A Phase Ib Study of the Safety and Pharmacology of Nilotinib to Prevent Paclitaxel-Induced Peripheral Neuropathy in Patients With Breast Cancer
Phase: PHASE1
Conditions: Anatomic Stage I Breast Cancer AJCC v8, Anatomic Stage IA Breast Cancer AJCC v8, Anatomic Stage IB Breast Cancer AJCC v8, Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage IIA Breast Cancer AJCC v8, Anatomic Stage IIB Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8, Anatomic Stage IIIB Breast Cancer AJCC v8, Anatomic Stage IIIC Breast Cancer AJCC v8, Prognostic Stage I Breast Cancer AJCC v8, Prognostic Stage IA Breast Cancer AJCC v8, Prognostic Stage IB Breast Cancer AJCC v8, Prognostic Stage II Breast Cancer AJCC v8, Prognostic Stage IIA Breast Cancer AJCC v8, Prognostic Stage IIB Breast Cancer AJCC v8, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8
Sponsor: Ohio State University Comprehensive Cancer Center

Protocol #: OSU 18317 
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Local Protocol #: 
OSU-18317 
 
ClinicalTrials.gov Identifier: NCT04205903 
 
FDA IND#: 143553 
 
TITLE: 
A PHASE Ib STUDY OF THE SAFETY AND PHARMACOLOGY OF 
NILOTINIB TO PREVENT PACLITAXEL-INDUCED PERIPHERAL 
NEUROPATHY IN PATIENTS WITH BREAST CANCER 
 
 
Principal Investigators: 
Nicole Williams, MD 
Division of Medical 
Oncology 
1800 Cannon Drive 
1310K Lincoln Tower 
Columbus, OH 43210 
Tel: (614) 293-0066 
Fax: (614) 293-7264 
Email: nicole.williams@osumc.edu  
 
Shuiying Hu, PhD 
Pharmaceutics & Pharmacology  
 
406 Biomedical Research Tower 
460 W. 12th Ave. 
Columbus, OH 43210 
Tel: (614) 685-8028 
Email: hu.1333@osu.edu 
 
 
Other Agent(s): Nilotinib, Paclitaxel 
 
Protocol Type: 
Original / Version #1.0 / Version Date: 11/1/2/2018 
Version #2: 2/19/2019 
Version #3: 03/01/2019 
Version #4: 10/22/2019 
Version #5: 12/31/2019 
Version #6: 04/24/2020 
Version #7: 11/03/2020 
 
    Version #8: 01/29/2021 
 
    Version #9: 08/20/2021 
 
    Version #10: 07/28/2023 
 
    Version #11: 10/17/2024 
 
Funding: National Cancer Institute 1R01CA238946-01 to Lustberg and Hu    04/01/2019

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Table of Contents 
 
TRIAL SUMMARY & SCHEMA ................................................................................................................. 4 
1.1 TRIAL DESIGN ......................................................................................................................................................... 4 
1.2 STUDY SCHEMA PHASE 1B ........................................................................................................................................ 4 
 
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................................................... 6 
2.1. Primary Objectives ................................................................................................................................................ 6 
2.2 Secondary Objectives ............................................................................................................................................. 6 
 
BACKGROUND ...................................................................................................................................... 6 
3.1 
CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY (CIPN) ................................................................................. 6 
3.2 COMPLICATIONS ASSOCIATED WITH CIPN .................................................................................................................... 7 
3.3 NEW STRATEGIES FOR PREVENTION OF CIPN: TARGETING PACLITAXEL TOXICITY ................................................................. 7 
3.4.1 CIPN 20 ................................................................................................................................................................ 9 
3.4.2 Other Assessments .............................................................................................................................................. 9 
3.5 RATIONALE AND FEASIBILITY ..................................................................................................................................... 9 
 
METHODOLOGY .................................................................................................................................. 10 
4.1 
ENTRY CRITERIA ............................................................................................................................................ 10 
4.1.1 
Inclusion Criteria ........................................................................................................................................... 10 
4.1.2 Exclusion Criteria ............................................................................................................................................... 11 
4.2. STUDY LOCATION AND SAMPLE ............................................................................................................................... 12 
4.3 REGISTRATION AND STRATIFICATION ......................................................................................................................... 12 
4.4 STUDY TREATMENT ............................................................................................................................................... 13 
4.5 CLINICAL ASSESSMENTS.......................................................................................................................................... 13 
4.6 EVALUATION OF NEUROPATHY SYMPTOMS ................................................................................................................ 13 
4.6.1 Patient Reported Outcomes .............................................................................................................................. 13 
4.7 DURATION OF THERAPY ......................................................................................................................................... 13 
4.8 DURATION OF FOLLOW UP ...................................................................................................................................... 14 
4.9 CRITERIA FOR REMOVAL FROM STUDY ....................................................................................................................... 14 
4.10 ADHERENCE ....................................................................................................................................................... 14 
 
PHARMACEUTICAL INFORMATION ...................................................................................................... 14 
5.1 
PACLITAXEL .................................................................................................................................................. 14 
5.1.1 Adverse Events of Paclitaxel .............................................................................................................................. 15 
Please see section 7.3 for detailed toxicities reported on paclitaxel. ......................................................................... 15 
5.1.2 Dose and Schedule of Paclitaxel ........................................................................................................................ 15 
5.2 NILOTINIB............................................................................................................................................................ 15 
Please see section 7.3 for detailed toxicities reported on nilotinib. Please note that these toxicities are for 
continuous dosing of drug but in this study only intermittent dosing will be used. Therefore, anticipated toxicity is 
expected to be much less. .......................................................................................................................................... 15 
 
POTENTIAL TOXICITY, DOSE MODIFICATIONS, AND MANAGEMENT ..................................................... 16 
6.1 ASSESSMENT OF DOSE LIMITING TOXICITIES ............................................................................................................... 18 
 
TREATMENT PLAN ............................................................................................................................... 20 
7.1 TREATMENT PLAN AND OVERVIEW ........................................................................................................................... 20 
7.2 STUDY CALENDAR ................................................................................................................................................. 21 
Study Calendar Phase Ib - Schedule A (weekly paclitaxel) 
Study Calendar Phase Ib - Schedule B (dose dense paclitaxel) 
*PLEASE SEE SECTION 8.1 FOR DETAILED PK SCHEDULE ...................................................................................................... 22 
*PLEASE SEE SECTION 8.1 FOR DETAILED PK SCHEDULE ...................................................................................................... 23 
7.3  ADVERSE EVENTS ASSOCIATED WITH NILOTINIB AND PACLITAXEL .................................................................................. 24 
7.3.1 Adverse Events Reported on Nilotinib Trials ..................................................................................................... 24 
7.3.2 Adverse Events Reported for Paclitaxel ............................................................................................................. 25 
 
CORRELATIVE STUDIES ........................................................................................................................ 27 
8.1 INTEGRATED CORRELATIVE STUDIES: PK OF NILOTINIB AND PACLITAXEL .......................................................................... 28 
8.2 INTEGRATED CORRELATIVE STUDIES: BIOMARKERS OF OATP1B1 .................................................................................. 30 
 
ADVERSE EVENT REPORTING ............................................................................................................... 31 
9.1 ATTRIBUTION OF THE ADVERSE EVENTS ..................................................................................................................... 31 

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9.2 DOCUMENTATION ................................................................................................................................................. 32 
9.3 REPORTING .......................................................................................................................................................... 32 
 
DATA REPORTING / REGULATORY REQUIREMENTS ............................................................................. 32 
10.1 ETHICAL AND REGULATORY CONSIDERATIONS ........................................................................................................... 32 
10.2 INSTITUTIONAL REVIEW BOARD ............................................................................................................................. 32 
10.3 INFORMED CONSENT ........................................................................................................................................... 33 
10.4 PATIENT CONFIDENTIALITY .................................................................................................................................... 33 
10.5 PUBLICATION AND RESEARCH FINDINGS .................................................................................................................. 33 
10.6 COMPLIANCE MONITORING .................................................................................................................................. 33 
10.7 DATA SAFETY MONITORING .................................................................................................................................. 33 
10.8 RESPONSIBILITY FOR DATA SUBMISSION .................................................................................................................. 34 
10.9 DATA AND RECORDS ............................................................................................................................................ 34 
10.10 SAFETY AND MONITORING .................................................................................................................................. 34 
10.11 ACCOUNTABILITY .............................................................................................................................................. 34 
10.12 DOCUMENTATION ............................................................................................................................................ 34 
10.13 REPORTING ...................................................................................................................................................... 35 
 
STATISTICAL CONSIDERATIONS ........................................................................................................... 36 
11.1 STUDY ENDPOINTS .............................................................................................................................................. 36 
DEFINITION OF PRIMARY ENDPOINT ............................................................................................................................... 36 
• 
SAFETY, TOLERABILITY AND RP2D OF NILOTINIB IN COMBINATION WITH PACLITAXEL. ...................................................... 36 
DEFINITION OF SECONDARY ENDPOINTS .......................................................................................................................... 36 
11.2 STUDY DESIGN AND SAMPLE SIZE CALCULATION ....................................................................................................... 37 
11.3 STATISTICAL DATA ANALYSIS ................................................................................................................................. 38 
 
REFERENCES ....................................................................................................................................... 39 
 
 
 
 
 

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 TRIAL SUMMARY & SCHEMA 
 
Abbreviated Title 
PHASE Ib STUDY OF SAFETY AND 
PHARMACOLOGY OF NILOTINIB TO 
PREVENT PACLITAXEL-INDUCED 
PERIPHERAL NEUROPATHY 
Trial Phase 
Ib 
Clinical Indication 
Stages I-III Breast Cancer  
Trial Type 
Single arm Phase 1b 
Type of control 
None  
Route of 
administration 
Oral nilotinib 
IV paclitaxel 
Trial Blinding 
None 
Treatment Groups  
All study subjects will receive nilotinib.  
Number of trial 
subjects 
Approximately up to 20 
Estimated enrollment 
period 
2 years 
Estimated duration of 
trial 
Patients will be followed for 6 months after last 
paclitaxel dose 
 
Duration of 
Participation 
Approximately 6-9 months including observation. 
Active treatment maximum 12 weeks 
 
 
1.1 Trial Design 
This is a phase Ib trial in men and women with stage I-III breast cancer who are initiating 
chemotherapy with paclitaxel. Intermittent doses of nilotinib will be administered (Day-
1 to Day 1; each dose administered with paclitaxel except cycle 1 day 1). Nilotinib will 
be administered orally once a day 24 hours before each paclitaxel infusion (excluding 
cycle 1 day 1) and then repeated approximately 30 minutes prior to paclitaxel infusion 
to evaluate DLTs, MTD, or MAD.  
 
 
1.2 Study Schema Phase 1b 
 
There are two paclitaxel dosing schedules administered in the clinic based on investigator 
discretion – either weekly paclitaxel or dose-dense paclitaxel given every two weeks. The study 
schemas below describe the interventions for the two dosing schedules. 

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Schedule A:  
• 
weekly dose of 80mg/m2, paclitaxel will be given weekly on days 1, 8, 15, of every 
21 days.  
• 
Nilotinib will be given orally on cycle 1 Days 7, 8, 14, 15 once a day 24 hours 
prior to the paclitaxel infusion and again 30 minutes prior to the paclitaxel infusion 
on days 8, 15.  
• 
During the cycle 1, PK will be obtained at baseline, during, and up to 6 hours after 
paclitaxel or nilotinib administration on the days shown above. 
• 
Patients will continue paclitaxel without nilotinib after cycle 1 as part of standard 
of care at the discretion of the treating investigator.  
 
