncol. 2011;12(9):841-851.  
27. Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs imatinib in patients with newly 
diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: 
ENESTnd 3-year follow-up. Leukemia. 2012;26(10):2197-2203.  
28. Larson RA, Kim D, Issaragrisil S, et al. Efficacy and Safety of Nilotinib (NIL) vs Imatinib 
(IM) in Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase 
(CML-CP): Long-Term Follow-Up (f/u) of ENESTnd. Blood. 2014;124(21):4541-4541.  
29. le Coutre PD, Giles FJ, Hochhaus A, et al. Nilotinib in patients with Ph+ chronic myeloid 
leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up 
results. Leukemia. 2012;26(6):1189-1194.  
30. Giles FJ, Kantarjian HM, le Coutre PD, et al. Nilotinib is effective in imatinib-resistant or -
intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia. 2012;26(5):959-
962.  

2015-0787 
January 18, 2018 
Page 51 of 53 
 
51 
 
31. Golas JM, Arndt K, Etienne C, et al. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual 
inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous 
leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res. 
2003;63(2):375-381.  
32. Gambacorti-Passerini C, Brummendorf TH, Kim DW, et al. Bosutinib efficacy and safety in 
chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-
month follow-up. Am J Hematol. 2014;89(7):732-742.  
33. Gambacorti-Passerini C, Khoury HJ, Kantarjian HM, et al. Bosutinib As Third-Line Therapy 
in Patients (Pts) with Chronic Phase Chronic Myeloid Leukemia (CP CML) Following Failure 
with Imatinib Plus Dasatinib and/or Nilotinib: 48-Month Update of a Phase 1/2 Study. Blood. 
2014;124(21):4559-4559.  
34. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic 
myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 
2012;119(15):3403-3412.  
35. Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus imatinib in newly diagnosed 
chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 
2012;30(28):3486-3492.  
36. Brummendorf TH, Cortes JE, de Souza CA, et al. Bosutinib versus imatinib in newly 
diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the 
BELA trial. Br J Haematol. 2015;168(1):69-81.  
37. Kantarjian HM, Cortes JE, Kim DW, et al. Bosutinib safety and management of toxicity in 
leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. 
Blood. 2014;123(9):1309-1318.  
38. Gambacorti-Passerini C, Cortes JE, Lipton JH, et al. Safety of bosutinib versus imatinib in 
the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia. Am J 
Hematol. 2014;89(10):947-953.  
39. Shah NP, Nicoll JM, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer 
polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and 
blast crisis chronic myeloid leukemia. Cancer Cell. 2002;2(2):117-125.  
40. Soverini S, Colarossi S, Gnani A, et al. Contribution of ABL kinase domain mutations to 
imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA 
Working Party on Chronic Myeloid Leukemia. Clin Cancer Res. 2006;12(24):7374-7379.  
41. Branford S, Rudzki Z, Walsh S, et al. Detection of BCR-ABL mutations in patients with 
CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations 
in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 
2003;102(1):276-283.  
42. Soverini S, Martinelli G, Rosti G, et al. ABL mutations in late chronic phase chronic myeloid 
leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater 
likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working 
Party on Chronic Myeloid Leukemia. J Clin Oncol. 2005;23(18):4100-4109.  

