Conditions: Squamous Cell Carcinoma of the Head and Neck
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
This study will be a prospective, single-institution, single-arm phase II study of Axitinib in patients with unresectable recurrent and metastatic head and neck squamous cell carcinoma. The subjects will be started on treatment with 5 mg of Axitinib twice a day continuously, with subsequent dose escalation to 7 mg and then 10 mg twice a day in the absence of grade 2 or worse toxicities. This will be followed by clinical and/or radiologic response assessment after 8 weeks and subsequently every 2 months until disease progression or intolerable toxicity.

Detailed description:

Arms:
arm 1: Participants will receive 5 mg of Axitinib twice a day continuously, with subsequent dose escalation to 7 mg and then 10 mg twice a day in the absence of grade 2 or worse toxicities

Interventions: intervention 1: Axitinib
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
1
UMCC 2016.040: Phase II Expansion Trial Evaluating Axitinib in Patients 
with Unresectable Recurrent, or Metastatic Head and Neck Cancer utilizing 
Choi Response Criteria 
Version 7.0 
03/15/2019 
Principal Investigators: 
PI: Paul Swiecicki, M.D. 
Co-Investigators & Consultants 
Medical Oncology: 
Co-PI: Francis P. Worden, M.D. 
Susan Urba, M.D. 
Otolaryngology: 
Thomas Carey, Ph.D. 
Research Staff 
Nurse Coordinators: 
Heidi Mason, N.P-C, M.S.N., O.C.N. 
Mary Beth DeRubeis, NP-C, M.S.N., 
O.C.N.
Leah Shults, RN, B.S.N., O.C.N.
Terri Jobkar, RN, B.S.N., O.C.N
Shantel Musser, RN, B.S.N
Statistician: 
Emily Bellile, M.S. 
NCT02762513


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
2 
 
 
TABLE OF CONTENTS 
1. INTRODUCTION............................................................................................................5 
1.1. Background....................................................................................................................5 
1.1.1. Molecular Formula and Molecular Activity............................................................5 
1.1.2. Clinical activity of Axitinib........................................................................................6 
1.1.3. Overall clinical safety.................................................................................................7 
1.2 Rationale for trial….......................................................................................................9 
2. HYPOTHESIS.................................................................................................................13 
3. OBJECTIVES..................................................................................................................14 
3.1. Primary objectives........................................................................................................14 
3.2. Secondary objectives....................................................................................................14 
4. STUDY DESIGN............................................................................................................14 
5. STUDY POPULATION.................................................................................................14 
5.1. Stage..............................................................................................................................14 
5.2. Inclusion Criteria.........................................................................................................15 
5.3. Exclusion Criteria........................................................................................................15 
5.4. Patient Registration.....................................................................................................17 
5.5. Life Style Guidelines....................................................................................................17 
6. TRIAL PROCEDURES.................................................................................................17 
6.1. Subject Enrollment......................................................................................................17 
6.2. Trial procedures..........................................................................................................17 
6.3. Initial Clinical Evaluation..........................................................................................19 
7.  STUDY PLAN..............................................................................................................19 
7.1. Study overview............................................................................................................19 
7.2. Study schema...............................................................................................................21 
8. TREATMENT PLAN...................................................................................................22 
8.1. Allocation to Treatment.............................................................................................22 
8.2. Drug Supplies..............................................................................................................22 
8.2.1. Formulation and Packaging...................................................................................22 
8.2.2. Administration.........................................................................................................22 
8.2.3. Dose escalations.......................................................................................................23 
8.2.4. Dose Interruption and Reductions........................................................................23 
8.2.4.1. Axitinib Dose Reduction for Hypertension........................................................25 
8.2.4.2. Axitinib Dose Reduction for Hemoptysis...........................................................25 
8.2.4.3. Axitinib Dose Reduction for Proteinuria...........................................................26 
8.2.4.4. Axitinib Dose Interruption for Surgery or Surgical Procedures....................26 
8.2.4.5. Thyroid Function Tests.......................................................................................26 
8.3. Drug Storage and Drug Accountability...................................................................26 
8.4. Concomitant Medication(s).......................................................................................27 
8.5. Rescue Therapy..........................................................................................................28 
9.  RESPONSE CRITERIA.............................................................................................29 
10. CRITERIA FOR DISCONTINUATION OF TREATMENT................................29 
11. SAFETY ASSESSMENTS........................................................................................30 
12. ADVERSE EVENT REPORTING...........................................................................30 
12.1. Adverse Events..........................................................................................................30 
12.2. Reporting Period.......................................................................................................30 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
3 
 
12.3. Definition of an Adverse Event................................................................................31 
12.4. Abnormal Test Findings...........................................................................................31 
12.5. Serious Adverse Events.............................................................................................32 
12.6. Hospitalization...........................................................................................................32 
12.7. Severity Assessment...................................................................................................33 
12.8. Causality Assessment.................................................................................................34 
12.9. Exposure In Utero......................................................................................................34 
12.10. Withdrawal Due to Adverse Events ......................................................................35 
12.11. Eliciting Adverse Event Information.....................................................................35 
12.12. Reporting Requirements.........................................................................................36 
12.12.1. Serious Adverse Event Reporting Requirements..............................................36 
12.12.2. Non-Serious Adverse Event Reporting Requirements.......................................37 
12.13. Data and Safety Monitoring...................................................................................37  
13. STATISTICAL METHODS.........................................................................................38 
13.1. Primary Objectives.........................................................................................................38 
13.2. Sample size justification..................................................................................................38 
13.3. Stopping rules for efficacy..............................................................................................38 
13.4. Analysis plan..................................................................................................................38 
14. DATA ANALYSIS...........................................................................................................39 
14.1 Analysis of Overall Survival.........................................................................................39 
14.2 Safety Analysis..............................................................................................................39 
14.3 Efficacy Analysis...........................................................................................................39 
15. QUALITY CONTROL AND QUALITY ASSURANCE..............................................40 
16. DATA HANDLING AND RECORD KEEPING...........................................................40 
16.1. Case Report Forms / Electronic Data Record.............................................................40 
16.2. Record Retention............................................................................................................40 
17. ETHICS..............................................................................................................................41 
17.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)................41 
17.2. Ethical Conduct of the Trial..........................................................................................41 
17.3. Subject Information and Consent.................................................................................41 
17.4. Reporting of safety issues and serious breaches of the protocol or ICH GCP..........42 
18. COMPLETION OF TREATMENT AND FOLLOW-UP.............................................42 
19. NCCN DISCONTINUATION CRITERIA.....................................................................42 
20. PUBLICATION OF TRIAL RESULTS..........................................................................42 
20.1. Communication of Results by Pfizer, Inc......................................................................42 
20.2. Publications by Investigators..........................................................................................43 
21. REFERENCES....................................................................................................................45 
FIGURES 
Figure 1. Molecular structure of Axitinib.................................................................................5 
Figure 2. Waterfall plot of tumor response to therapy in UMCC 2011.53...........................10 
Figure 3. Kaplan-Meier Analysis of Overall Survival in UMCC2011.52............................11 
Figure 4. Kaplan-Meier Analysis of Overall Survival by Choi Response............................13 
Figure 5. Study schema.............................................................................................................21 
 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
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TABLES 
Table 1. Receptor tyrosine kinase affinities and selectivity of Axitinib ..................................6 
Table 2 Treatment-Emergent,  All-Causality Adverse Events Summarized by Descending  
Frequency Occurring in at Least 10% of Subjects with Solid Tumors Receiving  
Single-Agent Axitinib...................................................................................................................8 
Table 3 Laboratory Test Results Reported for Subjects with Solid Tumors  
Receiving Single-Agent Axitinib n (%) at Maximum Grade...................................................9 
Table 4. UMCC 2011.53 Response Rates............................................................................... 10 
Table 5. Definition of Choi Criteria .........................................................................................11 
Table 6. Trial procedures............................................................................................................18 
Table 7. Available Axitinib Dose Levels.....................................................................................23 
Table 8. Criteria For Dose Modification For Axitinib Related Adverse Events  
Other Than Hypertension, Hemoptysis Or Proteinuria..........................................................24 
Table 9. Hypertension Management Plan For Axitinib...........................................................25 
 
 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
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1. INTRODUCTION 
 
1.1. Background 
 
Head and neck cancer comprises approximately 2-3% of all malignancies and account for about 
2-3% of all cancer-related deaths (1). Ninety-five percent of all head and neck cancers are 
squamous cell carcinomas.  Head and neck cancers (except for nasopharyngeal carcinoma) have 
traditionally been grouped together, based on common etiology, predisposing factors, histology, 
approaches to treatment (2).  Only 10% of patients present with distant metastases (3).  However, 
in the course of their illness, about half of head and neck patients present with or develop 
recurrent or metastatic disease (5). Prognosis in such patients is poor (7). The role of 
chemotherapy in this setting is palliative.  Survival in patients with recurrent or metastatic 
squamous cell carcinoma of the head and neck cancer (R/M SCCHN) is 6-9 months, even with 
aggressive therapy (8). Cisplatin and 5-fluorouracil have traditionally been the combination of 
choice in the treatment of incurable disease (2).  Single agents, such as methotrexate, can be used 
as well. Response rates to chemotherapy are low, between 10-30% for single-agent regimens and 
20-40% for multi-drug regimens (9, 10). However, the more efficacious regimens and 
combinations are fraught with toxicities and side effects that impair quality of life of the patients 
(9).  Currently, targeted therapies are being developed for a variety of cancers, with good clinical 
activity. They have been administered in patients with R/M SCCHN with promising results (4, 9, 
11). Since vascular endothelial growth factor (VEGF) plays a crucial role in tumorigenesis and 
metastasis of R/M SCCHN, this protocol aims to investigate clinical activity of Axitinib in this 
cancer type.  
 
