A Randomized Phase II Study of Ruxolitinib (NSC-752295) in Combination With BCR-ABL Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia (CML) Patients With Molecular Evidence of Disease
Phase: PHASE2
Conditions: Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Sponsor: SWOG Cancer Research Network

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PRIVILEGED COMMUNICATION  
FOR INVESTIGATIONAL USE ONLY 
TITLE 
SWOG 
 
A RANDOMIZED PHASE II STUDY OF RUXOLITINIB (NSC-752295) IN COMBINATION WITH 
BCR- ABL TYROSINE KINASE INHIBITORS IN CHRONIC MYELOID LEUKEMIA (CML) 
PATIENTS WITH MOLECULAR EVIDENCE OF DISEASE 
 
NCT #03654768 
 
STUDY CHAIRS: 
Srinivas K. Tantravahi, MBBS 
Huntsman Cancer Institute 
University of Utah 
Clinical Trials Office 
2000 Circle of Hope Drive 
Salt Lake City, UT 84112 
Phone: 801/585-9682 
FAX: 801/585-0160 
E-mail: Srinivas.tantravahi@hci.utah.edu 
Jerald P. Radich, M.D. (Medical Oncology) 
Fred Hutchinson Cancer Research Center 
1100 Fairview Avenue N, D4-100 
Seattle, WA 98109 
Phone: 206/667-4118 
FAX: 206/667-2917 
E- mail: jradich@fredhutch.org 
AGENTS: 
 
SWOG-Held IND Agents: 
Ruxolitinib (Jakafi®) (NSC-752295) (IND-138173)  
 
Commercially Available Agents: 
Bosutinib (Bosulif®) (NSC-TBD) 
Dasatinib (BMS-354825) (NSC-732517) 
Imatinib(Gleevec®) (STI-571)(NSC-716051) 
Nilotinib (Tasigna®) (NSC-747599) 
 
BIOSTATISTICIANS: 
 
Megan Othus, Ph.D. (Biostatistics) 
Anna Moseley, M.S. (Biostatistics) 
SWOG Statistics and Data Management Center 
Fred Hutchinson Cancer Research Center 
1100 Fairview Avenue North, M3-C102 
P.O. Box 19024 
 
Seattle, WA 981019-1024  
Phone: 206/667-4523  
FAX: 206/598-6189  
FAX:  206/667-4408 
E-mail: mothus@fredhutch.org 
E-mail: amoseley@fredhutch.org 
 
 
 
 
 

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PARTICIPANTS 
U.S.-Only Participants: 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG 

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TABLE OF CONTENTS 
TITLE  .......................................................................................................................................................... 1 
PARTICIPANTS ............................................................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................................... 3 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 5 
SCHEMA ....................................................................................................................................................... 6 
1.0 
OBJECTIVES.................................................................................................................................... 7 
1.1 
Primary Objective ............................................................................................................................. 7 
1.2 
Secondary Objectives ...................................................................................................................... 7 
1.3 
Additional Objectives ........................................................................................................................ 7 
2.0 
BACKGROUND ................................................................................................................................ 7 
2.1 
Knowledge Gap/Clinical Need to be Addressed .............................................................................. 7 
2.2 
How Study Results will Help Patients or Lead to New Paradigms in Clinical Cancer Research ..... 7 
2.3 
Background Data to Support the Intervention and/or Endpoint Measurements Selected ............... 8 
3.0 
DRUG INFORMATION ................................................................................................................... 14 
3.1 
Bosutinib ........................................................................................................................................ 14 
3.2 
Dasatinib (BMS-354825) (NSC-732517) ....................................................................................... 16 
3.3 
Imatinib (Gleevec®)(STI-571) (NSC-716051) ................................................................................ 22 
3.4 
Nilotinib (Tasigna®) (NSC-747599) ............................................................................................... 23 
3.5 
Ruxolitinib (Jakafi®) (NSC-752295) (IND-138173) ........................................................................ 30 
4.0 
DIAGNOSTIC CRITERIA ................................................................................................................ 33 
4.1 
Diagnostic Criteria .......................................................................................................................... 33 
4.2 
Chronic Phase ................................................................................................................................ 34 
4.3 
Risk Category Based on Hasford Score and Sokal Score ............................................................. 34 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................. 34 
5.1 
Disease Related Criteria ................................................................................................................ 35 
5.2 
Prior/Concurrent Therapy Criteria .................................................................................................. 35 
5.3 
Clinical/Laboratory Criteria ............................................................................................................. 35 
5.4 
Specimen Submission Criteria ....................................................................................................... 36 
5.5 
Regulatory Criteria ......................................................................................................................... 36 
6.0 
STRATIFICATION FACTORS ........................................................................................................ 37 
7.0 
TREATMENT PLAN ....................................................................................................................... 37 
7.1 
Treatment ....................................................................................................................................... 37 
7.2 
Drug Compliance Documentation .................................................................................................. 38 
7.3 
Concomitant and Prohibited Therapies and Supportive Care ....................................................... 38 
7.4 
Criteria for Removal from Protocol Treatment ............................................................................... 40 
7.5 
Discontinuation of Treatment ......................................................................................................... 41 
7.6 
Follow-Up Period ............................................................................................................................ 41 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS ............................................... 41 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 41 
8.2 
General Considerations ................................................................................................................. 41 
8.3 
Dose Modifications ......................................................................................................................... 42 
8.4 
Dose Modification Contacts ........................................................................................................... 44 
8.5 
Adverse Event Reporting Requirements........................................................................................ 44 
9.0 
STUDY CALENDARS .................................................................................................................... 50 
9.1 
Arm 1: Single Agent TKI................................................................................................................. 51 
9.2 
Arm 2: TKI + Ruxolitinib ................................................................................................................. 53 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ...................................................... 55 
10.1 
Molecular Response ...................................................................................................................... 55 
10.2 
Progression .................................................................................................................................... 55 
10.3 
Treatment Failure/Loss of Response** .......................................................................................... 56 
10.4 
Progression-Free Survival (PFS) ................................................................................................... 56 
10.5 
Overall Survival (OS) ..................................................................................................................... 56 
10.6 
Performance Status ....................................................................................................................... 56 
11.0 
STATISTICAL CONSIDERATIONS ............................................................................................... 57 
11.1 
Primary Endpoint: Rate of MR4.5 at 12 Months ............................................................................ 57 

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11.2 
Study Design Justification .............................................................................................................. 57 
11.3 
Secondary and Other Analyses ..................................................................................................... 57 
11.4 
Sample Size and Accrual Rate ...................................................................................................... 58 
11.5 
Data and Safety Monitoring Committee ......................................................................................... 58 
12.0 
DISCIPLINE REVIEW ..................................................................................................................... 58 
13.0 
REGISTRATION GUIDELINES ...................................................................................................... 58 
13.1 
Registration Timing ........................................................................................................................ 58 
13.2 
Investigator/Site Registration ......................................................................................................... 59 
13.3 
CTEP Registration Procedures ...................................................................................................... 59 
13.4 
CTSU Registration Procedures ...................................................................................................... 60 
13.5 
Oncology Patient Enrollment Network (OPEN) Registration Requirements .................................. 62 
13.6 
Exceptions to SWOG registration policies will not be permitted. ................................................... 63 
14.0 
DATA SUBMISSION SCHEDULE.................................................................................................. 64 
14.1 
Data Submission Requirement ...................................................................................................... 64 
14.2 
Master Forms ................................................................................................................................. 64 
14.3 
Data Submission Procedures ........................................................................................................ 64 
14.4 
Data Submission Overview and Timepoints .................................................................................. 65 
15.0 
SPECIAL INSTRUCTIONS ............................................................................................................. 67 
15.1 
Local BCR-ABL Quantification (REQUIRED) ................................................................................ 68 
15.2 
Specimens for Translational Medicine (Central BCR-ABL Quantification) and Banking (Optional 
for Patient) ...................................................................................................................................... 69 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................................... 69 
17.0 
BIBLIOGRAPHY ............................................................................................................................. 71 
18.0 
APPENDIX ...................................................................................................................................... 73 
18.1 
Intake Calendar – Bosutinib ........................................................................................................... 74 
18.2 
Intake Calendar - Dasatinib ........................................................................................................... 79 
18.3 
Intake Calendar - Imatinib .............................................................................................................. 84 
18.4 
Intake Calendar - Nilotinib .............................................................................................................. 89 
18.5 
Intake Calendar - Ruxolitinib .......................................................................................................... 94 
18.6 
Specimen Banking Instructions for the SWOG Biospecimen Bank ............................................... 99 
18.7 
Drugs Known to be Metabolized by CYP450 Isoenzyme 3A4 ..................................................... 100 
 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal: 
(Sign in at www.ctsu.org, and 
select the Regulatory > 
Regulatory Submission.) 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately 
at 1-866-651-2878 to receive 
further information and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN can be 
accessed at  
https://www.ctsu.org/OPEN_SYS  
TEM/ or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with 
any OPEN-related questions at  
ctsucontact@westat.com. 
Data collection for this study will 
be done exclusively through 
Medidata Rave. Please see the 
data submission section of the 
protocol for further instructions. 
Do not submit study data or 
forms to CTSU Data Operations. 
Do not copy the CTSU on data 
submissions. 
Other Tools and Reports: 
Institutions participating through 
the CTSU continue to have 
access to other tools and reports 
available on the SWOG CRA 
Workbench via the SWOG 
website (www.swog.org). 
The most current version of the study protocol and all supporting documents must be downloaded from 
the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires user log on with CTEP- 
IAM username and password. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS. 
For patient eligibility or data submission questions contact the SWOG Statistics and Data 
Management Center by phone or email: 
206/652-2267 
leukemiaquestion@crab.org 
For treatment or toxicity related questions contact the Study Chairs: Srinivas K. Tantravahi at 
801/585-9682 or Jerald Radich at 206/667-4118. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
The CTSU Website is located at https://www.ctsu.org. 

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ARM 2 
(Investigational) 
Continue current 
Single Agent TKI 
and add 
Ruxolitinib 
Continue current TKI 
+ 
Ruxolitinib 
x maximum 4 cycles* 
(or until a criterion for 
removal has otherwise 
been met) 
 
SCHEMA 
 
 
 
 
 
 
 
 
* 
One Cycle = 90 days. 
** After Cycle 4 of protocol therapy, patients will be removed from protocol therapy. After removal from 
protocol therapy, the patient may remain on single-agent TKI therapy at the discretion of the treating 
physician; however, it will not be considered “protocol therapy.” Treatment during follow-up will be 
at the discretion of the treating physician. 
Patient is receiving single agent TKI 
(Bosutinib, Dasatinib, Imatinib OR Nilotinib) 
RANDOMIZATION 
ARM 1 
(Control) 
Continue current 
Single Agent TKI 
Continue current TKI x 
maximum 4 cycles* 
(or until a criterion for 
removal has otherwise 
been met) 
Off Protocol Therapy** 
(follow up for 5 years after initial randomization) 

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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
a. 
To compare the rate of molecular response 4.5 (MR4.5) after 12 months of 
combination therapy with ruxolitinib plus a TKI (bosutinib, dasatinib, imatinib or 
nilotinib) versus a TKI alone, based on local PCR testing to measure BCR-ABL 
transcripts in chronic phase CML patients with molecular evidence of disease. 
 
1.2 
Secondary Objectives 
 
a. 
To estimate the frequency and severity of toxicities of each regimen in this patient 
population. 
 
b. 
To estimate progression free survival and overall survival of each regimen in this 
patient population. 
 
1.3 
Additional Objectives 
 
a. 
To describe patterns of MR4.5 and MR4.0 attainment and failure over the 3, 6, 9, 
and 12-month time points of each regimen in this patient population. 
 
b. 
To evaluate drug compliance based on patient reported drug intake calendars in 
this patient population. 
 
c. 
To describe the kinetics of response in this patient population (as measured by 
quantitative BCR-ABL/BCR ratio) in both arms over the 3, 6, 9, and 12-month time 
points. 
 
2.0 
BACKGROUND 
 
2.1 
Knowledge Gap/Clinical Need to be Addressed 
 
The bone marrow microenvironment in chronic phase CML is believed to contribute to 
tyrosine kinase inhibitor (TKI) resistance in leukemic stem cells (LSC). Resistance in LSCs 
results in minimal residual disease (MRD) in CML. This resistance is due to 
phosphorylation of STAT3, which creates a protective niche in the bone marrow. We 
hypothesize that the addition of the JAK2 inhibitor, ruxolitinib, to BCR-ABL TKIs in chronic 
phase CML patients will decrease the phosphorylation of STAT3, which will alter the 
protective bone marrow microenvironment, causing the LSCs to become susceptible to TKI 
induced apoptosis. In turn, this would be expected to result in eradication of MRD. 
 
2.2 
How Study Results will Help Patients or Lead to New Paradigms in Clinical Cancer 
Research 
 
Patients with chronic phase CML who have achieved deep molecular responses are often 
considered eligible to attempt discontinuation of their TKI. A subset of patients is able to 
successfully remain off protocol treatment, however 50-60% of patients will relapse quickly 
after stopping treatment, and this is because they harbor MRD in the bone marrow. If 
ruxolitinib successfully alters the bone marrow microenvironment such that MRD is 
eradicated, this will lead to more patients with very deep molecular responses to TKI 
therapy and more patients who are eligible for TKI discontinuation. Without MRD, it would 
follow that patients could maintain a prolonged treatment free remission and potentially be 
cured of CML. If this study is positive, follow-up trials could assess whether ruxolitinib can 
increase treatment-free remissions. 

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2.3 
Background Data to Support the Intervention and/or Endpoint Measurements Selected 
 
Chronic Myeloid Leukemia (CML) is clinically characterized by the presence of the 
Philadelphia chromosome. The Philadelphia chromosome is the result of a reciprocal 
translocation between chromosomes 9 and 22 (t(9;22)(q34;q11)) which forms the 
oncogene BCR-ABL. The expression of BCR-ABL results in the dysregulation of 
proliferation, differentiation and apoptotic pathways, culminating in the clinical scenario 
consistent with CML. 
 
The first generation BCR-ABL TKI imatinib, second generation TKIs, nilotinib, dasatinib 
and bosutinib, as well as the third generation TKI ponatinib have all proven to be very 
effective at inducing hematologic, cytogenetic and molecular remissions in CML patients. 
Current practice is to initiate therapy with a BCR-ABL TKI at the time of diagnosis and 
treatment is continued indefinitely. The initial studies done with imatinib produced an 
overall survival of 83% at fifteen years. The IRIS trial was the randomized Phase 3 trial 
comparing imatinib to interferon and low-dose cytarabine as front-line treatment in chronic 
phase CML. At the time this trial was conducted, regular molecular monitoring of BCR-ABL 
transcripts using RT-PCR was not standard of care. Therefore, molecular response data 
is not available on all imatinib treated patients on the IRIS trial. Despite this, 124 patients 
who had a complete cytogenetic response on imatinib also had blood available from 1 and 
4 years. These samples were retrospectively analyzed to measure BCR-ABL transcripts 
and at 1 year 53% of these patients had a major molecular response (MMR or 3-log 
reduction in BCR-ABL transcripts) and this increased to 80% by 4 years. At 1 year 22% of 
these patients had a 4-log reduction in BCR-ABL transcripts (MR4.0) which increased to 
41% by 4 years. (1) 
 
Bosutinib, dasatinib and nilotinib are approved for use as frontline therapy in CML. 
Dasatinib received this indication based on results of the DASISION trial in which patients 
were randomized to receive either imatinib 400mg PO daily or dasatinib 100mg PO daily 
for newly diagnosed, previously untreated chronic phase CML. Molecular responses were 
routinely monitored for patients on both arms of this trial, and the annual cumulative 
incidence of MMR and MR4.5 (4.5 log reduction in BCR-ABL transcripts) are reported in  
Table 1. (2) 
 
Table 1 Annual Cumulative Incidence of MMR and MR4.5 on the DASISION Trial 
 
Time 
Dasatinib 
Imatinib 
MMR (%) 
MR4,5 (%) 
MMR (%) 
MR4,5 (%) 
12 months 
46 
3 
28 
2 
24 months 
64 
17 
46 
8 
36 months 
69 
22 
55 
12 
48 months 
76 
37 
63 
30 
60 months 
76 
42 
64 
33 
 
The frontline indication for nilotinib was based on results of the ENESTnd trial which 
compared nilotinib 300mg PO BID to nilotinib 400mg PO BID to imatinib 400mg PO daily 
in newly diagnosed, previously untreated chronic phase CML patients. Nilotinib 300mg PO 
BID was chosen as the standard dose for frontline therapy, therefore all data from this point 
forward will refer to nilotinib at this dose unless otherwise specified. Annual cumulative 
incidence of MMR and MR4.5 are reported in Table 2. (3) 
 
 
 
 

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Table 2 Annual Cumulative Incidence of MMR and MR4.5 on the ENESTnd Trial 
 
Time 
Nilotinib 
Imatinib 
MMR (%) 
MR4,5 (%) 
MMR (%) 
MR4,5 (%) 
12 months 
44 
11 
22 
1 
24 months 
71 
25 
44 
9 
36 months 
73 
32 
53 
15 
48 months 
76 
40 
56 
23 
60 months 
77 
54 
60 
31 
 
The frontline indication for bosutinib was based on results of the BFORE trial which 
compared bosutinib 400mg PO daily to imatinib 400mg PO daily in newly diagnosed, 
previously untreated chronic phase CML patients. Annual cumulative incidence of MMR 
and MR4.5 are reported in Table 3. This trial is more recent, therefore, long-term data is 
not yet available is it is with DASISION and ENESTnd. (4) 
 
Table 3 Annual Cumulative Incidence of MMR and MR4.5 on the BFORE Trial 
 
Time 
Bosutinib 
Imatinib 
MMR (%) 
MR4.5 (%) 
MMR (%) 
MR4.5 (%) 
12 months 
47% 
8 
37 
3 
 
Depending on the sensitivity of the assay being used for RT-PCR, MR4.5 is equivalent to 
the previously used term, complete molecular response (CMR). This deep level of 
response has become a clinically relevant milestone as TKI discontinuation in patients with 
undetectable levels of BCR-ABL has become part of the standard management in CML. 
The first clinical trial to address the question of TKI discontinuation was the STIM trial which 
took place between 2007 and 2009. In this trial, CP-CML patients receiving imatinib who 
had achieved a CMR for a minimum of two years were instructed to discontinue their 
imatinib. They were monitored closely with monthly PCR in the first 6 months after 
discontinuation. With a median follow up of 77 months, 61% of patients relapsed, and 58% 
did so within 7 months of stopping treatment. Thirty-nine percent of patients remained off 
protocol treatment without a molecular recurrence. No one has relapsed later than 22 
months after discontinuing treatment. Importantly, at the time of molecular relapse, all 
patients were restarted on prior treatment and regained deep levels of molecular response. 
(5) Numerous other studies have looked at the possibility of discontinuing imatinib and the 
results have remained consistent across multiple trials. 
 
More recent trials have studied the possibility of discontinuing nilotinib, dasatinib and 
bosutinib. In one trial of 16 patients taking second generation TKIs after imatinib 
intolerance, had a median follow up of 13 months, and 69% of patients remained off 
protocol treatment. Of the 31% who relapsed, all did so within the first 4 months after 
discontinuation, and they all regained their prior response after reinitiating treatment. Large 
multi-center trials are currently ongoing to address the question of discontinuation of 
frontline nilotinib and frontline dasatinib. Data from the ENESTFreedom trial was presented 
at the ASCO annual meeting in 2016. This trial looked at discontinuation of nilotinib in 
patients who had been on treatment for a minimum of 3 years and had MR4.5 for a 
minimum of one year. Of the 190 patients who were eligible for discontinuation, 51% 
remained off protocol treatment without loss of MMR after a median follow up time of 49.4 
weeks. The remaining 49% lost MMR and reinitiated treatment with nilotinib. At the time of 
data cutoff, 98.8% of those who were placed back on therapy had regained MMR, and 
88.4% had regained MR4.5. (6) 
 

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Despite these promising findings, complete eradication of the disease has not been 
possible in the majority of patients because they harbor minimal residual disease (MRD). 
The presence of MRD frequently results in relapse of CML after discontinuation of 
treatment with BCR-ABL TKIs. Preclinical data suggests that MRD is the result of BCR- 
ABL independent drug resistance. More specifically, CML cells that reside in sanctuary 
sites such as the bone marrow adhere to fibronectin and demonstrate cell adhesion 
mediated drug resistance (CAM-DR). Even at increasing doses of BCR-ABL inhibitors, 
these cells are protected by this mechanism. The conditioned media in the bone marrow 
contains a variety of cytokines and growth factors which are capable of inducing STAT3- 
Y705 phosphorylation via the JAK-STAT pathway. This increased phosphorylation, and 
therefore activity, of STAT3-Y705 is correlated with protection against BCR-ABL TKI- 
induced cell death. This pathway functions independent from BCR-ABL, and therefore, 
inhibiting the phosphorylation of STAT3 via alternative pathways is required to eliminate 
this CAM-DR. (7) 
 
In CML cells grown in media conditioned with HS-5 bone marrow stromal cells, JAK2 
and TYK2, but not JAK1 or JAK3, were phosphorylated leading to increased STAT3 
activation. The inhibition of JAK2 and TYK2 leads to the complete inhibition of STAT3-
Y705 phosphorylation, thereby implicating the role of conditioned media-induced 
activation of JAK2 and TYK2 in STAT3-Y705 phosphorylation and resistance towards 
BCR-ABL TKI- induced cell death. (8) 
 
Studies using CML cell lines have successfully knocked down JAK2 and TYK2 using 
pan JAK inhibitors, ruxolitinib or siRNA technology. The double knock down of JAK2 and 
TYK2, but not the individual knock down of JAK2 or TYK2, led to the reversal of drug 
resistance 
against BCR-ABL TKIs in CML. (9) (Figure 1 * denotes statistical 
significance, # denotes no significant difference). 
 