 
 
 
 
 
Schedule B:  
• For dose dense schedule of 175mg/m2, paclitaxel will be given once every two weeks on 

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day 1.   
• Nilotinib will be given orally on cycle 1 Days 14, once a day 24 hours prior to the cycle 
2 paclitaxel infusion and again 30 minutes prior to the paclitaxel infusion on day 1.    
• During the cycle 1 & 2, PK will be obtained at baseline, during, and up to 6 hours after 
paclitaxel or nilotinib administration on the days shown above. 
• Patients will continue paclitaxel without nilotinib after cycle 2 as part of standard of care 
at the discretion of the treating investigator. 
 
 TRIAL OBJECTIVES AND ENDPOINTS  
 
2.1. Primary Objectives  
(1) To determine the recommended phase 2 dose (RP2D) of nilotinib in 
combination with paclitaxel for early stage breast cancer, defined as the lowest 
intermittent dose of nilotinib that can temporarily inhibit the function of OATP1B1 
without affecting the plasma pharmacokinetics of paclitaxel. 
(2) To determine the toxicity profile (based on CTCAE v. 5.0) of nilotinib in 
combination with paclitaxel in early stage breast cancer patients.  
 
2.2 Secondary Objectives  
(1) To determine the effect of paclitaxel on PK of nilotinib in the study population. 
To determine the effect of nilotinib on PK of paclitaxel in the study population. 
 
2.3  Exploratory Objectives: 
(1)   To evaluate quality of life and chemotherapy induced neuropathy symptoms 
using the CIPN20 questionnaire 
(2)   To determine the disease-free survival (DFS), event free survival (EFS) and   
overall survival (OS) of nilotinib in combination with paclitaxel.  
 
 
 
 BACKGROUND 
 
3.1 Chemotherapy-Induced Peripheral Neuropathy (CIPN) 
 
Breast cancer detection and treatment has improved significantly in recent years, with breast 
cancer patients currently comprising the largest groups of cancer survivors. However, more than 
30% of patients receiving chemotherapy experience chemotherapy-induced peripheral 
neuropathy (CIPN), which occurs as a result of several commonly used classes of chemotherapy 
drugs including taxanes, vinca alkaloids and platinum compounds. CIPN is predominantly a 
sensory neuropathy with symptoms of paresthesia and pain, but also includes a component of 
motor neuropathy. In many populations including the elderly and diabetics, as well as cancer 
patients, CIPN is also associated with not only pain, but also with falls and difficulty in walking 
and performing activities of daily living (ADLs).1-3 Although symptoms may improve over time 
in many patients, symptoms can persist for years, and for some patients, full reversibility of 
symptoms may never occur. In addition to peripheral nervous system impairments, chemotherapy 
treatment is also associated with central nervous system impairments, including detrimental 
changes to blood flow in frontal lobes of the brain, which are important for motivation and 
neurocognition, as well as in brain areas responsible for processing pain. Combined, these nervous 

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system changes induced by chemotherapy and CIPN hinder the ability for patients to perform 
various ADLs. 
 
3.2 Complications associated with CIPN 
 
Among the taxanes, the drug paclitaxel is associated with an acute pain syndrome, known as 
paclitaxel-associated pain syndrome (P-APS). This syndrome occurs within 7 days of drug 
administration, and recent studies suggest that patients with P-APS are also at increased risk of 
CIPN.4 As a consequence of this toxicity, dose modification and early completion of treatment 
may result and affect patients’ progress. Preventative and therapeutic interventions have been 
attempted but have had limited success or have produced additional toxicity. To date, no 
preventative strategy for CIPN has been confirmed by randomized placebo controlled trials. A 
recently reported study with duloxetine as treatment for CIPN was promising.5 Improved 
understanding of the pathophysiology of CIPN would help in the rational design of studies for the 
prevention and treatment of this very common cytotoxicity.  
 
3.3 New Strategies for Prevention of CIPN: Targeting Paclitaxel Toxicity 
 
To date, more than 40 randomized controlled clinical trials have been conducted to evaluate 
efficacy of prevention or treatment of peripheral neuropathy, but none have provided convincing 
evidence for a clinically-beneficial agent.6 These studies have been limited by the failure to 
develop interventions based on a firm mechanistic rationale. The translational exploration of 
many of the proposed intervention 
strategies has been hampered by findings 
that 
(i) 
paclitaxel 
has 
multiple 
intracellular targets, hence blocking a 
single injurious event will only have 
partial protective effects; and (ii) the 
protective approach may diminish the 
antitumor effects of paclitaxel given the 
potential overlap in cell death signaling 
pathways between normal cells and tumor 
cells. Therefore, an optimal approach is to 
simultaneously protect the peripheral 
nerves against toxicity from paclitaxel 
without affecting its therapeutic effects in 
tumors. The development of such an 
approach would rely on the identification of the critical differences between normal and malignant 
cells that drive toxic responses to paclitaxel. We recently found that paclitaxel accumulates in 
cells through a process mediated by the murine organic anion transporting polypeptide OATP1B2 
(OATP1B1 and OATP1B3 in humans; Fig 1).7 We also found that paclitaxel induces acute and 
chronic forms of neurotoxicity in mice in an OATP1B2-dependent manner, and that these 
phenotypes can be completely reversed by pre-treatment with the tyrosine kinase inhibitor (TKI) 
nilotinib (Fig 2).7 
Figure 1. Dependence of acute paclitaxel-induced peripheral neuropathy on 
OATP1B2. (A) Plasma levels of paclitaxel in wild-type and OATP1B2(-/-) mice (n=4); 
(B)  Mechanical allodynia as determined by a Von Frey Hairs test (n=8). Data present 
mean ± SE after one (A) or 2 (B) doses of paclitaxel (10 mg/kg, i.v.; time 0 and 72 h). The 
star (*) denotes significant differences from baseline and OATP1B2(-/-) mice (P<0.01). 

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Compared to other TKIs, nilotinib has features 
that suggest it might be an excellent modulator of 
paclitaxel toxicity, including good oral absorption, a 
relatively slow clearance, and a long half-life.8 In our 
studies, we aim to interrogate the response of the 
peripheral nervous system to the nilotinib-paclitaxel 
combination following acute or intermittent exposure to 
the TKI. Therefore, we anticipate that nilotinib will not 
be intrinsically toxic in such combination therapy 
regimens We have detailed, below, additional data that 
supports that the proposed once a day doses of nilotinib 
are lower than currently approved labeling doses for this 
drug, are safe, and do not increase paclitaxel toxicity 
(Please see section 3.6).    In order to assess the degree of 
OATP1B1 
inhibition 
by 
nilotinib, 
analysis 
of 
glycochenodeoxycholate 
sulfate 
(GCDGA-S) 
and 
chenodeoxycholate-24-glucuronide (CDCA-24G) levels 
will be performed in plasma samples as validated surrogate endogenous substrates of OATP1B1. 
Previous clinical studies have indicated that the area under the curve (AUC) of GCDCA-S can be 
increased >20-fold following treatment with OATP1B1 inhibitors, whereas CDCA-24G is only 
detectable after the administration of OATP1B1 inhibitors.9 Based on our preclinical studies, we 
expect that the administration of nilotinib will result in dose-dependent changes in levels of 
GCDAGA-S and CDCA-24G caused by inhibition of OATP1B1. Since the initial approval of the 
protocol, significant progress has been made in the identification of other endogenous biomarkers 
to assess the OATP1B transporter function. With rich clinical datasets, emerging evidence 
suggests that coproporphyrin-I (CP-I) and coproporphyrin-III (CPIII), compounds formed in the 
body as byproducts of heme synthesis, have higher selectivity and sensitivity and can be used to 
better assess in vivo OATP1B1 activity.10-12 Furthermore, we recently identified α-tocopherol as 
a DRG-specific OATP1B-type transporter biomarker that can be measured in the circulation13, 
analysis of additional biomarker CP-I, CPIII as well as α-tocopherol could provide more accurate 
assessment of OATP1B1 transporter activity with nilotinib, which could serve as a companion 
diagnostic to guide dose selection of pharmacological inhibitors in the future development of 
combinatorial regimens with chemotherapy drugs.  
Although combining paclitaxel with nilotinib could possibly reduce the incidence and 
severity of neuropathy, it is important to establish that the anticancer efficacy of paclitaxel is not 
compromised by nilotinib. We already confirmed that the OATP1B1 and OATP1B3 genes are 
expressed at low levels in MBC samples and that the cellular uptake and cytotoxicity of paclitaxel 
are not reduced by nilotinib in MBC cell lines.7 In addition, the nilotinib-paclitaxel combination 
was recently identified as a synergistic drug pair in vivo, resulting in tumor regressions in a MBC 
xenograft model, with no tumor regrowth observed for more than 80 days following the end of 
therapy.14 Although in vivo confirmation is required in patient-derived xenograft models that more 
faithfully represent the characteristics of primary human MBC,15 these initial observations 
indicate that combining paclitaxel with nilotinib has the potential to simultaneously reduce 
toxicities and increase anticancer effects. 
 
3.4. Measuring CIPN 
 
Patient reported outcomes (PRO) are the gold standard for evaluation of CIPN symptoms. 
Figure 2. Proposed model of paclitaxel-induced injury to 
the peripheral nervous system. Paclitaxel enters the 
nervous system through OATP1B2, ultimately leading to 
peripheral neuropathy (top). These effects can be blocked 
by the OATP1B2 inhibitor nilotinib (bottom). 

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Multiple validated instruments have been evaluated in large scale studies. For the purposes of this 
study, CIPN-20 will be used.16 
 
3.4.1 CIPN 20  
 
CIPN 20 is a validated instrument for longitudinal evaluation of neuropathy symptoms 
induced by chemotherapy. This 20-item self-report questionnaire includes three subscales 
evaluating sensory, motor and autonomic symptoms. It is easy to use and is completed by 
patients independently. This instrument was designed and validated to evaluate patients’ 
symptoms of CIPN during chemotherapy treatment with a number of chemotherapeutic 
agents, including taxanes.17 
 
3.4.2 Other Assessments 
 
Each participant will also have a diary to report daily changes in symptoms. Changes in the 
chemotherapy dosing, dose delays, discontinuation of therapy, and the amount of analgesic 
use during the study period will also be recorded by research coordinator. All toxicities will 
be assessed by CTCAE V5. 
 
3.5 Rationale and Feasibility 
There are multiple gaps in our understanding of CIPN despite its commonness and pervasive 
negative impact on drug adherence and quality of life in many cancer survivors. Safe and 
affordable strategies that may help prevent the onset or ameliorate joint symptoms are therefore 
needed. The overall objectives of this application are to evaluate a promising targeted therapy 
intervention for prevention of taxane induced CIPN in breast cancer patients by first confirming 
the MTD of the intermittent dosing of nilotinib with paclitaxel. The MTD will be evaluated in a 
future randomized phase II study to evaluate preliminary efficacy for prevention of CIPN.   
 
3.6 Preliminary safety and tolerability of nilotinib with paclitaxel 
 
Based on personal communication and a submitted confidential abstract, submitted International 
Conference on Molecular Targets and Cancer Therapeutics the preliminary data from the 
ongoing study at NCI (Clinicaltrials.gov ID NCT02379416) patients with solid tumors (n=30) 
treated for up to 41 cycles with weekly paclitaxel and twice daily nilotinib. The MTD was 80 
mg/m2 paclitaxel and nilotinib 300 mg bid, the combination has been well tolerated. There 
have been no paclitaxel dose delays due to myelosuppression and no QTC prolongation. 
No participants have terminated study protocol due to toxicity. Preliminary response data are 
promising, especially considering the PRs observed in pts who had previously been 
unresponsive to paclitaxel therapy.  Of the 24 pts assessable for response to date, there are 4 
confirmed partial responses (PRs; 17%, 1 pt with endometrial cancer, 1 pt with anal cancer and 
2 pts with granulosa cell of the ovary) and 12 pts with a best response of stable disease (SD; 
50%), including 6 pts with SD for ≥8 cycles. Mean time on study to date is 8.7 months (range: 2 
– 41 months). Three of 4 responding pts had undergone prior paclitaxel-based therapy and 
experienced a best response of only SD (1 pt) or progressive disease (2 pts) to 
carboplatin/paclitaxel or paclitaxel monotherapy, respectively.  Preliminary results from 
NCT02379416 are described below in Table 1. 
 