 
1.1.1. Molecular Formula and Molecular Activity 
 
Axitinib is a substituted indazole derivative that was discovered using structure-based drug 
design. The molecular formula is C22H18N4OS with molecular weight of 386.47. The chemical 
name is N-Methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide: 
 
 
Figure 1. Molecular structure of Axitinib (AG-013736) 
From: en.wikipedia.org/wiki/File:Axitinib.png 
 
 
 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
6 
 
 
 
 
Table 1. Receptor tyrosine kinase affinities and selectivity of Axitinib (4)  
 
Table 1. Receptor tyrosine kinase affinities 
and selectivity of Axitinib (4) 
Target 
Cell potency 
(IC50, nM) 
VEGFR-2 
0.2
VEGFR-1 
0.1
VEGFR-3 
0.1-0.3 
PDGFR-β 
1.6
KIT 
1.7
PDGFR-α
5.0
CSF-1R 
73
FGFR-1 
231
Flt3
>1000
 
Wilmes et al. (12) showed by dynamic contrast-enhanced magnetic resonance imaging (MRI) 
that tumors formed in immune-deficient mice from breast cancer cells had decreased blood 
flow/permeability in Axitinib-treated animals. Animal xenogaft models also demonstrated that 
Axitinib inhibits angiogenesis and tumor growth of colon cancer culture cells in host animals 
(13). 
 
1.1.2. Clinical activity of Axitinib 
 
Axitinib is a substituted indazole derivative that acts as a potent inhibitor of angiogenesis. It is a 
receptor tyrosine kinase inhibitor of VEGF receptors 1, 2, and 3, platelet-derived growth factor 
(PDGF) receptor beta and c-kit (13, 14). It has been evaluated in metastatic settings in a variety 
of cancers.  
 
Axitinib is FDA approved for the treatment of advanced renal cell carcinoma after failure of one 
prior systemic therapy. 
 
Axitinib has been most extensively studied in renal cell carcinoma. Rixe et al. reported on 
efficacy of axitinib in patients with renal cell carcinoma (RCC) who failed prior cytokine 
treatment (15). In this study, single-agent axitinib yielded objective response rate (ORR) of 
44.2%, with median duration of response of 23 months. Axitinib was also active in patients with 
RCC who previously progressed on sorafenib (16). In this population, Axitinib gave ORR of 
22.6%, with median duration of response of 17.5 months. Median PFS was 7.4 months. A 
recently reported phase III trial compared Axitinib with sorafenib in patients with metastatic 
RCC is second-line setting (17). Median PFS was significantly longer with the former (6.7 
months vs. 4.7 months, HR of 0.665, P<0.0001). ORR was 19.4% for axitinib and 9.4% for 
sorafenib (P=0.0001).  


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
7 
 
 
Axitinib has shown clinical activity in various histologic subtypes of advanced thyroid cancer, 
with objective response rate of 30% and stable disease in an additional 38% (18), with resultant 
disease control rate of 68%. Median progression-free survival (PFS) was 18.1 months.  
 
 Schiller et al. (19) reported on efficacy of axitinib in patients with advanced non-small cell lung 
cancer (NSCLC), mostly adenocarcinoma (75%), most were pretreated (72%). Partial response 
(PR) was observed in 9% of patients, disease control rate was 41%. Median PFS was 4.9 months. 
 
Axitinib was also studied in patients with advanced pancreatic cancer in combination with 
gemcitabine (20, 21). An initial, phase II trial offered a promising result of improved overall 
survival (OS) with axitinib plus gemcitabine vs. gemcitabine alone (6.9 months vs. 5.6 months, 
which was not statistically significant, however). However, a subsequent phase III trial did not 
show any survival advantage to the combination (21).  
 
In all of these studies, the starting dose of Axitinib was 5 mg twice a day (BID). In most studies, 
Axitinib dose was titrated up from a starting dose of 5 mg BID in 1 – 3 mg increments in patients 
tolerating Axitinib. Those subjects who could tolerate Axitinib with no adverse events related to 
Axitinib above Common Terminology Criteria for Adverse Events (CTCAE)  Grade 2 for 
consecutive 2 week periods were permitted to increase their dose step-wise to 7 mg BID and then 
to 10 mg BID, unless their BP was >150/90 mm Hg or the subject was receiving 
antihypertensive medication. All ongoing studies allow Axitinib dose reductions to as low as 2 
mg BID for treatment-related adverse events. Except for an increase in hand-foot syndrome and 
slight increase in the incidence of hypertension, it appears that the patients dose titrated to 
between 6-10 mg BID doses do not experience increased toxicities if they have previously 
tolerated 5 mg BID starting dose. 
 
Growth factors such as VEGF and epidermal growth factor (EGF) have been implicated in the 
growth of cancer cells in head and neck cancer (reviewed in ref 22, 23, 24). Therefore, a phase 2 
trial of Axitinib in metastatic head and neck cancer is warranted. Furthermore, despite numerous 
lines of evidence suggesting that growth factors and cytokines play a role in SCCHN, these 
molecules and their dynamics have not been studied systematically in such patients, nor have 
predictive markers of response to targeted therapies been elucidated in patients with SCCHN. 
 
1.1.3. Overall clinical safety. 
 
Overall, the adverse events reported in Axitinib clinical studies are considered manageable, 
generally reversible and expected for this class of agents. A Pfizer, Inc. summary of observed 
Axitinib toxicity gathered on 515 subjects treated with single-agent Axitinib is listed below 
(Tables 2 and 3). 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
8 
 
Table 2 Treatment-Emergent, All-Causality Adverse Events Summarized by Descending 
Frequency Occurring in at Least 10% of Subjects with Solid Tumors Receiving 
Single-Agent Axitinib (N =515, ref 6) 
MedDRA Preferred Term 
All Grades n (%) 
Grade 3+ n (%) 
Fatigue 
284 
(55.1) 
56 
(10.9) 
Diarrhoea 
254 
(49.3) 
29 
(5.6) 
Hypertension 
246 
(47.8) 
92 
(17.9) 
Anorexia 
197 
(38.3) 
12 
(2.3) 
Nausea 
177 
(34.4) 
6 
(1.2) 
Dysphonia 
175 
(34.0) 
0 
(0.0) 
Palmar-plantar erythrodysaesthesia syndrome 
134 
(26.0) 
33 
(6.4) 
Weight decreased 
132 
(25.6) 
19 
(3.7) 
Headache 
122 
(23.7) 
8 
(1.6) 
Cough 
113 
(21.9) 
5 
(1.0) 
Constipation 
109 
(21.2) 
2 
(0.4) 
Dyspnoea 
102 
(19.8) 
32 
(6.2) 
Arthralgia
100 
(19.4) 
11 
(2.1) 
Proteinuria
95 
(18.4) 
15 
(2.9) 
Vomiting 
93 
(18.1) 
6 
(1.2)
Pain in extremity
91 
(17.7) 
11 
(2.1) 
Stomatitis 
81 
(15.7) 
7 
(1.4) 
Rash 
79 
(15.3) 
2 
(0.4) 
Mucosal inflammation 
78 
(15.1) 
3 
(0.6) 
Back pain 
75 
(14.6) 
9 
(1.7) 
Dyspepsia 
75 
(14.6) 
1 
(0.2) 
Abdominal pain 
71 
(13.8) 
16 
(3.1) 
Hypothyroidism 
71 
(13.8) 
0 
(0.0) 
Dizziness 
62 
(12.0) 
2 
(0.4) 
Dysgeusia
61 
(11.8) 
0 
(0.0) 
Dry skin 
57 
(11.1) 
1 
(0.2) 
Epistaxis
55 
(10.7) 
0 
(0.0) 
Insomnia 
53 
(10.3) 
0 
(0.0) 
Musculoskeletal pain
53 
(10.3) 
5 
(1.0) 
Oedema peripheral 
53 
(10.3) 
0 
(0.0) 
Pyrexia 
53 
(10.3) 
0 
(0.0) 
 
 
Laboratory test abnormalities are summarized in Table 3 and are excerpted from NCCN Request 
for Proposals (6). 
 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
9 
 