2015-0787 
January 18, 2018 
Page 52 of 53 
 
52 
 
43. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy 
caused by BCR-ABL gene mutation or amplification. Science. 2001;293(5531):876-880.  
44. Redaelli S, Piazza R, Rostagno R, et al. Activity of bosutinib, dasatinib, and nilotinib against 
18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009;27(3):469-471.  
45. O'Hare T, Eide CA, Deininger MW. Bcr-Abl kinase domain mutations, drug resistance, and 
the road to a cure for chronic myeloid leukemia. Blood. 2007;110(7):2242-2249.  
46. Roche-Lestienne C, Lai JL, Darre S, Facon T, Preudhomme C. A mutation conferring 
resistance to imatinib at the time of diagnosis of chronic myelogenous leukemia. N Engl J Med. 
2003;348(22):2265-2266.  
47. Bradeen HA, Eide CA, O'Hare T, et al. Comparison of imatinib mesylate, dasatinib (BMS-
354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: 
high efficacy of drug combinations. Blood. 2006;108(7):2332-2338.  
48. Branford S, Melo JV, Hughes TP. Selecting optimal second-line tyrosine kinase inhibitor 
therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL 
mutation status really matter? Blood. 2009;114(27):5426-5435.  
49. Cortes J, Jabbour E, Kantarjian H, et al. Dynamics of BCR-ABL kinase domain mutations in 
chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. 
Blood. 2007;110(12):4005-4011.  
50. Hughes T, Saglio G, Branford S, et al. Impact of baseline BCR-ABL mutations on response 
to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol. 
2009;27(25):4204-4210.  
51. Muller MC, Cortes JE, Kim DW, et al. Dasatinib treatment of chronic-phase chronic myeloid 
leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood. 
2009;114(24):4944-4953.  
52. Shah NP, Rousselot P, Schiffer CA, et al. Seven-Year (yr) Follow-up of Patients (pts) with 
Imatinib-Resistant or -Intolerant Chronic-Phase Chronic Myeloid Leukemia (CML-CP) 
Receiving Dasatinib in Study CA180-034, Final Study Results. Blood. 2014;124(21):520-520.  
53. O'Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic 
myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. 
Cancer Cell. 2009;16(5):401-412.  
54. Zabriskie MS, Eide CA, Tantravahi SK, et al. BCR-ABL1 compound mutations combining 
key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive 
leukemia. Cancer Cell. 2014;26(3):428-442.  
55. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia 
chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783-1796.  
56. Cortes JE, Kim D, Pinilla-Ibarz J, et al. Long-Term Follow-up of Ponatinib Efficacy and 
Safety in the Phase 2 PACE Trial. Blood. 2014;124(21):3135-3135.  
57. Cortes J, Lipton JH, Rea D, et al. Phase 2 study of subcutaneous omacetaxine mepesuccinate 
after TKI failure in patients with chronic-phase CML with T315I mutation. Blood. 
2012;120(13):2573-2580.  

2015-0787 
January 18, 2018 
Page 53 of 53 
 
53 
 
58. Cortes J, Digumarti R, Parikh PM, et al. Phase 2 study of subcutaneous omacetaxine 
mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of 
tyrosine kinase inhibitors. Am J Hematol. 2013;88(5):350-354.  
59. Cortes JE, Kantarjian HM, Rea D, et al. Final analysis of the efficacy and safety of 
omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid 
leukemia: Results with 24 months of follow-up. Cancer. 2015.  
60. Jabbour E and Kantarjian H. Chronic myeloid leukemia: 2014 update on diagnosis, 
monitoring, and management. Am J Hematol. 2014;89(5):547-556.  
61. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib 
in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 
2011;378(9807):1931-1939.  
62. Pemovska T, Johnson E, Kontro M, et al. Axitinib effectively inhibits BCR-ABL1(T315I) 
with a distinct binding conformation. Nature. 2015;519(7541):102-105.  
63. O'Hare T, Walters DK, Stoffregen EP, et al. Combined Abl inhibitor therapy for minimizing 
drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib. 
Clin Cancer Res. 2005;11(19 Pt 1):6987-6993.  
64. Shah NP, Kasap C, Weier C, et al. Transient potent BCR-ABL inhibition is sufficient to 
commit chronic myeloid leukemia cells irreversibly to apoptosis. Cancer Cell. 2008;14(6):485-
493.  
65. O'Hare T, Eide CA, Agarwal A, et al. Threshold levels of ABL tyrosine kinase inhibitors 
retained in chronic myeloid leukemia cells determine their commitment to apoptosis. Cancer 
Res. 2013;73(11):3356-3370.  
66. Cleeland CS, Mendoza TR, Wang XS, et al. Assessing symptom distress in cancer patients: 
the M.D. Anderson Symptom Inventory. Cancer. 2000;89(7):1634-1646.  
67. Williams LA, Garcia Gonzalez AG, Ault P, et al. Measuring the symptom burden associated 
with the treatment of chronic myeloid leukemia. Blood. 2013;122(5):641-647.