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Table 1. Preliminary Data from NCT02379416 
Condition 
Number of Patients 
Paclitaxel Dose Delays due to Myelosuppression 
0 
Paclitaxel Dose Delays due to QTC Elongation 
0 
Termination from Study due to Toxicity 
0 
Partial Responses to Paclitaxel after Prior Unresponsiveness 
4 (of the 24 with available data) 
Maintained Stable Disease 
12 (of the 24 with available data) 
*6 for 8 or more months 
 
 
 
 
 
 
Given the intermittent dosing of nilotinib, we expect toxicity to be very low. Additionally, 
all our preclinical modeling suggests no pharmacokinetic interaction between paclitaxel and 
nilotinib. Additionally, in phase 1b, interaction between the two drugs will be closely 
monitored.  
 
 
 METHODOLOGY 
 
4.1 Entry Criteria 
 
4.1.1 Inclusion Criteria 
 
1. Men or Women with a known diagnosis of breast cancer stages I-III 
2. Be eligible for weekly or dose dense single agent paclitaxel therapy based on 
physician assessment 
3. Be ≥18 years of age. 
4. Have an ECOG performance status ≤ 2  
 Patients with ECOG scores of 3 or greater typically do not receive 
chemotherapeutic intervention 
5. Demonstrate adequate organ and marrow function as defined in Table 2. 
 
Table 2. Adequate Organ and Marrow laboratory values 
 
Laboratory values 
Leukocytes 
≥ 2,000/µL 
Absolute neutrophil count 
≥ 1,500/µL 
Platelets 
≥ 100,000/µL 
Total bilirubin 
≤ UNL 
AST (SGOT)/ALT (SGPT) 
≤ 2.5 × Institutional upper limit of 
normal*  
 
Data collected from 30 patients with solid tumors treated with up to 41 cycles of weekly paclitaxel and twice daily 
with nilotinib. MTD = 80mg/m2 paclitaxel and 300 mg nilotinib bid. Mean time on study is 8.7 months (2-41). 

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Creatinine 
Within normal institutional limits OR  
≥50mL/min 
for 
patients 
with 
creatinine levels above institutional 
normal. 
QTc 
<450 milliseconds 
 
6. If a female subject is with child bearing potential, she must have a negative 
pregnancy test at screening. 
7. Female subjects of child-bearing potential and men must agree to use adequate 
contraception prior to study entry, for the duration of study participation and for 
3 months after completion of study treatment administration. Adequate 
contraception includes methods such as oral contraceptives, double barrier 
method (condom plus spermicide or diaphragm), or abstaining from sexual 
intercourse. 
8. Be willing and able to understand and sign the written informed consent 
document. 
9. Demonstrate adequate electrolyte values as defined below. Hypokalemia and/or 
hypomagnesemia must be corrected prior to initiating nilotinib: 
 Calcium 8.6-10.5mg/dL 
 Magnesium 1.6-2.6mg/dL 
 
4.1.2 Exclusion Criteria 
 
1. Known distant metastatic disease 
2. Is HER2+ and is receiving paclitaxel in conjunction with trastuzumab 
+/- pertuzumab  
3. Has experienced > grade 1 neuropathy during previous therapies for 
early stage breast cancer.  
4. Has experienced prior treatment-related toxicities that have not recovered to 
grade 1 or less (except for alopecia). 
5. Has a history of grade 3-4 immediate hypersensitivity reaction to paclitaxel. 
6. Has a history of clinically significant allergic reactions attributed to compounds 
of similar chemical or biologic composition to nilotinib or paclitaxel. 
7. Has uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
8. Is currently pregnant or breast feeding as there is an unknown but potential risk 
for adverse events in nursing infants secondary to treatment of the mother with 
nilotinib and paclitaxel. 
9. Has any other medical or psychiatric condition that in the opinion of the 
investigator would make the study therapy unsafe for the patient. 
10. Has gastrointestinal (GI) disorders or impairment of GI function that is likely to 
significantly alter the absorption of nilotinib 
11. Has a marked baseline abnormal heart rhythm such as prolongation of QT/QTc 
interval (e.g., repeated demonstration of a QTc of > 450msec) 
12. Has a history of additional risk factors for TdP (e.g., heart failure, hypokalemia, 

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hypomagnesemia, family history of Long QT Syndrome) 
13. Uses potent CYP3A4 inhibitors (grapefruit juice, cyclosporine, ketoconazole, 
ritonavir) and if treatment cannot be either safely discontinued or switched to a 
different medication prior to starting nilotinib. 
14. Has a known diagnosis of HIV and is currently taking combination antiretroviral 
therapy known or suspected to affect paclitaxel PK. 
15. Is concurrently using potent OATP1B1 inhibitors, including antibiotics 
(rifampicin, rifamycin SV, systemic fusidic acid, clarithromycin, erythromycin, 
roxithromycin, telithromycin), antiretrovirals (indinavir, saquinavir, ritonavir), 
cyclosporine, and gemfibrozil. 
 
Please note: Anthracycline regimens are often used sequentially with paclitaxel based regimens 
in breast cancer. However, whether anthracyclines are used prior or after paclitaxel treatment 
has not been shown to significantly impact outcomes. Prior exposure to anthracyclines or 
subsequent anthracyclines should not impact our study. Therefore, any patient who meets the 
above eligibility criteria and is receiving single dose paclitaxel over the duration of the present 
study is still eligible, regardless of prior anthracycline regimens. 
 
4.2. Study Location and Sample 
 
This study will be open for accrual at the Stefanie Spielman James Comprehensive Breast 
Center, part of The Ohio State University Comprehensive Cancer Center. Patient eligibility 
will be determined according to the eligibility criteria listed. The study will enroll up to 
approximately up to 20 patients in this phase Ib trial.  
 
4.3 Registration and Stratification  
 
To register a patient, the following documents must be completed by the study coordinator: 
(1) Patient Consent Form - signed 
(2) Patient HIPAA Authorization Form - signed 
(3) Consent Documentation Note 
(4) Eligibility Checklist - completed & signed 
(5) Source documents verifying every inclusion & exclusion criteria. Note: Every inclusion and 
exclusion criteria must be documented in the patient’s medical record (emails or other notes 
outside the medical record will not be considered source documentation) 
(6) Results from baseline tests required per the Study Calendar.  
(7) Registration Form - completed 
Upon receipt of all required registration documents and upon verification the patient meets all 
eligibility criteria, the study coordinator will: 
• Assign the patient a study sequence ID. 
• Register the patient on the study. 
Following registration, patients should begin protocol treatment within 14 business days. Issues 
that would cause treatment delays should be discussed with the Principal Investigator as soon as 
possible. If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled, after discussion with the Principal Investigator and 
study coordinator.  
 
All the patients enrolled in this study will receive nilotinib. 
 

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4.4 Study Treatment 
 
In Schedule A (weekly paclitaxel), the starting dose of nilotinib will be 100mg p.o. once per 
day on 2 occasions 24hrs before and 30 min before paclitaxel on C1D7, C1D8, C1D14, 
C1D15.  Paclitaxel will be given at 80 mg/m
2 throughout all dose levels (unless dose reduction 
is needed for other clinically standard criteria). In Schedule B (dose dense paclitaxel), nilotnib 
will be given as 100mg p.o. once per day on two occasions 24hrs before and 30min before 
paclitaxel on C1D14 and C2D1. Duration of paclitaxel for both schedules is for 4 cycles of  
doses unless there is a clinical indication to terminate therapy earlier per treating physician. 
Paclitaxel will be administered in the standard regimen and followed the package insert and 
institutional guidelines for its administration and management of hypersensitive reactions 
(both acutely and for subsequent doses) will be followed (Section 1.2 study schema).  
 
4.5 Clinical Assessments 
 
Participants will be evaluated for toxicity at baseline and on D1 of each cycle as part of clinic 
visit. In addition, clinical research coordinator will evaluate patients as part of a research 
encounter prior to each infusion. Toxicity evaluation of neuropathy will be recorded based on 
CTCAE criteria v. 5 for sensory and motor neuropathy in addition to CIPN 20. 
 
4.6 Evaluation of Neuropathy Symptoms 
 
4.6.1 Patient Reported Outcomes 
Patient reported outcomes (PRO) are the gold standard for evaluation of CIPN symptoms. 
Multiple validated instruments have been evaluated in large scale studies. For the purposes of this 
study, CIPN-20 will be used.16 Each participant will also have a diary to report daily changes in 
symptoms. Changes in the chemotherapy dosing, dose delays, discontinuation of therapy, and the 
amount of analgesic use during the study period will also be recorded by research coordinator. 
 
4.7 Duration of Therapy  
 
In Schedule A (weekly paclitaxel), nilotinib will be given only on C1D7, C1D8, C1D14, C1D15. 
Patients will remain on study until C4D21 of paclitaxel (unless they come off due to progression 
of disease) for the purpose of monitoring for the occurrence of neuropathy as defined by NCI 
CTCAE V5 and data on quality of life using CIPN20 questionnaire. In Schedule B (dose dense 
paclitaxel), nilotnib will be given on C1D14 and C2D1 only. Patient will remain on study until 
Cycle 4 Day 1. Further continuation of paclitaxel will be at the discretion of the treating 
investigator. In the absence of treatment delays due to adverse event(s), patient will stay on study 
until one of the following criteria applies: 
 
• 
Therapy completion,  
• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 

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4.8 Duration of Follow up 
 
Patients will be followed 3 months and 6 months after completion of paclitaxel. Patients removed 
from study for unacceptable adverse event(s) will be followed until resolution or stabilization of 
the adverse event.  
 
4.9 Criteria for Removal from Study 
 
The following criteria will be used for removal of patients from the study: (1) patient withdraws 
their participation; (2) patient has a disease progression or dies (whichever occurs first); (3) the 
study is terminated by the Principal Investigator; (4) patient develops neuropathy or other 
condition that prohibits continued treatment with paclitaxel; (5) pregnancy or failure to practice 
appropriate contraception. The reason for study removal and the date the patient is removed must 
be documented in the Case Report Form. 
 
4.10 Adherence 
 
Participant adherence to the study intervention will be encouraged and monitored in several 
ways. Subjects will be encouraged to maintain a daily diary in which to check off the doses of 
study drug when taken. At study visits, participants will return their pill containers to study 
personnel, who will count and record leftover pills. 
 