Table 3 Laboratory Test Results Reported for Subjects with Solid Tumors Receiving Single-Agent 
Axitinib n (%) at Maximum Grade (6)
Group/Parameter 
N 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Total 
Chemistry 
Amylase
88 
16 (18.2) 
3 (3.4) 
2 (2.3) 
0 (0.0) 
21 (23.9) 
Aspartate Aminotransferase (AST) 
456 
131 (28.7) 
28 (6.1) 
13 (2.9) 
0 (0.0) 
172 (37.7) 
Alanine Aminotransferase (ALT) 
456 
109 (23.9) 
36 (7.9) 
10 (2.2) 
0 (0.0) 
155 (34.0) 
Bilirubin (Total) 
456 
58 (12.7) 
23 (5.0) 
1 (0.2) 
1 (0.2) 
83 (18.2) 
Alkaline Phosphatase
456 
141 (30.9) 
30 (6.6) 
7 (1.5) 
0 (0.0) 
178 (39.0) 
Bicarbonate 
342 
101 (29.5) 
9 (2.6) 
1 (0.3) 
0 (0.0) 
111 (32.5) 
Creatinine
456 
141 (30.9) 
31 (6.8) 
1 (0.2) 
3 (0.7) 
176 (38.6) 
Creatine Kinase
7 
2 (28.6) 
0 (0.0) 
0 0.0) 
0 (0.0) 
2 (28.6) 
Hypoalbuminemia 
456 
132 (28.9) 
43 (9.4) 
13 (2.9) 
0 (0.0) 
188 (41.2) 
Hypernatremia
456 
22 (4.8) 
1 (0.2) 
0 (0.0) 
0 (0.0) 
23 (5.0) 
Hyponatremia 
456 
119 (26.1) 
0 (0.0) 
22 (4.8) 
0 (0.0) 
141 (30.9) 
Hyperkalemia 
456 
90 (19.7) 
29 (6.4) 
9 (2.0) 
0 (0.0) 
128 (28.1) 
Hypokalemia 
456 
58 (12.7) 
0 (0.0) 
7 (1.5) 
0 (0.0) 
65 (14.3) 
Hypercalcemia 
240 
31 (12.9) 
2 (0.8) 
1 (0.4) 
1 (0.4) 
35 (14.6) 
Hypocalcemia 
240 
40 (16.7) 
12 (5.0) 
2 (0.8) 
2 (0.8) 
56 (23.3) 
Hyperglycemia 
456 
200 (43.9) 
63 (13.8) 
16 (3.5) 
6 (1.3) 
285 (62.5) 
Hypoglycemia 
456 
55 (12.1) 
13 (2.9) 
2 (0.4) 
1 (0.2) 
71 (15.6) 
Hypophosphatemia
69 
0 (0.0) 
6 (8.7) 
2 (2.9) 
0 (0.0) 
8 (11.6)-
Lipase
88 
10 (11.4) 
3 (3.4) 
3 (3.4) 
1 (1.1) 
17 (19.3) 
Hematology 
Hemoglobin
456 
170 (37.3) 
36 (7.9) 
1 (0.2) 
11 (2.4) 
218 (47.8) 
Platelets 
454 
100 (22.0) 
4 (0.9) 
1 (0.2) 
1 (0.2) 
106 (23.3) 
White Blood Cells 
456 
74 (16.2) 
15 (3.3) 
0 (0.0) 
2 (0.4) 
91 (20.0) 
Neutrophils (Abs) 
454 
40 (8.8) 
9 (2.0) 
4 (0.9) 
1 (0.2) 
54 (11.9) 
Lymphocytes (Abs) 
423 
85 (20.1) 
75 (17.7) 
33 (7.8) 
3 (0.7) 
196 (46.3) 
Urinalysis 
Urine Protein 
476 
73 (15.3) 
88 (18.5) 
14 (2.9) 
0 (0.0) 
175 (36.8) 
 
1.2. Rationale for Trial 
 
Based off the known translational data and targeted mechanism of Axitinib, UMCC 2011.53 ‘A 
Phase II Trial Evaluating Axitinib in Patients with Unresectable, Recurrent, or Metastatic Head 
and Neck Cancer’ accrued patients between 2012-2014. This study included patients with 
unresectable recurrent or distant metastatic (R/M HNSCC) at any line of therapy as long as their 
ECOG performance status was 0-2.  It was powered with the primary objective of detecting an 
improvement in 6-month progression free survival.  Of particular note, tumor response was 
judged by RECIST v1.0 with planned treatment cessation if radiologic progression was noted. 
 
Forty-two patients were enrolled and available for safety analysis of which only 30 were 
available for efficacy.  We noted that many patients in this cohort had significant clinical 
improvement as witnessed by symptomatic improvement, improved energy, and increased 
performance status.  However, interval imaging of patients demonstrated evidence of 
mild/moderate tumor swelling with cystic attenuation and edema suggestive of drug effect. In 
some of the patients, this likely treatment response was interpreted as progression per RECIST 
v1.0.  Planned interim analyses were conducted as to investigate efficacy as based on 6 month 
progression free survival (PFS).  The first a priori interim analysis was performed after 
enrollment of 20 patients and marginal benefit was seen hence a second interim analysis was 
performed after enrollment of 30 patients evaluable for efficacy.  Using the endpoint of 6 month 
PFS, the study was stopped due to futility as the observed rate for patients on axitinib was 27%. 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
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Final results of this trial were recently published (55).  Although the trial was considered 
negative on grounds of lack in improvement of PFS compared to historical controls (3.7 months 
(95% CI 3.5-5.7), observed responses and survival data suggested significant efficacy in a 
heavily pre-treated population (disease control rate (DCR) of 76.7%, median OS of 10.9 months 
(95% CI 6.4-17.8)) (Table 8, Figure 3, Figure 4). In addition, Axitinib was extremely well 
tolerated with no bleeding episodes or reductions due to home blood pressure readings. 
 
Table 4: UMCC 2011.53 Response Rates 
 
Response 
RECIST v1.0 
Choi Criteria 
Complete Response 
0 (0%) 
0 (0%) 
Partial Response 
2 (6.7%) 
19 (65%) 
Stable Disease 
21 (70%) 
2 (6.9%) 
Progressive Disease 
7 (23%) 
8 (27.6%) 
Disease Control Rate 
76.6% 
80.8% 
Overall Response 
6.7% 
65% 
 
 
Figure 2: Waterfall Plot of Tumor Response to Therapy in UMCC 2011.53 
 
 
Figure 3: Kaplan-Meier Analysis of Overall Survival in UMCC 2011.53 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
11 
 
 
 
We strongly believe that Axitinib is a promising therapeutic, merits further consideration as a 
novel therapeutic in R/M HNSCC, and that the results of the UMCC 2011.53 are misleading for 
several reasons.  First, we note the impressive overall survival (median 10.9 months) observed in 
the heavily pretreated UMCC 2011.53 population with a low incidence of grade 3 or 4 toxicities.  
The current first line therapy in newly diagnosed R/M HNSCC is a triplet therapy (the 
‘EXTREME’ regimen) consisting of Cetuximab, Cisplatin, and 5-flurouracil which has been 
shown to be associated with a median OS of 10.1 months with relatively high rate of grade 3 or 4 
toxicities(82%) (9).  In studies of patients failing first line therapy, median overall survival (OS) 
is typically on the order of 4-8 months.  Ninety percent of the patients in our study had previous 
lines of therapy in the R/M setting suggestive of significant survival benefit with Axitinib 
therapy. 
 
We believe that the reason UMCC 2011.53 demonstrated impressive OS but did not demonstrate 
improvement in PFS (and hence was stopped for futility) is that tumor response to therapy 
(swelling, cystic attenuation) was registered as progression by RECIST v1.0.  Similar results 
regarding responses have been described with tyrosine kinase inhibitors, most notably in 
advanced gastrointestinal stromal tumors (GISTs).  To account for these alternate radiologic 
changes, an alternate set of response criteria have been proposed for patients treated with 
tyrosine kinase inhibitors known as the Choi Criteria (Table 9). In one study, it was 
demonstrated that radiologic changes defined by Choi Criteria correlated with patient directed 
endpoints (PFS, DSS, OS) whereas RECIST did not capture these correlations. 
 
Table 5: Definition of Choi Criteria 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
12 
 
 
 
We have reviewed all the radiographic images for all of the patients on UMCC 2011.53 by Choi 
Criteria as a hypothesis generating exploratory analysis.  Of note, only 29/30 patients evaluable 
for response had imaging for which the Choi Criteria could be applied.  In addition, imaging was 
not optimized for interpreting images with alternate radiologic criteria.  Preliminary exploratory 
analyses demonstrate that (23/29) 65% of patients enrolled on UMCC 2011.53 had a response 
(PR) by Choi Criteria with an additional 2 patients achieving stable disease (6.9%) (Table 4).  
 
Furthermore, overall survival was found to be significantly improved in patients with a response 
by Choi Criteria versus non-responders (KM estimate of OS (95% CI): 13.2(10.3,18.7) months 
versus 5.1 (2.5, 8.8) months) (Figure 5).  Further analyses was limited as treatment decisions 
were made off of RECIST but predicted survival at 12 months was 63% (95% CI: 38-80%) in 
patients with a response versus 20% (95% CI: 3-47%) in non-responders. 
 
Figure 4: Kaplan-Meier Analysis of Overall Survival by Choi Response in UMCC 2011.53 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
13 
 
 
Given the existing literature in other malignancies treated with tyrosine kinase inhibitors, 
mechanism of action of Axitinib, and our exploratory analysis in evaluating response with 
alternate criteria we feel that use of Choi Criteria for assessment for tumor response and 
treatment decisions is more appropriate for ongoing R/M HNSCC trials.  We believe that 
improvements in survival endpoints (ie PFS) may be underestimated in the existing UMCC 
2011.53 cohort as Axitinib was stopped in the setting of a RECIST progression despite Choi 
response. 
 