Figure 1 
 
 
These studies led to the belief that pharmacologic inhibition of the JAK2-TYK2-STAT3 
pathway could overcome the bone marrow microenvironment-mediated drug 
resistance leading to the eradication of MRD in patients with CML. Ruxolitinib is an 
inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) with selective 
inhibition of JAK1 and JAK2, and modest to marked selectivity against TYK2. (10) 
Quintarelli et al. published data suggesting that ruxolitinib works synergistically with 
imatinib, dasatinib and nilotinib in the presence of HS-5 bone marrow stromal cells. 
Figure 2 demonstrates that the combination of ruxolitinib with imatinib (Figure 2a), 
dasatinib (Figure 2b) or nilotinib (Figure 2c) showed significantly greater toxicity in K562 
cells than a single agent TKI. (11) 

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Imatinib (nM) 
Figure 2 
 
 
 
 
The synergism was stronger with ruxolitinib plus nilotinib or dasatinib than it was with 
imatinib. (Figure 3) (12) The difference in synergy, as well as the difference in rates of 
MR4.5 with second generation TKIs compared to imatinib on the ENESTnd and DASISION 
trials are the primary reasons to study the combination of ruxolitinib plus second generation 
TKIs rather than imatinib. 
 
Figure 3 
 
K562 cells in HS-5/SCM 
6000 
4000 
2000 
1000 
500 
250 
0 
0.38 
0.39 
0.31 
0.17 
0.08 
0.08 
0.61 
0.75 
0.71 
0.73 
0.73 
0.71 
0.58 
0.55 
0.65 
0.65 
0.63 
0.63 
0.56 
0.58 
0.59 
0.57 
0.60 
0.64 
0.26 
0.27 
0.17 
0.18 
0.11 
0.10 
0.37 
0.36 
0.37 
0.38 
0.23 
0.25 
0.21 
0.27 
0.13 
0.15 
0.15 
0.16 
0.00 
0.00 
0.00 
0.08 
0.04 
0.09 
0.05 
0 
30 
100 
300 
600 
1200 
2400 
Ruxolitinib (Nm) 
 
 
 
 
 
Figure 2a 
Figure 2b 

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K562 cells in HS-5/SCM 
Dasatinib (Nm) 
5 
0.40 
0.35 
0.32 
0.34 
0.05 
0.55 
0.60 
0.82 
0.79 
0.85 
0.86 
3 
0.63 
0.65 
0.79 
0.87 
0.81 
0.82 
2 
0.48 
0.49 
0.74 
0.76 
0.78 
0.80 
1 
0.26 
0.23 
0.09 
0.16 
0.35 
0.36 
0.44 
0.44 
0.18 
0.5 
0.15 
0.16 
0.17 
0.1 
0.01 
0.01 
0.03 
0.02 
0.01 
0.04 
0.04 
0.00 
0.00 
0.03 
0.02 
0.03 
0.01 
0.03 
0.04 
 
0 
30 
1000 
300 
600 
1200 
2400 
 
Ruxolitinib (Nm) 
K562 cells in HS-5/SCM 
1500 
1000 
500 
100 
50 
10 
0 
0.47 
0.47 
0.46 
0.67 
0.74 
0.75 
0.74 
0.31 
0.33 
0.34 
0.34 
0.44 
0.60 
0.70 
0.71 
0.69 
0.47 
0.30 
0.30 
0.63 
0.63 
0.65 
0.69 
0.45 
0.48 
0.44 
0.47 
0.39 
0.39 
0.42 
0.46 
0.18 
0.16 
0.25 
0.20 
0.05 
0.00 
0.05 
0.17 
0.09 
0.05 
0.04 
0.00 
0.00 
0.00 
0.08 
0.04 
0.09 
0.05 
0 
30 
100 
300 
600 
1200 
2400 
 
Ruxolitinib (Nm) 
 
A Phase I clinical trial using ruxolitinib in combination with nilotinib in patients with chronic 
phase CML was recently completed at Moffitt Cancer Center. This was a dose escalation 
trial of 11 chronic phase CML patients being treated with nilotinib. Ruxolitinib dosing was 
5mg BID, 10mg BID and 15 mg BID in cohorts 1-3, respectively. Combination therapy was 
continued for six months, at which point ruxolitinib was discontinued. No DLTs occurred at 
any dose level, and no dose reductions were needed. Only one grade 3/4 treatment 
emergent adverse event occurred, which was hypophosphatemia that was replaced with 
oral supplementation. Ruxolitinib 15 mg BID was considered safe and tolerable in this 
patient population. Of the first 10 patients on study, 4 (40%) of them achieved MR4.5, after six 
months on trial. Fatigue assessments were completed in seven patients prior to 
beginning combination therapy, and again after 3 and 6 months on study, and there was a 
non-significant improvement in fatigue severity scores with combination therapy. Patient 
plasma was collected from four patients at baseline and again after ≥28 days of ruxolitinib 
therapy. A plasma inhibitory assay was run using the patient samples in KU812 cells to 
measure the change in STAT3-Y705 phosphorylation before and after ruxolitinib treatment. A 
significant decrease in pSTAT3-Y705 was noted with all four patient samples, thus 
proving the on-target effect of ruxolitinib. Furthermore, a Phase I trial using ruxolitinib in 
combination with imatinib, dasatinib or nilotinib is ongoing at MD Anderson Cancer Center. 
The results of this trial are forthcoming. 
 
2.4 
RT-PCR for BCR-ABL 
 
Chronic myeloid leukemia is characterized by the Philadelphia chromosome which is the 
Nilotinib (Nm) 

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result of a reciprocal translocation between chromosomes 9 and 22. This translocation 
results in the fusion gene BCR-ABL1. BCR-ABL1 is integral to the pathogenesis of CML 
and causes constitutive ABL tyrosine kinase activity which results in dysfunctional 
proliferation, differentiation and a block in apoptosis. (13) 
 
Treatment of chronic phase CML is with BCR-ABL1 tyrosine kinase inhibitors. These drugs 
bind in the ABL kinase domain thereby inhibiting the function of BCR-ABL and restoring 
normal proliferation, differentiation and apoptosis. 
 
Close monitoring of response in CML is imperative to the management of these patients. 
Responses are assessed as hematologic, cytogenetic and molecular responses, with a 
hematologic assessment being the least sensitive method of monitoring disease status, 
and molecular assessment using reverse transcriptase polymerase chain reaction (RT- 
PCR) being the most sensitive. Cytogenetic response is assessed by using standard G- 
banding karyotype testing on the bone marrow aspirate, and the ideal response to TKI 
therapy is a complete cytogenetic response (CCyR) after 12 months of treatment. A CCyR 
indicates that none of the 20 metaphases tested show the presence of the Philadelphia 
chromosome. Once patients have achieved a CCyR, monitoring of response to therapy 
can only be done using RT-PCR to measure the level of BCR-ABL transcripts in the 
peripheral blood. (14) The National Comprehensive Cancer Network guidelines for the 
management of CML recommended monitoring patients with RT-PCR in the peripheral 
blood every 3 months. Responses must be reported using the International Scale (IS) 
which uses a conversion factor to standardize PCR results so they may be compared 
across different laboratories. Unfortunately, not all laboratories in the United States use the IS, 
and therefore results from those labs are not comparable to those reported on IS. (15,16) 
 
Responses are measured based on the BCR-ABL transcript log-reduction from a 
standardized baseline (100% on the international scale, IS). The desired response is 
dependent on the length of time a patient has been treated with TKIs. Typically, the 
sensitivity of the PCR assay ranges from a 4 to 5-log reduction from the 100% IS, and in 
many cases, anything beyond a 4.5-log reduction becomes undetectable. (17,18) 
 
All subjects on this study must have detectable BCR-ABL transcripts identified by RT-PCR 
done on the peripheral blood in order to be eligible to enroll. Per the NCCN guidelines, RT- 
PCR for BCR-ABL will be done on the peripheral blood every 3 months while on trial for 
routine monitoring of disease status. The primary endpoint of this study is a 4.5 log 
reduction in BCR-ABL transcripts from 100% IS after 12 months on study. It is known that 
there is some variability in PCR testing between different laboratories based on the control 
gene used as well as the sensitivity of the assay. (19) In order to reduce variability, all 
assays must be performed in CLIA approved laboratories that report results using the 
International Scale. 
 
2.5 
Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to 
measure differences of intervention effects. The anticipated accrual in the ethnicity/race and 
sex categories is shown in the table below. 
 
Note that the anticipated accrual data is based on the accrual for the most recent SWOG 
CML study, S0325 
 
 

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DOMESTIC PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian/ 
Alaska Native 
0 
0 
0 
0 
0 
Asian 
1 
0 
0 
0 
1 
Native 
Hawaiian or 
Other Pacific 
Islander 
0 
1 
0 
0 
1 
Black or 
African 
American 
1 
2 
0 
0 
3 
White 
27 
49 
1 
1 
78 
More Than 
One Race 
0 
1 
0 
0 
1 
Total 
29 
53 
1 
1 
84 
 
3.0 
DRUG INFORMATION 
 
Investigator Brochures 
 
For information regarding Investigator Brochures, please refer to SWOG Policy 15. 
 
For this study, bosutinib, dasatinib, imatinib and nilotinib are commercially available; therefore, 
Investigator Brochures are not applicable to these drugs. Information about commercial drugs is 
publicly available in the prescribing information and other resources. 
 
For this study, ruxolitinib is investigational and is being provided under an IND held by SWOG. For 
INDs filed by SWOG, the protocol serves as the Investigator Brochure for the performance of the 
protocol. In such instances submission of the protocol to the IRB should suffice for providing the 
IRB with information about the drug. However, in cases where the IRB insists on having the official 
Investigator Brochure from the company, further information may be requested by contacting the 
SWOG Operations Office at 210/614-8808. 
 
3.1 
Bosutinib 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Bosutinib is a tyrosine kinase inhibitor. Bosutinib inhibits 
the Bcr-Abl kinase that promotes CML; it is also an inhibitor of Src-family kinases 
including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms 
of Bcr-Abl expressed in murine myeloid cell lines. Bosutinib did not inhibit the 
T315I and V299L mutant cells. In mice, treatment with bosutinib reduced the size 
of CML tumors relative to controls and inhibited growth of murine myeloid tumors 
expressing several imatinib-resistant forms of Bcr-Abl. 
 
b. 
PHARMACOKINETICS 
 
1. 
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 dose proportional 

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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. Following 
administration of a single dose of BOSUTINIB (500 mg) with food to 
healthy subjects, the absolute bioavailability was 34%. 
 
2. 
Distribution - After administration of a single dose of BOSUTINIB 500 mg 
with food in patients with CML, bosutinib had a mean apparent volume of 
distribution ± standard deviation of 6080 ± 1230 L. Bosutinib was highly 
bound to human plasma proteins in vitro (94%) and ex vivo in healthy 
subjects (96%), and binding was not concentration-dependent. 
 
3. 
Metabolism - Bosutinib is primarily metabolized by CYP3A4. The major 
circulating metabolites identified in plasma are oxydechlorinated (M2) 
bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib 
(25% of parent exposure), with bosutinib N-oxide (M6) as a minor 
circulating metabolite. All the metabolites were deemed inactive. 
 
4. 
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. In 
six healthy male subjects given a single oral dose of [14C] radiolabeled 
bosutinib, 91.3% of the dose was recovered in feces and 3% of the dose 
recovered in urine. 
 
c. 
ADVERSE EVENTS 
 
1. 
Adverse effects reported in > 20% of subjects treated with bosutinib 
include: diarrhea, nausea, thrombocytopenia, rash, vomiting, abdominal 
pain, respiratory tract infection, anemia, pyrexia, liver test abnormalities, 
fatigue, cough, and headache. 
 
2. 
Adverse effects reported in 4% to 20% of subjects include: febrile 
neutropenia, pericardial effusion, tinnitus, hypertension, gastritis, 
gastrointestinal hemorrhage (anal hemorrhage, gastric hemorrhage, 
gastrointestinal hemorrhage, hematemesis, hematochezia, intestinal 
hemorrhage, 
lower 
gastrointestinal 
hemorrhage, 
melena, 
rectal 
hemorrhage, upper gastrointestinal hemorrhage), pain, hepatotoxicity 
(includes allergic hepatitis, ascites, cholestasis, drug-induced liver injury, 
hepatic steatosis, hepatitis toxic, hepatocellular injury, hepatotoxicity, liver 
disorder, liver injury) drug hypersensitivity, electrocardiogram QT 
prolonged (includes electrocardiogram QT prolonged, long QT syndrome), 
blood 
creatine 
phosphokinase 
increased, 
amylase 
increased, 
hyperkalemia, dehydration, hypophosphatemia, myalgia, dysgeusia, 
urticaria, pruritus, renal impairment, body fluid retention, leukopenia. 
 
3. 
Serious adverse effects reported in ≤ 3% of subjects include: 
granulocytopenia, pericarditis, acute pancreatitis, anaphylactic shock, 
respiratory failure, pulmonary hypertension, pulmonary edema, erythema 
multiforme, exfoliative rash, drug eruption, Stevens-Johnson syndrome. 
 

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4. 
Due to potential drug interactions, a complete patient medication list, 
should be screened prior to initiation of and during treatment with 
bosutinib. 
 
CYP3A inhibitors: Avoid the concomitant use of strong or moderate 
CYP3A inhibitors with BOSUTINIB as an increase in bosutinib plasma 
concentration is expected. 
 
CYP3A Inducers: Avoid the concomitant use of strong or moderate CYP3A 
inducers with BOSUTINIB as a large reduction in exposure is expected. 
 
Proton Pump Inhibitors: In a dedicated cross-over drug-interaction trial in 
healthy volunteers. 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. 
 
5. 
Pregnant and lactation: Pregnancy Category D. It is not known whether 
bosutinib is excreted in human milk. Because many drugs are excreted in 
human milk and because of the potential for serious adverse reactions in 
nursing infants from bosutinib, a decision should be made whether to 
discontinue nursing or to discontinue the drug, taking into account the 
importance of the drug to the mother. 
 
d. 
DOSING AND ADMINISTRATION 
 
Dosing – See treatment plan (Section 7.2). 
 
Administration: Administer orally, with food. Patients should not take antacids, 
proton pump inhibitors or H2 antagonists. If antacids are absolutely necessary, 
they must be taken at least 2 hours before or 2 hours after dosing of bosutinib. 
 
e. 
HOW SUPPLIED 
 
Bosutinib is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert. 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
Refer to the current FDA-approved package insert. 
 
3.2 
Dasatinib (BMS-354825) (NSC-732517) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: BMS-354825 is a potent, broad spectrum ATP-competitive 
inhibitor of 5 critical oncogenic tyrosine kinase families: BCR-ABL, SRC family 
kinases, c-KIT, ephrin (EP) receptor kinases, and PDGFβ receptor. Each of these 
protein kinases has been strongly linked to multiple forms of human malignancies. 
 
b. 
PHARMACOKINETICS 
 
Approximate Solubility: BMS-354825 is insoluble in water and slightly soluble in 
ethanol and methanol. 
 
c. 
ADVERSE EFFECTS 

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1. 
Adverse Effects 
 
The following is a description of major adverse events associated with 
BMS-354825 therapy. A list of Comprehensive Adverse Events and 
Potential Risks (CAEPR) in NCI-CTCAE Version 5.0 terms is listed below. 
For additional information, see the Investigator Brochure and the package 
insert. 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
For Dasatinib (BMS-354825, Sprycel, NSC 732517) 
 
The Comprehensive Adverse Event and Potential Risks list 
(CAEPR) provides a single list of reported and/or potential adverse 
events (AE) associated with an agent using a uniform presentation of 
events by body system. Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements' 
https://ctep.cancer.gov/protocolDevelopment/adverse_effects.htmfor 
further clarification. 
 
Frequency is provided based on 2937 patients. 
 
Below is the CAEPR for dasatinib (BMS-354825). 
 
Version 2.7, September 10, 2018 
 
Adverse Events with Possible 
Relationship to Dasatinib (BMS-354825, Sprycel) 
(CTCAE 5.0 Term) 
[n= 2937] 
Likely (>20%) 
Less Likely (<=20%) Rare but Serious 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
Febrile neutropenia 
CARDIAC DISORDERS 
Pericardial effusion 
Heart failure 
Left ventricular 
systolic dysfunction 
Myocardial infarction 
GASTROINTESTINAL DISORDERS 
Diarrhea 
Abdominal distension 
Nausea 
Abdominal pain 
Anal mucositis 
Constipation 
Dyspepsia 
Gastrointestinal 
hemorrhage2
Mucositis oral 
Rectal mucositis 
Small intestinal 
Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 

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Adverse Events with Possible 
Relationship to Dasatinib (BMS-354825, Sprycel) 
(CTCAE 5.0 Term) 
[n= 2937] 
Likely (>20%) 
Less Likely (<=20%) Rare but Serious 
Fatigue 
Edema limbs 
Fever 
General disorders 
and administration 
site conditions - 
Other (superficial 
Generalized edema 
Non-cardiac chest pain 
Pain 
INFECTIONS AND INFESTATIONS 
Infection3 
INVESTIGATIONS 
Neutrophil 
count 
decreased 
Alanine 
aminotransferase 
increased 
Electrocardiogram 
QT corrected 
interval prolonged 
Platelet count 
decreased 
Aspartate 
aminotransfera
se increased 
Weight gain 
Weight loss 
White blood cell 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
Tumor lysis syndrome 
Hypocalcemia 
Hypokalemia 
Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
Myalgia 
Arthralgia 
Growth suppression 4
Musculoskeletal and 
connective tissue 
disorder 
– Other 
Musculoskeletal and 
connective tissue 
disorder 
NERVOUS SYSTEM DISORDERS 
Headache 
Dizziness 
Intracranial 
Leukoencephalopathy 
Reversible 
posterior 
leukoencephalopat
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
Gynecomastia2
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Dyspnea 
Cough 

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Adverse Events with Possible 
Relationship to Dasatinib (BMS-354825, Sprycel) 
(CTCAE 5.0 Term) 
[n= 2937] 
Likely (>20%) 
Less Likely (<=20%) Rare but Serious 
Pleural effusion 
Laryngeal mucositis 
Pharyngeal mucositis 
Pneumonitis 
Tracheal mucositis 
Pulmonary hypertension 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Rash 
maculo-papular 
Alopecia 
Erythema multiforme 
Pruritus 
Stevens-
Johnson 
Rash acneiform 
Toxic 
Epidermal 
VASCULAR DISORDERS 
Flushing 
 
1 
This table will be updated as the toxicity profile of the agent is revised. 
Updates will be distributed to all Principal Investigators at the time 
of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
2 
Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal 
hemorrhage, 
Colonic 
hemorrhage, 
Duodenal 
hemorrhage, 
Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric 
hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-
abdominal 
hemorrhage, 
Jejunal 
hemorrhage, 
Lower 
gastrointestinal 
hemorrhage, 
Oral 
hemorrhage, 
Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, 
and 
Upper 
gastrointestinal 
hemorrhage 
under 
the 
GASTROINTESTINAL DISORDERS SOC. 
3 
Infection includes all 75 sites of infection under the INFECTIONS 
AND INFESTATIONS SOC. 
4 
Effects on growth and development have been observed in 
pediatric patients and may include epiphyses delayed fusion, 
osteopenia, growth retardation, and gynecomastia 
5 
Gastrointestinal ulcer includes Anal ulcer, Colonic ulcer, Duodenal 
ulcer, Esophageal ulcer, Gastric ulcer, Ileal ulcer, Jejunal ulcer, 
Rectal 
ulcer, 
and 
Small 
intestine 
ulcer 
under 
the 
GASTROINTESTINAL DISORDERS SOC. 
 