 
 PHARMACEUTICAL INFORMATION 
 
5.1 Paclitaxel   
 
Taxanes (including paclitaxel, docetaxel and nab-paclitaxel) are among the most active cytotoxic 
agents for the treatment of breast cancer.18-20 Paclitaxel was originally isolated from the bark of 
the Pacific yew tree (taxus brevifolia) and subsequently found to have anti-tumor properties in the 
early 1970s.21, 22 Its mechanism of action relates to binding and stabilization of microtubules 
causing inhibition of their depolymerization, leading to mitotic arrest.23 Paclitaxel is hydrophobic 
and has poor solubility in water. Therefore, this agent is solubilized in 50% polyoxyethylated 
castor oil (Cremophor EL) and 50% ethanol. Cremaphor EL vehicle is associated with 
hypersensitivity reactions which require premedication with corticosteroids and histamine 
receptor blockers to minimize its incidence and severity.24 The majority of hypersensitivity 
reactions occur during the first 1-2 administrations of paclitaxel, which has led to studies 
demonstrating that these premedications can be safely withdrawn in patients for whom 
hypersensitivity to paclitaxel formulation does not develop after the first 2 treatments.25 
 
Paclitaxel administered intravenously at a dose of 175 mg/m2 for 3 hours every third week has 
emerged as an active and safe initial and salvage therapy for early stage breast cancer with 
associated response rates around 30-40% and survival of about 19 months in patients with 
untreated early stage breast cancer.18, 26 Since the activity of paclitaxel is directly related to the 
cell cycle, shortening the interval between treatments might improve efficacy.27 In addition, 
paclitaxel administered in a more continuous manner exhibits pro-apoptotic and antiangiogenic 
properties, increasing its antineoplastic effects.28 Indeed, subsequent randomized studies 
confirmed that weekly paclitaxel administration at 80mg/m2 was superior to every-3-week 
schedules in treatment of early stage and operable breast cancer.29-31 Weekly paclitaxel almost 

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doubled the time to progression and increased the response rate from 29% to 42% without 
affecting quality of life in patients with stages I-III breast cancer.29 Additionally, dose dense 
paclitaxel at 175 mg/m2 has also been shown to be an effective regimen in breast cancer.32  
 
5.1.1 Adverse Events of Paclitaxel  
 
Please see section 7.3 for detailed toxicities reported on paclitaxel.  
 
5.1.2 Dose and Schedule of Paclitaxel  
 
This study will utilize the weekly paclitaxel schedule and the dose dense paclitaxel schedule, as 
these regimens have been extensively found to have superior efficacy to 3 week schedule 
paclitaxel.29-31 We are therefore proposing the use of either the standard weekly 80 mg/m2 
paclitaxel dose schedule or the 175 mg/m2 dose dense paclitaxel every two weeks dose schedule. 
The information on the safety profile of the combination and effect of nilotinib pharmacokinetics 
of paclitaxel will be collected in this trial.  
 
5.2 Nilotinib  
 
Nilotinib (TasignaR) will be purchased in doses specified. Nilotinib is indicated for the treatment 
of adult and pediatric patients greater than or equal to 1 year of age with newly diagnosed 
Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. For 
CML, Nilotinib is taken twice daily at approximately 12-hour intervals and must be taken on an 
empty stomach. No food should be consumed for at least 2 hours before the dose is taken and for 
at least 1 hour after the dose is taken.  Please note this is not the dosing recommended for this 
proposal and we are proposing once daily intermittent dosing.  
 
5.2.1 Adverse Events of Nilotinib 
 
Please see section 7.3 for detailed toxicities reported on nilotinib. Please note that these toxicities 
are for continuous dosing of drug but in this study only intermittent dosing will be used. Therefore, 
anticipated toxicity is expected to be much less. 
 
5.2.2 Dose and Schedule of Nilotinib 
 
The recommended dose of nilotinib in CML is 300 mg orally twice daily. However, in this study 
nilotinib will be administered p.o. once per day on 2 occasions 24hrs before and 30 min before 
paclitaxel on unless DLT encountered. A total of up to 4 nilotinib dose levels will be considered; 
50, 100, 200, and 300mg in the phase Ib portion of the trial (Tables 3a and 3b). The maximum 
sample size will be 20 with cohort size of 2. The first cohort of patients will be enrolled at dose 
level 1 (nilotinib 100 mg). After each cohort is treated and evaluated for toxicity and efficacy as 
defined in the context of this trial, these data will inform our dynamic, adaptive model to 
determine dose escalation decisions based on changes to estimated probabilities for toxicity and 
for efficacy given the data observed. Then next cohort of patients will be treated on the dose level 
determined from the Bayesian adaptive model.  
 
Nilotinib must be taken on an empty stomach and no food should be consumed for at least 2 
hours before the dose is taken. Food should be avoided for at least 1 hour after the dose is taken. 
All participants in the study will be advised of this.  

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5.3  Paclitaxel and nilotinib interactions 
 
Based on the NCI data Clinicaltrials.gov ID NCT02379416, the risk of myelosuppression and 
dose delays with our regimen of intermittent nilotinib dosing is expected to be unlikely. Based on 
our recent preclinical experience of nilotinib given in combination with paclitaxel, we anticipate 
that nilotinib will not affect the disposition profile of paclitaxel and vice versa. The expectation 
that nilotinib is unlikely to influence the pharmacokinetics of paclitaxel would be consistent with 
previously reported studies confirming that other OATP1B1-inhibiting TKIs identified from our 
screens, such as axitinib, and sorafenib, do not alter the systemic exposure to paclitaxel. The above 
noted NCI study confirmed our preclinical anticipation, there were no observed adverse PK 
interactions between nilotinib and paclitaxel. Although the drug-drug interaction in a clinical 
setting is highly unlikely, we will perform real-time PK analyses for both paclitaxel, nilotinib and 
in combination for parent and metabolites.  
 
 
 POTENTIAL TOXICITY, DOSE MODIFICATIONS, AND MANAGEMENT 
 
Toxicity will be monitored during study visits and telephone calls using the National Cancer 
Institute Common Terminology Criteria for Adverse Events version 5.0 (CTCAE) of the National 
Cancer 
Institute 
will 
be 
used: 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_5x7.pdf). Any Grade 1 or greater toxicities will be reported as adverse events.  
 
Patients with any Grade ≥3 adverse reactions or with an absolute QTc≥ 500msec,or increase 
of baseline QTc of > 60msec during the first cycle will count toward DLT determination. If a 
patient has a DLT, nilotinib will be stopped and paclitaxel will be continued per treating 
physician. See Section 6.1 for the definition of DLTs.   
 
Table 3a. Phase 1b dose modifications for nilotinib and paclitaxel 
during cycle 1 – Schedule A (weekly paclitaxel) 
 
Dose Level 
Nilotinib 
(Refer to study schema)  
Weekly Paclitaxel 
(mg/m2 IV on days 1, 
8, 15) 
Level -1 
50 mg 
 
(one 50 mg capsule once 
daily 24 hours before and 
day 
of 
paclitaxel 
treatment)  
80 
Level 1 
 
(Starting dose 
level) 
100 mg  
 
(two 50 mg capsules once 
daily 24 hours before and 
day 
of 
paclitaxel 
treatment) 
80 

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Level 2 
200mg 
 
 (four 50mg capsules once 
daily 24 hours before and 
day 
of 
Paclitaxel 
treatment) 
80 
Level 3 
300mg  
 
(six 50mg capsules once 
daily 24 hours before and 
day 
of 
paclitaxel 
treatment) 
80 
 
 
 
 
 
 
 
Table 3b. Phase 1b dose modifications for nilotinib and paclitaxel during 
cycle 1 – Schedule B (dose dense paclitaxel) 
 
 
 
Dose Level 
Nilotinib 
(Refer to study schema)  
Dose 
dense  
Paclitaxel 
(mg/m2 IV)  
Level -1 
50 mg 
 
(one 50 mg capsule once 
daily 24 hours before 
and day of paclitaxel 
treatment  
175 
Level 1 
 
(Starting dose 
level) 
100 mg  
 
(two 50 mg capsules 
once daily 24 hours 
before 
and 
day 
of 
paclitaxel treatment 
175 
Level 2 
200mg 
 
 (four 50mg capsules 
once daily 24 hours 
before 
and 
day 
of 
Paclitaxel treatment) 
175 
Level 3 
300mg  
 
(six 50mg capsules once 
daily 24 hours before 
and day of paclitaxel 
treatment  ) 
175 
 

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We do not anticipate significantly increased toxicities given intermittent dosing of drug and 
administration of drug nilotinib only during cycles 1 and 2, if using the dose dense schedule, and 
excellent tolerability and lack of myelosuppression with continuous dosing noted in 
Clinicaltrials.gov ID NCT02379416. 
 
 
Dose levels for phase Ib will follow Tables 3a and 3b.  Movement across these levels will be per 
statistical models as outlined in section 11.2 
 
 
Nilotinib is started at dose level 1. Dose escalations and de-escalations will be based on the 
observed dose limiting toxicities and efficacy (OATP1B1 inhibition) of the patients who have 
been treated as described in section 11.2.  
 
Dose modification after cycle 1 (and cycle 2 for the dose dense schedule) for paclitaxel will be 
left up to treating physician discretion since patients are no longer on nilotinib.  
 
 
Note: In order to receive weekly paclitaxel during cycle 1 the following criteria must be met: 
 
• 
ANC ≥ 1000/μL 
• 
Platelets ≥ 75,000/μL 
• 
No grade 3 toxicity 
 
If paclitaxel is held for any indication, nilotinib will not be administered.  If nilotinib is held for 
any indication, paclitaxel can be given based on treating physician discretion but the patient will 
need to come off study. In phase 1b, if any dose holds of nilotinib or paclitaxel for any reason 
other than dose-limiting toxicity, happens within the first cycle, will need to discuss with PI 
whether participant needs to be replaced.  
 
In order to initiate nilotinib, the following criteria must be met: 
 
• 
Calcium ≥8.6mg/dL 
• 
Magnesium ≥1.6.dL 
 
If these criteria are not met, treatment must be delayed until toxicity is improved to grade 2 or 
better. Hypokalemia and/or hypomagnesemia must be corrected prior to initiating nilotinib. 
Filgrastim may not be used during cycle 1 or cycle 2 for weekly paclitaxel. For the dose dense 
schedule, standard of care pegfilgastrim will be used to maintain adequate blood counts per 
routine care practice. 
 
For any grade ≥ 2 QTC prolongation or any grade ≥ 2 cardiac event, nilotinib should be held as 
per the United States Prescribing Information for nilotinib, and cardiology should be consulted 
prior to restarting the patient on nilotinib. 
 
 
6.1 Assessment of Dose Limiting Toxicities 
 

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The DLT observation period for this trial will be the first cycle for schedule A and the second 
cycle during schedule B; thus, toxicities observed during the specified DLT period of treatment 
will be used to direct decisions related to dose escalation and ultimately to determine the RP2D. 
Patients who do not complete the first cycle for schedule A and cycle  1 and 2 for schedule B of 
combination treatment for reasons other than toxicity or other treatment-related reasons will not 
be considered evaluable for DLT and will be replaced with another patient at that dose level.   
 
Grading of toxicities will be assessed by the use of Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0. DLTs will consist of any adverse events that are at least possibly 
attributed to nilotinib in the first cycle of phase Ib schedule A and in cycle 2 for schedule B and are 
further defined as follows: 
We acknowledge that the toxicities due to nilotinib and paclitaxel can be similar and any possible 
attribution to nilotinib will count toward DLT determination if it fits definitions below. Further, 
if the adverse event is not a known toxicity specific to paclitaxel and is felt to be at least possibly 
related to treatment, we will conservatively attribute it as possibly related to nilotinib. All adverse 
events of the specified grades will count as DLTs except those that are clearly and incontrovertibly 
due to disease progression or extraneous causes. 
 