Therefore, we propose a trial examining the use of Axitinib in R/M HNSCC using the Choi 
Criteria for response assessment.  We would power this cohort to detect a 20% improvement in 6 
month overall survival compared to historical data (from 50% to 70% at 6 months).  This cohort 
would consist of 37 patients and treatment plan would be identical to the previous UMCC 
2011.53 protocol with the exception that Choi criteria would be used to evaluate response.  In 
addition, treatment with Axitinib would be continued if patients were felt to be deriving clinical 
benefit. 
 
2. HYPOTHESIS: 
 
2.1 Administration of Axitinib to patients with R/M SCCHN will result in an improvement in 6 
month overall survival compared to historical control 
 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
14 
 
2. 2 Use of the Choi Criteria to assess response to Axitinib will yield more accurate assessment 
regarding tumor response in R/M SCCHN 
 
3. OBJECTIVES: 
 
3.1 Primary objective 
 
To determine the 6 month overall survival in patients with unresectable recurrent and 
metastatic head and neck cancer treated with Axitinib 
 
3.2 Secondary objectives 
 
1. To determine the overall survival of patients treated with Axitinib 
2. To determine the progression free survival of patients treated with Axitinib 
3. To determine the disease control rate at 16 weeks and response rate as defined by 
Choi Criteria 
4. To determine the duration of response (as defined by Choi Criteria) of patients treated 
with Axitinib 
5. To assess the toxicities associated with the treatment of Axitinib of patients treated 
with Axitinib 
 
4. STUDY DESIGN: 
 
This study will be a prospective, single-institution, single-arm phase II study of Axitinib in 
patients with unresectable recurrent and metastatic head and neck squamous cell carcinoma with 
ECOG performance status 0-2, for recurrent or metastatic head and neck cancer. The subjects 
will be started on treatment with 5 mg of Axitinib twice a day continuously, with subsequent 
dose escalation to 7 mg and then 10 mg twice a day in the absence of grade 2 or worse toxicities. 
This will be followed by clinical and/or radiologic response assessment after 8 weeks and 
subsequently every 2 months until disease progression (defined per Choi criteria, or obvious 
progression on clinical or laryngoscopic/endoscopic exam) or intolerable toxicity (defined as 
below).  Patients with confirmed progressive disease who, in the investigator’s opinion, continue 
to receive benefit from Axitinib treatment and who meet the criteria for treatment may continue 
to receive treatment as described in Section 8.3.  Axitinib should be discontinued if there is 
further evidence of progression defined as an additional 10% or greater increase in tumor burden 
volume from time of initial progression (including all target lesions and new measurable lesions). 
 
During treatment on this protocol, all patients will be evaluated for safety as detailed below. 
 
5. STUDY POPULATION: 
 
5.1. Stage: 
 
 
Unresectable, recurrent or metastatic squamous cell carcinoma of head and neck.  
 
5.2. Inclusion Criteria: 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
15 
 
 
 
1. Histologically documented squamous cell head and neck cancer with or without 
metastases, not amenable to curative treatment; or the patient has documented refusal of curative 
treatment. 
 
2. Presence of measurable disease by CT scan or 
a. for cutaneous squamous cell carcinoma not present on CT imaging but present on 
physical exam with lesion(s) greater than >/= 10mm 
b. patients with non-target lesions are permissible per PI discretion 
 
3. Adequate bone marrow, hepatic, and renal function (including absence of proteinuria, 
 
PT<1.5, WBC≥ 3x109 cells/ml, ANC ≥ 1.5x109 cell/ml, platelets  ≥75,000 cells/mm3, 
hemoglobin ≥ 9.0 g/dL, concentrations of total serum bilirubin within 1.5 x upper limit of normal 
(ULN), AST, ALT within 2.5x institutional upper limits of normal unless there are liver 
metastases in which case AST and ALT  within 5.0 x ULN, serum creatinine clearance ≥ 30 
ml/min),  urinary protein <2+ by urine dipstick (if dipstick is ≥2+ then a 24-hour urine collection 
can be done and the patient may enter only if urinary protein is <2 g per 24 hours). 
 
4. Age ≥18 years. 
 
5. ECOG performance status of 0-2. 
 
6. Life expectancy of ≥12 weeks. 
 
7. No evidence of preexisting uncontrolled hypertension as documented by 2 baseline 
blood pressure readings taken at least 30 minutes apart. The baseline systolic blood pressure 
readings must be ≤140 mm Hg, and the baseline diastolic blood pressure readings must be ≤90 
mm Hg. Patients whose hypertension is controlled by antihypertensive therapies are eligible. 
 
8. Women of childbearing potential must have a negative serum or urine pregnancy test 
within 3 days prior to treatment. 
 
9. Signed and dated informed consent document indicating that the patient (or legally 
acceptable representative) has been informed of all pertinent aspects of the trial prior to 
enrollment. 
 
10. Willingness and ability to comply with scheduled visits, treatment plans, including 
willingness to take Axitinib, laboratory tests, and other study procedures. 
            11. If a curative treatment option in the form of chemoradiation exists in a patient with 
unresectable disease, this has to be attempted first and must have failed, unless the patient has 
documented refusal of curative treatment. 
 
 
5.3. Exclusion Criteria: 
 
 
1. Central lung lesions involving major blood vessels (arteries or veins) or a tumor 
encasing major blood vessels (i.e. carotid artery).  
 
2. Active hemoptysis (defined as >1/2 tsp of bright red blood per day). 
 
3. Gastrointestinal abnormalities causing impaired absorption requiring intravenous 
alimentation, prior surgical procedures affecting absorption including gastric resection, treatment 
for active peptic ulcer disease in the past 6 months, active gastrointestinal bleeding, unrelated to 
cancer, as evidenced by hematemesis, hematochezia or melena in the past 3 months without 
evidence of resolution documented by endoscopy or colonoscopy, malabsorption syndromes. 
 
4. Previous treatment with anti-angiogenesis agents including thalidomide, or inhibitors 
of epidermal growth factor (EGF), platelet derived growth factor (PDGF), or fibroblast growth 
factors (FGF) receptors within 30 days preceding study entrance. 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
16 
 
 
5. Current use or anticipated inability to avoid use of drugs that are known strong 
CYP3A4/5 inhibitors (atazanavir, boceprevir, conivaptan, clarithromycin, grapefruit or grapefruit 
juice, indinavir, itraconazole, ketoconazole, nelfinavir, nefazodone, posaconazole, ritonavir,  
saquinavir, telaprevir, telithromycin, voriconazole ). 
 
6. Current use or anticipated inability to avoid use of drugs that are known strong 
CYP3A4/5 inducers (carbamazepine, dexamethasone, fosphenytoin, phenytoin, phenobarbital, 
rifabutin, rifampin, rifapentin, St. John’s wort). 
7. Active seizure disorder or evidence of untreated or progressive brain metastases, spinal 
cord compression, or carcinomatous meningitis.  
a. Subjects with brain metastases are eligible if they have been treated and there 
is no CT or MRI evidence for at least 4 weeks after CNS metastasis treatment 
is complete. 
 
8. A serious uncontrolled medical disorder or active infection that would impair their 
ability to receive study treatment. 
 
9. History of a malignancy (other than head and neck cancer) except those treated with 
curative intent for skin cancer (other than melanoma), in situ breast or in situ cervical cancer, or 
those treated with curative intent for any other cancer with no evidence of disease for 2 years. 
 
10. Major surgery <4 weeks or radiation therapy <2 weeks of starting the study treatment. 
Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at least one 
measurable lesion that has not been irradiated. 
a. Radiotherapy is defined as whole brain radiation, external beam radiation 
therapy (EBRT), or stereotactic brain radiation (SBRT). 
 
11. Dementia or significantly altered mental status that would prohibit the understanding 
or rendering of informed consent and compliance with the requirements of this protocol. 
 
12. Patients (male and female) having procreative potential who are not willing or not 
able to use adequate contraception or practicing abstinence. 
 
13. Women who are pregnant or breast-feeding. 
14. Patients with history of bleeding diathesis, arterial thromboembolism, current use of 
therapeutic anticoagulation with oral vitamin K antagonists, factor Xa inhibitors, heparin 
products, oral direct thrombin inhibitors, or presence of non-healing wounds. Low-dose 
anticoagulants for maintenance of patency of central venous access device or prevention of deep 
venous thrombosis is allowed.  
 
15. Patients residing in prison.  
 
16. Prior experimental therapy within 30 days of planned start of this trial. 
 
17. HIV virus infection irrespective of viral load, treatment status, or CD4 count, or  
acquired immunodeficiency syndrome (AIDS)-related illness. HIV testing is not required by this 
protocol. 
 
18. Any of the following within the 12 months prior to study drug administration: 
myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, cerebrovascular accident or transient ischemic attack. 
 
19. History of deep vein thrombosis or pulmonary embolism within 6 month of 
anticipated starting of Axitinib. 
            20. Availability of curative treatment option for the patient’s cancer, whether surgery, 
chemotherapy, radiation, or combination thereof, unless the patient has documented refusal of 
curative treatment.   
 
21. Increased risk of wound dehiscence or presence of non-healing wounds. 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
17 
 
 
5.4. Patient Registration.  
 
All patients will be registered with the University of Michigan Rogel Cancer Center Oncology 
Clinical Trials Support Unit (O-CTSU) prior to initiating treatment. The patient or their 
representative will sign and date the informed consent for the trial. 
 