Adverse events reported on Dasatinib (BMS-354825, Sprycel) trials, 
but for which there is insufficient evidence to suggest that there 
was a reasonable possibility that Dasatinib (BMS-354825, Sprycel) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and 
lymphatic system disorders - Other (pancytopenia) 

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CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other 
(cardiomegaly); Cardiac disorders - Other (heart rate increased); Chest 
pain - cardiac; Myocarditis; Palpitations; Pericarditis; Sinus tachycardia; 
Ventricular tachycardia 
CONGENITAL, FAMILIAL AND GENETIC DISORDERS - Congenital, 
familial and genetic disorders - Other (Keratosis follicular) 
EAR AND LABYRINTH DISORDERS - Ear pain; Middle ear inflammation; 
Tinnitus; Vertigo 
EYE DISORDERS - Blurred vision; Dry eye; Eye disorders - Other (optic 
nerve neuritis); Periorbital edema 
GASTROINTESTINAL DISORDERS - Anal fissure; Ascites; Colitis; Dry 
mouth; Dysphagia; Esophagitis; Flatulence; Gastritis; Gastrointestinal 
disorders - Other (enteritis); Gastrointestinal disorders - Other (oral soft 
tissue disorder); Gastrointestinal disorders - Other (tongue eruption); 
Gastrointestinal ulcer3; Ileus; Oral pain; Pancreatitis; Periodontal disease; 
Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
-Chills; Edema face; Edema trunk; Flu like symptoms; Gait disturbance; 
General disorders and administration site conditions - Other 
(temperature intolerance); Localized edema; Malaise 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatobiliary disorders 
- Other (cholestasis) 
IMMUNE SYSTEM DISORDERS - Anaphylaxis 
INJURY,  POISONING AND PROCEDURAL COMPLICATIONS - 
Bruising 
INVESTIGATIONS -  Alkaline phosphatase increased; Blood bilirubin 
increased; Cardiac troponin T increased; CD4 lymphocytes 
decreased; CPK increased; Creatinine increased; Electrocardiogram T 
wave abnormal; GGT increased; Investigations – Other (bone 
densitometry);Investigations - Other (thermometry abnormal); 
Lymphocyte count decreased; Lymphocyte count increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; 
Hyperkalemia; Hyperuricemia; Hypoalbuminemia; Hypomagnesemia; 
Hyponatremia 
MUSCULOSKELETAL  AND  CONNECTIVE  TISSUE  DISORDERS  - 
Arthritis; Back pain; Bone pain; Chest wall pain; Generalized muscle 
weakness; Muscle cramp; Musculoskeletal and connective tissue 
disorder Other (muscle stiffness); Musculoskeletal and connective tissue 
disorder Other (nuchal rigidity); Musculoskeletal and connective tissue 
disorder - Other (tendonitis); Myositis; Osteoporosis; Pain in extremity; 
Rhabdomyolysis 
NEOPLASMS   BENIGN,  MALIGNANT   AND   UNSPECIFIED   (INCL 
CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified 
(incl cysts and polyps) - Other (hemangiomatosis) 
NERVOUS SYSTEM DISORDERS - Acoustic nerve disorder NOS; 
Amnesia; Cognitive disturbance; Concentration impairment; Dysarthria; 
Dysgeusia; Ischemia cerebrovascular; Lethargy; Peripheral motor 
neuropathy; Peripheral sensory neuropathy; Seizure; Somnolence; 
Syncope; Transient ischemic attacks; Tremor 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia; 
Libido decreased; Suicidal ideation 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria; 
Urinary frequency 
REPRODUCTIVE  SYSTEM  AND  BREAST  DISORDERS  -  Irregular 
menstruation 

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RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult 
respiratory distress syndrome; Bronchospasm; Epistaxis; Hypoxia; 
Oropharyngeal pain; Pulmonary edema; Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; 
Dry skin; Hair color changes; Hyperhidrosis; Nail loss; Pain of skin; 
Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Purpura; 
Skin and subcutaneous tissue disorders - Other (acute febrile neutrophilic 
dermatosis); Skin and subcutaneous tissue disorders - Other 
(panniculitis); Skin ulceration; Urticaria 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypertension; 
Hypotension; Phlebitis; Superficial thrombophlebitis; Thromboembolic 
event; Vasculitis 
 
Note: Dasatinib (BMS-354825, Sprycel) in combination with other agents 
could cause an exacerbation of any adverse event currently known to be 
caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
2. 
Drug Interactions: BMS-354825 is primarily metabolized by the human 
CYP3A4 enzyme, is a significant inhibitor of CYP3A4, and is a weak 
inhibitor of CYP1A2, CYP2D6, CYP2C9, and CYP2C19. It may decrease 
the metabolic clearance of drugs that are significantly metabolized by the 
CYP3A4 enzyme. Due to the potential of BMS-354825 to prolong the 
QT/QTc, use caution when administering BMS-354825 with other potential 
QTc-prolonging medications. Due to the possibility of gastrointestinal, 
cardiac, and cutaneous hemorrhage, avoid using medications that inhibit 
platelet function or anticoagulants with BMS-354825. 
 
BMS-354825 is not a P-glycoprotein inhibitor. 
 
3. 
Pregnancy and Lactation: Females of child bearing potential should avoid 
pregnancy, which may include use of effective contraception during 
treatment and for 30 days after the final dose. 
 
d. 
DOSING AND ADMINISTRATION  
 
See Section 7.0 Treatment Plan. 
 
Administration: Administer orally, with or without food.  Tablets should be 
swallowed whole and cannot be crushed or broken. Grapefruit juice should not 
be consumed during study drug therapy, as P450 enzyme inhibition may increase 
drug exposure. In vitro solubility data indicate that dasatinib may have decreased 
solubility and absorption at pH > 4. Patients should not take antacids, proton 
pump inhibitors or H2 antagonists. If antacids are absolutely necessary, they must 
be taken at least 2 hours before or 2 hours after dosing of dasatinib. 
 
e. 
HOW SUPPLIED 
 
Dasatinib is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert. 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
Refer to the current FDA-approved package insert. 
 

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3.3 
Imatinib (Gleevec®)(STI-571) (NSC-716051) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Imatinib is a tyrosine kinase inhibitor that inhibits the BCR- 
ABL tyrosine kinase, the constitutive abnormal gene product of the Philadelphia 
chromosome in chronic myeloid leukemia (CML). Inhibition of this enzyme blocks 
proliferation and induces apoptosis in BCR-ABL positive cell lines. Imatinib also 
 
inhibits tyrosine kinases for platelet-derived growth factor (PDGF), stem cell 
factor (SCF), c-Kit, and cellular events mediated by PDGF and SCF. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Imatinib is well absorbed after oral administration. Cmax occurs 
within 2-4 hours after dosing. Mean absolute bioavailability is 98%. 
 
2. 
Distribution: Plasma protein binding, predominately to albumin and α1- acid 
glycoprotein, is approximately 95% for imatinib and its primary metabolite. 
 
3. 
Metabolism: Imatinib is primarily metabolized by CYP3A4, with minor 
contributions by CYP1A2, CYP2D6, CYP2C9, and CYP2C19. CGP74588, 
the main circulating active metabolite formed predominantly by CYP3A4, 
demonstrates in vitro potency similar to the parent drug. The elimination half-
lives of imatinib and CGP74588 are approximately 18 and 40 hours, 
respectively, following oral administration. 
 
4. 
Elimination: Imatinib is eliminated predominately in the feces and mostly as 
metabolites. Approximately 81% of the dose is eliminated within 7 days, in 
feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted 
for 25% of the dose (5% urine, 20% feces). Typically, clearance of imatinib in 
a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-
year-old patient weighing 100 kg the clearance will increase to 14 L/h. The 
inter-patient variability of 40% in clearance does not warrant initial dose 
adjustment based on body weight and/or age but indicates the need for close 
monitoring for treatment-related toxicity. 
 
c. 
ADVERSE EFFECTS 
 
1. 
Possible Side Effects of Commercial Drug Name: 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
Adverse effects reported in > 20% of subjects treated with imatinib include: 
edema, weight gain, nausea, diarrhea, vomiting, pain, rash, fatigue, 
headache, nasopharyngitis and upper respiratory tract infections, cough, 
myalgia, 
cytopenias, 
and 
hemorrhage. 
 
Adverse effects reported in 4% to 20% of subjects include: hepatotoxicity, 
renal toxicity, gastrointestinal perforations, dizziness, hearing loss, 
insomnia, sinusitis, pyrexia, and dyspepsia. 
 
Serious adverse effects reported in ≤ 3% of subjects include: heart failure 
and left ventricular dysfunction, bullous dermatologic reactions (e.g., 
erythema multiforme and Stevens-Johnson syndrome), tumor lysis 

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syndrome, new malignancy, swelling of the brain, and reports of motor 
vehicle accidents. 
 
2. 
Pregnancy and Lactation: 
Based on human and animal data, imatinib crosses the placenta and can 
cause fetal harm, including teratogenicity, spontaneous abortions, and 
congenital anomalies. Pregnancy should be avoided during imatinib 
treatment and highly effective contraception should be used for at least 
two weeks after stopping treatment. Imatinib and its active metabolite are 
excreted into human milk; a breastfed infant could receive up to 10% of 
the maternal therapeutic dose based on body weight. Women should not 
breastfeed during treatment and for one month after the last imatinib dose. 
The risk of infertility in females or males of reproductive potential has not 
been studied in humans. 
 
3. 
Drug Interactions: Imatinib is primarily metabolized by CYP3A4, with minor 
contributions by CYP1A2, CYP2D6, CYP2C9, and CYP2C19. Concomitant 
administration of imatinib with inhibitors and inducers of CYP3A may alter the 
pharmacokinetic or pharmacodynamics properties of imatinib. Imatinib is a 
potent competitive inhibitor of CYP2C9, CYP2D6, and CYP3A4/5. Imatinib 
will increase plasma concentrations of CYP3A4 metabolized drugs (e.g., 
triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain 
HMG-CoA reductase inhibitors, etc.). Use caution when administering 
imatinib with CYP2C9, CYP2D6, and CYP3A4/5 substrates that have a 
narrow therapeutic window (e.g. warfarin). Grapefruit juice may also increase 
plasma concentrations of imatinib; avoid grapefruit juice. See Section 7.3 for 
details. 
 
d. 
DOSING & ADMINISTRATION  
 
See Section 7.0 Treatment Plan 
 
e. 
HOW SUPPLIED 
 
1. 
Imatinib (Gleevec®) is commercially available and will not be supplied. 
Refer to the current FDA-approved package insert. 
 
f. 
DRUG ORDERING & ACCOUNTABILITY 
 
2. 
Refer to the current FDA-approved package insert. 
 
3.4 
Nilotinib (Tasigna®) (NSC-747599) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Nilotinib (Tasigna®) is an inhibitor of the BCR-ABL kinase. 
Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of 
ABL protein. Nilotinib inhibited BCR-ABL mediated proliferation of murine leukemic 
cell lines and human cell lines derived from patients with Ph+ CML. Under the 
conditions of the assays, nilotinib was able to overcome  imatinib  resistance 
resulting 
from 
BCR-ABL 
kinase 
mutations. 
Nilotinib 
inhibits 
the 
auto- 
phosphorylation of the following kinases at IC50 values as indicated: BCR-ABL (20 to 
60 nM), PDGFR (69 nM), c-KIT (210 nM), CSF-1R (125 to 250 nM), and DDR1 
(3.7 nM). 
 

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b. 
PHARMACOKINETICS 
 
1. 
Absorption: The absolute bioavailability of nilotinib has not been 
determined. As compared to an oral drink solution (pH of 1.2 to 1.3), 
relative bioavailability of nilotinib capsule is approximately 50%. Peak 
concentrations of nilotinib are reached 3 hours after oral administration. 
Steady-state nilotinib exposure was dose-dependent with less than dose- 
proportional increases in systemic exposure at dose levels higher than 400 
mg given as once daily dosing. Compared to the fasted state, the systemic 
exposure (AUC) increased by 82% when the dose was given 30 minutes 
after a high fat meal. The bioavailability of nilotinib is increased with food, 
thus nilotinib must not be taken with food. No food should be consumed 
for at least 2 hours before and for at least 1 hour after the dose is taken. 
 
2. 
Distribution: Single dose administration of two 200mg nilotinib capsules 
each dispersed in 1 teaspoon of applesauce and administered within 15 
minutes was shown to be bioequivalent to a single dose administration of 
two 200mg intact capsules. The blood-to-serum ration of nilotinib is 0.68. 
Serum protein binding is approximately 98% on the basis of in vitro 
experiments. Median steady-state trough concentration of nilotinib was 
decreased by 53% in patients with total gastrectomy compared to patients 
who had not undergone surgeries 
 
3. 
Metabolism: Main metabolic pathways identified in healthy subjects are 
oxidation and hydroxylation. Nilotinib is the main circulating component in 
the serum. None of the metabolites contribute significantly to the 
pharmacological activity of nilotinib. 
 
4. 
Elimination: The apparent elimination half-life estimated from the multiple 
dose pharmacokinetic studies with daily dosing was approximately 17 
hours. Inter-patient variability in nilotinib AUC was 32% to 64%. Steady 
state conditions were achieved by Day 8. An increase in serum exposure 
to nilotinib between the first dose and steady state was approximately 2- 
fold for daily dosing and 3.8-fold for twice daily dosing. After a single dose 
of radiolabeled nilotinib in healthy subjects, more than 90% of the 
administered dose was eliminated within 7 days: mainly in feces (93% of 
the dose). Parent drug accounted for 69% of the dose. Age, body weight, 
gender, or ethnic origin did not significantly affect the pharmacokinetics of 
nilotinib. 
 
c. 
ADVERSE EFFECTS 
 
1. 
Possible Side Effects of nilotinib: 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by body 
system. In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset 
of AEs (SPEER) is a list of events that are protocol specific exceptions to 
expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification. Frequency is provided based on 

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737 patients. Below is the CAEPR for Nilotinib. 
 
Version 2.0, September 6, 20221 
 
 Adverse Events with Possible  
 Relationship to Nilotinib 
 (CTCAE 5.0 Term) 
[n= 737] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
Eosinophilia 
 
 
Febrile neutropenia 
 
CARDIAC DISORDERS 
 
Chest pain - cardiac 
 
 
 
Pericardial effusion 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
 
 
 
 
Ascites 
Constipation 
 
 
Diarrhea 
 
 
 
Dyspepsia 
 
 
 
Gastric hemorrhage 
Nausea 
 
 
 
Pancreatitis 
 
Vomiting 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Edema limbs 
 
Fatigue 
 
 
Fever 
 
 
 
Non-cardiac chest pain  
 
Pain 
 
INFECTIONS AND INFESTATIONS 
Upper respiratory 
infection 
 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
Bruising 
 
INVESTIGATIONS 
 
Alanine 
aminotransferase 
increased 
 
 
Blood bilirubin 
increased 
 
 
CPK increased 
 
 
Cholesterol high 
 
 
 
Electrocardiogram QT 
corrected interval 
prolonged 
 
GGT increased 
 

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 Adverse Events with Possible  
 Relationship to Nilotinib 
 (CTCAE 5.0 Term) 
[n= 737] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
Lipase increased 
 
 
Lymphocyte count 
decreased 
 
Neutrophil count 
decreased 
 
 
Platelet count 
decreased 
 
 
 
Serum amylase 
increased 
 
 
Weight gain 
 
 
White blood cell 
decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
Hyperglycemia 
 
 
Hyperkalemia 
 
 
Hyperlipidemia 
 
 
Hypertriglyceridemia 
 
 
Hypocalcemia 
 
 
Hypokalemia 
 
 
Hyponatremia 
 
 
Hypophosphatemia 
 
 
 
Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
Arthralgia 
 
 
 
Back pain 
 
 
Bone pain 
 
 
Chest wall pain 
 
 
Flank pain 
 
 
Generalized muscle 
weakness 
 
 
Muscle cramp 
 
Myalgia 
 
 
 
Neck pain 
 
 
Pain in extremity 
 
NERVOUS SYSTEM DISORDERS 
 
Aphonia 
 
 
Dizziness 
 
 
Dysesthesia 
 
 
Dysgeusia 
 
Headache 
 
 
 
Paresthesia 
 

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 Adverse Events with Possible  
 Relationship to Nilotinib 
 (CTCAE 5.0 Term) 
[n= 737] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
Peripheral motor 
neuropathy 
 
 
Peripheral sensory 
neuropathy 
 
PSYCHIATRIC DISORDERS 
 
Insomnia 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Cough 
 
 
 
Dyspnea 
 
 
Epistaxis 
 
 
Oropharyngeal pain 
 
 
 
Pleural effusion 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 
 
Dry skin 
 
 
Eczema 
 
 
Hyperhidrosis 
 
Pruritus 
 
 
 
Rash acneiform 
 
Rash maculo-papular 
 
 
VASCULAR DISORDERS 
 
Hypertension 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of 
revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2The relative early occurrence of some of these deaths relative to the 
initiation of Tasigna (nilotinib) suggests the possibility that ventricular 
repolarization abnormalities may have contributed to their occurrence. 
 
Adverse events reported on Nilotinib trials, but for which there is 
insufficient evidence to suggest that there was a reasonable 
possibility that Nilotinib caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and 
lymphatic system disorders - Other (pancytopenia) 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Atrioventricular 
block complete; Palpitations; Sinus bradycardia; Sinus tachycardia; 
Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Vertigo 
EYE DISORDERS - Dry eye; Eye disorders - Other (eyelid edema); Eye 
disorders - Other (eye pruritis); Vitreous hemorrhage 

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GASTROINTESTINAL DISORDERS - Abdominal distension; Flatulence 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Flu like symptoms; Malaise; Sudden death NOS2 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other 
(hepatic function abnormal) 
INFECTIONS AND INFESTATIONS - Conjunctivitis; Folliculitis; 
Infections and infestations - Other (gastroenteritis) 
INVESTIGATIONS - Alkaline phosphatase increased; Aspartate 
aminotransferase increased; Investigations - Other (globulins 
decreased); Weight loss 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; 
Hyperphosphatemia; Hypoalbuminemia; Hypomagnesemia; Metabolism 
and nutrition disorders - Other (diabetes mellitus) 
PSYCHIATRIC DISORDERS - Anxiety; Depression 
RENAL AND URINARY DISORDERS - Urinary frequency 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Pulmonary edema 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Urticaria 
VASCULAR DISORDERS - Flushing 
 
Note: Nilotinib in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the 
other agent, or the combination may result in events never previously 
associated with either agent. 
 
 
2. 
Pregnancy and Lactation: Pregnancy Category D. Based on its 
mechanism of action and findings in animals, nilotinib may cause fetal 
harm when administered to a pregnant woman. Women should be advised 
to avoid becoming pregnant while on nilotinib. If this drug is used during 
pregnancy, or if the patient becomes pregnant while taking this drug, the 
patient should be apprised of the potential hazard to the fetus. Women of 
childbearing potential should use effective contraceptives if taking 
nilotinib. Sexually active female patients taking nilotinib should use 
adequate contraception. 
 
It is not known whether nilotinib is excreted in human milk. Because 
many drugs are excreted in human milk and because of the potential for 
serious adverse reactions in nursing infants from nilotinib, a decision 
should be made whether to discontinue nursing or to discontinue the 
drug, taking into account the importance of the drug to the mother. 
 
3. 
Drug Interactions: Nilotinib undergoes metabolism by CYP3A4, and 
concomitant administration of strong inhibitors (e.g., ketoconazole, 
itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, 
ritonavir, saquinavir, telithromycin, voriconazole) or inducers (e.g., 
dexamethasone, 
phenytoin, 
carbamazepine, 
rifampin, 
rifabutin, 
rifapentine, phenobarbital) of CYP3A4 can increase or decrease nilotinib 
concentrations significantly. The administration of nilotinib with agents that 
are strong CYP3A4 inhibitors should be avoided. Concomitant use of 
nilotinib with medicinal products and herbal preparations (e.g., St. John’s 
Wort) that are potent inducers of CYP3A4 is likely to reduce exposure to 
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nilotinib, concomitant use of alternative therapeutic agents with less 
potential for CYP3A4 induction should be selected. 
 
Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 
inhibitor, at 400 mg once daily for 6 days, systemic exposure (AUC) to 
nilotinib was increased approximately 3-fold. 
 
Rifampicin: In healthy subjects receiving the CYP3A4 inducer, rifampicin, 
at 600 mg daily for 12 days, systemic exposure (AUC) to nilotinib was 
decreased approximately 80%. 
 
Nilotinib has pH-dependent solubility, with decreased solubility at higher 
pH. Drugs such as proton pump inhibitors that inhibit gastric acid secretion 
to elevate the gastric pH may decrease the solubility of nilotinib and reduce 
its bioavailability. In healthy subjects, co-administration of a single 400 mg 
dose of nilotinib with multiple doses of esomeprazole (a proton-pump 
inhibitor) at 40 mg daily decreased the nilotinib AUC by 34%. Increasing 
the dose of nilotinib when co-administered with such agents is not likely to 
compensate for the loss of exposure. Since proton pump inhibitors affect 
pH of the upper GI tract for an extended period, separation of doses may 
not eliminate the interaction. The concomitant use of proton pump 
inhibitors with nilotinib is not recommended. In healthy subjects, no 
significant change in nilotinib pharmacokinetics was observed when a 
single 400 mg dose of nilotinib was administered 10 hours after and 2 
hours before famotidine (an H2 blocker). Therefore, when the concurrent 
use of a H2 blocker is necessary, it may be administered approximately 
10 hours before and approximately 2 hours after the dose of nilotinib. 
Administration 
of 
an 
antacid 
(aluminum 
hydroxide/magnesium 
hydroxide/simethicone) to healthy subjects, 2 hours before or 2 hours after 
a single 400 mg dose of nilotinib did not alter nilotinib pharmacokinetics. 
Therefore, if necessary, an antacid may be administered approximately 2 
hours before or approximately 2 hours after the dose of nilotinib. 
 
Avoid administration of nilotinib with agents that may increase nilotinib 
exposure (e.g., strong CYP3A4 inhibitors) or anti-arrhythmic drugs 
(including, but not limited to amiodarone, disopyramide, procainamide, 
quinidine and sotalol) and other drugs that may prolong QT interval 
(including, but not limited to chloroquine, clarithromycin, haloperidol, 
methadone, moxifloxacin and pimozide). 
 
Nilotinib is a substrate of the efflux transporter P-glycoprotein (P-gp, 
ABCB1). If nilotinib is administered with drugs that inhibit P-gp, increased 
concentrations of nilotinib are likely, and caution should be exercised. 
 
In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8 
and CYP2C9, and decrease the concentrations of drugs which are 
eliminated by these enzymes. 
 
Avoid grapefruit products and other foods that are known to inhibit 
CYP3A4. 
 
Due to potential drug interactions, a complete patient medication list 
should be screened prior to initiation of and during treatment with nilotinib. 
See Section 8.0 Toxicities to be Monitored and Dosage Modifications 
 

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d. 
DOSING & ADMINISTRATION  
 
See Section 7.0 Treatment Plan 
 
e. 
HOW SUPPLIED 
 
Nilotinib is commercially available and will not be supplied. Refer to the 
current FDA-approved package insert. 
 
3.5 
Ruxolitinib (Jakafi®) (NSC-752295) (IND-138173) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Ruxolitinib, a kinase inhibitor, inhibits Janus Associated 
Kinases (JAKs) JAK1 and JAK2 signaling associated with myelofibrosis 
and polycythemia vera. JAK signaling involves recruitment of  STATs  (signal 
transducers and activators of transcription) to cytokine receptors, activation 
and subsequent localization of STATs to the nucleus leading to modulation of 
gene expression. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Ruxolitinib appears to be well absorbed; oral absorption was 
estimated to be at least 95%. Maximal ruxolitinib plasma concentrations 
are achieved within 1 to 2 hours after oral administration. 
 
2. 
Distribution: The mean volume of distribution at steady state in patients 
with myelofibrosis and polycythemia vera is 72 L (intersubject variability of 
29%) and 75 L (intersubject variability of 23%), respectively. In vitro, it is 
approximately 97% bound to plasma proteins, mostly to albumin. 
 