Hematologic DLTs 
• 
Grade 4 neutropenia  
• 
Grade ≥ 3 neutropenia, complicated by a fever 
• 
Grade 4 thrombocytopenia 
• 
Grade 3 thrombocytopenia, 
complicated by bleeding 
 
Non-hematologic DLTs 
• 
Any CTCAE version 5.0 Grade ≥ 3 non-hematologic toxicity, unless 
the event is clearly unrelated to treatment -- EXCEPT the following: 
– Grade ≥ 3 nausea, vomiting, or diarrhea that resolves to Grade ≤2 
within 48 hours, with or without medical intervention or prophylaxis. 
– Grade ≥ 3 fatigue lasting for 1 week or longer. 
– Transient (< 14 days) increase in LFTs (of ≤ 1 Grade in severity) 
compared to baseline levels in patients with baseline liver metastases. 
– Grade 3 maculopapular rash for which symptoms are easily managed 
with supportive care and no evidence of superinfection or limitation 
of self-care ADLs. 
– Grade ≥ 3 electrolyte abnormality lasting longer than 72 hours, 
unless the patient has clinical symptoms in which case all grade ≥ 3 
abnormalities regardless of duration. Grade ≥ 3 amylase or lipase 
elevation not associated with symptoms or clinical manifestation of 
pancreatitis do not need to be counted. 
 
Patients with an absolute QTc≥ 500msec, QTc< 320msec, or increase of baseline QTc of > 
60msec. 
 
If, during the DLT observation period, a patient experiences a toxicity that does not 
clearly fit any of the above DLT criteria but in the opinion of the investigator is highly 
clinically significant, the toxicity may be considered a DLT after discussion with the 

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Principal Investigator. 
 
 TREATMENT PLAN 
 
7.1 Treatment Plan and Overview 
 
Eligible patients will be approached by study personnel in the clinics at Stefanie Spielman 
Comprehensive Breast Center. The person obtaining informed consent will tell the patient that 
1) participation is voluntary, 2) participation or non-participation will not affect their usual care 
and management, and 3) patient confidentiality will be maintained in the event that the results 
of the study are published. The potential toxicities associated with nilotinib will be explained 
fully to the patient. Patients will be informed of the need for, blood tests, physical 
examinations, questionnaires prior to entry into the study and at several specified intervals 
during study period. Patients will be provided with a consent form to review, and all questions 
will be answered.  
 
In this phase Ib study, all participants will receive nilotinib during first cycle (Schedule A with 
weekly paclitaxel) and during the second cycle (Schedule B with dose dense paclitaxel).  
 
Schedule A (weekly paclitaxel): On cycle 1 days 1, 8, 15 paclitaxel infusion will be given at a 
dose of 80mg/m2 as shown in Schema. Duration of paclitaxel is for 12 weekly doses unless 
there is a clinical indication to terminate therapy per treating physician.   
 
• On cycle 1 day 7 and day 14, nilotinib will be taken once a day 24 hours before 
paclitaxel infusion. On day 8 and day 15, nilotinib will be taken once a day 30 minutes 
before paclitaxel infusion.  
 
• Clinic visits and or research visits (see calendar) will take place prior to nilotinib 
administration, 24 hour before paclitaxel infusion to ensure that patients are cleared for 
therapy. When no nilotinib is being administered, patients are seen on day of paclitaxel 
infusion.  
 
Schedule B (dose dense paclitaxel): On cycle 1 day 1 paclitaxel infusion will be given at a dose 
of 175mg/m2 every 2 weeks as shown in Schema. Duration of paclitaxel is for 4 doses unless 
there is a clinical indication to terminate therapy per treating physician.   
 
• On cycle 1 day 14, nilotinib will be taken once a day 24 hours before paclitaxel infusion. 
On day 1 cycle 2, nilotinib will be taken once a day 30 minutes before paclitaxel 
infusion.  
 
• Clinic visits and or research visits (see calendar) will take place prior to nilotinib 
administration, 24 hour before paclitaxel infusion to ensure that patients are cleared for 
therapy. When no nilotinib is being administered, patients are seen on day of paclitaxel 
infusion.  
 
Self-report diaries (adverse events, record of study drug doses taken/missed) will be collected, 
and pill count will be recorded by the research coordinator. Medications and supplements will 
be reviewed with participants. A history and physical examination will be performed at 
beginning of each cycle. Study drugs will be dispensed once at the initiation of study protocol 
with enough pills for a cycle of treatment. Pill compliance will be conducted with the start of 

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each cycle through pill counts and pill diaries to ensure proper reconciliation and adherence.  
 
If the patient’s chemotherapy is held, the patients should also hold study medication.  
 
 
7.2 Study Calendar 
 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy. In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 
48 hours prior to initiation of the next cycle of therapy. All study clinic visits starting with cycle 
1, day 1 have +/- 2 day window, unless otherwise noted. Off-treatment follow up will occur at 3 
months and at 6 months after completion of paclitaxel therapy.  Patients removed from study for 
unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse 
event.  (see study calendars, below)

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Study Calendar Phase Ib – Schedule A (weekly paclitaxel) 
 
Pre 
study  
C
1 
D
1 
C1 
D7 
C1 
D8 
C1
D 
14 
C1 
D 
15 
C2 
D1 
C2 
D8 
C2 
D 
15 
C3-4 
D1 
C3-
4 
D8 
C3-4 
D 15 
 (3 
month 
follow up after 
completion of 
paclitaxel) 
6 month follow 
up) 
after 
completion of 
paclitaxel 
Nilotinib 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Paclitaxel 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Informed 
consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent 
Meds 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Physical Exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance 
Status  
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
CBC w/ diff, 
plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum 
chemistry 
magnesium 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
ECG 
(perfomed 
in 
triplicate) 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
Adverse Event 
evaluation by 
CRC 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B-HCG 
for 
premenopausa
l women 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PK studies* 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
CIPN 20 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
 
X 
X 
*Please see section 8.1 for detailed PK schedule 

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Study Calendar Phase Ib – Schedule B (dose dense paclitaxel) 
 
Pre 
study  
C1 
D1 
C1D 
14 
C2D1 
C3D1 
C4D1 
 (3 month follow up 
after 
completion 
of 
paclitaxel) 
6 month follow up) 
after completion of 
paclitaxel 
Nilotinib 
 
 
X 
X 
 
 
 
 
Paclitaxel 
 
X 
 
X 
X 
X 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Concurrent Meds 
X 
X 
X 
 
X 
 
X 
X 
Physical Exam 
X 
X 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
X 
 
 
 
 
 
 
Weight  
X 
X 
X 
X 
X 
X 
X 
X 
Performance Status  
X 
X 
X 
X 
X 
 
X 
X 
CBC w/ diff, plts 
X 
X 
X 
X 
X 
X 
 
 
Serum chemistry magnesium 
X 
X 
X 
X 
X 
 
 
 
ECG (perfomed in triplicate) 
X 
X 
X 
 
 
 
 
 
Adverse Event evaluation by 
CRC 
 
X 
X 
X 
X 
X 
X 
X 
B-HCG for premenopausal 
women 
 
X 
 
 
 
 
 
 
PK studies*(175mg/m2) 
 
X 
X 
X 
 
 
 
 
CIPN 20 
X 
X 
 
X 
X 
 
X 
X 
*Please see section 8.1 for detailed PK schedule 
 
 

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7.3  Adverse Events Associated with Nilotinib and Paclitaxel  
 
 
7.3.1 Adverse Events Reported on Nilotinib Trials  
 
• Blood and lymphatic system disorders: myelosuppression, including grade 3-4 
thrombocytopenia, neutropenia and anemia, serious hemorrhagic events including 
intracranial hemorrhage. 
 
• Cardiac disorders:  QTC prolongation, ischemia, pericardial effusions, hypertension. 
 
• Eye disorders: N/A 
 
• Gastrointestinal disorders: pancreatitis and elevated serum lipase, upper abdominal 
pain, nausea, constipation or diarrhea. 
 
• General disorders and administration site conditions:  fatigue, pyrexia, asthenia, fluid 
retention. 
 
• Hepatobiliary disorders: AST/ALT elevations, hyperbilirubinemia. 
 
• Investigations: elevated lipase, hyperglycemia, elevated bilirubin, elevated ast, elevated 
alt, elevated alkaline phosphatase, elevated lipoprotein cholesterol, elevated total 
cholesterol, elevated blood triglycerides. 
 
• Metabolism and nutrition disorders: hyperglycemia, electrolyte abnormalities, 
including hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia. Nilotinib 
capsules contain lactose. 
 
• Musculoskeletal and connective tissue disorders: myalgias, arthralgias, muscle spasm. 
 
• Nervous system disorders: headache. 
 
• Psychiatric disorders: N/A 
 
• Renal and urinary disorders:  N/A 
 
• Respiratory, thoracic and mediastinal disorders: pleural effusions. 
 
• Skin and subcutaneous tissue disorders: dry skin, alopecia. 
 
• Vascular disorders: peripheral arterial occlusive disease (increased frequency at higher 
doses.  
 
There are no genotoxicity, carcinogenicity, developmental and reproductive studies conducted 
with nilotinib. Women of childbearing potential should not become pregnant or breastfeed and 
men should not father a child during the study. All subjects must use acceptable contraceptive 

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measures during the treatment of nilotinib and 3 months after the last dose of the investigational 
drug. 
 
If a patient is suspected to be pregnant, nilotinib should be IMMEDIATELY discontinued and the 
study physician contacted. A positive urine test must be confirmed by a serum pregnancy test. If 
it is confirmed that the patients is not pregnant, the patient may resume dosing with nilotinib. 
 
If a female patient becomes pregnant during therapy or within 3 months after the last dose of 
nilotinib, or if abortion occurs, whether accidental, therapeutic, or spontaneous, it should always 
be classified as serious. Any congenital anomaly/birth defect in a child conceived during the study 
or within 12 months after the last dose of nilotinib to a female patient within 12 months after the 
last dose of nilotinib should be recorded and reported as an SAE. 
 
• Female patients should not breastfeed a baby while on this study. 
• Female patients must NEVER donate ova while or after being treated with nilotinib. 
 
All patients are prohibited from donating blood while on study and for 12 months after the last 
dose of nilotinib. 
 
For any grade ≥ 2 QTC prolongation or any grade ≥ 2 cardiac event, nilotinib should be held as 
per the United States Prescribing Information for nilotinib, and cardiology should be consulted 
prior to restarting the patient on nilotinib. 
 
7.3.2 Adverse Events Reported for Paclitaxel 
 
Consult the package insert for the most current and comprehensive list of side effects. 
 
• Hematologic: The most common DLT is myelosuppression, primarily leukopenia. 
 
• Anaphylaxis and severe hypersensitivity reactions: Patients with a history of severe 
hypersensitivity reactions to products containing Cremophor® EL (e.g., cyclosporin for 
injection concentrate and teniposide for injection concentrate) should not be treated with 
paclitaxel. In order to avoid the occurrence of severe hypersensitivity reactions, all 
patients treated with paclitaxel should be premedicated with corticosteroids (such as 
dexamethasone), diphenhydramine and H2 antagonists (such as famotidine or ranitidine). 
Since most of these reactions occur during the first 2 infusions, discontinuation of these 
premedications may be a consideration at the discretion of the treating physician. Minor 
symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not 
require interruption of therapy. However, severe reactions, such as hypotension requiring 
treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria 
require immediate discontinuation of paclitaxel and aggressive symptomatic therapy. 
Patients who have developed severe hypersensitivity reactions should not be re-
challenged with paclitaxel. 
 
• Cardiac: Cardiovascular events observed with paclitaxel include hypotension and 
bradycardia. Severe conduction abnormalities have been documented in < 1% of patients 
during Paclitaxel therapy and in some cases requiring pacemaker placement. If patients 
develop significant conduction abnormalities during paclitaxel infusion, appropriate 

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therapy should be administered and continuous cardiac monitoring should be performed 
during subsequent therapy with paclitaxel. 
 