5.5. Life Style Guidelines 
 
During the study female patients of childbearing potential must take precautions to prevent 
pregnancy since the effects on the fetus are unknown. Male patients with partners of childbearing 
potential must take precautions to prevent pregnancy of the partner since the effects of these 
drugs on sperm are unknown. These restrictions should remain in force for 6 months from the 
last dose of Axitinib. Drug interaction studies with oral contraceptives have not been performed, 
so barrier methods of contraception or abstinence should be considered. Adequate contraception 
should be discussed with the physician before the treatment start.  
 
 
 
6. TRIAL PROCEDURES 
 
6.1. Subject Enrollment 
 
Once eligibility is verified the clinical representative will confirm by facsimile that the patient 
has been accepted into the trial. If the patient fails to start treatment within 14 days of registration 
the clinical representative should be contacted before the start of treatment. 
 
6.2. Trial procedures 
 
During treatment on this protocol, all patients will be followed and monitored as follows: 
 
 
 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
18 
 
Table 6. Trial Procedures. 
 
 
1- Following completion of 12 cycles, assessments will be obtained every 8 weeks. 
2- Comprehensive Panel includes Basic Panel (Na, K, Cl, CO2, BUN, Cr, Gluc), 
AST/SGOT, ALT/SGPT, Alk Phos, T.bili, Alb, Ca, Total Protein. Also will obtain 
magnesium.  
3- Urine dipstick may be done in clinic or lab. 
4- Serum or plasma Thyroid Function Tests (Free T4 and TSH) should be performed within 
14 days of starting treatment. Subsequently, TSH should be done every 2 weeks X 2, then 
following completion of even numbered cycles of chemotherapy. 
Required 
studies 
Pre-
therapy12 
Cycle 
1, 
Day 
1 
1 
week 
2 
weeks 
3 
weeks 
4 
weeks 
8 
weeks 
Following 
each 
cycle thru 
12 cycles1 
Following 
completion 
of even 
numbered 
cycles  
Survival11 
Clinic visit 
X 
X 
  
X 
  
X 
X 
X 
X  
 
H&P 
X 
X10 
  
X 
  
X 
X 
X 
 X 
 
Vital signs and 
PS 
X 
X 
  
X 
  
X 
X 
X 
 X 
 
PTT, PT, INR 
X 
 
  
  
  
  
  
  
  
 
CBC, Diff, 
platelets 
X 
X9 
  
X 
  
X 
X 
X 
 X 
 
Comprehensive 
Panel, Mg2 
X3 
X9 
  
X 
  
X 
X 
X 
 X 
 
Urine dip3 
X 
 
  
  
  
X 
X 
X 
 X 
 
TSH, free T44 
X 
X9, 
  
X 
  
X 
  
X 
 
Clinical 
toxicity 
assessment 
  
 
  
X 
  
X 
X 
X 
X 
 
Radiologic 
imaging for 
tumor 
measurement5 
X 
 
  
  
  
  
 X 
  
X 
 
Pregnancy 
Test6 
 
X9 
  
  
  
  
  
  
  
 
Informed 
Consent 
X 
 
  
  
  
  
  
  
  
 
Planned dose 
escalation7 
  
 
  
X 
X 
  
  
  
  
 
Telephone 
assessment of 
toxicities8 
  
 
X 
  
X 
  
  
  
  
 
Survival 
Monitoring 
 
 
X 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
19 
 
5- Radiologic imaging of the areas involved with recurrent/metastatic disease, such as the 
neck, chest, or other areas if needed because of the location of the metastatic disease; 
baseline within 28 days prior to treatment. On study assessments, may be within +/- 2 
weeks. Imaging will be interpreted by Choi Criteria, interpretation to be performed by 
centralized UMCC Tumor Response and Assessment Core (TRAC). 
6- Pregnancy test (urine or serum) will be performed for women of childbearing age within 
3 days before first dose of Axitinib and if clinical concern for pregnancy arises. 
7- Dose escalation is planned at 2 weeks (to 7 mg BID) and 3 weeks (to 10 mg BID), in the 
absence of toxicities grade 2 or greater. Dose escalation may be resumed after 1 week if 
all toxicities have diminished to grade 1 or less (see below), and measures have been 
taken to reasonably prevent recurrence of these toxicities with the higher dose. 
8- Telephone call to the patient must be made by a study staff member (RN or MD with a 
current nursing/medical license) at 1 and 3 weeks. During these calls, toxicity assessment 
will be conducted, per patient report, and toxicity management advice given, including 
initiation or titration of anti-hypertensive treatment. During the Week 3 call, if toxicities 
are grade 1 or less dose escalation to 10 mg BID will be made. 
9- All baseline labs are required within 14 days of starting treatment (Cycle 1, Day 1).   
10- H&P not required on Cycle 1, Day 1 if performed for screening within 72 hours 
11- Survival assessment can be done by phone and will be performed once every three 
months (+/- 1 month) 
12- Labs are eligible for screening if obtained within the past 28 days 
 
6.3 Initial Clinical Evaluation 
 
1. Complete history and physical exam. 
2. CBC with differential and platelet count (CBCDP) ; within 14 days prior to start of 
treatment 
3. Serum chemistry profile to include: comprehensive panel (Na, K, Cl, CO2, BUN, Cr, 
 
Gluc, AST/SGOT, ALT/SGPT, Alk Phos, T.bili, Alb, Ca, Total Protein), serum 
 
magnesium; within 14 days prior to start of treatment.  
4. Urine dip (in clinic or lab) 
5. TSH, free T4; within 14 days prior to start of treatment 
6. Pregnancy test (serum or urine Beta-HCG) in women of childbearing potential; 
within 3 days prior to start of treatment. 
7. Radiologic imaging of the areas involved with recurrent/metastatic disease, such as 
the neck, chest, or other areas if needed because of the location of the metastatic 
disease; within 28 days prior to treatment.  
 
 
7.  STUDY PLAN 
 
7.1. Study overview 
 
The patients will receive 5 mg Axitinib twice a day. Dose escalation is planned at 2 weeks (to 7 
mg BID) and at 3 weeks (to 10 mg BID), in the absence of toxicities grade 2 or greater. Dose 
escalation may be resumed at next visit if all toxicities have diminished to grade 1 or less (see 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
20 
 
below) since last follow-up. Each patient will be seen in clinic at 2, 4, 8 weeks after initiation of 
treatment and at monthly intervals thereafter, unless more frequent follow-up is clinically 
indicated.   
 
During follow-up visits, we will assess the toxicities, including checking vital signs, review of 
systems, physical exam and CBCDP, comprehensive metabolic panel, test for proteinuria.  TSH 
should be checked within 14 days of cycle 1, day 1 then should be done every 2 weeks for two 
assessments.   Following completion of these assessments, TSH should be checked following the 
completion of even numbered cycles of chemotherapy. 
 
Telephone call to the patient must be made by a study staff member (licensed RN or MD) at 1 
and 3 weeks. During these calls, toxicity assessment will be conducted, per patient report, and 
toxicity management advice given, including initiation or titration of anti-hypertensive treatment. 
During the Week 3 call, if toxicities are grade 1 or less since last follow-up, dose escalation to 10 
mg BID will be made. Dose escalation may be resumed at least 1 week later if all toxicities have 
diminished to grade 1 or less (see below), and measures have been taken to reasonably prevent 
recurrence of these toxicities with the higher dose since last follow-up.  
 
The response to treatment will be assessed clinically at each visit, as well as by appropriate 
radiologic imaging, starting at 8 weeks +/- 2 weeks and then at 8-week intervals, +/- 2 weeks.  
Tumor response to therapy will be interpreted by Choi Criteria with interpretation performed by 
UMCC Tumor Response and Assessment Core. Patients will be taken off trial for significant side 
effects, per patient preference, or for noncompliance with treatment plan.  Beyond progression, 
survival will be assessed every 12 weeks. Patients will also be followed for 28 days after 
cessation of study participation for safety monitoring. Patients with confirmed progressive 
disease who, in the investigator’s opinion, continue to receive benefit from Axitinib treatment 
and who meet the criteria for treatment may continue to receive treatment as described in Section 
8.3.  Axitinib should be discontinued if there is further evidence of progression defined as an 
additional 10% or greater increase in tumor burden volume from time of initial progression 
(including all target lesions and new measurable lesions). 
 
 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
21 
 
7.2 Study schema  
 
Figure 5. Study schema 
 
 
1 Patients with confirmed progressive disease who, in the investigator’s opinion, continue to 
receive benefit from Axitinib treatment and who meet the criteria for treatment may continue to 
receive treatment as per Section 8.3. 
2 Patients who do not complete at least one month of treatment nor undergo tumor-reimaging for 
reasons other than progression of disease will be considered non evaluable for the primary 
endpoint and will be replaced unless tumor progression is obvious by clinical exam. All patients 
who received at least 1 dose of Axitinib under this protocol will be included in the safety 
analysis 
3Response will be assessed by Choi Criteria 
4Survival assessment can be done by phone and will be performed once every three months (+/- 
1 month)


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
22 
 
8. TREATMENT PLAN: 
 
 
8.1. Allocation to Treatment 
 
This trial is open label. All subjects will receive Axitinib. The starting dose of Axitinib will be 5 
mg orally twice daily. The dose will be escalated to 10 mg orally BID (see below) or modified as 
needed for toxicities (see below). 
 