3. 
Metabolism: Ruxolitinib is metabolized primarily by CYP3A4 and lesser 
extent by CYP2C9. 
 
4. 
Elimination: After a single oral radiolabeled dose to healthy adults, 
elimination was primarily through metabolism with 74% of radioactivity 
excreted in urine and 22% excreted in feces. Unchanged drug accounted 
for less than 1% of the excreted total radioactivity. The mean elimination 
half-life of ruxolitinib is approximately 3 hours, and the mean half-life of 
ruxolitinib with metabolites is approximately 5.8 hours. 
 
c. 
ADVERSE EFFECTS 
 
1. 
Adverse Effects: 
 
Adverse Events with Possible Relationship to Ruxolitinib 
Likely (> 20%) 
Less Likely (4 – ≤ 20%) 
Rare but Serious 
(≤ 3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
Thrombocytopenia 
Hematoma 
Platelet count decreased 
CARDIAC DISORDERS 
Hypertension 
GASTROINTESTINAL DISORDERS 

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Adverse Events with Possible Relationship to Ruxolitinib 
Likely (> 20%) 
Less Likely (4 – ≤ 20%) 
Rare but Serious 
(≤ 3%) 
Diarrhea 
Constipation 
Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue 
Cough 
Night sweat 
Insomnia 
INFECTIONS AND INFESTATIONS 
Bronchitis 
Pneumonia 
Urinary tract infection 
Upper respiratory tract 
infection 
Herpes zoster 
METABOLISM AND NUTRITION DISORDERS 
Decrease appetite 
MUSCULOSKELETAL AND CONNECTIVE TISSURE DISORDERS 
Muscle spasm 
Musculoskeletal pain 
Pain in extremity 
Back pain 
Arthralgia 
NERVOUS SYSTEM DISORDERS 
Dizziness 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Dyspnea 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Pruritis 
Rash 
 
2. 
Pregnancy and Lactation: 
 
Ruxolitinib has a rating of pregnancy risk category C. There are no 
adequate and well-controlled studies of ruxolitinib in pregnant women. 
Ruxolitinib was embryotoxic and fetotoxic in rats and rabbits (increases in 
post-implantation loss and reduced fetal weights). The potential risk of 
teratogenicity for humans is unknown. The use of ruxolitinib during 
pregnancy should be avoided. Women of childbearing potential should use 
effective contraceptives while taking ruxolitinib. 
 
Women taking ruxolitinib should not breast-feed. In lactating rats, 
ruxolitinib and/or its metabolites were excreted into the milk with a 
concentration that was 13-fold higher than the maternal plasma 
concentration. It is not known whether ruxolitinib is excreted in human milk. 
 
3. 
Drug Interactions: 
 
Ruxolitinib is metabolized primarily by CYP3A4 and lesser extent by 
CYP2C9. Therefore, co-medications inhibiting CYP3A4 and CYP2C9 
enzymes might increase the exposure to ruxolitinib. 
 
Agents that may alter plasma concentration of ruxolitinib: 
Strong CYP3A4 inhibitors: in healthy subjects receiving ketoconazole, a 

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strong CYP3A4 inhibitor, at 200 mg twice daily for four days, the AUC of 
ruxolitinib increased by 91% and the half-life was prolonged from 3.7 to 
6.0 hours. 
 
When administering ruxolitinib with strong CYP3A4 inhibitors, the total 
daily dose of ruxolitinib should be reduced to approximately 50% of the 
dose rounding up to the nearest dosage strength. Patients should be 
closely monitored for cytopenias and the dose should be titrated based on 
safety and efficacy. 
 
Mild or moderate CYP3A4 inhibitors: in healthy subjects receiving 
erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for four 
days, there was a 27% increase in the AUC of ruxolitinib. No dose 
adjustment is recommended when ruxolitinib is co administered with mild 
or moderate CYP3A4 inhibitors (e.g. erythromycin). Patients should be 
closely monitored for cytopenias when initiating therapy with a moderate 
CYP3A4 inhibitor. 
 
Concomitant moderate CYP2C9 and CYP3A4 inhibitors (including a dual 
enzyme inhibitor as a single agent, e.g. Fluconazole): Based on in silico 
modeling, an AUC increase of ruxolitinib of 102%, 190% or 330% is 
predicted when co-administered with 100 mg, 200 mg or 400 mg 
fluconazole, respectively. A 50% dose reduction should be considered 
when concomitantly administering medicinal products which are moderate 
inhibitors of CYP2C9 and CYP3A4. Avoid the concomitant use of JAKAVI 
with fluconazole doses of greater than 200 mg daily. 
 
Due to potential drug interactions, a complete patient medication list, 
including investigational drug name, should be screened prior to initiation 
of and during treatment with investigational drug name. See Section 8.0. 
 
d. 
DOSING & ADMINISTRATION  
 
See Section 7.0 Treatment Plan 
 
e. 
HOW SUPPLIED 
 
1. 
Ruxolitinib is investigational for this study and will supplied free of charge 
by Incyte, Corporation for distribution by Catalent. 
 
2. 
For this study, ruxolitinib tablets will be supplied at a strength of 5 mg. 
Each bottle will contain 60 tablets. 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
1. 
Based on available stability data, ruxolitinib should be stored in tight 
packaging (water permeation < 5 mg/day/liter), controlled room 
temperature between 15°C to 30°C (59°F to 86°F) and protected from 
light. The immediate release drug product should be stored in high density 
polyethylene (HDPE) bottles with induction sealing and child-resistant 
closure under the storage condition of “Do not store above 30°C”. 
Additionally, an in-use period is assigned to all dosage strengths. The 
product 
packaging 
in 
which 
drug 
is 
provided 
from 
the 

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manufacturer/distributor meets the necessary storage requirements; no 
on- site repackaging is required. 
 
g. 
DRUG ORDERING & ACCOUNTABILITY 
 
1. 
Sites may order a starter supply of ruxolitinib at the time of local IRB 
approval of the protocol. Drug is not patient-specific, so one order of drug 
may be used for multiple patients. Sites should re-order drug as necessary 
based on local patient and site study needs. 
 
Drug may be ordered by submitting the completed Ruxolitinib Drug Order 
Form, according to the instructions on the form. The order form may be 
accessed from the protocol abstract page of the SWOG website 
(www.swog.org) or from the CTSU website (www.ctsu.org). 
 
2. 
Drug Handling and Accountability 
 
a. 
The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, 
disposition, and return or disposal of all drugs received from the 
supplier using the NCI Drug Accountability Record Form (DARF) 
available at http://ctep.cancer.gov. 
 
b. 
Electronic logs are allowed as long as a print version of the log 
process is the exact same appearance as the current NCI DARF. 
If the trial is a placebo control trial – indicate that separate 
DARFs are needed for each patient to also include the placebo 
drug supply. 
 
3. 
Drug Return and/or Disposition Instruction 
 
a. 
Drug Returns: Unused drug supplies must NOT be returned. 
Unused drug must be disposed of per local institutional 
guidelines. 
 
b. 
Drug expiration: Indicate drug expiration date on the DARF 
under Manufacturer and Lot # and use the drug lots with shorter 
expiration date first). 
 
4. 
Contact Information 
 
Questions about drug orders, transfers, returns, or accountability 
should be addressed to Jozefa Lomski at Catalent 
(jozefa.lomski@catalent.com). 
 
4.0 
DIAGNOSTIC CRITERIA 
 
4.1 
Diagnostic Criteria 
 
All stages of CML require confirmation of the Philadelphia chromosome or variants of 
the (9;22) translocation by cytogenetics or by FISH, or patients must test positive for BCR-
ABL by RT-PCR. Secondary chromosomal abnormalities in addition to the Philadelphia 
chromosome will not result in a change in phase of disease.  Only the criteria in Section 
4.2 below will be used to determine diagnosis of Chronic Phase disease. Definitions 
for Accelerated Phase and Blast Phase are located in protocol Section 10.2. 

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4.2 
Chronic Phase 
 
Chronic Phase is defined by the presence of all of the following criteria: 
 
a. 
< 15% blasts in peripheral blood and bone marrow. 
 
b. 
< 30% blasts plus promyelocytes in peripheral blood and bone marrow. 
 
c. 
< 20% basophils in the peripheral blood. d. 
≥ 100 x 109/L (≥ 100,000/mm3) 
platelets. 
d. 
No  evidence  of  extramedullary  leukemic  involvement,  with  the  exception  of 
hepatosplenomegaly. 
 
e. 
If the marrow is inaspirable ("dry tap"), then all requirements in Sections 4.2a -  4.2e 
above must be met, except for the marrow requirements in 4.2a - b, and a bone 
marrow biopsy must be performed and read as consistent with chronic phase. 
 
4.3 
Risk Category Based on Hasford Score and Sokal Score 
 
Hasford and Sokal score calculators are available at 
http://bloodref.com/myeloid/cml/sokal- hasford. 
 
The risk category is determined from the Hasford Score as follows:  
 
Score 
Risk Category 
Score ≤ 780 
Low risk 
780 < Score ≤ 1480 
Intermediate risk 
1,480 < Score 
High risk 
 
The risk category is determined from the Sokal Score as follows:  
 
Score 
Risk Category 
Score < 0.8 
Low risk 
0.8 < score ≤ 1.2 
Intermediate risk 
1.2 < score 
High risk 
 
The advantage of using the Hasford score is that the Sokal score contains a subset of this 
data (age, spleen size, blast % and platelet count). Accordingly, collection of this more 
complete data  set will  allow both scores to be analyzed  for  prognostic information; 
however, whichever score was calculated at patient’s initial diagnosis will be collected. 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered eligible 
for randomization. For each criterion requiring test results and dates, please record this information on 
the Onstudy Form and submit via Medidata Rave® (see Section 14.0). Any potential eligibility issues 
should be addressed to the SWOG Statistics and Data Management Center in Seattle at 206/652-
2267 or leukemiaquestion@crab.org prior to randomization. NCI policy does not allow for waiver of 
any eligibility criterion (http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
 
In calculating days of tests and measurements, the day a test or measurement is done is considered 
Day 0. Therefore, if a test is done on a Monday, the Monday 4 weeks later would be considered Day 
28.  This allows for efficient patient scheduling without exceeding the guidelines. If Day 7 or 21 falls 
on a weekend or holiday, the limit may be extended to the next working day. 

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5.1 
Disease Related Criteria 
 
a. 
Patients must have a diagnosis of chronic phase chronic myeloid leukemia without 
any history of progression to accelerated or blast phase CML (as defined in Section  
4.0). No new bone marrow aspiration and biopsy is needed to prove diagnosis prior 
to randomization; however, documentation stating the patient is in chronic phase is 
required. 
 
b. 
Patients must have detectable BCR-ABL transcripts measured by RT-PCR at a 
CLIA-approved laboratory and reported on the International Scale (IS) with a value 
of > 0.0032% IS and ≤ 1.0% IS within 21 days prior to randomization. The RT- PCR 
assay must have the sensitivity to detect a 4.5 log reduction in BCR-ABL transcripts 
from 100% IS (must be able to detect (0.0032% IS or lower). 
 
5.2 
Prior/Concurrent Therapy Criteria 
 
a. 
Patients must have been on TKI therapy for CML for at least 12 months prior to 
randomization. Hydroxyurea prior to initiation of TKI is allowed. 
 
b. 
Patients must be currently receiving treatment with bosutinib (within the allowable 
dose range of 200-500 mg daily), nilotinib (within the allowable dose range of 150-
400 mg BID or a cumulative daily dose of 300-800 mg), imatinib (within the 
allowable dose range of 300-400 mg daily), or dasatinib (within the allowable dose 
range of 40-140 mg daily). They must have received their current TKI for a minimum 
of 6 months prior to randomization and must be expected to remain on the same 
TKI for the next 12 months. 
 
c. 
Patient must not have a history of resistance to any prior TKI drug. If patient has 
received more than one TKI, the reason for changing treatment must have been 
something other than resistance or inadequate response to the prior TKI (for 
example, intolerance to the prior TKI) and the treatment change must have occurred 
≥6 months prior to randomization. 
 
d. 
Patients must not be receiving any other investigational agents. 
 
5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must be ≥ 18 years of age. 
 
b. 
Patients must have complete history and physical examination within 28 days prior 
to randomization. 
 
c. 
If clinically indicated, patients must have QTcF interval < 500 ms (by Fridericia 
calculation) on a 12-lead EKG within 7 days prior to randomization. 
 
QTcF = QT/(RR)0.33 
 
(QTcF = QT interval divided by the cube root of the RR [heart rate] in seconds) 
 
d. 
Patients must have platelets ≥ 100,000/mm3 (100.0 x 109/L), ANC > 1,000/mm3 
(1.0 x 109/L), and hemoglobin ≥ 8 g/dL within 7 days prior to randomization. 
 
e. 
Patients must have ALT and AST ≤ 2.5 x IULN within 7 days prior to randomization. 
 

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f. 
Patients must have total bilirubin ≤ 1.5 x IULN within 7 days prior to randomization 
(unless the patient has a known diagnosis of Gilbert’s Syndrome). 
 
g. 
Patients  must  have  a  serum  creatinine  ≤1.5  x  IULN  within  7  days  prior  to 
randomization. 
 
h. 
Prior malignancy is allowed providing it does not require concurrent therapy. 
Exception: Active hormonal therapy is allowed. 
 
i. 
Patients must not be pregnant or nursing due to the teratogenic potential of the 
drugs used on this study. Women of child-bearing potential must have a negative 
serum pregnancy test within 7 days prior to randomization. Women/men of 
reproductive potential must have agreed to use an effective contraceptive 
method during treatment and for 30 days after discontinuation of study drug. A 
woman is considered to be of "reproductive potential" if she has had menses at 
any time in the preceding 12 consecutive months. In addition to routine 
contraceptive methods, "effective contraception" also includes heterosexual 
celibacy and surgery intended to prevent pregnancy (or with a side-effect of 
pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or 
bilateral tubal ligation. However, if at any point a previously celibate patient 
chooses to become heterosexually active during the time period for use of 
contraceptive measures outlined in the protocol, he/she is responsible for 
beginning contraceptive measures. 
 
j. 
Patients known to be HIV+ are eligible provided they meet all other eligibility 
criteria and have undetectable HIV viral loads on their most recent viral load test 
which must have been performed in the last 6 months. 
 
5.4 
Specimen Submission Criteria 
 
Pre-randomization specimens for 5.4b (central BCR-ABL quantification) may be 
drawn at the same time or within 21 days of the specimens for 5.4a (local BCR-ABL 
quantification). 
 
a. 
Specimens (peripheral blood) must be collected and submitted to a CLIA-
approved laboratory as outlined in Section 15.1, within 21 days prior to 
randomization. BCR- ABL transcripts must be measured using RT-PCR and 
results must be reported using the International Scale. The RT-PCR assay must 
have the sensitivity to detect a 4.5 log reduction in BCR-ABL transcripts from 
100% IS (must be able to detect0.0032% IS or lower). 
 
b. 
Patients must be offered participation in submission of specimens for central 
BCR- ABL quantification and banking for future research. This submission is 
highly encouraged as an important protocol endpoint. With patient’s consent, 
specimens must be collected as outlined in Section 15.2, within 42 days prior to 
randomization. 
 
5.5 
Regulatory Criteria 
 
a. 
Patients must be informed of the investigational nature of this study and must 
sign and give informed consent in accordance with institutional and federal 
guidelines. 
 
b. 
As a part of the OPEN registration process (see Section 13.3 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that 

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the current (within 365 days) date of institutional review board approval for this 
study has been entered in the system. 
 
6.0 
STRATIFICATION FACTORS 
 
A dynamic  allocation  scheme  will  be  used  to  balance  the  randomization  on  the  following 
stratification factors. (20) 
 
6.1 
Time on TKI therapy prior to randomization (≥ 1 and < 4 years versus ≥ 4 years). Note: 
This will be total time on any TKI therapy. 
 
6.2 
Current TKI (bosutinib versus dasatinib versus imatinib versus nilotinib). 
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Dr. Srinivas K. Tantravahi at 
801/585-9682 or Dr. Jerald Radich at 206/667-4118. For dosing principles or questions, 
please consult the SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" at 
http://swog.org (then select “About” on the menu and then click on "Policies & Procedures" and 
choose Policy 38). 
 
7.1 
Treatment 
 
Refer to the NCCN guidelines for complete supportive care and prophylactic guidelines for 
treatment of patients with TKI (https://www.nccn.org/patients/guidelines/cml/). 
 
Prior to initiation of protocol therapy, all patients must have serum lipase and serum 
amylase testing to establish baseline values. After the baseline visit, the serum lipase and 
the serum amylase need to be drawn and checked only on the patients taking nilotinib. 
 
a. 
Arm 1: Single Agent TKI 
 
For patients in Arm 1: Cycle 1, Day 1 is defined as the day of randomization. 
 
Agent 
Dose 
Route 
Day 
Schedule* 
Bosutinib 
200-500 mg^ 
PO 
1-90 
Daily, every cycle 
OR 
Dasatinib 
40-140 mg^ 
PO 
1-90 
Daily, every cycle 
OR 
Imatinib 
300-400 mg^ 
PO 
1-90 
Daily, every cycle 
OR 
Nilotinib 
150-400 mg^  
OR 
Cumulative daily dose 
of at least 300mg^ 
PO 
PO 
1-90 
1-90 
BID, every cycle 
Daily, every cycle 
 
(total daily dose is between 300 mg – 800 mg) 

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* Note: One cycle = 90 days 
^ Within the outlined dose range, dose is at the discretion of the treating physician, 
and should be the same as the dose the patient was receiving prior to 
randomization. Patients who have had dose modifications prior to study 
enrollment may continue to be treated at the modified dose (the dose they were 
receiving 
at 
the 
time 
of 
randomization), 
but 
no 
further 
dose 
reductions/modifications are allowed (see Section 8.0). 
 
b. 
Arm 2: TKI + Ruxolitinib 
 
For patients in Arm 2: Cycle 1, Day 1 is defined as the first day of ruxolitinib 
administration. Prior to initiation of protocol therapy, patients in Arm 2 must also 
have lipid profile testing, to include total cholesterol, LDL cholesterol and 
triglycerides to establish baseline values. 
 
Agent 
Dose 
Route 
Day 
Schedule* 
Ruxolitinib 
15 mg 
 
PO 
1-90 
BID, every cycle 
(total daily dose is 30 mg) 
AND 
TKI (bosutinib, dasatinib, imatinib, or nilotinib) 
Bosutinib 
200-500 mg^ 
PO 
1-90 
Daily, every cycle 
OR 
Dasatinib 
40-140 mg^ 
PO 
1-90 
Daily, every cycle 
OR 
Imatinib 
300-400 mg^ 
PO 
1-90 
Daily, every cycle 
OR 
Nilotinib 
150-400 mg^ OR 
PO 
1-90 
BID, every cycle 
 
Cumulative daily 
dose of at least 
300 mg^ 
PO 
1-90 
Daily every cycle 
 
(total daily dose is between 300 mg – 800 mg) 
* 
Note: One cycle = 90 days 
^ 
Within the outlined dose range, dose is at the discretion of the treating 
physician, and should be the same as the dose the patient was receiving 
prior to randomization. Patients who have had dose modifications prior to 
study enrollment may continue to be treated at the modified dose (the dose 
they were receiving at the time of randomization), but no further dose 
reductions/modifications are allowed (see Section 8.0). 
 
7.2 
Drug Compliance Documentation 
 
Drug compliance will be recorded by patients in the Intake Calendar (see Appendices 18.1- 
18.5). Institutional CRAs will review and ascertain patient adherence with protocol therapy 
at the end of treatment for each cycle. Calendar should be kept in the patient's research 
chart. Sites utilizing the CIRB must use the Intake Calendar provided Sites not utilizing the 
CIRB may utilize institutional pill diaries or other source documentation in place of the 
Intake Calendar at the discretion of the treating physician. 
 
7.3 
Concomitant and Prohibited Therapies and Supportive Care 

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a. 
Concomitant Therapies 
 
Supportive care measures will be provided per local institutional policies 
and procedures in accordance with NCCN guidelines. 
 
b. 
Prohibited Therapies 
 
The following should not be taken with Ruxolitinib: 
 
• 
Grapefruit juice 
• 
Potent systemic inhibitors of CYP3A4. See Appendix 18.7. 
• 
Fluconazole doses > 200 mg 
 
The following medications are contraindicated with TKIs, however if the patient is 
already taking these medications at study entry then they are allowed to continue. 
If they need to start one of these medications while on trial than approval must be 
obtained from the study chair. 
 
Lists of CYP inhibitors or inducers are accessible from: https://drug-  
interactions.medicine.iu.edu/MainTable.aspx 
OR consult local 
institutional 
pharmacists. 
 
TKI 
Interactions 
Bosutinib 
• 
H2 antagonists or proton pump inhibitors 
• 
Potent systemic inhibitors of CYP3A4 such as but 
not limited to boceprevir, clarithromycin, 
conivaptan, grapefruit juice, indinavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, telaprevir, telithromycin, voriconazole) 
• 
Potent systemic inducers of CYP3A4 such as but 
not limited to rifampin, phenytoin, 
carbemazepime, phenobarbital, rifabutin, 
dexamethasone, St John’s Wort 
Dasatinib 
• 
H2 antagonists or proton pump inhibitors 
• 
Potent systemic inhibitors of CYP3A4 such as but 
not limited to boceprevir, clarithromycin, 
conivaptan, grapefruit juice,               indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, telithromycin, 
voriconazole) 
• 
Potent systemic inducers of CYP3A4 such as but 
not limited to rifampin, phenytoin, 
carbemazepime, phenobarbital, rifabutin, 

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TKI 
Interactions 
Imatinib 
• 
H2 antagonists or proton pump inhibitors 
• 
Warfarin 
• 
Potent systemic inhibitors of CYP2C9, 
CYP2D6, and CYP3A4/5 
• 
Potent systemic inhibitors of CYP3A4, and to a 
lesser extent of CYP1A2, CYP2D6, CYP2C9, 
and CYP2C19, such as but not 
limited to alfentanil, boceprevir, clarithromycin, 
cyclosporine, conivaptan, diergotamine, 
ergotamine, fentanyl, grapefruit juice, 
indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir, pimozide, posaconazole, quinidine, 
ritonavir, saquinavir, sirolimus, tacrolimus, 
telaprevir, telithromycin, voriconazole) 
• 
Potent systemic inducers of CYP3A4 such as but 
not limited to rifampin, phenytoin, 
carbemazepime, phenobarbital, rifabutin, 
dexamethasone, St John’s Wort 
Nilotinib 
• 
H2 antagonists or proton pump inhibitors 
• 
Drugs known to prolong the QT interval 
• 
Avoid food 2 hours before and 1 hour after 
taking a dose 
• 
Warfarin 
• 
Potent systemic inhibitors of CYP3A4 such as but 
not limited to boceprevir, clarithromycin, 
conivaptan, grapefruit juice, indinavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, telaprevir, telithromycin, voriconazole) 
• 
Potent systemic inducers of CYP3A4 such as but 
not limited to rifampin, phenytoin, 
carbemazepime, phenobarbital, rifabutin, 
dexamethasone St John’s Wort
 
c. 
Management of Ruxolitinib Withdrawal Syndrome 
 
Following discontinuation of ruxolitinib, patients with Myelofibrosis (MF) and 
Polycythemia Vera (PV) have experienced recurrence of symptoms related to their 
myeloproliferative neoplasms over a period of approximately one week. Some 
patients with MF have experienced one or more of the following adverse events 
after discontinuing ruxolitinib: fever, respiratory distress, hypotension, DIC or multi- 
organ failure. If one or more of these occur after discontinuation of, or while 
tapering the dose of ruxolitinib, evaluate for and treat any intercurrent illness and 
consider restarting or increasing the dose of ruxolitinib. Patients should not 
interrupt or discontinue ruxolitinib without consulting their physician. 
 