• Neurologic: The frequency and severity of neurologic events are dose-dependent. 
Peripheral neuropathy is rarely severe and may be the cause of paclitaxel discontinuation 
in 1% of patients. Sensory symptoms usually improve or resolve within several months 
of completion of treatment. Serious neurologic events such as grand mal seizures, 
syncope, ataxia and neuroencephalopathy are rare. Although the occurrence of peripheral 
neuropathy is frequent, the development of severe symptomatology is unusual and 
requires a dose reduction of 20% or greater for all subsequent courses of paclitaxel. 
 
• Gastrointestinal: The most common GI toxicities, which include nausea, vomiting, 
diarrhea and mucositis, are typically mild or moderate in severity. These respond well to 
supportive care with anti- emetics such as prochlorperazine, anti-diarrheal agents such as 
loperamide and topical analgesics for mucositis. Weekly administration of paclitaxel at 
80 mg/m2 is rarely associated with nausea/vomiting and antiemetic pre-medication is 
generally not needed prior to infusion. If patient experience significant nausea/vomiting 
during or post-infusion, appropriate antiemetic(s) may be added as prophylaxis prior to 
infusion at the treating physician’s discretion. 
 
• Injection Site Reaction: Injection site reactions, including reactions secondary to 
extravasation, were usually mild and consisted of erythema, tenderness, skin 
discoloration, or swelling at the injection site. These reactions have been observed more 
frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin 
reactions at a site of previous extravasation following administration of paclitaxel at a 
different site, i.e., ―recall‖, has been reported rarely. Rare reports of more severe events 
such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been 
received as part of the continuing surveillance of paclitaxel safety. In some cases the 
onset of the injection site reaction either occurred during a prolonged infusion or was 
delayed by a week to ten days. Given the possibility of extravasation, it is advisable to 
closely monitor the infusion site for possible infiltration during drug administration. If 
extravasation is discovered or the patient develops localized infusion reaction the 
following cold compression protocol is recommended: 
 
o Immediately after medical treatment is completed, apply ice pack to the affected 
for 15-20 minutes at least 4 times per day for the first 24-48 hours by any of the 
following means: 
 Cool wash cloth 
 Instant cool/ice pack 
o The limb should be elevated at all times and exercised at least every 4-6 hours to 
reduce immobility. 
 
• Other: Although 60% of all patients experience arthralgia and myalgia, there is no 
consistent relationship between the dose or schedule of paclitaxel and the frequency or 
these events. The symptoms, which usually begin 2 or 3 days after paclitaxel treatment, 
are generally transient. Almost all patients receiving paclitaxel experience alopecia. Nail 
changes (changes in pigmentation or discoloration of nail bed; lifting of the nails) are 
uncommon with frequency of about 2%. Occasionally, edema is seen at a rate of about 

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5%. It is usually of mild severity and gradually reversible following discontinuation of 
paclitaxel. 
 
• Pregnancy: Paclitaxel can cause fetal harm when administered to a pregnant woman. 
Administration of paclitaxel during the period of organogenesis to rabbits at doses of 3.0 
mg/kg/day (about 0.2 the daily maximum recommended human dose on a mg/m2 basis) 
caused embryo and fetotoxicity, as indicated by intrauterine mortality, increased 
resorptions, and increased pregnancy loss. There are no adequate and well-controlled 
studies in pregnant women. If paclitaxel is used during pregnancy, or if the patient 
becomes pregnant while receiving this drug, the patient should be apprised of the 
potential hazard to the fetus. Women of childbearing potential should be advised to avoid 
becoming pregnant. 
 
• Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of 
paclitaxel has not been studied. Paclitaxel has been shown to be clastogenic in vitro 
(chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). 
Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay. 
Administration of paclitaxel prior to and during mating produced impairment of fertility 
in male and female rats at doses equal to or greater than 1 mg/kg/day (about 0.04 the daily 
maximum recommended human dose on a mg/m2 basis). At this dose, paclitaxel caused 
reduced fertility and reproductive indices, and increased embryo- and fetotoxicity. 
 
 
7.3.3 Management of QTC prolongation during study 
For participants who have a QTC greater than 480 msec while receiving nilotinb, the 
following measures are required: 
 
1) Withhold nilotinib, and perform an analysis of serum potassium and magnesium, 
and if below lower limit of normal, correct with supplements to within normal 
limits.  Concomitant medication usage must be reviewed 
2) Resume within 14 days at prior dose if QTc returns to less than 450msec and to 
within 20msec of baseline.  Repeat ECG in triplicate with weekly dosing of 
nilotinib 
3) Discontinue nilotinib and end study participation if QTc remains elevated to 
greater than 480msec after 14 days drug hold 
 
Patients who have a marked baseline prolongation of QT/QTc interval (e.g., repeated 
demonstration of a QTc of > 450msec) or a history of additional risk factors for TdP 
(e.g., heart failure, hypokalemia, family history of Long QT Syndrome) will be excluded 
from study. Patients with an absolute QTc≥ 500msec, QTc< 320msec or increase of 
baseline QTc of > 60msec will discontinue treatment but will still be followed.  
 
 
 CORRELATIVE STUDIES 
 
The focus of this trial will be an assessment of safety, tolerability and determination of a 
recommended future phase II dose of the study regimen. The future phase II component of the 
trial will ascertain the efficacy of nilotinib vs placebo in preventing paclitaxel-related 

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neuropathy. Correlatives for the trial are as follows:  
 
The effect of nilotinib on pharmacokinetics (PK) of paclitaxel and the effect of paclitaxel on PK 
of nilotinib will be evaluated to ensure that these agents do not have clinically significant 
interactions.  We will evaluate real time PK data to ensure that there is no adverse negative effect 
on paclitaxel PKs. We will assess all patient data for the first 6 patients before proceeding, to 
ensure that all PKs are within expected level of no interaction between the two drugs.  
 
8.1 Integrated Correlative Studies: PK of Nilotinib and Paclitaxel 
 
The effect of nilotinib on the PK of paclitaxel, as well as the effect of paclitaxel on the PK of 
nilotinib will be studied.  
 
Based on our recent preclinical experience of nilotinib given in combination with paclitaxel, we 
anticipate that nilotinib will not affect the disposition profile of paclitaxel and vice versa. The 
expectation that nilotinib is unlikely to influence the pharmacokinetics of paclitaxel would be 
consistent with previously reported studies confirming that other OATP1B1-inhibiting TKIs 
identified from our screens, such as axitinib, and sorafenib, do not alter the systemic exposure to 
paclitaxel. The noted NCI study confirmed our preclinical anticipation, there were no observed 
adverse PK interactions between nilotinib and paclitaxel. Although the drug-drug interaction in a 
clinical setting is highly unlikely, we will perform real-time PK analyses for both paclitaxel, 
nilotinib and in combination for parent and metabolites. 
 
The PK assessments of nilotinib and paclitaxel are summarized below. 
 
8.1.1 Schedule for collection of specimen(s): 
 
During the Phase Ib trial, PK will be obtained at baseline (within 15 min of pre-dose), during drug 
administration (within 5 min of the end of infusion), and at 4 defined time-points ranging up to 
4.5 hours after drug administration, for up to 6 blood withdrawals for paclitaxel. The PK of 
nilotinib will be measured at pre- and post-dose for a total of 7 blood samplings. The PK of both 
paclitaxel and nilotinib will be assessed prior to administration of nilotinib, prior to administration 
of paclitaxel, during the administration of paclitaxel, and at 3 defined time-points ranging up to 
2.5 hours after paclitaxel administration, for up to 7 blood samplings for combination treatment.  
 
For Schedule A: weekly dose of 80mg/m2 paclitaxel 
• The PK of paclitaxel will be measured on Day 1 (paclitaxel given as a single agent) at the 
following times: 
 
• Pre-dose (within 15 min) 
• Immediately prior to end of infusion of paclitaxel (within 5 min) 
• 0.5 hour after end of infusion (±5 min) 
• 1.5 hour after end of infusion (±5 min) 
• 2.5 hours after end of infusion (±5 min) 
• 4.5 hours after end of infusion (±5 min) 
 
• The PK of nilotinib will be measured during Day 7. Nilotinib is given as a single agent, 24 
hours prior to paclitaxel infusion at following times: 

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• Pre-dose (within 15 min) 
• 0.5 hour after taking the pill (±5 min) 
• 1.5 hour after taking the pill (±5 min) 
• 2 hours after taking the pill (±5 min) 
• 3 hours after taking the pill (±5 min) 
• 4 hours after taking the pill (±10 min) 
• 6 hour after taking the pill (±10 min) 
 
• The PK of nilotinib and paclitaxel will be measured on Day 8. Nilotinib given 30 min before 
paclitaxel infusion at the following times: 
 
• Pre-dose of nilotinib (within 15 min) 
• Prior to starting paclitaxel infusion (within 5 min) 
• Immediately prior to end of infusion of paclitaxel (within 5 min) 
• 0.5 hour after end of paclitaxel infusion (±5 min) 
• 1.5 hours after end of paclitaxel infusion (±5 min) 
• 2.5 hours after end of paclitaxel infusion (±5 min) 
• 4 hours after end of paclitaxel infusion (±10 min) 
 
For Schedule B: Every two weeks dose dense of 175mg/m2 paclitaxel 
• The PK of paclitaxel will be measured on Day 1 (paclitaxel given as a single agent) at the 
following times: 
 
• Pre-dose (within 15 min) 
• 1.5 hour after infusion of paclitaxel (within 5 min)  
• Immediately prior to end of infusion of paclitaxel (within 5 min) 
• 0.5 hour after end of infusion (±5 min) 
• 1.5 hour after end of infusion (±5 min) 
• 2.5 hours after end of infusion (±5 min) 
 
• The PK of nilotinib will be measured during Day 14, nilotinib is given as a single agent, 24 
hr prior to paclitaxel infusion at following times: 
 
• Pre-dose (within 15 min) 
• 0.5 hour after taking the pill (±5 min) 
• 1.5 hour after taking the pill (±5 min) 
• 2 hours after taking the pill (±5 min) 
• 3 hours after taking the pill (±5 min) 
• 4 hours after taking the pill (±10 min) 
• 6 hour after taking the pill (±10 min) 
 
• The PK of nilotinib and paclitaxel will be measured on Cycle 2 Day 1, nilotinib is given 30 
min before paclitaxel infusion at the following times: 
 
• Pre-dose of nilotinib (within 15 min) 
• Prior to starting paclitaxel infusion (within 5 min) 
• 1.5 hour after infusion of paclitaxel (within 5 min) 

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• Immediately prior to end of infusion of paclitaxel (within 5 min) 
• 0.5 hour after end of paclitaxel infusion (±5 min) 
• 1.5 hours after end of paclitaxel infusion (±5 min) 
• 2.5 hours after end of paclitaxel infusion (±5 min) 
 
8.1.2 Procedure for collection of specimen(s): 
 
Samples should be collected via a peripheral blood draw in the contralateral arm to the infusion. 
In the event when a patient has poor venous access and has an existing and functional central 
venous catheter, sampling through the central line is acceptable. Patients without venous access 
will be allowed to have a port placed prior to initiation of study therapy per discretion of the 
treating physician. Patients without a port will have an option of having a central line inserted 
during treatment visits, especially on days that require timed blood draws. Each sample will be 
collected into a 6-mL lithium heparin (green top) vacutainer tube. Immediately after collection, 
the tube is inverted 8-10 times to ensure proper mixing and place tube on ice until centrifugation. 
The PK specimen will then be centrifuged at 1,200 xg for 10 min at 4°C within 1 hour of sample 
collection. The plasma layer will be transferred into three (3) 2-mL cryovials in roughly equal 
proportions and frozen immediately at (-70) oC.  An accompanied PK requisition form must be 
completed for each course of PK sampling. A copy of the completed form must be included with 
the shipment of the samples for analysis. 
 