8.2. Drug Supplies 
 
This trial will utilize the commercially available, marketed Axitinib. Pfizer, Inc. will provide the 
medication free of charge. 
 
8.2.1. Formulation and Packaging 
 
Axitinib will be supplied as 1-mg and 5-mg film coated tablets for oral administration (Table 7). 
The appropriate dose may be achieved by any combination of these tablets during the dose 
titration phase, and pills will be counted into prescription bottles accordingly. Every effort will 
be made to simplify dosage (decrease the number of tablets, and limit to a single kind of tablets, 
either 1-mg or 5-mg) once stable dose is achieved. The tablets may not be split in order to 
achieve the desired dose. At each visit, patient will be asked how many doses were missed and 
when. This information will be recorded in the patient study record. Please see “Patient Follow-
up Form”. 
 
 
8.2.2. Administration 
 
Axitinib will be administered orally at 5 mg twice a day (morning and evening), starting on Day 
1 of the study. Tablets can be taken with or without food, at approximately the same time each 
day. Doses should be taken approximately 12 hours apart. Patients should be instructed that if 
they vomit any time after taking a dose, that they must not “make it up” with an extra dose, but 
instead resume subsequent doses as prescribed. On day of visit patient may hold their morning 
dose until assessed by clinic. Missed doses may be taken late, up to 3 hours before the next 
scheduled dose, otherwise should be skipped.  
 
The patients will be asked to bring medication bottles to each follow-up visit, and remaining pills 
in bottle will be counted at each visit to document compliance. This information will be recorded 
in each patient’s data file. 
 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
23 
 
Table 7. Available Axitinib Dose Levels 
Dose level
Dose
Dispensed as
+2
10 mg BID 
2x5mg tablets BID
+1
7 mg BID
1x5mg tablets + 2x1mg tablets BID
0 (starting dose)
5 mg BID 
1x5mg tablets BID
-1
3 mg BID 
3x1mg tablets BID
-2
2 mg BID 
2x1 mg tablets BID
 
 
Patients experiencing drug reaction greater than CTCAE Grade 2 should undergo dose 
modification as recommended in section 8.2.4. 
 
 
8.2.3. Dose escalations 
 
Dose escalation is planned at 2 weeks (to 7 mg BID) and at 3 weeks (to 10 mg BID), in the 
absence of toxicities grade 2 or greater since last follow-up. Dose escalation may be resumed 
after at least 1 week if all toxicities have diminished to grade 1 or less since last follow-up. Each 
patient will be seen in clinic at 2, 4, 8 weeks after initiation of treatment and at monthly intervals 
thereafter, unless more frequent follow-up is clinically indicated.  Telephone call to the patient 
must be made by a study staff member (a doctor or a nurse) at 1 and 3 weeks, +/- 3 days. During 
these calls, toxicity assessment will be conducted, per patient report, and toxicity management 
advice given. During the Week 3 call, if toxicities are grade 1 or less since last follow-up, 
Axitinib dose escalation to 10 mg BID will be made. Dose escalation up to 10 mg po BID may 
be resumed after at least 1 week if all toxicities have diminished to grade 1 or less (see below), 
and measures have been taken to reasonably prevent recurrence of these toxicities with the 
higher dose. The contents of each planned and patient-initiated phone called will be recorded in 
patient’s study record.  
 
If a patient has a dose reduction for study drug related toxicity, the dose may be considered for 
re-escalation in patients who tolerate the lower dose without toxicities above Grade 1 for at least 
1 week, and measures have been taken to reasonably prevent recurrence of these toxicities with 
the higher dose.  
 
8.2.4. Dose Interruption and Reductions 
Adverse events and other symptoms will be graded according to the current Common 
Terminology for Adverse Events version 4.03 (CTCAE v4.03). This section contains 
management of adverse events except hypertension, hemoptysis and proteinuria which are 
discussed in subsequent sections. 
 
Patients developing a treatment-related CTCAE Grade 1 or 2 adverse event will have their dose 
continued at the same dose level. Patients developing a treatment-related CTCAE Grade 3 or 
above adverse event will have dose reductions as described below. 
 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
24 
 
Treatment delays due to drug-related toxicity > 2 weeks will result in discontinuation of 
treatment.  Patients removed from treatment for intolerable toxicity will still be followed for 
survival. 
The criteria for dose modification for study drug related adverse events is summarized Table 8 
below. 
 
Table 8. Criteria for Dose Modification for Axitinib Related Adverse Events other than 
Hypertension, Hemoptysis, or Proteinuria 
Related Adverse Events 
Intervention 
Grade 1 
Continue at same dose level 
May escalate dose per protocol 
Manage toxicities as medically necessary 
Grade 2 
Continue at same dose level 
Manage toxicities as medically necessary 
Grade 3 nonhematologic 
drug-related toxicity 
Decrease dose to one lower dose level 
Manage toxicities as medically necessary 
Treatment may be interrupted up to 2 weeks per investigator 
discretion 
Grade 4 nonhematologic 
drug-related toxicity or Grade 4 
hematologic toxicity* 
 
*Patients who develop grade 4 
lymphopenia may continue 
study treatment without 
interruption.  
 
Interrupt dosing (up to 2 weeks); re-start at one lower dose 
level as soon as improvement to CTCAE Grade 2.  If patient 
requires dose reduction below 2 mg BID, discontinue trial 
participation.  Manage toxicities as medically necessary 
 
Guidelines for dose reductions for specific adverse events are provided in the following sections. 
 
 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
25 
 
 
 
 
8.2.4.1. Axitinib Dose Reduction for Hypertension 
 
Patients treated with Axitinib will monitored for hypertension closely in the office. Blood 
pressure will be monitored closely at routine visits.  If hypertension is noted at the time of the 
initial encounter, it will be checked 5 minutes after sitting quietly. 
  
Guidance on dose interruption and reduction for hypertension is summarized in Table 9 below. If 
“white coat hypertension” is suspected by the clinician same anti-hypertensive regimen and dose 
of Axitinib can be continued.
Table 9. Hypertension Management Plan for Axitinib 
Degree of Blood Pressure Elevation
2 BP readings separated by at least 30 min show systolic 
pressure 141-160 mm Hg OR diastolic pressure 91-100 mm 
Hg
2 BP readings separated by at least 30 min show systolic
Pressure 161 or above OR diastolic pressure 101 or above
Recurrent hypertension following previous dose
reduction (2 BP readings separated by at least 30 min show 
systolic pressure 141-160 mm Hg OR diastolic pressure 91-
100 mm Hg
Hypertensive urgency or emergency while on study drug, 
with any blood pressure level above 140/90
Management
If not on maximal antihypertensive treatment, institute new or 
additional antihypertensive medication and maintain dose of 
study drug. If on maximal antihypertensive treatment (3 
agents including a diuretic, and no further safe and efficacious 
escalation of antihypertensive therapy is deemed possible by 
the investigators), reduce study drug to one lower dose level.
Interrupt dosing; adjust antihypertensive medication; as soon 
as BP is 140/90  mm Hg or less, restart study drug at one 
lower dose level.
Repeat study drug dose reduction by one lower dose level. If a 
patient requires dose reduction below 2 mg BID, take off 
study.
Take patient off study immediately. Manage as medically 
appropriate, in the appropriate hospital setting.
 
If study drug is held, patients receiving antihypertensive medications should monitor closely for 
hypotension.  Plasma half-life of Axitinib is 2 – 4 hours and BP usually decreases within 1-2 
days following dose interruption. 
 
8.2.4.2. Axitinib Dose Reduction for Hemoptysis 
 
Bleeding from the lungs as evidenced by hemoptysis will be graded according to the site specific 
hemorrhage category of CTCAE v4.03. 
 
Treatment with Axitinib will be discontinued for hemoptysis of >½ tsp of bright red blood 
per day. In addition, a radiologic assessment (e.g., chest x-ray) should be considered for patients 
who have hemoptysis >½ tsp of bright red blood per day. If the hemoptysis resolves to baseline 
within 1 week and there is no evidence of disease cavitation, treatment with Axitinib may 
continue at the current dose level. Patients who experience hemoptysis without resolution to 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
26 
 
baseline within 1 week, or with evidence of disease cavitation should discontinue from treatment 
with Axitinib. 
 
8.2.4.3. Axitinib Dose Reduction for Proteinuria 
 
At documentation of >1+ proteinuria by dipstick, patients should have a 24-hour urine collection 
for total protein. Axitinib dosing may continue while waiting for test results. 
 
If ≤2 g proteinuria/24 hours is reported, treatment with Axitinib may continue without dose 
reduction. 
 
If >2 g proteinuria/24 hours is reported, treatment with Axitinib should be interrupted. A 
twenty-four hour urine collection for total protein and creatinine clearance should be performed 
weekly until results show ≤2 g proteinuria/24 hours, at which time treatment with Axitinib 
may be restarted at one lower dose level. Patients, once restarted on Axitinib, will have 
every-2-weeks monitoring for proteinuria by semiquantitative testing (e.g., dipstick) as long as 
the proteinuria reading is  higher than 1+. The 24-hour urine collection to monitor the degree of 
proteinuria should be repeated every 4 weeks until it has decreased to <500 mg/24 hours. 
If recurrent >2 g proteinuria/24 hours is reported, treatment with Axitinib should be 
interrupted again. Twenty-four hour urine collection for total protein and creatinine clearance 
should be performed every 2 weeks until results show ≤2 g proteinuria/24 hours, at which time 
treatment with Axitinib may be restarted at one lower dose level. If a patient requires dose 
reduction below 2 mg BID, stop trial participation. 
 