7.4 
Criteria for Removal from Protocol Treatment 
 
a. 
Progression of disease or treatment failure/loss of response to treatment (as 
defined in Sections 10.2 and 10.3). 
 

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b. 
Unacceptable toxicity. 
 
c. 
Treatment delay (either TKI or ruxolitinib) for any reason > 28 consecutive days. 
 
d. 
Patient completes 4 cycles of protocol therapy. 
 
e. 
Change in TKI therapy while on protocol therapy. 
 
f. 
The patient may withdraw from the protocol treatment at any time for any reason. 
 
7.5 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off 
Protocol Treatment Notice. 
 
7.6 
Follow-Up Period 
 
All patients will be followed until death or 5 years after randomization, whichever 
occurs first. 
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
a. 
Serious Adverse Event (SAE) reporting and Routine toxicity reporting 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events) Version 5.0 for toxicity and Serious Adverse Event reporting. A copy of 
the CTCAE Version 5.0 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov). All appropriate treatment areas should have access to a 
copy of the CTCAE Version 5.0. 
 
8.2 
General Considerations 
 
a. 
TKI dose modifications are allowed as outlined below and as approved by the 
Study Chair. For modifications made with Study Chair approval, written 
documentation of the approval must be obtained, kept in the patient chart, and 
submitted as outlined in Section 14.4. 
 
b. 
Missed doses will not be made up. 
 
c. 
If multiple toxicities are experienced, dose modifications will be based on the 
toxicity requiring the largest dose reduction. 
 
d. 
Reductions are based on the dose being given at the end of the preceding cycle 
and are based on toxicities observed since the prior toxicity evaluation. Patients 
will be monitored according to NCTN guidelines; however, patients on Arm 2 (TKI 
+ Ruxolitinib) should have toxicity evaluations every 30 days for the first cycle of 
protocol therapy. 
 
e. 
If a drug must be permanently discontinued, the patient must be removed from 
protocol therapy (see Section 7.4). 
 

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f. 
For dose reductions of oral medications, dose should be reduced to the nearest 
available pill/tablet/capsule strength to the calculated reduction. 
 
g. 
For infections requiring hospitalization or patients requiring transfer to an intensive 
care unit, discuss with the Study Chair to determine whether dose modification or 
removal from protocol therapy is required. Any such discussion must be 
documented in the patient chart. 
 
8.3 
Dose Modifications 
 
a. 
Bosutinib, Dasatinib, Imatinib, and Nilotinib 
 
In the event of the occurrence of an adverse event known to be related to TKI use, 
the TKI dose will be modified as per the respective label. Any additional dose 
modifications must be approved by the Study Chair. The dose modification should 
be noted on the S1712 Treatment Form. 
 
Patients who have had dose modifications prior to study enrollment may continue 
to be treated at the modified dose (the dose they were receiving at the time 
of randomization). 
 
b. 
Ruxolitinib 
 
1. 
Dose Level Table 
 
Dose Level 
Dose 
0 (starting dose) 
15 mg PO BID (30 mg total daily) 
-1 
10 mg PO BID (20 mg total daily) 
-2 
5 mg PO BID (10 mg total daily) 
-3 
Hold drug 
 
2. 
Dose Modifications 
 
a. 
Thrombocytopenia or Neutropenia 
 
Interrupt treatment for platelets counts less than 50 x 109/L 
or absolute neutrophil count (ANC) less than 0.5 x 109/L. 
 
After recovery of platelet counts to > 50 x 109/L and ANC to > 
0.75 x 109/L, dosing may be restarted. The table below 
shows the maximum allowable dose of ruxolitinib that may be 
used when restarting after a dose interruption. 
 
Current Platelet Count 
Ruxolitinib Dose 
75 - <100 x 109/L 
Next lower dose level for at least 
14 days and if platelets remain 
≥ 75 x 109/L, may increase by 
one dose level 

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50 - < 75 x 109/L 
Decrease dose level by 2 levels 
for at least 14 days; if platelets 
remain ≥ 50 
x 109/L may 
increase dose by one dose level 
< 50 x 109/L 
Hold ruxolitinib 
 
Following treatment interruption for ANC below 0.5 x 109/L, 
after ANC recovers to 0.75 x 109/L or greater, restart dosing 
at one dose level below the dose being given at the time of 
interruption. 
 
b. 
Dose Modifications for Anemia 
 
Patients with a baseline hemoglobin ≥ 10 g/dL 
 
Hemoglobin 
Ruxolitinib Dose* 
10 - < 12 g/dL 
No dose reduction required 
8 - < 10 g/dL 
Reduce by 1 dose level for at least 14 days; if 
patient is asymptomatic from anemia, or if 
hemoglobin returns to ≥ 10 g/dL, may increase 
dose back up by 1 dose level. 
< 8 g/dL 
Hold ruxolitinib until hgb > 8g/dL then resume 
ruxolitinib at one dose level below the previous 
dose. 
*Maximum doses are displayed. When restarting, begin with 
a dose that is one dose level below the dose being given at the 
time of interruption. 
 
Patients with a baseline hemoglobin of 8-10 g/dL 
 
If hemoglobin falls > 1 g/dL below baseline, reduce ruxolitinib 
by one dose level for at least 14 days. If hemoglobin returns to 
within 
1 g/dL of baseline level, may increase ruxolitinib back to 
the previous dose. If hemoglobin falls > 1 g/dL again, 
permanently reduce ruxolitinib dose by one dose level. 
 
c. 
Dose Modifications for Non-Hematologic Toxicity 
 
Adverse Event Grade 
Dose Adjustments 
Any Grade 1 or 2 toxicity No dose reduction required. Monitor 
patient closely and manage with 
supportive care as needed 
Any Grade 3 toxicity* 
Hold ruxolitinib until toxicity resolves 
to ≤ Grade 1 or baseline. May 
resume ruxolitinib at the previous 
dose or at one dose level below the 
previous dose at the discretion of the 
treating physician. 
Any  recurrent  Grade  
3  toxicity after 2 dose 
reductions 
Discontinue ruxolitinib; remove from 
protocol therapy 

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Any Grade 4 toxicity 
Dose Level -3 (hold ruxolitinib) until 
toxicity resolves to ≤ Grade 1 or 
baseline, then resume at Dose Level 
-1. 
* Dose modifications are not required for electrolyte 
abnormalities that resolve, with or without intervention, to < 
Grade 2. 
 
8.4 
Dose Modification Contacts 
 
For treatment or dose modification questions, please contact DrSrinivas K. 
Tantravahi at 8001/585-9682 or Dr. Jerald Radich at 206/667-4118. 
 
8.5 
Adverse Event Reporting Requirements 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
 
• 
The reporting period (course/cycle) is correct; and 
• 
AEs are recorded and complete (no missing fields) and the form is query free 
(fields added to the form during study build do not need to be query free for the 
integration call with CTEP-AERS to be a success). 
 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form. Both NCI and protocol- 
specific reporting rules evaluate the AEs submitted for expedited reporting. A report is 
initiated in CTEP-AERS using information entered in Medidata Rave for AEs that meet 
reporting requirements. The CRA completes the report by accessing CTEP-AERS via a 
direct link on the Medidata Rave Expedited Reporting Evaluation form. 
 
In the rare occurrence, that Internet connectivity is lost; a 24-hour notification is to be made 
to CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 24-hour 
notification that was phoned in must be entered immediately into CTEP-AERS using the 
deep link from Medidata Rave. 
 
NCI requirements for SAE reporting are available on the CTEP website: 
• 
NCI  Guidelines  for  Investigators:  Adverse  Event  Reporting  Requirements  is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid  
elines.pdf. 
 
If you have questions about this process, please contact the SAE Program Manager 
210- 614-8808 or email adr@swog.org. 
 
The CTEP-AERS electronic reporting system “Help” feature has detailed instructions in 
the section "Submitting Reports for RAVE Users". 
 
a. 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as 
well as those who will enroll in future studies using similar agents. Adverse 

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events are reported in a routine manner at scheduled times during a trial. 
(Directions for routine reporting are provided in Section 14.0.) Additionally, 
certain adverse events must be reported in an expedited manner to allow for 
more timely monitoring of patient safety and care. The following guidelines 
prescribe expedited adverse event reporting for this protocol. 
 
b. 
Reporting method 
 
This study requires that expedited adverse events be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS). 
CTEP's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  A 
CTEP-AERS  report  must  be  submitted  to  the  SWOG  Operations  Office 
electronically   via   the   CTEP-AERS   Web-based   application   located   at  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_  
events.htm. 
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 8.1) via CTEP- 
AERS. When Internet connectivity is disrupted, a 24-hour notification is to be 
made to SWOG by telephone at 210-614-8808 or by email at adr@swog.org. 
Once Internet connectivity is restored, a 24-hour notification that was made by 
phone or using adr@swog.org must be entered electronically into CTEP-AERS 
by the original submitter at the site. 
 
When the adverse event requires expedited reporting, submit the report within 
the number of calendar days of learning of the event, as specified in Table 8.1 
or 8.2, as applicable. 
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local 
policy and procedures. 
 
e. 
Expedited reporting for commercial agents 
 
Commercial reporting requirements are provided in Table 8.1. The commercial 
agents used in this study are dasatinib, nilotinib, imatinib and bosutinib. If there 
is any question about the reportability of an adverse event or if on-line CTEP- 
AERS cannot be used, please telephone or email the SAE Program at the 
Operations Office, 210/614-8808 or adr@swog.org, before preparing the 
report. 
 
Note that while Arm 2 utilizes the same commercial agents as Arm 1, Arm 
2 will not utilize the expedited reporting for commercial agent 
instructions, as commercial agents are not administered independently of 
investigational agent on Arm 2. 
 
 
 
 

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Table 8.1. Expedited reporting requirements for adverse events experienced by 
patients on study Arm 1 who have received the commercial drugs listed in 8.5e 
above within 30 days of the last administration of the commercial agent. 
 
ATTRIBUTION 
 
Grade 4 
 
Grade 5a 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated or Unlikely 
CTEP-AERS 
 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
CTEP-AERS 
 
CTEP-AERS 
CTEP-AERS: Indicates an expedited report is to be submitted via CTEP-AERS 
within 10 calendar days of learning of the eventb 
. 
a This includes all deaths within 30 days of the last dose of treatment with a 
commercial agent(s), 
regardless of attribution. Any death that occurs 
more than 30 days after the last dose of treatment with a commercial 
agent(s) and is attributed (possibly, probably, or definitely) to the agent(s) 
and is not due to cancer recurrence must be reported according to the 
instructions above. 
b Submission of the on-line CTEP-AERS report plus any necessary 
amendments generally completes the reporting requirements. You may, 
however, be asked to submit supporting clinical 
data to the Operations 
Office in order to complete the evaluation of the event. If requested, the 
specified data should be sent within 5 calendar days by fax to 210-614-0006. 
 
f. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of 
the investigational agent as part of the trial. Reporting requirements are 
provided in  Table 8.2. The investigational agents used in Arm 2 of this study 
is ruxolitinib. If there is any question about the reportability of an adverse event 
or if on-line CTEP- AERS cannot be used, please telephone or email the 
SAE Specialist at the Operations Office, 210/614-8808 or adr@swog.org, 
before preparing the report. 
 
Table 8.2: Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under a Non-CTEP IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1 Ruxolitinib (Arm 2) 
 

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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death 
2) A life-threatening adverse event 
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for 
≥ 24 hours 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon 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. (FDA, 21 CFR 312.32; ICH E2A and 
ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to 
the NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found 
in Section 8.5f. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 
24 hours of learning of the AE, followed by a complete expedited report within 5 
calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite 
require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
• Grade 3 adverse events 
May 5, 2011 
 

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g. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Late Phase 2 and Phase 3 Studies Utilizing an Agent under 
a non-CTEP-IND (Arms 1 and 2): 
 
1. 
Group-specific instructions. 
 
Supporting Documentation Submission - Within 5 calendar days 
submit the following to the SWOG Operations Office by fax to 210-614- 
0006 or mail to the address below: 
• 
Printed copy of the first page of the CTEP-AERS report 
• 
Copies of clinical source documentation of the event 
• 
If applicable, and they have not yet been submitted to the 
SWOG Statistics and Data Management Center, and, copies of 
Off Treatment Notice and/or Notice of Death. 
 
2. 
The adverse events listed below also require expedited reporting for this trial: 
• 
Grade 3 or 4 anemia requiring transfusion of packed red blood cells 
• 
Grade 4 thrombocytopenia requiring transfusion of platelets 
• 
Grade 4 neutropenia requiring ruxolitinib dose modifications 
 
h. 
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
1. 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy). A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 
SWOG requires all secondary malignancies that occur following treatment 
with an agent under a Non-NCI IND to be reported via CTEP-AERS. Three 
options are available to describe the event. 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
Second Malignancy: A second malignancy is one unrelated to the 
treatment of a prior malignancy (and is NOT a metastasis from the 
initial malignancy). Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/d 
ocs/aeguidelines.pdf 
 
2. 
Any supporting documentation should be submitted to CTEP per NCI 
guidelines 
for 
AE 
reporting 
located 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/
d ocs/aeguidelines.pdf. 
 

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A copy of the report and the following supporting documentation must also 
be submitted to SWOG Operations Office within 30 days by fax to 210- 
614-0006 or mail to the address below: 
 
• 
a copy of the pathology report confirming the AML/ALL/MDS diagnosis 
• 
(if available) a copy of the cytogenetics report 
 
SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, Texas 78229 
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial. 
 
i. 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
 
1. 
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Pregnancy Loss Pregnancy loss is defined in CTCAE as “Death in utero.” 
Pregnancy loss should be reported expeditiously as Grade 4 “Pregnancy 
loss” under the Pregnancy, puerperium and perinatal conditions SOC. 
 
A Pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP- 
AERS recognizes this event as a patient death. 
 
3. 
Death Neonatal Death neonatal is defined in CTCAE as “Newborn death 
occurring during the first 28 days after birth. A neonatal death should be 
reported expeditiously as Grade 4 “Death neonatal” under the General 
disorders and administration SOC. 
 
Neonatal death should NOT be reported as a Grade 5 event under the General 
disorders and administration SOC as currently CTEP-AERS recognizes this event 
as a patient death. 
 
NOTE: When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, or 
“Neonatal loss”, the Pregnancy Information Form should also be completed and 
faxed with any additional medical information to 301-230-0159. The potential risk of 
exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) should 
be documented in the “Description of Event” section of the CTEP-AERS report. 
 
The Pregnancy Information Form is available at:  
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm 
 
 

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9.0 
STUDY CALENDARS 
 
Study calendars for each treatment arm are below.  Please note the following for both 
treatment arms: 
 
• 
Forms are found on the protocol abstract page on the SWOG website (www.swog.org) and on 
the CTSU website (www.ctsu.org). Forms submission guidelines are found in Section  14.0. 
 
• 
Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment 
administration, toxicity assessment for continuous treatment, disease assessment, specimen 
collection and follow-up activities) must follow the established SWOG guidelines  as  outlined  in  
https://www.swog.org/sites/default/files/docs/2017-  10/Best%20Practices%20upddate.pdf. 
 

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9.1 
Arm 1: Single Agent TKI 
 
Pre RegJ 
Cycle 
1 
(Days 
1-90) 
Cycle 2 
(Days 91- 
180) 
Cycle 3 
(Days 
181-
270) 
Cycle 4 
(Days 
271-
360) 
End of 
Treatme
nt Visit 
Follow Up 
A 
REQUIRED STUDIES 
History / Physical Exam 
X N 
X N 
X 
X 
X 
X 
X 
Performance Status 
X 
Toxicity Notation B 
X N 
X N 
X 
X 
X 
X 
X I 
Intake Calendar C 
X 
X 
X 
X 
LABORATORY STUDIES 
CBC, Diff Plts B 
X H 
X H 
X 
X 
X 
X 
Comprehensive Metabolic Panel B,D 
X 
X IH 
X 
X 
X 
X 
Serum LipaseL 
X H 
X 
X 
X 
X 
X 
Serum AmylaseL 
X H 
X 
X 
X 
X 
X 
Serum Pregnancy Test 
XK 
Disease Assessment (Local BCR-ABL) E 
X 
X 
X 
X 
X 
X 
X-RAYS / SCANS 
12-Lead EKGM 
X 
SPECIMEN SUBMISSION 
Whole Blood for Central BCR-ABL & Banking 
X 
X 
X 
X 
X 
X 
PROTOCOL TREATMENT G 
Bosutinib, Dasatinib, Imatinib or Nilotinib 
X 
X 
X 
X 
X G 
X G 
Click here for Footnote. 
 
NOTE: For patients in Arm 1:  Cycle 1, Day 1 is defined as the day of randomization. 

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Footnotes for Calendar 9.1 
 
A 
Patients will be followed for up to 5 years from initial randomization. Follow up should be per NCCN standard of care guidelines and per 
institutional standards. 
Prior to progression: At minimum, the patient must be seen every 3-6 months and PCR for BCR-ABL 
quantification must be performed. BCR-ABL quantification results will be reported according to Section 14.4c. Post-progression: Patients 
will be followed for survival and must be seen every 6 months until 2 years after registration and then annually until 5 years after registration. 
B 
Patients on Arm 1 will be managed according to NCCN guidelines for treatment of chronic phase CML. At minimum, patients will be examined 
in the outpatient setting every 3 months (or more often if clinically indicated, at the discretion of the treating physician). 
C 
CRA will review the Intake Calendar at the end of each cycle (see Appendices 18.1-18.5). 
D 
To include measurements of ALT, AST, total bilirubin, serum creatinine, magnesium, and phosphorus. 
E 
See Section 15.1. For pre-registration only, may be drawn within 21 days or at same time as central BCR ABL. For all other time points, must 
be drawn at the same time as central BCR-ABL. 
F 
See Section 15.2. For pre-registration only, may be drawn within 21 days or at the same time of the local BCR ABL. For all other time points, 
must be drawn at the same time as local BCR-ABL. 
G 
Patient will be treated with the TKI and at the dose they were receiving prior to randomization (see Section 7.1). After Cycle 4 of protocol 
therapy, patients will 
be removed from protocol therapy. After removal from protocol therapy, treatment during follow-up will be at the 
discretion of the treating physician (including continued single-agent TKI). 
H 
To be completed prior to treatment on Cycle 1 Day 1 for safety assessment; however, if the test/assessment has been performed within 7 days 
prior to Cycle 1 Day 1, it need not be repeated prior to treatment. 
I 
Report AEs of interest (new non-melanoma skin cancer, hepatitis reactivation, worsening of musculoskeletal pain, second malignancies, 
Herpes zoster, or hospital admission for sepsis) on the S1712 Follow-up form during follow up. 
J 
Preregistration laboratory assessments must be completed within 7 days prior to registration. See Section 5.0.  
K 
Pregnancy testing is required for females of childbearing potential.  See Section 5.3h. 
L 
Serum amylase and serum lipase testing is required for all patients prior to treatment initiation. During the study treatment, continued serum 
amylase and serum lipase testing is required only for patients taking nilotinib and must be performed monthly while on protocol treatment, and 
per drug label, NCCN guidelines, and institutional standards during follow-up. 
M 
If clinically indicated. 
N 
See Section 5.3b. Patients must have toxicity notation within 28 days prior to randomization. 

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9.2 
Arm 2: TKI + Ruxolitinib 
 
Pre RegK 
Cycle 
1 
(Days 
1-90) 
Cycle 2 
(Days 91- 
180) 
Cycle 3 
(Days 
181-
270) 
Cycle 4 
(Days 
271-
360) 
End of Treatment 
Visit 
Follow Up A 
REQUIRED STUDIES 
History / Physical Exam 
X P 
Monthly P 
X 
X 
X 
X 
X 
Performance Status 
X 
Toxicity Notation 
X P 
Monthly P 
X 
X 
X 
X 
X I 
Intake Calendar C 
X 
X 
X 
X 
LABORATORY STUDIES 
CBC, Diff Plts B 
X H 
Monthly B, 
H
X 
X 
X 
X 
Comprehensive 
Metabolic Panel B, D 
X H 
Monthly B, 
H
X 
X 
X 
X 
Serum LipaseN 
XH 
X 
X 
X 
X 
X 
Serum AmylaseN 
XH 
X 
X 
X 
X 
X 
Serum Pregnancy Test 
XL 
Lipid Panel H, M 
X 
Disease Assessment (Local BCR-ABL) 
E 
X 
X 
X 
X 
X 
X 
X-RAYS / SCANS 
12-Lead EKGO 
X 
XJ 
SPECIMEN SUBMISSION 
Whole Blood for Central BCR-
ABL & Banking F 
X 
X 
X 
X 
X 
X 
PROTOCOL TREATMENT G 
Bosutinib, Dasatinib Imatinib or Nilotinib 
X 
X 
X 
X 
X G 
X G 
Ruxolitinib 
X 
X 
X 
X 
Click here for footnotes. 
NOTE: For patients in Arm 2:  Cycle 1, Day 1 is defined as the first day of ruxolitinib administration. 