8.1.3 Procedure for analysis of specimen(s): 
 
We anticipate that OATP1B1 function can be modulated by nilotinib without simultaneously 
influencing the systemic clearance of paclitaxel. This would be consistent with our prior work 
indicating that the plasma concentration-time profiles of paclitaxel are inversely related to 
corresponding drug levels in liver, and that the presence of Kolliphor EL in the clinical paclitaxel 
formulation is the main determinant of drug disposition properties, and that this excipient masks 
an effect of OATP1B-type transporters on paclitaxel levels in plasma. This hypothesis will be 
prospectively tested in all patients enrolled on the Phase 1b study by evaluating the plasma 
pharmacokinetics of paclitaxel when given either alone or with nilotinib. Plasma samples will be 
analyzed in real time for paclitaxel and its main liver metabolites by LC/MS/MS in the laboratory 
of Dr.  Shuiying Hu in the College of Pharmacy. In addition, we anticipate that paclitaxel will not 
alter the absorption and distribution profiles of nilotinib, considering that the principal elimination 
pathway of nilotinib, CYP3A4-mediated metabolism, is insensitive to inhibition by paclitaxel. To 
confirm this hypothesis, plasma samples will be also analyzed for nilotinib by UPLC/MS/MS. All 
pharmacokinetic parameters will be calculated using standard non-compartmental methods. 
 
8.1.4 Procedure for banking of specimen(s): 
 
After samples are analyzed, any unused, leftover samples will be retained to allow for other 
biomarker analysis in the future as the pre-clinical research progresses. Samples will be stored 
indefinitely in -70 oC freezers in the laboratory of Dr. Shuiying Hu, 460 12th Ave, 436D BRT, 
Columbus, OH, 43210. No genetic testing will take place on leftover samples. 
 
8.2 Integrated Correlative Studies: Biomarkers of OATP1B1 
 
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glycochenodeoxycholate sulfate (GCDGA-S) and chenodeoxycholate-24-glucuronide (CDCA-
24G) levels will be performed as validated surrogate endogenous substrates of OATP1B. Previous 
clinical studies have indicated that the AUC of GCDCA-S can be increased >20-fold following 
treatment with OATP1B1 inhibitors, whereas CDCA-24G is only detectable after the 
administration of OATP1B1 inhibitors. Based on our preclinical studies, we expect that the 
administration of nilotinib will result in dose-dependent changes in levels of GCDAGA-S and 
CDCA-24G caused by inhibition of OATP1B1. With recent significant progress in the 
identification of endogenous OATP1B1 biomarkers, we will measure newly emerged biomarkers 
with higher selectivity and sensitivity, such as CP-I, CP-III, as well as α-tocopherol which can 
serves as a bona fide DRG-specific endogenous biomarker of OATP1B-type transporter function. 
This will be done using the same plasma samples already collected for paclitaxel and nilotinib 
analyses during the phase Ib, and provide more reliable prediction of nilotinib inhibition of 
OATP1B transporter function. Within each cohort of patients, plasma samples obtained at 
baseline and at timed-intervals after the first nilotinib dose will be collected and subjected to 
LC/MS/MS in a negative multiple reaction monitoring mode to quantify concentrations of the test 
compounds. Concentrations of total and unbound nilotinib will also be determined in the same 
samples by validated assays based on LC/MS/MS and micro-equilibrium dialysis, respectively. 
This information will be utilized to confirm that plasma levels of nilotinib associated with the 
applied test doses are in the anticipated ranges and are consistent with the inhibition constant of 
nilotinib for OATP1B1 derived from cell culture studies. 
 
 ADVERSE EVENT REPORTING 
 
Adverse event: Any unfavorable and unintended sign (including abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure, 
regardless of whether it is considered related to the medical treatment or procedure; also an 
“unanticipated problem” of any nature (e.g., psychological or social harm) (designated as 
unrelated, definitely related, probably related, or possibly related; see below) 
 
Serious adverse event: Any adverse event that is fatal or life threatening, is permanently disabling, 
requires inpatient hospitalization or prolongs hospitalization, or results in a congenital anomaly 
or birth defect. 
 
Life-threatening event: Any adverse event in which the subject is at immediate risk of death from 
the reaction as it occurs; does not include a reaction that, if it were to occur in a more serious 
form, might cause death 
 
Unexpected event: Any adverse event that is not identified in nature, severity, or frequency in the 
investigator brochure, study protocol, consent form, or IND application; or the event was more 
serious than anticipated.  
 
 
 
9.1 Attribution of the Adverse Events 
 
Definite:  AE is CLEARLY RELATED to the study treatment.  
Probable: AE is LIKELY RELATED to the study treatment. 
Possible: AE MAY BE RELATED to the study treatment.  

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Unlikely: AE is DOUBTFULLY RELATED to the study treatment. 
Unrelated: AE is CLEARLY NOT related to the study treatment 
 
9.2 Documentation  
 
CTCAE version 5.0 will be utilized for AE reporting. All appropriate treatment areas should have 
access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
For expedited reporting purposes only: 
 
• AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
 
All adverse events must be documented in detail within the medical record. The patient will be 
observed and monitored carefully until the condition resolves, stabilizes, or its cause is identified. 
All adverse events, including laboratory abnormalities, will be followed up according to good 
medical practices. Information to be recorded includes the following: 
 
1. Specific type of reaction. 
2. Duration of reaction. 
3. Severity/grade of reaction according to the NCI Common Terminology Criteria for 
Adverse Events v5.0 (CTCAE). 
4. Suspected cause of the reaction (i.e. possibly or probably related to one of the 
following: study intervention, progression of disease, concurrent medications, 
concurrent illness, or other factors). 
5. Patient’s response to medical interventions. 
 
9.3 Reporting  
 
Adverse events during standard chemotherapy are not attributable to study intervention (gait and 
balance assessment) and therefore not subject to reporting. However, they will be collected in 
order to evaluate associations with gait and balance deficits. Since it is difficult to discern which 
AEs may impact gait and balance testing, all AEs will be collected, not just neuropathy symptoms. 
Although unlikely, some unrelated symptoms may impact gait and balance and may also be 
indirectly related to neuropathy symptoms (e.g. cytopenias and fatigue may impact balance and 
gait).  
 
 
 DATA REPORTING / REGULATORY REQUIREMENTS 
 
10.1 Ethical and Regulatory Considerations 
 
This trial will be conducted in compliance with the protocol, Good Clinical Practice guidelines, 
and all applicable regulatory requirements. 
 
10.2 Institutional Review Board 
 

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The Principal Investigator will have obtained written approval to conduct the study from The 
Ohio State University IRB and the Clinical Scientific Review Committee of the James Cancer 
Hospital and Solove Research Institute. All amendments must be approved by the Institutional 
Review Board of The Ohio State University prior to implementation. 
 
10.3 Informed Consent 
 
All potential candidates for the study will be given a copy to read of the consent form for the 
study. The Principal Investigator and/or designee will explain all aspects of the study in lay 
language and answer all the candidate’s questions regarding the study. If the candidate desires to 
participate in the study, she will be asked to sign the Informed Consent. The study agent will not 
be released to a subject without a signed Informed Consent. Elements of informed consent include 
explanations of 1) the purpose of the trial, 2) what the study entails, 3) alternate treatments, 4) 
expenses and inconveniences to be incurred, 5) discomfort and risks to the subject, 6) whether she 
will receive payment for participation in the study, 7) contact person to call in the event of an 
emergency, 8) subject rights as a result of illness or injury from trial participation, 9) subjects 
right to withdraw from the trial at any time without prejudice, 10) confidentiality of trial 
participation. 
 
10.4 Patient Confidentiality  
 
The information obtained during the conduct of this study is considered confidential and will not 
be released without the written permission of the subject, except as necessary for monitoring by 
the FDA or other regulatory agencies. All laboratory specimens will be labeled with coded 
identifiers in order to maintain confidentiality. Signed consent forms, data sheets, and laboratory 
notebooks will be kept in locked cabinets in Dr. Nicole Williams’ office and/or research 
laboratories. 
 
10.5 Publication and Research Findings 
 
Publications of the research findings will present data in a format that will not reveal the identity 
of the participants. 
 
10.6 Compliance Monitoring 
 
In accordance with IRB guidelines, the study program will be reviewed by the IRB every 12 
months or less. Deviations from the protocol must be documented in the medical record and 
reported immediately to the PI. Deviations that meet the criteria for Immediate Event Reporting 
(http://orrp.osu.edu/irb/event/index.cfm) such as those that increase risks to subjects and/or 
compromise scientific integrity will be reported immediately to the IRB. 
 
10.7 Data Safety Monitoring 
 
The data and safety monitoring plan will involve the continuous evaluation of safety, data quality 
and data timeliness. Investigators will conduct continuous review of data and patient safety at 
their regular Disease Group meetings (at least monthly) and the discussion will be documented in 
the minutes. The PI of the trial will review toxicities and responses of the trial where applicable 
at these disease center meetings and determine if the risk/benefit ratio of the trial changes. 
Frequency and severity of adverse events will be reviewed by the PI and compared to what is 

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known about the agent/device from other sources; including published literature, scientific 
meetings and discussions with the sponsors, to determine if the trial should be terminated before 
completion. Serious adverse events and responses will also be reviewed by the OSUCCC Data 
and Safety Monitoring Committee (DSMC). The PI will also submit a progress report biannually 
that will be reviewed by the committee per the DSMC plan. All reportable Serious Adverse Events 
(SAE) will also be reported to the IRB of record as per the policies of the IRB. 
 
10.8 Responsibility for Data Submission  
 
Data are to be submitted via OnCore on a real-time basis, but no less than once every 2 weeks. 
 
10.9 Data and Records 
 
Primary source documents will include forms routinely used at the Stefanie Spielman 
Comprehensive Breast Center, namely the Breast Patient Information Form, clinic and office 
notes as well as laboratory and radiology reports, including documentation found in the 
electronic medical record (EPIC). 
 
10.10 Safety and Monitoring 
 
Adverse events will be monitored by self-reporting of signs and symptoms. Patients will 
maintain a daily diary of time of drug intake and any possible ill effects, with instructions to 
contact the PI or Research Nurse to discuss and manage any possible side effects. 
 
10.11 Accountability 
 
Study drug, nilotinib, will be provided at no cost to the patient. Pill bottles will be provided to 
the patient, with the start date and number of pills recorded. The drugs will be provided in 
sufficient supply for one cycle of taxane chemotherapy. Pill bottles will be collected at each 
cycle’s follow-up visits, and any unused capsules will be documented and counted to ensure 
proper adherence. The pill bottle will be returned to the patient after pill reconciliation until 
the end of study protocol. Additionally, there will be no charge for research-related blood work. 
Imaging is considered as part of standard of care testing. 
 
10.12 Documentation  
 
All adverse events must be documented in detail within the medical record. The patient will be 
observed and monitored carefully until the condition resolves, stabilizes, or its cause is identified. 
All adverse events, including laboratory abnormalities, will be followed up according to good 
medical practices. Information to be recorded includes the following: 
1. Specific type of reaction.  
2. Duration of reaction. 
3. Severity/grade of reaction according to the NCI Common Terminology Criteria for 
4. Adverse Events 5.0 (CTCAE). 
5. Suspected cause of the reaction (i.e. possibly or probably related to one of the following: 
study treatment, progression of disease, concurrent medications, concurrent illness, or 
other factors).  
6. Changes made in the administration of the study drugs and other actions taken to 
alleviate the clinical event.  

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7. Patient’s response to medical interventions. 
 