8.2.4.4. Axitinib Dose Interruption for Surgery or Surgical Procedures 
 
If surgery is required, treatment with Axitinib must be interrupted at least 24 hours before the 
procedure and the patient’s blood pressure should be monitored closely for hypotension. Patients 
may resume Axitinib seven days after minor surgery and 2-3 weeks after major surgery, 
assuming wound has completely healed and no wound healing complications, at the discretion of 
the prescribing physician.  
 
8.2.4.5. Thyroid Function Tests 
 
Patients receiving Axitinib should be monitored for signs and symptoms of hypothyroidism, such 
as fatigue, deepening of voice, cold intolerance, constipation, anorexia, periorbital edema, 
myxedema, or changes in skin or hair. Hypothyroidism should be treated per standard medical 
practice to maintain euthyroid state. Dose reduction or interruption should not be made for 
thyroid abnormalities alone. 
 
8.3 Treatment Beyond Disease Progression 
 
As described in Section 1.2, traditional imaging response criteria may not fully capture response 
to tyrosine-kinase inhibitors, particularly anti-angiogenic agents.  Although the Choi Criteria 
have been proposed for evaluating response to tyrosine kinase inhibitors, these response criteria 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
27 
 
likely still do not fully capture patients who may derive clinical benefit despite radiologic 
evidence of PD. 
 
Subjects will be permitted to continue on Axitinib treatment beyond initial Choi defined PD as 
long as they meet the following criteria: 
 
- 
Investigator-assessed clinical benefit and do not have rapid disease progression 
- 
Tolerance of study drug 
- 
Stable performance status 
- 
Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (i.e. CNS metastases) 
- 
Subject provides written informed consent prior to receiving any additional Axitinib 
treatment, using an informed consent describing any reasonably foreseeable risk or 
discomforts, or other alternative treatment options. 
 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. 
 
All decisions to continue treatment beyond initial progression must be documented in the study 
records. Subjects will be re-consented with an informed consent describing any reasonably 
foreseeable risks or discomforts. 
 
Subjects should discontinue study therapy upon further evidence of further progression, defined 
as an additional 10% or greater increase in tumor burden volume from time of initial progression 
(including all target lesions and new measurable lesions). 
 
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 15 
mm). Any new lesion considered non-measurable at the time of initial progression may become 
measurable and therefore included in the tumor burden measurement if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes, which must have an increase 
in short axis to at least 15 mm). 
 
For statistical analysis that include the investigator-assessed progression date, subjects who 
continue treatment beyond investigator-assessed, Choi Response defined progression will be 
considered to have investigator-assessed progressive disease at the time of the initial progression 
event. 
 
8.4. Drug Storage and Drug Accountability 
 
A co-investigator or an approved representative (e.g., research pharmacists) will ensure that all 
trial drugs are stored in a secure area, under recommended storage conditions and in accordance 
with applicable regulatory requirements.  
 
The research pharmacy will assist with management of drug storage and accountability. Drug 
accountability forms will be used to maintain accurate records of receipt, dispensing and return 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
28 
 
of trial medication. Any drug that is not dispensed at the end of the trial or any returned drug 
supplies should be returned to Pfizer Inc., or disposed of in accordance with instructions received 
in writing from Pfizer, Inc. 
 
8.5. Concomitant Medication(s) 
 
In vitro studies with human liver microenzymes and recombinant CYP450 enzymes indicated 
that Axitinib metabolism was primarily mediated by the drug-metabolizing enzyme CYP3A, 
and to a lesser extent by CYP1A2. Additionally, the drug also undergoes N-glucuronidation in 
liver microsomes of some species. Clinically, there is likelihood that Axitinib plasma 
concentrations may be increased in the presence of co-administered potent inhibitors of the 
CYP3A and glucuronosyl transferase enzymes. The potential exists for drug-drug interactions 
with strong CYP3A4/5 inhibitors and inducers.  
 
Axitinib metabolism may be induced in patients taking strong CYP3A4/5 inducers and inhibitors 
as these may alter Axitinib plasma concentrations. 
 
The following potent CYP3A4/5 strong inhibitors and CYP3A4/5 strong inducers are prohibited: 
 
CYP3A4/5 INHIBITORS (Strong) 
CYP3A4/5 INDUCERS (Strong) 
Atazanavir 
Boceprevir 
Coniveptan 
Clarithromycin 
Grapefruit and grapefruit juice 
Indinavir 
Itraconazole 
Ketoconazole 
Nefazodone 
Nelfinavir 
Posaconazole 
 
Carbamazepine 
Dexamethasone 
Fosphenytoin 
Phenytoin 
Phenobarbital 
Rifampin 
Rifapentin 
Rifabutin 
St. John’s Wort 
Ritonavir 
Saquinavir 
Telaprevir 
Telithromycin 
Voriconazole 
 
 
 
 
Other CYP3A4/5 inhibitors and inducers are allowed per investigator’s discretion.  
 
Since CYP1A2 is also known to be induced in chronic smokers, there is likelihood 
that Axitinib plasma concentrations may be reduced in these individuals.  Based on preclinical 
and extensive clinical experience, clinically significant drug interactions are unlikely. 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
29 
 
 
8.6. Rescue Therapy 
 
No mechanistically specific antagonists for Axitinib are available and standard supportive 
measures should be used in the case of excessive pharmacological effects or adverse reaction. 
 
9.  RESPONSE CRITERIA 
 
 
The Choi Criteria will be used to assess tumor response to therapy.  Interpretation will be 
performed by centralized UMCC Tumor Response and Assessment Core (TRAC). If density 
measurements are not available and cannot be accurately measured by photography or imaging, 
response can be dictated by measurement alone (i.e.for cutaneous squamous cell carcinomas that 
are not visualized on CT scan but are measurable on physical exam only). Non-target lesions are 
also permissible in which case overall assessment would be limited to complete response, stable 
disease, and progressive disease. 
 
Complete Response: 
- 
Disappearance of all lesions 
- 
No new lesions 
 
Partial Response: 
- 
A decrease in size1 of ≥ 10% or a decrease in tumor density (HU) ≥ 15% on CT 
- 
No new lesions 
- 
No obvious progression of non-measurable disease 
 
Stable Disease 
- 
Does not meet the criteria for CR, PR, or PD 
- 
No symptomatic deterioration attributed to tumor progression 
 
Progressive Disease 
- 
An increase in tumor size of ≥ 10% and dose not meet criteria of PR by tumor density 
(HU) on CT 
- 
New lesions 
- 
New intratumoral nodules or increase in the size of the existing intratumoral nodules 
 
1- The sum of longest diameters of target lesions as defined in RECIST 
 
10. CRITERIA FOR DISCONTINUATION OF TREATMENT 
 
1. Unacceptable toxicity. 
2. Intercurrent illness, which prevents further administration of treatment. 
3. Patient preference. 
4. Confirmed PD and Investigator determination that the patient is no longer benefiting from 
treatment with Axitinib (per section 8.3) 
5. Treatment delays due to drug-related toxicity > 2 weeks. 
6. Non-compliance with treatment.  


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
30 
 
7. If the disease becomes amenable to resection or (chemo) radiation with curative intent as a 
result of Axitinib treatment, Axitinib will be stopped, and the alternative treatment instituted that 
would offer the best chance of cure for the patient. Such patients will be included in safety and 
efficacy analysis. 
 
 
11. SAFETY ASSESSMENTS 
 
The safety of Axitinib should be evaluated using the standard clinical practice, with special 
attention paid to hypertension, proteinuria, thrombosis, hemoptysis, bleeding risk, and 
concomitant medications. Patients receiving Axitinib should be monitored for signs and 
symptoms of hypothyroidism, such as fatigue, deepening of voice, cold intolerance, constipation, 
anorexia, periorbital edema, myxedema, or changes in skin or hair. Hypothyroidism should be 
treated per standard medical practice to maintain euthyroid state. 
 
 
12. ADVERSE EVENT REPORTING 
 
12.1. Adverse Events 
 
All observed or volunteered adverse events regardless of suspected causal relationship to 
Axitinib will be reported as described in the following sections. 
 
For all adverse events the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event requiring immediate notification to Pfizer, Inc. or its 
designated representative. For all adverse events sufficient information should be obtained by the 
investigator to determine the causality of the adverse event. The investigator is required to assess 
causality. For adverse events with a causal relationship to Axitinib, follow-up by the investigator 
is required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer, Inc. concurs with that assessment. 
 
12.2. Reporting Period 
 
Adverse events reporting, including suspected, unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations. For serious adverse events, the 
reporting period to Pfizer, Inc. or its designated representative begins from the time that the 
subject has taken at least one dose of trial treatment through the last subject visit. Any serious 
adverse event occurring any time after the reporting period must be promptly reported if a causal 
relationship to Axitinib is suspected. 
 
Adverse events should be recorded on the CRF from the time the subject has taken at least one 
dose of trial treatment through last subject visit. 
 