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Footnotes: Calendar 9.2 
 
A 
Patients will be followed for up to 5 years from initial randomization. Follow up should be per NCCN standard of care guidelines and per 
institutional standards. 
Prior to progression: At minimum, the patient must be seen every 3-6 months and PCR for BCR-ABL 
quantification must be performed. BCR-ABL quantification results will be reported according to Section 14.4c. Post-progression: Patients 
will be followed for survival and must be seen every 6 months until 2 years after registration and then annually until 5 years after registration. 
B 
Patients on Arm 2 will have CBC with differential and CMP every two weeks for the first two months of treatment and monthly 
thereafter for the duration of protocol treatment.  Otherwise, patients will be managed according to NCCN guidelines for treatment of 
chronic phase CML. 
C 
CRA will review the Intake Calendar at the end of each cycle (see Appendices 18.1-18.5). 
D 
To include measurements of ALT, AST, total bilirubin, serum creatinine, magnesium, and phosphorus. 
E 
See Section 15.1. For pre-registration only, may be drawn within 21 days or at same time as central BCR ABL. For all other time points, must 
be drawn at the same time as central BCR-ABL. 
F 
See Section 15.2. For pre-registration only, may be drawn within 21 days or at the same time of the as local BCR-ABL. For all other time points, 
must be drawn at the same time as local BCR-ABL. 
G 
Patient will be treated with the TKI and at the dose they were receiving prior to randomization (see Section 7.1). After Cycle 4 of protocol 
therapy, patients will 
be removed from protocol therapy. After removal from protocol therapy treatment during follow-up will be at the 
discretion of the treating physician (including continued single-agent TKI). 
H 
To be completed prior to treatment on Cycle 1 Day 1 for safety assessment; however, if the test/assessment has been performed within 7 days 
prior to Cycle 1 Day 1, it need not be repeated prior to treatment. 
I 
Report AEs of interest (new non-melanoma skin cancer, hepatitis reactivation, worsening of musculoskeletal pain, second malignancies, 
Herpes zoster, or hospital admission for sepsis) on the S1712 Follow-up form during follow up. 
J 
For patients taking nilotinib, to be performed seven days after beginning ruxolitinib, with any dose changes and regularly during treatment at 
the discretion of 
the treating physician to assess drug interaction effects on QTc interval. This is performed for patient safety, as potential 
interaction of ruxolitinib with TKI is not 
well characterized. For patients on bosutinib, dasatinib, or imatinib, to be performed as clinically 
indicated. 
K 
Preregistration laboratory assessments must be completed within 7 days prior to registration.  See Section 5.0.  
L 
Pregnancy testing is required for females of childbearing potential.  See Section 5.3h. 
M 
Patients must be fasting for at least 8 hours. Lipid panel must include total cholesterol, LDL cholesterol and triglycerides. Lipid panel must be 
performed 8-12 weeks after initiation of ruxolitinib therapy. 
N 
Serum amylase and serum lipase testing is required for all patients prior to treatment initiation. During the study treatment, continued serum 
amylase and serum lipase testing is required only for patients taking nilotinib and must be performed monthly while on protocol treatment, and 
per drug label, NCCN guidelines, and institutional standards during follow-up. 
O 
If clinically indicated. 
P 
See Section 5.3b. Patients must have toxicity notation within 28 days prior to randomization. 

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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
10.1 
Molecular Response 
 
RT-PCR to measure BCR-ABL transcripts will be evaluated on the peripheral blood to 
assess for molecular response. This will be done in commercial labs as standard of care 
monitoring. All labs must report the results using the International Scale (IS) and the RT- 
PCR assay must have the sensitivity to detect a 4.5 log reduction in BCR-ABL transcripts 
from 100% IS (must be able to detect at least 0.0032% IS or lower). 
 
a. 
Molecular Response 4.5 (MR4.5) 
 
The patient’s BCR-ABL/BCR ratio must be at least 31,623 times (4.5 logs) smaller 
than100% IS, i.e., must demonstrate a 4.5-log reduction relative to 100% IS. When 
reported on the International Scale, this response is equivalent to a value of ≤ 
0.0032%. 
 
b. 
Molecular Response 4.0 (MR4.0) 
 
The patients BCR-ABL/BCR ratio must be at least 10,000 times (4.0 logs) smaller 
than100% IS , i.e., must demonstrate a 4.0-log reduction relative to100% IS. When 
reported on the International Scale, this response is equivalent to a value of ≤ 
0.01%. 
 
c. 
Complete Cytogenetic Response (CCyR) 
 
On the International Scale, this response is equivalent to a value of ≤1%. 
 
d. 
Major Molecular Response (MMR) 
 
On the International Scale, this response is equivalent to a value of ≤0.1%. 
 
10.2 
Progression 
 
Progression to accelerated or blast phase CML at any time while on trial therapy. 
 
a. 
Accelerated Phase 
 
Accelerated Phase is defined by any of the following: 
 
1. 
≥ 15% blasts in the peripheral blood or bone marrow, but < 30% blasts in 
both the peripheral blood and bone marrow. 
 
2. 
≥ 30% blasts plus promyelocytes in peripheral blood and bone marrow. 
 
3. 
≥ 20% basophils in the peripheral blood. 
 
b. 
Blast Phase 
 
Blast Phase is defined by any of the following: 
 
1. 
≥ 30% blasts in peripheral blood or bone marrow. 
 
2. 
Appearance of extramedullary involvement proven by biopsy (other than 
hepatosplenomegaly, which does not require biopsy) (e.g., chloroma). 
 

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10.3 
Treatment Failure/Loss of Response** 
 
Any of the following events occurring while a patient is continuously on TKI therapy would 
constitute treatment failure: 
 
• 
Loss of complete cytogenetic response at any point in time. 
 
For patients whose pre-randomization PCR is above MMR (0.1%), a rise above 1% 
should be followed by a repeat PCR in 2-4 weeks. If the repeat is again above 1%, 
this will be considered a loss of response. 
 
• 
Loss of major molecular response (MMR) at any point in time. 
 
In patients with a pre-randomization PCR below MMR (<0.1%), a rise above 0.1% 
should be followed by a repeat PCR in 2-4 weeks. If the repeat is again above 
0.1%, this will be considered a loss of response. 
 
** For treatment failure/loss of response assessment, the increase in PCR should 
be confirmed with a second test to be performed within 2-4 weeks of the initial test, 
before the patient is removed from protocol therapy. 
 
10.4 
Progression-Free Survival (PFS) 
 
Progression-free survival is measured from the date of randomization on study until the 
first of treatment failure/loss of response, progression, (see Section 10.3) or death from 
any cause. Observations are censored at the date of last follow-up for patients last known 
to be alive without report of treatment failure/loss of response or progression. 
 
10.5 
Overall Survival (OS) 
 
Overall survival will be measured for all patients from the date of randomization until death 
from any cause with observations censored at the date of last contact for patients last 
known to be alive. 
 
10.6 
Performance Status 
 
Patients will be graded according to the Zubrod performance status scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, office 
work. 
 
2 
Ambulatory and capable of self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours. 
 
3 
Capable of limited self-care, confined to bed or chair more than 50% of 
waking hours. 
 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair. 
 

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11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Primary Endpoint: Rate of MR4.5 at 12 Months 
 
Molecular response will be assessed pre-randomization and after each cycle of protocol 
therapy. Patients who achieve and then lose MR4.5 status before 12 months will be 
considered MR4.5 failures for the primary endpoint. Patients without 12-month MR4.5 data 
will be considered failures with respect to the primary endpoint. The number of patients 
with missing 12-month MR4.5 data will be summarized descriptively for each arm. 
 
 
11.2 
Study Design Justification 
 
The primary objective of this randomized Phase II trial is to compare the rate of MR4.5 at 
12 months in the combination arm with that of the single agent arm. Patients will be 
randomized 1:1 with randomization stratified by single-agent TKI (bosutinib versus 
dasatinib versus imatinib versus nilotinib) and number of prior years of single-agent therapy 
(≥ 1 and < 4 years versus ≥ 4 and ≤ 10 years). The investigators will also evaluate 
molecular response levels at 3, 6, and 9 months after randomization. For each time point, 
measurements collected within ±1 month of the landmark time will be used in analyses. 
 
Based on the data from cumulative incidence of MR4.5 in the DASISION and ENESTnd 
trials, the study assumes a 12-month MR4.5 rate of 10% in the single agent arm (null 
hypothesis) and the study is powered to detect a 12-month MR4.5 rate of 35% in the 
combination arm (alternative hypothesis). The true conversion rate to MR4.5 may depend 
on how long patients have been on single-agent therapy before randomization and their 
current TKI, so randomization will be stratified by number of prior years of single-agent 
therapy (≥ 1 and < 4 years versus ≥ 4 and ≤ 10 years) and current TKI. The 25% absolute 
difference in MR4.5 rate (10% versus 35%) was selected as clinically significant. 
 
Up to 37 eligible patients per arm will be accrued. After 19 patients have 12-month MR4.5 
data on each arm, an interim analysis will be performed. If the MR4.5 rate in the single- 
agent TKI arm is higher than the MR4.5 rate in the combination arm, accrual to the trial will 
be stopped with the conclusion that the combination therapy does not improve 12-month 
MR4.5 rates. The final analysis will use a logistic regression model stratified by the 
randomization stratification factors. Seventy-four (74) eligible patients (37 per arm) and a 
one-sided significance level of 10% provide 89% power. If there is no difference in the 
MR4.5 rates between arms (null hypothesis), the probability of stopping the trial early is 
39%. If the MR4.5 rates in the two arms are 10% (single-agent) versus 35% (combination, 
alternative hypothesis), the probability of stopping the trial early is 2%. Patients will be 
enrolled in one stage. 
 
11.3 
Secondary and Other Analyses 
 
In each arm, overall survival and progression-free survival will be estimated using 
the 
Kaplan-Meier method. In each arm, any toxicity occurring with at least a 5% 
probability is likely to be observed at least once (85% probability). 
 
In each arm, patterns of MR4.5 and MR 4.0 attainment and failure over the 3, 6, 9, and 
12 months will be summarized descriptively. 
 
Drug compliance will be summarized descriptively for each arm. 
 
BCR-ABL/BCR will be analyzed as a quantitative endpoint, with the endpoint transformed 
as appropriate. Linear regression models will be used to assess associations between 
treatment arm and the quantitative endpoint. 

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11.4 
Sample Size and Accrual Rate 
 
a. 
Estimate of Sample Size: 
 
74 eligible patients. If 10 patients enrolled are ineligible, a total of 84 patients will 
be required. 
 
b. 
Estimate of Accrual Rate: 
 
Intergroup study S0325 for newly diagnosed CML patients enrolled 293 patients 
over 27 months, or approximately 11 patients per month. Based on historical data, 
approximately 65% of newly diagnosed CML patients could potentially be eligible 
for this trial one year after diagnosis. Eligible patients must have been on their 
current TKI for a minimum of 6 months and on any TKI for a minimum of 1 year 
and a maximum of 10 years at the time of enrollment. Based on this data, we 
estimate that we could enroll 5 patients per month on this trial and complete accrual 
within 1.5 years. 
 
11.5 
Data and Safety Monitoring Committee 
 
A Data and Safety Monitoring Committee will oversee the conduct of the study. The 
Committee consists of four members from outside of the SWOG, 3 SWOG members, 3 
non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting). The members of this Committee will receive confidential reports 
every 6 months from the SWOG Statistics and Data Management Center, and will meet at 
the Group's bi-annual meetings as necessary. The Committee will be responsible for 
decisions regarding possible termination and/or early reporting of the study. 
 
Toxicity will be monitored on an ongoing basis. Starting when there are at least 15 eligible 
patients on each arm, twice a year (for the semi-annual SWOG DSMC meeting), the study 
team will compare between arms the rates of Grade 3 or higher anemia, neutropenia, or 
thrombocytopenia possibly, probably, or definitely related to treatment. If the observed 
toxicity rate is more than 15% higher in the combination arm compared to the single-agent 
arm, the DSMC will consider early closure of the study due to excess toxicity on the 
combination arm. In the case that the toxicity rate is more than 15% higher in the 
combination arm compared to the single-agent arm, the study team may propose changes 
to the protocol to manage toxicities on the combination arm for DSMC review and potential 
approval to allow the study to continue accrual under the different management guidelines. 
 
12.0 
DISCIPLINE REVIEW 
 
Discipline review is not necessary for this study. 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Patients must be registered prior to initiation of protocol treatment (no more than seven 
calendar days prior to planned start of treatment). 
 
For patients in Arm 1: Cycle 1, Day 1 is defined as the day of randomization. 
 
For patients in Arm 2: Cycle 1, Day 1 is defined as the first day of ruxolitinib administration. 
 
NOTE: If a patient was assigned a SWOG patient ID prior to registration, that patient ID 

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must be used at the time of study registration. For questions about entering a previously 
assigned patient ID, please contact the Statistics and Data Management Center, at 
206/652-2267. 
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a Cooperative Group. Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of 
a complete investigator registration packet to CTEP. 
 
13.3 
CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored clinical trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical 
site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site 
contact) must complete their annual registration using CTEP’s web-based Registration and 
Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
 
RCR utilizes five-person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
(e.g., Roster Update Management System (RUMS), OPEN, Rave); 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access 
all CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) 
covering their practice sites on the FDA Form 1572 in RCR to allow the following: 
 
• 
Added to a site roster; 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in 
OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 

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In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug shipment, 
or as the CI on the DTL must be rostered at the enrolling site with a participating 
organization (i.e., Alliance). 
 
Additional 
information 
is 
located 
on 
the 
CTEP 
website 
at  
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
13.4 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
a. 
IRB Approval: 
 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National 
Clinical Trials Network (NCTN) and NCI Community Oncology Research Program 
(NCORP) Research Bases after March 1, 2019, all U.S.-based sites must be 
members of the NCI Central Institutional Review Board (NCI CIRB). In addition, 
U.S.-based sites must accept the NCI CIRB review to activate new studies at the 
site after March 1, 2019. Local IRB review will continue to be accepted for studies 
that are not reviewed by the CIRB, or if the study was previously open at the site 
under the local IRB. International sites should continue to submit Research Ethics 
Board (REB) approval to the CTSU Regulatory Office following country-specific 
regulations. 
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet 
for Local Context (SSW) to the CIRB using IRBManager to indicate their intent to 
open the study locally. In order for the SSW approval to be processed, the 
Signatory Institution must inform the CTSU which CIRB-approved institutions 
aligned with the 
Signatory Institution are participating in the study. The NCI 
CIRB’s approval of the SSW is automatically communicated to the CTSU 
Regulatory Office, but sites are required to contact the CTSU Regulatory Office 
at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network. Site preferences can be set at 
the network or protocol level. Questions about establishing site preferences 
can be addressed to the CTSU Regulatory Office by emailing the email address 
above or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU 
Regulatory Office using the Regulatory Submission Portal located in the Regulatory 
section of the CTSU website. Acceptable documentation of local IRB/REB approval 
includes: 
 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria to complete processing of the 
IRB/REB approval record: 
 
• 
Holds an Active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian 
sites only) and on at least one participating roster; 

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• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 
1572 in the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol. 
 
b. 
Additional Requirements 
Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled 
all regulatory criteria including but not limited to the following: 
 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
 
c. 
Downloading Site Registration Documents: 
 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and 
its supporting documents is restricted and is based on person and site roster 
assignment housed in the CTSU Regulatory Support System (RSS). To participate, 
the institution and its associated investigators and staff must be associated with the 
LPO or a PO on the protocol. 
 
• 
Log on to the CTSU members’ website (https://www.ctsu.org) using your 
CTEP-IAM username and password; 
• 
Click on Protocols in the upper left of your screen 
o 
Enter the protocol number in the search field at the top of the 
protocol tree, or 
o 
Click on the By Lead Organization folder to expand, then select 
[Corresponding Organization], and protocol number [NCI Protocol #]; 
• 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB initiative, IRB data will load 
automatically to the CTSU as described above.) 
 
d. 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office via the 
Regulatory Submission Portal on the CTSU website. 
 
To access the Regulatory Submission Portal log on to the CTSU members’ website 
Regulatory Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in 
order to receive further instruction and support. 
 
e. 
Checking Your Site’s Registration Status: 
 
You can verify your site’s registration status on the members’ side of the CTSU 
website. 
 
• 
Log on to the CTSU members’ website; 
• 
Click on Regulatory at the top of your screen; 
• 
Click on Site Registration; 

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• 
Enter your 5-character CTEP Institution Code and click on Go. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined above. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks.. 
 
13.5 
Oncology Patient Enrollment Network (OPEN) Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet. The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
 
Requirements for OPEN access: 
 
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrar(s) must 
hold the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• 
Patient has met all eligibility criteria within the protocol stated timeframes and the 
affirmation of eligibility on the Registration Worksheet has been signed by the 
registering investigator or another investigator designate. Site staff should refer to  
Section 5.0 to verify eligibility. 
• 
All patients have signed an appropriate consent form and HIPAA authorization 
form (if applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. Please print this confirmation for your records. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet. The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 

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d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional. Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
l. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
n. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
All site staff will use OPEN to enroll patients to this study. Access OPEN at 
https://open.ctsu.org or from the OPEN link on the CTSU members’ website. Further 
instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org, https://open.ctsu.org, or from the OPEN Patient Registration link on 
the SWOG CRA Workbench. For any additional questions, contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
13.6 
Exceptions to SWOG registration policies will not be permitted. 
 

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a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible. Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see below for details. 
 
14.3 
Data Submission Procedures 
 
a. 
Data collection for this study will be done exclusively through the Medidata Rave® 
clinical data management system. Medidata Rave is a clinical data management 
system being used for data collection for this trial/study. Access to the trial in Rave 
is controlled through the CTEP-IAM system and role assignments. To access Rave 
via iMedidata: 
• 
Site staff will need to be registered with CTEP and have a valid and 
active CTEP-IAM account; and 
• 
Assigned one of the following Rave roles on the relevant Lead 
Protocol Organization (LPO) or Participating Organization roster at the 
enrolling site: Rave CRA, Rave Read Only, Rave CRA (LabAdmin), 
Rave SLA, or Rave Investigator. Refer to  
https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required. 
o 
To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a 
minimum of an AP registration type; 
o 
To hold Rave Investigator role, the individual must be registered as an 
NPIVR or IVR; and 
o 
To hold Rave Read Only role, site staff must hold an Associates (A) 
registration type. 
 
If the study has a Delegation of Tasks Log (DTL), individuals requiring write 
access to Rave must also be assigned the appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in Regulatory Support System 
(RSS), all persons with Rave roles assigned on the appropriate roster will be sent 
a study invitation e-mail from iMedidata. To accept the invitation, site staff must log 
into the Select Login (https://login.imedidata.com/selectlogin) using their CTEP- 
IAM user name and password, and click on the “accept” link in the upper right- 
corner of the iMedidata page. Site staff will not be able to access the study in Rave 
until all required Medidata and study specific trainings are completed. Trainings 
will be in the form of electronic learnings (eLearnings), and can be accessed by 

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clicking on the link in the upper right pane of the iMedidata screen. If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under 
the study name in iMedidata instead of the Rave EDC link; once the successful 
completion of the eLearning has been recorded, access to the study in Rave will 
be granted, and a Rave EDC link will display under the study name. 
 
Site staff that have not previously activated their iMedidata/Rave account at the 
time of initial registration approval for the study in RSS will also receive a separate 
invitation from iMedidata to activate their account. Account activation instructions 
are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ website in the 
Data Management > Rave section at www.ctsu.org/RAVE/ or by contacting the 
CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
b. 
You may also access Rave® via the SWOG CRA Workbench via the SWOG 
website (www.swog.org). 
 
For difficulties with the CRA Workbench, please email technicalquestion@crab.org. 
. 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU), please 
refer to the CTSU Participation Table. 
 
14.4 
Data Submission Overview and Timepoints 
 
a. 
WITHIN 7 DAYS AFTER RANDOMIZATION: 
 
Submit the following: 
 
S1712 Onstudy Form 
 
Bone marrow biopsy report confirming diagnosis (upload reports via the Source 
Documentation: Baseline form in Rave®) 
 
RT-PCR report from CLIA-certified laboratory with baseline BCR-ABL transcript 
levels reported on the International Scale (upload reports via the Source 
Documentation: Baseline form in Rave®) 
 
Specimens as outlined in Section 15.0 
 
b. 
ARM 2 ONLY: WITHIN 15 DAYS AFTER EACH OF THE FOLLOWING TIME 
POINTS DURING CYCLE 1: WEEK 1, DAY 1; WEEK 12, DAY 1: 
 
Submit the following: 
 
S1712 Lipid Profile Results form 
 
c. 
ARM 2 ONLY: WITHIN 15 DAYS AFTER EACH OF THE FOLLOWING TIME 
POINTS DURING CYCLE 1: WEEK 1, DAY 1; WEEK 3, DAY 1; WEEK 5, DAY 1; 
WEEK 7, DAY 1; WEEK 9, DAY 1: 
 
Submit the following: 
 
S1712 CBC with Differential Results form 
 
 

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d. 
WITHIN 15 DAYS AFTER EACH CYCLE OF TREATMENT**: 
 
Submit the following: 
 
S1712 Treatment Form 
 
S1712 Adverse Event Form** 
 
** For  patients  in  Arm  2: The  S1712  Adverse  Event  Form  is  submitted 
MONTHLY for the first 3 months of protocol therapy. 
 