10.13 Reporting  
 
According to FDA regulations (21 CFR 312.32), IND safety reports shall address “any adverse 
experience associated with the use of a drug that is both serious and unexpected.” The IRB will 
be notified of any adverse event that occurs on the study regardless of severity. 
 
 
Federal policy [45 CFR 46.116(b)(5)] also requires that investigators inform subjects of any 
important new information that might affect their willingness to continue participating in the 
research. When an adverse event necessitates changes to the consent/assent form(s) and/or 
protocol, or that notification is given to currently or previously enrolled subjects, an amendment 
request will be submitted in conjunction with the adverse event report. The IRB will make a 
determination whether any new findings, new knowledge, or adverse effects should be 
communicated to subjects. 
 
In accordance with IRB guidelines, serious adverse events will be reported within 10 days of the 
investigator’s or research staff members’ learning of the event to The Ohio State University 
Institutional Review Board. OSU IRB Event Reports should be submitted through BuckIRB at: 
http:/orrp.osu.edu/irb/buck-IRB/. Events resulting in temporary or permanent interruption of 
study activities by the investigator or sponsor to avoid potential harm to subjects should be 
reported within 48 hours whenever possible. In addition, all adverse events regardless of severity 
will be reported in the same manner within 10 calendar days of the investigator’s or research staff 
members’ learning of the event. 
 
All events that may represent unanticipated problems involving risks to subjects or others will be 
promptly reported (as described above), regardless of whether they occur during or after the study, 
or involve a subject who has withdrawn from or completed study participation. If changes to the 
research or consent process are proposed as a result of the event or if additional information will 
be provided to current and/or past participants, an amendment request will also be submitted for 
IRB review. In addition, all adverse events regardless of grade will be reported as per the FDA 
reporting requirements below (21 CFR Part 312) including Grade 1 and Grade 2 events, which 
will be reported within 10 calendar days whether participants were hospitalized or not. 
 
Related events involving risk but not meeting the prompt reporting requirements will also be 
reported to the IRB in summary form at the time of continuing review. 
 
Phase I Studies: Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 
 
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 

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             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 
              ) 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 electronic submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframe 
Grade 3-5 Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
 
Not resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
 
 
Not required 
 
 
24 hour 5 calendar days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
     o “24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically 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 electronically 
within 10 calendar days of learning of the AE. 
Serious 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 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
Effective Date: May 5, 2011 
 
 
 
STATISTICAL CONSIDERATIONS 
 
11.1 Study endpoints 
 
Definition of Primary Endpoint 
 
• Safety, tolerability and RP2D of nilotinib in combination with paclitaxel.  
 
Definition of Secondary Endpoints 
 
• PK endpoints such as AUC, CL, Vd, and t1/2 for nilotinib and paclitaxel. 

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• Quality of life using CIPN-20 questionnaire, disease-free survival (DFS), event 
free survival (EFS) and overall survival (OS) of nilotinib in combination with 
paclitaxel.  
 
 
11.2 Study Design and Sample Size Calculation 
 
The primary objective of the Phase 1b study is to obtain data to support the selection of an optimal, 
safe nilotinib dose that can temporarily inhibit the function of OATP1B1 in patients with breast 
cancer without affecting the plasma pharmacokinetics of paclitaxel. The proposed study design is 
derived from an adaptive Bayesian method for dose-finding based on trade-offs between the 
probabilities of treatment efficacy and toxicity (EffTox). In this design, treatment efficacy is 
defined as statistically significant inhibition of OATP1B1 activity by nilotinib, without causing 
changes in the pharmacokinetic profiles of paclitaxel. Tolerability of the combination regimen 
will be evaluated within the first 4 weeks of treatment (cycles 1 & 2). Doses are selected for 
successive patient cohorts based on a set of efficacy-toxicity trade-off contours that partition the 
two-dimensional outcome probability domain. Priors are established by solving for hyper-
parameters that optimize the fit of the model to elicited mean outcome probabilities. Published 
studies have demonstrated that, under a wide range of dose-outcome scenarios, the EffTox method 
has high probabilities of making correct decisions as compared to classic dose-escalation studies 
such as the ‘3+3 Design’ in which the assessment is mainly based on establishing the dose levels 
associated with dose-limiting toxicity (DLT). Moreover, the EffTox method allows treatment of 
most patients at doses with desirable efficacy-toxicity trade-offs. In the proposed Phase 1b study, 
the maximum sample size will be 20 with cohort size of 2. A total of 4 nilotinib dose levels will 
be considered, including 50 mg (dose level -1), 100 mg (dose level 1), 200 mg (dose level 2), and 
300 mg (dose level 3), with the goal to find an optimal dose.  
 
During the proposed EffTox Phase 1b study, both efficacy and toxicity will be monitored and 
these data used to iteratively inform the dynamic, adaptive model to make dose escalation or de-
escalation decisions. Efficacy in this setting will be OATP1B1 inhibition as defined by a ≥5-fold 
increase in the AUC of GCDCA-S from pre- to post-treatment and/or detectable CDCA-24G 
levels post-treatment; although preliminary data in other populations suggest a potentially much 
larger effect, a 5-fold increase would be sufficiently large to indicate effective inhibition.  
 
We specified prior distributions and threshold probabilities of efficacy and toxicity for this model; 
the maximum allowable probability of toxicity will be 0.33, the minimum probability of efficacy 
will be 0.90, and cut-offs of 0.10 will be used for both stopping probability criteria. The maximum 
sample size will be 20 with cohort size of 2. The first cohort of patients will be enrolled at dose 
level 1 (nilotinib 100 mg). After each cohort is treated and evaluated for toxicity and efficacy as 
defined in the context of this trial, these data will inform our dynamic, adaptive model to 
determine dose escalation decisions based on changes to estimated probabilities for toxicity and 
for efficacy given the data observed. Then next cohort of patients will be treated on the dose level 
determined from the Bayesian adaptive model. This iterative process is repeated until the 
maximum sample size or pre-defined stopping criteria are reached.  For this phase 1b study, our 
primary objective is to select an optimal, safe nilotinib dose that can temporarily inhibit the 
function of OATP1B1 in patients with breast cancer without affecting the plasma 
pharmacokinetics of paclitaxel. We are interested in both toxicity (DLT) and efficacy (OATP1B1 
inhibition). The traditional 3+3 design can determine the MTD only accounting for the associated 

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DLTs at each dose level, but could not determine the optimal dose level using both toxicity and 
efficacy. Therefore, an adaptive Bayesian method for dose-finding based on trade-offs between 
the probabilities of treatment efficacy and toxicity (EffTox) will be used. 
 
After all evaluable patients have been treated, the recommended dose for the phase II will be the 
highest dose level that satisfies those two EffTox dose acceptability rules (dose has acceptable 
toxicity if Prob[prob (Toxicity) < 0.33|data] ≥ 0.1;  dose has acceptable efficacy if 
Prob[proc(Efficacy) <.90|data)≥0.1). A feature of this study design is that we are not bound to 
start our dosing at the lowest dose but rather an expected effective dose; thus, the first cohort will 
be treated at dose level 1 (100 mg). Assessment of OATP1B1 inhibition and paclitaxel plasma 
levels will be performed within one week of sample collection to avoid delays in enrollment of 
patients on subsequent dose levels. These models will identify admissible sets of doses, where a 
modification will be that no untested doses will be skipped during dose escalation. The prior 
hyper-parameters will be computed based on the assumed prior means Prob(Toxicity | dose) = 
{0.02, 0.04, 0.06, 0.08}, and Prob(Efficacy | dose) = {0.2, 0.4, 0.6, 0.8}, for each of the 4 nilotinib 
dose levels, respectively, with the overall prior effective sample size (ESS) of 1. Simulations are 
carried out using EffTox version 5.0.0, with 2000 replications per scenario, and the operating 
characteristics of this design are summarized in Table 4 If it is highly likely (ie, probabilities 
>0.90) that more than one dose is associated with acceptable rates of efficacy and toxicity, the 
next cohort of patients will be treated at the dose associated with the stronger degree of OATP1B1 
inhibition. The trial will be conducted using EffTox Software (version 5.0.0) developed by MD 
Anderson. Adverse events will be classified and attributed using NCI-CTCAE v5.0 and will be 
summarized within and across dose levels. 
 
Table 4: Operating characteristics of the EffTox study design planned, where PT is the probability 
of toxicity and PE is the probability of efficacy 
 
 
11.3 Statistical Data Analysis 
Scenario Model 
characteristics 
Nilotinib dose level 
-1 (50 mg) 
1 (100 mg) 
2 (200 mg) 
3 (300 mg) 
None 
1 
True PT, PE 
0.02, 0.20 
0.04, 0.40 
0.06, 0.80 
0.08, 1.00 
-- 
Utility (trade-off) 
-3.02 
-2.04 
-0.10 
0.73 
-- 
% selected 
0 
0 
7 
93 
0 
# patients treated 
0.0 
2.0 
3.3 
14.6 
-- 
2 
True PT, PE 
0.05, 0.10 
0.10, 0.50 
0.15, 0.85 
0.33, 0.95 
-- 
Utility (trade-off) 
-3.55 
-1.64 
-0.07 
-0.22 
-- 
% selected 
0 
0 
45 
48 
7 
# patients treated 
0.0 
2.1 
8.1 
9.0 
-- 
3 
True PT, PE 
0.01, 0.50 
0.10, 0.70 
0.20, 0.90 
0.50, 1.00 
-- 
Utility (trade-off) 
-1.51 
-0.66 
0.00 
-0.67 
-- 
% selected 
0 
4 
83 
8 
6 
# patients treated 
0.0 
2.9 
12.8 
3.7 
-- 
4 
True PT, PE 
0.01, 0.70 
0.20, 0.80 
0.30, 1.00 
0.60, 1.00 
-- 
Utility (trade-off) 
-0.51 
-0.43 
0.00 
1.00 
-- 
% selected 
0 
30 
62 
0 
8 
# patients treated 
0.1 
6.2 
11.7 
1.1 
-- 

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Adverse events (AEs) will be classified and attributed using NCI CTCAE v5.0 and will be 
summarized within and across dose levels using descriptive statistics. The overall number and 
percentage of patients experiencing AEs and toxicities will be summarized and reported as across 
all event types, non-hematologic AEs, hematologic AEs, and for each type. Specific focus will be 
in summarizing any neuropathy-related AEs by dose level and how this corresponds to our 
measures of OATP1B1 inhibition. All patients who have received at least one dose of the 
therapeutic agents will be evaluable for toxicity and tolerability. 
 
Overall response rate (partial response + complete response) will be summarized and 95% exact 
binomial confidence interval will be provided.  Progression Free Survival (PFS) will be defined 
as the time from initiation of therapy to the time of RECIST progression or death.  Overall 
Survival (OS) will be defined as time from initiation of therapy to death.  Event free survival 
(EFS) will be defined as time from initiation to breast cancer disease progression. Survival will 
initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% 
CI.  Survival will be further modeled using Cox proportional hazards models resulting in HRs 
with 95% CI, allowing for adjustment for critical covariates such as age, gender, race/ethnicity.    
 
We will explore PK endpoints such as AUC, CL, Vd, and t1/2 computed using non-
compartmental and compartmental methods.  Our 6 hour PK sampling schedule is sufficient to 
provide complete PK profile to characterize for the rest of parameters, based on well-established 
PK profile for both paclitaxel and nilotinib. We will use graphical analyses as well as repeated 
measure models (linear or nonlinear mixed models, generalized estimating equations [GEE]) to 
assess the PK and PD markers described above in relation to clinical treatment outcomes, 
recognizing some inherent limitations due to sample size. 
 
 
 
 
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