If EKG was performed, the S1712 EKG Results Form (Note that for Arm 2, the  
S1712 EKG Results Form is required on Cycle 1, Day 8 for patients taking 
nilotinib.) 
 
S1712 Disease Assessment Form 
 
RT-PCR report from CLIA-certified lab with BCR-ABL transcript level reported on 
the International Scale. (Upload reports via the Source Documentation: Follow-up 
form in Rave®.) 
 
Specimens as outlined in Section 15.0 
 
e. 
WITHIN 28 DAYS OF DISCONTINUATION OF TREATMENT: 
 
Submit the following: 
 
Off Protocol Treatment Notice  
 
Final S1712 Treatment Form 
 
Final S1712 Adverse Event Form 
 
f. 
WITHIN 15 DAYS OF PROGRESSION OR LOSS OF RESPONSE: 
 
Submit the following: 
 
S1712 Disease Assessment Form (if the patient was still on protocol treatment) 
 
or 
 
S1712 Follow-Up Form (if the patient was off protocol treatment) documenting 
date, site and method for determining progression or loss of response. 
 
RT-PCR report from CLIA-certified lab with BCR-ABL transcript level reported on 
the International Scale. (Upload reports via the Source Documentation: Follow-up 
form in Rave®.) 
 
If applicable, bone marrow exam, pathology, cytogenetics, mutational analysis, 
FISH and flow cytometry reports (whichever are performed). (Upload reports via 
the Source Documentation: Follow-up form in Rave®.) 
 
 
 
 

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g. 
AFTER OFF PROTOCOL THERAPY, EVERY 3-6 MONTHS* UNTIL 5 YEARS 
AFTER RANDOMIZATION: 
 
Submit the following: 
 
S1712 Follow Up Form 
 
Late Effects Form (if prior to treatment for progression or relapse or a second 
primary, and prior to non-protocol treatment, the patient experiences any severe 
[Grade ≥ 3] long term toxicity that has not been previously reported) 
 
* 
Patients will be followed per NCCN standard of care guidelines and per 
institutional standards. At minimum, the patient must be seen every 3-6 
months and PCR for BCR-ABL quantification must be performed. BCR-ABL 
quantification results will be reported on the S1712 Follow Up Form each time 
the quantification is performed. 
 
h. 
WITHIN 28 DAYS OF KNOWLEDGE OF DEATH:  
 
Submit the following: 
 
Notice of Death 
 
Forms listed in Section 14.4d (if the patient was still on protocol treatment) or 
S1712 Follow-Up Form (if the patient was off protocol treatment). 
 
15.0 
SPECIAL INSTRUCTIONS 
 
Specimen 
Pre-Reg 
(within 21 
days prior to 
registration) 
Pre-Reg 
(within 42 
days prior to 
registration) 
Cycle 2 (prior 
to initiation of 
therapy on 
Cycle 2) 
Cycle 3 
(prior to 
initiation of 
therapy on 
Cycle 3) 
Cycle 4 
(prior to 
initiation of 
therapy on 
Cycle 4) 
End of 
Treatment 
(within 28 
days after 
completion of 
therapy on 
Cycle 4) 
Follow 
Up 
Local BCR- ABL 
(required) 
***
X 
 
X 
X 
X 
X 
X* 
Central BCR- 
ABL & 
Banking 
(optional for 
patient) 
X 
X 
X 
X 
X 
X** 
NOTES 
(Central 
may be 
drawn at 
same time 
or within 
21 days of 
the local 
draw) 
(Central 
may be 
drawn at 
same time 
or within 
21 days of 
the local 
draw) 
(Local and 
central 
must be 
drawn 
together) 
(Local 
and 
central 
must be 
drawn 
together) 
(Local 
and 
central 
must be 
drawn 
together) 
(Local 
and 
central 
must be 
drawn 
together) 
See 
footnotes 
* 
Every 3-6 months until 5 years after randomization. 
** 6 months after off protocol treatment, at the same time specimens are being drawn for local BCR-
ABL quantification, if possible. 
***  Local specimens are NOT submitted to the repository. 

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NOTE: Pre-registration specimen submissions require a patient ID prior to randomization. 
 
To obtain a patient ID prior to registration: 
Use the SWOG specimen tracking system 
https://crawb.crab.org/TXWB/ctsulogon.aspx. Select “Specimen Tracking” and use the “Log a 
Specimen” link from the Specimen Tracking Home page. Use the “No Patient ID yet?” link and enter 
demographic information for the patient on the next page. This will assign a SWOG patient ID number 
which will remain the patient’s ID number. If the patient does register to the study, it is 
important to 
remember to use this patient ID number on the OPEN system so the specimens will match with the 
correct patient. Specimens will be destroyed if the patient is not subsequently registered to the study. 
 
Note: Testing of banked biospecimens will not occur until an amendment to this treatment protocol (or 
separate correlative science protocol) is reviewed and approved in accordance with National Clinical 
Trials Network (NCTN) policies. 
 
15.1 
Local BCR-ABL Quantification (REQUIRED) 
 
For pre-registration only, specimens for central BCR-ABL quantification may be 
collected/drawn at the same time or within 21 days of the local BCR-ABL 
quantification (for patients consenting to central BCR-ABL specimen submission). 
At every other time point, the specimens for local BCR-ABL quantification and 
central BCR-ABL quantification must be collected/drawn together. 
 
Specimens for local BCR-ABL quantification by RT-PCR must be submitted to the site’s 
preferred local CLIA-approved laboratory. The RT-PCR assay must have the sensitivity to 
detect a 4.5 log reduction (at least 0.0032 % IS). 
 
a. 
Collect the volume of blood required by the local laboratory. Peripheral blood must 
be collected and submitted at the following times (see Section 9.0): 
 
1. 
Pre-registration* (within 21 days prior to randomization) 
 
2. 
Cycle 2 (prior to initiation of therapy on Cycle 2) 
 
3. 
Cycle 3 (prior to initiation of therapy on Cycle 3)** 
 
4. 
Cycle 4 (prior to initiation of therapy on Cycle 4)** 
 
5. 
End of Treatment (within 28 days after completion of therapy on Cycle 4)** 
 
6. 
Every 3-6 months until 5 years after randomization 
 
* 
See Section 15.0 for instructions on obtaining a SWOG patient ID prior 
to randomization for pre-registration specimen submission. 
** Only submitted if the patient completes treatment on the specified cycle. 
 
b. 
Specimen Collection and Submission 
 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
Sites will collect and submit specimens per local institutional standard procedures. 
 
c. 
BCR-ABL Quantification Results (on the International Scale) 
 
The BCR-ABL quantification result on the International Scale (IS) must be reported 

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on the appropriate eCRF in Rave and the associated report must be uploaded as 
a PDF file to the appropriate Source Documentation form in Rave (see Section  
14.4). 
 
15.2 
Specimens for Translational Medicine (Central BCR-ABL Quantification) and Banking 
(Optional for Patient) 
 
For pre-registration only, specimens for central BCR-ABL quantification may be 
collected/drawn at the same time or within 21 days of the local BCR-ABL 
quantification (for patients consenting to central BCR-ABL specimen submission). 
At every other time point, the specimens for local BCR-ABL quantification and 
central BCR-ABL quantification must be collected/drawn together. 
 
With patient’s consent, specimens for translational medicine and banking must be 
submitted to the SWOG Biospecimen Bank – Leukemia Division, Lab #200. 
 
a. 
With patient’s consent, peripheral blood must be submitted at the following times 
(see Section 9.0) 
 
1. 
Pre-registration* (within 42 days prior to randomization) 
2. 
Cycle 2 (prior to initiation of therapy on Cycle 2)** 
3. 
Cycle 3 (prior to initiation of therapy on Cycle 3)** 
4. 
Cycle 4 (prior to initiation of therapy on Cycle 4)** 
5. 
End of Treatment (within 28 days after completion of therapy on Cycle 4)** 
6. 
Six months after off protocol treatment, at the same time specimens are 
being drawn for local BCR-ABL quantification, if possible. 
 
*  
See Section 15.0 for instructions on obtaining a SWOG patient ID prior to 
randomization for pre-registration specimen submission. 
** Only submitted if the patient completes treatment on the specified cycle. 
 
b. 
Specimen Collection Instructions 
 
Collect approximately 30 mL of whole blood in EDTA vacutainer tubes 
(purple/lavender top) and gently invert to mix (5-10 times). No additional 
processing of specimens is required. Do not freeze. 
 
Specimen collection kits are not being provided for this submission; sites will 
use institutional supplies. 
 
c. 
Specimen Submission Instructions 
 
All specimen submissions for this study must be entered and tracked using the 
SWOG online Specimen Tracking system. Complete specimen collection and 
submission instructions can be accessed on the SWOG Specimen Submission 
webpage (https://www.swog.org/clinical-trials/biospecimen-
resources/biospecimen-  processing-and-submission-procedures#LeukemiaBank).If  
any  submission instructions on the webpage are discrepant from protocol 
instructions, the protocol instructions should be followed. 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for 
the conduct and monitoring of clinical investigations; they also represent sound research 
practice: 
 

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Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the 
Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46). 
 
Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312. 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due January 31, 
April 30, July 31 and October 31. 
 
Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 

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17.0 
BIBLIOGRAPHY 
 
1 
Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow- 
up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 355:2408-17, 2006. 
 
2 
Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, et al. Dasatinib versus imatinib 
in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 362:2260-70, 2010. 
 
3 
Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, et al. Nilotinib versus imatinib 
for newly diagnosed chronic myeloid leukemia. N Engl J Med. 362:2251-9, 2010. 
 
4 
Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib Versus Imatinib for Newly 
Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol. 
2018;36(3):231-237. 
 
5 
Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F, et al. Discontinuation of imatinib 
in patients with chronic myeloid leukaemia who have maintained complete molecular remission 
for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 
11:1029-35, 2010. 
 
6 
Hochhaus A, Masszi T, Giles FJ, Radich JP, Ross DM, Gomez Casares MT, et al. Treatment-
free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) 
treated with frontline nilotinib: Results from the ENESTFreedom study. ASCO Meeting Abstracts. 
34:7001, 2016. 
 
7 
Nair RR, Tolentino JH, Argilagos RF, Zhang L, Pinilla-Ibarz J, Hazlehurst LA. Potentiation 
of Nilotinib-mediated cell death in the context of the bone marrow microenvironment requires 
a promiscuous JAK inhibitor in CML. Leuk Res. 36:756-63, 2012. 
 
8 
Nair RR, Tolentino JH, Argilagos RF, Zhang L, Pinilla-Ibarz J, Hazlehurst LA. Potentiation 
of Nilotinib-mediated cell death in the context of the bone marrow microenvironment requires 
a promiscuous JAK inhibitor in CML. Leuk Res. 36:756-63, 2012. 
 
9 
Nair RR, Tolentino JH, Argilagos RF, Zhang L, Pinilla-Ibarz J, Hazlehurst LA. Potentiation 
of Nilotinib-mediated cell death in the context of the bone marrow microenvironment requires 
a promiscuous JAK inhibitor in CML. Leuk Res. 36:756-63, 2012. 
 
10 
Savani BN, Mielke S, Adams S, Uribe M, Rezvani K, Yong AS, et al. Rapid natural killer 
cell 
recovery determines 
outcome  after 
T-cell-depleted 
HLA-identical  stem 
cell 
transplantation in patients with myeloid leukemias but not with acute lymphoblastic leukemia. 
Leukemia. 21:2145-52, 2007. 
 
11 
Quintarelli C, De Angelis B, Errichiello S, Caruso S, Esposito N, Colavita I, et al. Selective strong 
synergism of Ruxolitinib and second generation tyrosine kinase inhibitors to overcome bone 
marrow stroma related drug resistance in chronic myelogenous leukemia. Leuk Res. 38:236-
42, 2014. 
 
12 
Quintarelli C, De Angelis B, Errichiello S, Caruso S, Esposito N, Colavita I, et al. Selective strong 
synergism of Ruxolitinib and second generation tyrosine kinase inhibitors to overcome bone 
marrow stroma related drug resistance in chronic myelogenous leukemia. Leuk Res. 38:236-
42, 2014. 
 
13 
Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid 
leukemia. N Engl J Med. 341:164-72, 1999. 

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Page 72 
Version Date: 08/09/2023 
  
 
 
 
14 
NCCN NCCN. Version 1.2016 Chronic Myelogenous Leukemia Guidelines. 
 
15 
NCCN NCCN. Version 1.2016 Chronic Myelogenous Leukemia Guidelines. 
 
16 
Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J, et al. Monitoring CML patients 
responding to treatment with tyrosine kinase inhibitors: review and recommendations for 
harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain 
mutations and for expressing results. Blood 108:28-37, 2006. 
 
17 
Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J, et al. Monitoring CML patients 
responding to treatment with tyrosine kinase inhibitors: review and recommendations for 
harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain 
mutations and for expressing results. Blood 108:28-37, 2006. 
 
18 
Hughes TP, Kaeda J, Branford S, Rudzki Z, Hochhaus A, Hensley ML, et al. Frequency of major 
molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic 
myeloid leukemia. N Engl J Med 349:1423-32, 2003. 
 
19 
Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J, et al. Monitoring CML patients 
responding to treatment with tyrosine kinase inhibitors: review and recommendations for 
harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain 
mutations and for expressing results. Blood 108:28-37, 2006. 
 
20 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in 
the controlled clinical trial. Biometrics (1):103-15, 1975. 

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Version Date: 08/09/2023 
  
 
 
18.0 
APPENDIX 
 
18.1 
Intake Calendar - Bosutinib 
 
18.2 
Intake Calendar - Dasatinib 
 
18.3 
Intake Calendar – Imatinib 
 
18.4 
Intake Calendar – Nilotinib 
 
18.5 
Intake Calendar - Ruxolitinib 
 
18.6 
Specimen Banking Instructions for the SWOG Biospecimen Bank 
 
18.7 
Drugs Known to be Metabolized by CYP450 Isoenzyme 3A4 

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Version Date: 08/09/2023 
  
 
 
18.1 
Intake Calendar – Bosutinib 
 
SWOG Patient ID  
 
Patient Initials (L, F, M)   
 
 
SWOG Study #   
 
Institution/Affiliate _____________________ 
 
 
Physician ________________________ 
 
Instructions for the participant:  
This is a monthly calendar on which you are to record the number of tablets you take each day. Be 
sure you have enough calendars to last until your next appointment. If you develop any side effects 
from the tablets, mark this on the calendar on the day you note the effect. Bring you calendars with 
you each time you have an appointment.  
If you have questions contact: ________________________ 
Telephone: _________________ 
Your next appointment is: _________________________ 
Date Dispensed: ______________ 
• 
Bosutinib should be taken once daily with food. 
• 
Your nurse or doctor will review your prescribed dose with you. 
• 
Record all doses or missed doses in this pill diary. 
• 
Tablets should be swallowed whole and not crushed, cut or broken. 
• 
Tablets can be taken in the morning or evening but should be taken at 
approximately the same time. 
• 
If a dose is missed beyond 12 hours, skip the dose and take the usual 
prescribed dose on the following day. 
• 
If you miss a dose mark down as “0” and write the reason for missing your dose 
under the “comments” below. 
• 
Several drugs and supplements interact with bosutinib and need to be avoided 
while you are taking it. Your doctor/nurse will give you a handout with 
complete information about what drugs and supplements to avoid that you 
should refer to while taking bosutinib. 
• 
Avoid grapefruit, grapefruit juice, and supplements that contain grapefruit extract 
during treatment with bosutinib. 
• 
Avoid antacid medicines. 
• 
Open only one bottle at a time when taking out your dose. Do not transfer pills 
from one bottle to another. 
• 
Store bottles at room temperature and protect from light. 
• 
If you think you are having any side effects, feel sick, or have any other questions 
about your pills, please call your doctor/nurse at the number above. 
• 
Take your doses this cycle as your doctor has written them in the special 
instructions below. 
 
Special instructions: [Note to Investigators: Please include instructions for when to take 
dose, as appropriate to each patient at each visit.] 
 
 
 
 
 
 

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Version Date: 08/09/2023 
  
 
BOSUTINIB INTAKE CALENDAR (page 1 of 3) 
 
 
Date 
Day 
Was Dose 
Taken? 
Total # of 
Tablets Taken? 
Dose of 
Tablets 
What Time? 
    /    /   
1 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
2 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
3 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
4 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
5 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
6 
□ Yes □ No 
  
mg 
    _: 
am/pm 
    /    /   
7 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
8 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
9 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
10 
□ Yes □ No 
 
  
mg 
  
: 
am/pm 
Comments: 
Clinician Review – date and initials 

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Page 76 
Version Date: 08/09/2023 
  
 
 
 
BOSUTINIB INTAKE CALENDAR (page 2 of 3) 
 
Date 
Day 
Was Dose 
Taken? 
Total # of 
Tablets Taken? 
Dose of 
Tablets 
What Time? 
    /    /   
11 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
12 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
13 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
14 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
15 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
16 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
17 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
18 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
19 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
20 
□ Yes □ No 
 
  
mg 
  
: 
am/pm 
Comments: 
Clinician Review – date and initials 

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Page 77 
Version Date: 08/09/2023 
  
 
 
BOSUTINIB INTAKE CALENDAR (page 3 of 3) 
 
Date 
Day 
Was Dose 
Taken? 
Total # of 
Tablets Taken? 
Dose of 
Tablets 
What Time? 
    /    /   
21 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
22 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
23 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
24 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
25 
□ Yes □ No 
  
mg 
    _: 
am/pm 
    /    /   
26 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
27 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
28 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
29 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
30 
□ Yes □ No 
 
  
mg 
  
: 
am/pm 
Comments: 
Clinician Review – date and initials 

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Version Date: 08/09/2023 
  
 
 
BOSUTINIB END OF CYCLE (90-DAY) INVENTORY – FOR CLINIC USE 
 
Cycle    
 
 
FINAL REVIEW AND COLLECTION 
 
NOTES: 
Patient Signature: 
Date:     /    /   
 
MD/RN Signature: 
Date:     /    /   
  
 
 
 
[Note to investigators: Cycles of bosutinib are longer than 30 days, so please distribute additional 
calendar pages with adjusted calendar days to be as patient-friendly as possible. Please ensure that 
patients understand the length of the cycle that they are to take.] 

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Version Date: 08/09/2023 
  
 
 
18.2 
Intake Calendar - Dasatinib 
 
SWOG Patient ID 
Patient Initials (L, F, M) 
SWOG Study #  
 
Institution/Affiliate 
Physician   
 
Instructions for the participant: 
The chart below is a 30-day intake calendar for dasatinib on which you are to record the number 
of dasatinib tablets you take each day. Be sure you have enough calendars to last until your next 
appointment. If you develop any side effects from the tablets, mark this on the calendar on the 
day you note the effect. Bring your calendars with you each time you have an appointment. 
If you have questions contact: 
 
Telephone:   
  
Your next appointment is: 
Date Dispensed:    
 
• 
Dasatinib should be taken once daily 
• 
Your nurse or doctor will review your prescribed dose with you. 
• 
Record all doses or missed doses in this pill diary. 
• 
Tablets may be taken with or without food, but should be taken with a glass of water.  
They should be swallowed whole and not crushed or broken. Avoid grapefruit or grapefruit 
juice. 
• 
Tablets can be taken in the morning or evening but should be taken at approximately the 
same time each day. 
• 
If you miss a dose mark down as “0” and write the reason for missing your dose under the 
“comments” below. 
• 
If doses are missed because of side effects, they should not be made up. If vomiting 
occurs within 30 minutes of taking a dose, that dose may be repeated. 
• 
You should skip doses that are missed by more than 12 hours. 
• 
Open only one bottle at a time when taking out your dose. Do not transfer pills from one 
bottle to another. 
• 
Store bottles at room temperature and protect from light. 
• 
Bring your study pills and this diary to every clinic visit. 
• 
If you think you are having any side effects, feel sick, or have any other questions about 
your pills, please call your doctor/nurse at the number above. 
• 
Take your doses this cycle as your doctor has written them in the special instructions 
below. 
• 
Several drugs and supplements interact with dasatinib and need to be avoided while you 
are taking it. Your doctor/nurse will give you a handout with complete information about 
what drugs and supplements to avoid that you should refer to while taking dasatinib. 
• 
You should avoid grapefruit, grapefruit juice and antacids while taking dasatinib. 
Special instructions: [Note to Investigators: Please include instructions for when to take 
dose, as appropriate to each patient at each visit.] 

S1712 
Page 80 
Version Date: 08/09/2023 
  
 
DASATINIB INTAKE CALENDAR (page 1 of 3) 
 
Date 
Day 
Was Dose 
Taken? 
Total # of 
Tablets Taken? 
Dose of 
Tablets 
What Time? 
    /    /   
1 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
2 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
3 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
4 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
5 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
6 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
7 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
8 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
9 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
10 
□ Yes □ No 
 
  
mg 
  
: 
am/pm 
Comments: 
Clinician Review – date and initials 

S1712 
Page 81 
Version Date: 08/09/2023 
  
 
DASATINIB INTAKE CALENDAR (page 2 of 3) 
 
Date 
Day 
Was Dose 
Taken? 
Total # of 
Tablets Taken? 
Dose of 
Tablets 
What Time? 
    /    /   
11 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
12 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
13 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
14 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
15 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
16 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
17 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
18 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
19 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
20 
□ Yes □ No 
 
  
mg 
  
: 
am/pm 
Comments: 
Clinician Review – date and initials 

S1712 
Page 82 
Version Date: 08/09/2023 
  
 
DASATINIB INTAKE CALENDAR (page 3 of 3) 
 
Date 
Day 
Was Dose 
Taken? 
Total # of 
Tablets Taken? 
Dose of 
Tablets 
What Time? 
    /    /   
21 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
22 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
23 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
24 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
25 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
26 
□ Yes □ No 
  
mg 
    _: 
am/pm 
    /    /   
27 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
28 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
29 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
30 
□ Yes □ No 
 
  
mg 
  
: 
am/pm 
Comments: 
Clinician Review – date and initials 

S1712 
Page 83 
Version Date: 08/09/2023 
  
 
 
DASATINIB END OF CYCLE (90-DAY) INVENTORY – FOR CLINIC USE 
 
Cycle    
 
 
FINAL REVIEW AND COLLECTION 
 
NOTES: 
Patient Signature: 
Date:     /    /   
 
MD/RN Signature: 
Date:     /    /   
  
 
 
[Note to investigators: Cycles of dasatinib are longer than 30 days, so please distribute additional 
calendar pages with adjusted calendar days to be as patient-friendly as possible. Please ensure that 
patients understand the length of the cycle that they are to take.] 

S1712 
Page 84 
Version Date: 08/09/2023 
  
 
 
18.3 
Intake Calendar - Imatinib 
 
SWOG Patient ID 
Patient Initials (L, F, M) 
SWOG Study #  
 
Institution/Affiliate 
Physician   
 
Instructions for the participant: 
The chart below is a 30-day intake calendar for imatinib on which you are to record the number of 
imatinib tablets you take each day. Be sure you have enough calendars to last until your next 
appointment. If you develop any side effects from the tablets, mark this on the calendar on the 
day you note the effect. Bring your calendars with you each time you have an appointment. 
If you have questions contact: 
 
Telephone:   
  
Your next appointment is: 
Date Dispensed:    
 
• 
Imatinib should be taken once daily 
• 
Your nurse or doctor will review your prescribed dose with you. 
• 
Record all doses or missed doses in this pill diary. 
• 
All doses of imatinib should be taken with a meal and a large glass of water. Imatinib can 
be dissolved in water or apple juice for patients having difficulty swallowing. 
• 
Tablets can be taken in the morning or evening but should be taken at approximately the 
same time each day. 
• 
If you miss a dose mark down as “0” and write the reason for missing your dose under the 
“comments” below. 
• 
If doses are missed because of side effects, they should not be made up. If vomiting 
occurs within 30 minutes of taking a dose, that dose may be repeated. 
• 
You should skip doses that are missed by more than 12 hours. 
• 
Do not take any other medications 2 hours before or 2 hours after taking imatinib. 
• 
Open only one bottle at a time when taking out your dose. Do not transfer pills from one 
bottle to another. 
• 
Store bottles at room temperature and protect from light. 
• 
Bring your study pills and this diary to every clinic visit. 
• 
If you think you are having any side effects, feel sick, or have any other questions about 
your pills, please call your doctor/nurse at the number above. 
• 
Take your doses this cycle as your doctor has written them in the special instructions 
below. 
• 
Several drugs and supplements interact with imatinib and need to be avoided while you 
are taking it. Your doctor/nurse will give you a handout with complete information about 
what drugs and supplements to avoid that you should refer to while taking imatinib. 
• 
You should avoid grapefruit, grapefruit juice and antacids while taking imatinib. 
Special instructions: [Note to Investigators: Please include instructions for when to take 
dose, as appropriate to each patient at each visit.] 

S1712 
Page 85 
Version Date: 08/09/2023 
  
 
IMATINIB INTAKE CALENDAR (page 1 of 3) 
 
Date 
Day 
Was Dose 
Taken? 
Total # of 
Tablets Taken? 
Dose of 
Tablets 
What Time? 
    /    /   
1 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
2 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
3 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
4 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
5 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
6 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
7 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
8 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
9 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
10 
□ Yes □ No 
 
  
mg 
  
: 
am/pm 
Comments: 
Clinician Review – date and initials 

S1712 
Page 86 
Version Date: 08/09/2023 
  
 
IMATINIB INTAKE CALENDAR (page 2 of 3) 
 
Date 
Day 
Was Dose 
Taken? 
Total # of 
Tablets Taken? 
Dose of 
Tablets 
What Time? 
    /    /   
11 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
12 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
13 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
14 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
15 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
16 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
17 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
18 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
19 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
20 
□ Yes □ No 
 
  
mg 
  
: 
am/pm 
Comments: 
Clinician Review – date and initials 

S1712 
Page 87 
Version Date: 08/09/2023 
  
 
IMATINIB INTAKE CALENDAR (page 3 of 3) 
Date 
Day 
Was Dose 
Taken? 
Total # of 
Tablets Taken? 
Dose of 
Tablets 
What Time? 
    /    /   
21 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
22 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
23 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
24 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
25 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
26 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
27 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
28 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
29 
□ Yes □ No 
  
mg 
  
: 
am/pm 
    /    /   
30 
□ Yes □ No 
 
  
mg 
  
: 
am/pm 
Comments: 
Clinician Review – date and initials 

S1712 
Page 88 
Version Date: 08/09/2023 
  
 
IMATINIB END OF CYCLE (90-DAY) INVENTORY – FOR CLINIC USE 
 
Cycle    
 
 
FINAL REVIEW AND COLLECTION 
 
NOTES: 
Patient Signature: 
Date:     /    /   
 
MD/RN Signature: 
Date:     /    /   
  
 
 
 
[Note to investigators: Cycles of imatinib are longer than 30 days, so please distribute additional 
calendar pages with adjusted calendar days to be as patient-friendly as possible. Please ensure that 
patients understand the length of the cycle that they are to take.] 

S1712 
Page 89 
Version Date: 08/09/2023 
  
 
 
18.4 
Intake Calendar - Nilotinib 
 
SWOG Patient ID 
Patient Initials (L, F, M) 
SWOG Study #  
 
Institution/Affiliate 
Physician   
 
Instructions for the participant: 
The chart below is a 30-day intake calendar for nilotinib on which you are to record the number of 
nilotinib capsules you take each day. Be sure you have enough calendars to last until your next 
appointment. If you develop any side effects from the capsules, mark this on the calendar on the 
day you note the effect. Bring your calendars with you each time you have an appointment. 
If you have questions contact: 
 
Telephone:   
  
Your next appointment is: 
Date Dispensed:    
 
• 
Nilotinib should be taken twice daily 
• 
Your nurse or doctor will review your prescribed dose with you. 
• 
Record all doses or missed doses in this pill diary. 
• 
Capsules should be taken without food on an empty stomach and should be taken with a 
glass of water. Avoid eating food for at least two hours before and at least one hour after 
the dose is taken. Avoid grapefruit or grapefruit juice. 
• 
Capsules should be swallowed whole and not crushed or broken. 
• 
Capsules should be taken in the morning and in the evening at approximately the same 
time each day. 
• 
If you miss a dose mark down as “0” and write the reason for missing your dose under the 
“comments” below. 
• 
If doses are missed because of side effects, they should not be made up. 
• 
You should skip doses that are missed by more than 6 hours. 
• 
Do not take any other medications 2 hours before taking nilotinib. 
• 
Open only one bottle at a time when taking out your dose. Do not transfer pills from one 
bottle to another. 
• 
Store bottles at room temperature and protect from light. 
• 
Bring your study capsules and this diary to every clinic visit. 
• 
If you think you are having any side effects, feel sick, or have any other questions about 
your capsules, please call your doctor/nurse at the number above. 
• 
Take your doses this cycle as your doctor has written them in the special instructions 
below. 
• 
Several drugs and supplements interact with nilotinib and need to be avoided while you 
are taking it. Your doctor/nurse will give you a handout with complete information about 
what drugs and supplements to avoid that you should refer to while taking nilotinib. 
Special instructions: [Note to Investigators: Please include instructions for when to take 
dose, as appropriate to each patient at each visit.] 

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Version Date: 08/09/2023 
  
 
NILOTINIB INTAKE CALENDAR (page 1 of 3) 
 
Date 
mm/dd/yy 
DAY 
Was 
Dose 
Taken? 
Total 
# 
of 
Capsules 
Taken? 
Dose 
of 
Capsules 
What Time? 
    /    /   
1 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
1 second dose 
□ Yes  □ No 
mg   
: 
am/pm 
    /    /   
2 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
2 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
3 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
3 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
4 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
4 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
5 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
5 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
6 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
6 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
7 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
7 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
8 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
8 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
9 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
9 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
10 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
10 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
Comments: 
Clinician Review – date and initials 

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Page 91 
Version Date: 08/09/2023 
  
 
NILOTINIB INTAKE CALENDAR (page 2 of 3) 
 
Date 
mm/dd/yy 
DAY 
Was 
Dose 
Taken? 
Total 
# 
of 
Capsules 
Taken? 
Dose 
of 
Capsules 
What Time? 
    /    /   
11 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
11 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
12 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
12 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
13 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
13 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
14 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
14 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
15 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
15 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
16 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
16 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
17 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
17 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
18 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
18 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
19 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
19 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
20 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
20 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
Comments: 
Clinician Review – date and initials 

S1712 
Page 92 
Version Date: 08/09/2023 
  
 
NILOTINIB INTAKE CALENDAR (page 3 of 3) 
 
Date 
mm/dd/yy 
DAY 
Was 
Dose 
Taken? 
Total 
# 
of 
Capsules 
Taken? 
Dose 
of 
Capsules 
What Time? 
    /    /   
21 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
21 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
22 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
22 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
23 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
23 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
24 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
24 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
25 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
25 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
26 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
26 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
27 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
27 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
28 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
28 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
29 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
29 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
    /    /   
30 first dose 
□ Yes  □ No 
mg 
: 
am/pm 
30 second dose 
□ Yes  □ No 
mg 
: 
am/pm 
Comments: 
Clinician Review – date and initials 

S1712 
Page 93 
Version Date: 08/09/2023 
  
 
 
NILOTINIB END OF CYCLE (90-DAY) INVENTORY – FOR CLINIC USE 
 
Cycle    
 
 
FINAL REVIEW AND COLLECTION 
 
NOTES: 
Patient Signature: 
Date:     /    /   
 
MD/RN Signature: 
Date:     /    /   
  
 
 
 
[Note to investigators: Cycles of nilotinib are longer than 30 days, so please distribute additional 
calendar pages with adjusted calendar days to be as patient-friendly as possible. Please ensure that 
patients understand the length of the cycle that they are to take.] 

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Version Date: 08/09/2023 
  
 
 
18.5 
Intake Calendar - Ruxolitinib 
 
SWOG Patient ID 
Patient Initials (L, F, M) 
SWOG Study #  
 
Institution/Affiliate 
Physician   
 
Instructions for the participant: 
The chart below is a 30-day intake calendar for ruxolitinib on which you are to record the number 
of ruxolitinib tablets you take each day. Be sure you have enough calendars to last until your next 
appointment. If you develop any side effects from the tablets, mark this on the calendar on the 
day you note the effect. Bring your calendars with you each time you have an appointment. 
If you have questions contact: 
 
Telephone:   
  
Your next appointment is: 
Date Dispensed:    
 
• 
Ruxolitinib should be taken twice daily 
• 
Your nurse or doctor will review your prescribed dose with you. 
• 
Record all doses or missed doses in this pill diary. 
• 
Tablets may be taken with or without food but should be taken with a glass of water. 
Avoid eating food for eat least one hour after the dose is taken. Avoid grapefruit or 
grapefruit juice. 
• 
Tablets should be swallowed whole and not crushed or broken. 
• 
Tablets should be taken in the morning and in the evening at approximately the same 
time each day. 
• 
If you miss a dose mark down as “0” and write the reason for missing your dose in the 
comments column next to the dose that was missed. 
• 
If doses are missed because of side effects, they should not be made up. 
• 
You should skip doses that are missed by more than 6 hours. 
• 
Open only one bottle at a time when taking out your dose. Do not transfer tablets from 
one bottle to another. 
• 
Store bottles at room temperature and protect from light. 
• 
Bring your study tables and this diary to every clinic visit. You will take ruxolitinib with a 
nurse (not at home) on the days you come in for appointments. 
• 
Do not throw away any study capsule bottles. Your doctor or nurse will collect them. 
• 
If you think you are having any side effects, feel sick, or have any other questions about 
your capsules, please call your doctor/nurse at the number above. 
• 
Take your doses this cycle as your doctor has written them in the special instructions 
below. 
• 
Several drugs and supplements interact with ruxolitinib and need to be avoided while you 
are taking it. Your doctor/nurse will give you a handout with complete information about 
what drugs and supplements to avoid that you should refer to while taking ruxolitinib. 
Special instructions: [Note to Investigators: Please include instructions for when to take 
dose, as appropriate to each patient at each visit.] 

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Version Date: 08/09/2023 
  
 
RUXOLITINIB INTAKE CALENDAR (page 1 of 3) 
 
Date 
mm/dd/yy 
DAY 
Was Dose 
Taken? 
Total # of 
Capsules 
Taken? 
What Time? 
Comments 
    /    /   
1 first 
dose 
□ Yes  □ No 
: 
am/pm 
1 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
2 first 
dose 
□ Yes  □ No 
: 
am/pm 
2 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
3 first 
dose 
□ Yes  □ No 
: 
am/pm 
3 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
4 first 
dose 
□ Yes  □ No 
: 
am/pm 
4 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
5 first 
dose 
□ Yes  □ No 
: 
am/pm 
5 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
6 first 
dose 
□ Yes  □ No 
: 
am/pm 
6 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
7 first 
dose 
□ Yes  □ No 
: 
am/pm 
7 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
8 first 
dose 
□ Yes  □ No 
: 
am/pm 
8 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
9 first 
dose 
□ Yes  □ No 
: 
am/pm 
9 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
10 first 
dose 
□ Yes  □ No 
: 
am/pm 
10 second 
dose 
□ Yes  □ No 
: 
am/pm 
Additional Comments: 
Clinician Review – date and initials 

S1712 
Page 96 
Version Date: 08/09/2023 
  
 
RUXOLITINIB INTAKE CALENDAR (page 2 of 3) 
 
Date 
mm/dd/yy 
DAY 
Was Dose 
Taken? 
Total # of 
Capsules 
Taken? 
What Time? 
Comments 
    /    /   
11 first 
dose 
□ Yes  □ No 
: 
am/pm 
11 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
12 first 
dose 
□ Yes  □ No 
: 
am/pm 
12 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
13 first 
dose 
□ Yes  □ No 
: 
am/pm 
13 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
14 first 
dose 
□ Yes  □ No 
: 
am/pm 
14 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
15 first 
dose 
□ Yes  □ No 
: 
am/pm 
15 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
16 first 
dose 
□ Yes  □ No 
: 
am/pm 
16 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
17 first 
dose 
□ Yes  □ No 
: 
am/pm 
17 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
18 first 
dose 
□ Yes  □ No 
: 
am/pm 
18 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
19 first 
dose 
□ Yes  □ No 
: 
am/pm 
19 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
20 first 
dose 
□ Yes  □ No 
: 
am/pm 
20 second 
dose 
□ Yes  □ No 
: 
am/pm 
Additional Comments: 
Clinician Review – date and initials 

S1712 
Page 97 
Version Date: 08/09/2023 
  
 
RUXOLITINIB INTAKE CALENDAR (page 3 of 3) 
 
Date 
mm/dd/yy 
DAY 
Was Dose 
Taken? 
Total # of 
Capsules 
Taken? 
What Time? 
Comments 
    /    /   
21 first 
dose 
□ Yes  □ No 
: 
am/pm 
21 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
22 first 
dose 
□ Yes  □ No 
: 
am/pm 
22 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
23 first 
dose 
□ Yes  □ No 
: 
am/pm 
23 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
24 first 
dose 
□ Yes  □ No 
: 
am/pm 
24 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
25 first 
dose 
□ Yes  □ No 
: 
am/pm 
25 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
26 first 
dose 
□ Yes  □ No 
: 
am/pm 
26 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
27 first 
dose 
□ Yes  □ No 
: 
am/pm 
27 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
28 first 
dose 
□ Yes  □ No 
: 
am/pm 
28 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
29 first 
dose 
□ Yes  □ No 
: 
am/pm 
29 second 
dose 
□ Yes  □ No 
: 
am/pm 
    /    /   
30 first 
dose 
□ Yes  □ No 
: 
am/pm 
30 second 
dose 
□ Yes  □ No 
: 
am/pm 
Additional Comments: 
Clinician Review – date and initials 

S1712 
Page 98 
Version Date: 08/09/2023 
  
 
RUXOLITINIB END OF CYCLE (90-DAY) INVENTORY – FOR CLINIC USE 
 
Cycle    
 
 
Tablet bottle(s) returned? Yes / No (circle one) 
 
# of tablets returned (to be completed by RN or MD) 
 
FINAL REVIEW AND COLLECTION 
 
NOTES: 
Patient Signature: 
Date:     /    /   
 
MD/RN Signature: 
Date:     /    /   
  
 
 
 
[Note to investigators: Cycles of ruxolitinib are longer than 30 days, so please distribute additional 
calendar pages with adjusted calendar days to be as patient-friendly as possible. Please ensure that 
patients understand the length of the cycle that they are to take.] 

S1712 
Page 99 
Version Date: 08/09/2023 
  
 
 
18.6 
Specimen Banking Instructions for the SWOG Biospecimen Bank 
 
Specimen Receipt, Processing, and Storage 
Upon receipt, the SWOG Biospecimen Bank will process peripheral blood. At pre- 
registration, the whole blood will be processed for plasma and peripheral blood 
mononuclear cells (PBMCs) using a ficoll-hypaque gradient. At all other time points, the 
whole blood will be processed for plasma and white blood cells using a red blood cell lysing 
technique. Plasma will be stored in 1-mL aliquots in a -80°C freezer. PBMCs and white 
blood cells are aliquoted in 1 x 107 cells per vial with freezing media, and stored in a liquid 
nitrogen freezer in vapor phase until distribution. 
 
The Central BCR-ABL specimens for translational medicine, at the six months after off 
protocol treatment timepoint, will not be banked. 
 
At the end of the study, the SWOG Statistics and Data Management Center will notify the 
Bank to distribute specimens. Frozen cell vials will be distributed for BCR-ABL in one batch 
to: 
 
Radich Laboratory 
Fred Hutchinson Cancer Research 
Center 1100 Fairview Avenue N, D4-385 
Seattle, WA 98109 
E-mail: jradich@fredhutch.org 

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Version Date: 08/09/2023 
  
 
 
18.7 
Drugs Known to be Metabolized by CYP450 Isoenzyme 3A4 
 
CYP3A3/4 
Substrates 
Acetaminophen 
Aifentanil 
Alosetron 
Alprazolam 
Amiodarone 
Amitriptyline (minor) 
Amlodipine 
Anastrozole 
Androsterone 
Antipyrine 
Astemizole 
Atorvastatin 
Benzphetamine 
Bepridil 
Bexarotene 
Bromazepam 
Bromocriptine 
Budesonide 
Bupropion (minor) 
Buspirone 
Busutfan 
Caffeine 
Cannabinoids 
Carbamazepine 
Cevimeline 
Cerivastatin 
Digitoxin 
Diltiazem 
Disopyramide 
Docetaxel 
Dolasetron 
Donepezil 
Doxorubicin 
Doxycycline 
Dronabinol 
Enalapril 
Erylhromycin 
Estradiol  
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestene 
Dofetilide (minor) 
Felodipine 
Fentanyl 
Fexotenadine 
Finaxteride 
Fluoxetine 
Chlorpromazine 
Cimetidine 
Cisapride 
Citałopram 
Clarithromycin 
Clindamycin 
Clomipramine 
Clonazepam 
Clozapine 
Cocaine 
Codeine (demethylation) 
Cortisol 
Cortisone 
Cyclobenzaprine (demethylation) 
Cyclophosphamide 
Cyclosporine 
Dapsone 
Dehydroepiandrostendione 
Delavirdine 
Desmethyldiazepam 
Dexamethasone 
Dextromethorphan (minor, N- 
demethylation) 
Diazepam (minor; hydroxylation, N- 
demethylation) 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Niludipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Omeprazole (sulfonation) 
Ondansetron 
Oral contraceptives 
Orphenadrine 
Paclitaxel 
Pantoprazole 
Pimozide 
Pioglitazone 
Pravastatin 
Prednisone 
Progesterone 
Proguanil 
Propafenone 

S1712 
Page 101 
Version Date: 08/09/2023 
  
 
FLUTAMIDE 
Substrates 
Glyburide 
Granisetron 
Halofantrine 
Hydrocortixone 
Hydroxyarginine 
lfosfamide 
lmipramine 
lndinavir 
lsradipine 
ltraconazole 
Ketoconazole 
Lansoprazole (minor) 
Letrozole 
Levobupivicaine 
Lidocaine 
Loratadine 
Losartan 
Lovastatin 
Methadone 
Mibefradil 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine (N-demethylation) 
Montelukast 
Navelbine 
Toremifene 
Trazodone 
Tretinoin 
Triazolam 
Troglitazone 
Troleandomycin 
Venlafaxine (N-demethylation) 
Verapamil 
Vinblastine 
Quercetin 
Quetiapine 
Quinidine 
Quinine 
Repaglinide 
Retinoic acid 
Rifampin 
Risperidone 
Ritonavir 
Salmeterol 
Saquinavir 
Sertindole 
Sertraline 
Sibutramine 
Sildenafil citrate 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Temazepam 
Teniposide 
Terfenadine 
Testosterone 
Tetrahydrocannabinol 
Theophylline 
Tiagabine  
Tolterodine 
Vincristine 
Warfarin (R-warfarin) 
Yohimbine 
Zaleplon (minor pathway) 
Zatoestron 
Zileuton 
Ziprasidone 
Zolpidem 
Zonisamide 
INDUCERS 
Carbamazepine 
Dexamethasone 
Ethosuximide 
Glucocorticoids 
Griseofulvin 
Nafcillin 
Nelfinavir 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifampin 
Rofecoxib (mild) 
St John’s wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
INHIBITORS 

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Version Date: 08/09/2023 
  
 
Amiodarone 
Anastrozole 
Azithromycin 
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (weak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
lndinavir 
lsoniazid 
ltraconazole 
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole (moderate) 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole (weak) 
Oxiconazole 
Paroxetine (weak) 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Troglitazone 
Troleandomycin 
Valproic acid (weak) 
Verapamil 
Zafirlukast 
Zileuton 
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In : Lacy CF, Armstrong 
LL, Goldman MP, Lance LL eds. Drug Information Handbook 8th ed. Hudson, OH; 
LexiComp Inc. 2000: 1364-1371)