If a patient begins a new anticancer therapy, the adverse event reporting period for non-serious 
adverse events ends at the time the new treatment is started. Death must be reported if it occurs 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
31 
 
during the serious adverse event reporting period after the last dose of investigational product, 
irrespective of any intervening treatment. 
 
12.3. Definition of an Adverse Event 
 
An adverse event is any untoward medical occurrence in a clinical investigation subject 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage. Examples of adverse events include but are not limited 
to:  
- Abnormal test findings; 
- Clinically significant symptoms and signs; 
- Changes in physical examination findings; 
- Hypersensitivity. 
Additionally, they may include the signs or symptoms resulting from exposure in Utero. 
 
Worsening of signs and symptoms of the malignancy under trial should be reported as adverse 
events in the appropriate section of the CRF . Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as adverse events. 
 
12.4. Abnormal Test Findings 
 
The criteria for determining whether an abnormal objective test finding should be reported as an 
adverse event are as follows: 
- Test result is associated with accompanying symptoms; and/or 
- Test result requires additional diagnostic testing or medical/surgical intervention; and/or 
- Test result leads to a change in trial dosing outside of protocol-stipulated dose 
adjustments or discontinuation from the trial, significant additional concomitant drug 
treatment, or other therapy; and/or 
- Test result is considered to be an adverse event by the investigator 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event. Any abnormal test result that is determined to be an error does not 
require reporting as an adverse event. 
 
12.5. Serious Adverse Events 
 
A serious adverse event or serious adverse drug reaction is any untoward medical occurrence at 
any dose that: 
- Results in death; 
- Is life-threatening (immediate risk of death); 
- Requires inpatient hospitalization or prolongation of existing hospitalization; 
- Results in persistent or significant disability/incapacity; 
- Results in congenital anomaly/birth defect. 
 
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as serious adverse events unless the outcome is fatal during the trial or 
within the safety reporting period. Hospitalizations due to signs and symptoms of disease 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
32 
 
progression should not be reported as serious adverse events. If the malignancy has a fatal 
outcome during the study or within the safety reporting period, then the event leading to death 
must be recorded as an adverse event and as a serious adverse event with CTC grade 5 (See  
Severity Assessment). Medical and scientific judgment should be exercised in determining 
whether an event is an important medical event. An important medical event may not be 
immediately life-threatening and/or result in death or hospitalization. However, if it is 
determined that the event may jeopardize the subject and may require intervention to prevent one 
of the other outcomes, the important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
 
12.6. Hospitalization 
 
Adverse events reported from clinical studies associated with hospitalization or prolongation of 
hospitalization are considered serious. Any initial admission (even if less than 24 hours) to a 
healthcare facility meets these criteria. Admission also includes transfer within the hospital to an 
acute/intensive care unit (e.g., from the psychiatric wing to a medical floor, medical floor to a 
coronary care unit, neurological floor to a tuberculosis unit). 
Hospitalization does not include the following: 
- Rehabilitation facilities; 
- Hospice facilities; 
- Respite care (e.g., caregiver relief); 
- Skilled nursing facilities; 
- Nursing homes; 
- Routine emergency room admissions; 
- Same day surgeries (as outpatient/same day/ambulatory procedures). 
 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event. Examples include: 
- Admission for treatment of a preexisting condition not associated with the development 
of a new adverse event or with a worsening of the preexisting condition (e.g., for work-up 
of persistent pre-treatment lab abnormality); 
- Social admission (e.g., subject has no place to sleep); 
- Administrative admission (e.g., for yearly physical exam); 
- Protocol-specified admission during a clinical trial (e.g., for a procedure required by the 
trial protocol); 
- Optional admission not associated with a precipitating clinical adverse event (e.g., for 
elective cosmetic surgery); 
- Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject; 
- Admission exclusively for the administration of blood products. 
 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as adverse events. However, the medical condition for which the procedure was 
performed should be reported and it meets the definition of an adverse event. For example, an 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
33 
 
acute appendicitis that begins during the adverse event reporting period should be reported as the 
adverse event, and the resulting appendectomy should be recorded as treatment of the adverse 
event. 
 
 
12.7. Severity Assessment 
 
If required on the adverse event case report forms, the investigator will use the following 
definitions of severity in accordance with National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03 to describe the maximum intensity of the 
adverse event. If the event is serious, the CTCAE grade reported in the adverse event CRF must 
be consistent with the description of CTCAE grade included in the narrative section of the 
serious adverse event report. 
 
 
GRADE  
Clinical Description of Severity 
   0  
 
no change from normal or reference range  
   1  
 
mild adverse event 
   2   
  
moderate adverse event 
   3  
 
severe adverse event 
   4  
 
life-threatening or disabling adverse event 
   5  
 
death related to adverse event 
 
Note the distinction between the severity and the seriousness of an adverse event. A severe event 
is not necessarily a serious event. For example, a headache may be severe (interferes 
significantly with subject's usual function) but would not be classified as serious unless it met 
one of the criteria for serious adverse events, listed above. 
 
 
12.8. Causality Assessment 
 
The investigator’s assessment of causality must be provided for all adverse events (serious and 
non-serious), the investigator must record the causal relationship in the CRF, as appropriate, and 
report such an assessment in accordance with the serious adverse reporting requirements if 
applicable. An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that Axitinib caused or contributed to an adverse event. If the investigator 
does not know whether or not Axitinib caused the event, then the event will be handled as 
“related to investigational product” for reporting purposes, as defined by Pfizer, Inc. (See Section 
on Reporting Requirements). If the investigator's causality assessment is “unknown but not 
related to investigational product,” this should be clearly documented on trial records. 
 
In addition, if the investigator determines a serious adverse event is associated with trial 
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse event 
reporting requirements, if applicable. 
 
12.9. Exposure In Utero 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
34 
 
 
An Exposure In Utero (EIU) occurs if: 
 
1. A female becomes, or is found to be, pregnant either while receiving or having been directly 
exposed to (e.g., environmental exposure) Axitinib, or the female becomes, 
or is found to be, pregnant after discontinuing and/or being directly exposed to Axitinib 
(maternal exposure); 
 
2. A male has been exposed, either due to treatment or environmental, to Axitinib prior to or 
around the time of conception and/or is exposed during the partner 
pregnancy (paternal exposure). 
 
If any study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with Axitinib, the investigator must submit this information to Pfizer, 
Inc. on an Exposure in Utero Form. In addition, the investigator must submit information 
regarding environmental exposure to Pfizer, Inc. product in a pregnant woman (e.g., a nurse 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or spillage) 
using the Exposure in Utero Form. This must be done irrespective of whether an adverse event 
has occurred and within 24 hours of awareness of the pregnancy. The information submitted 
should include the anticipated date of delivery (see below for information related to induced 
termination of pregnancy). 
 
Follow-Up is conducted to obtain pregnancy outcome information on all Exposure in Utero 
reports with an unknown outcome. The investigator will follow the pregnancy until completion 
or until pregnancy termination (ie, induced abortion) and then notify Pfizer, Inc. of the outcome. 
The investigator will provide this information as a follow up to the initial Exposure in Utero 
Form. The reason(s) for an induced abortion should be specified. An EIU report is not created 
when an ectopic pregnancy report is received since this pregnancy is not usually viable. Rather, a 
serious adverse event case is created with the event of ectopic pregnancy. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as a serious 
adverse event (ie, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly 
[including that in an aborted fetus, stillbirth or neonatal death]), the investigator should follow 
the procedures for reporting serious adverse events. 
 
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth 
(ie, no minimum follow-up period of a presumably normal infant is required before an Exposure 
in Utero Form can be completed). The “normality” of an aborted fetus can be assessed by gross 
visual inspection, unless pre-abortion test findings are suggestive of a congenital anomaly. 
 
Additional information about pregnancy outcomes that are classified as serious adverse events 
follows: 
- “Spontaneous abortion” includes miscarriage and missed abortion. 
- All neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as serious adverse events. In addition, any infant death after 1 month that the 
investigator assesses as possibly related to the in utero exposure to Axitinib should be reported. 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
35 
 
 
Additional information regarding the Exposure in Utero may be requested by the investigator. 
Further follow-up of birth outcomes will be handled on a case-by-case basis (e.g., follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator must obtain permission from the subject’s partner in order to conduct any follow-up 
or collect any information. 
 
12.10. Withdrawal Due to Adverse Events  
 
Withdrawal due to adverse event should be distinguished from withdrawal due to insufficient 
response, according to the definition of adverse event noted earlier, and recorded on the 
appropriate adverse event CRF page. 
 
When a subject withdraws due to a serious adverse event, the serious adverse event must be 
reported in accordance with the reporting requirements defined below. 
 
12.11. Eliciting Adverse Event Information 
 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the trial subject. In addition, each trial subject will be questioned 
about adverse events. 
 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
36 
 
12.12. Reporting Requirements 
 
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
event. If a serious adverse event occurs, it will be reported via submission of Pfizer, Inc. 
Investigator-Initiated Research Serious Adverse Event (IIR SAE) form, according to guidelines 
provided in  Pfizer, Inc. IIR Safety Reporting Reference Manual Version 3, and IIR SAE Form 
Completion Guide, or Form FDA 3500 A (Med Watch Form) . This will be faxed to Pfizer, Inc. 
U.S. Clinical Trial Department at 1-866-997-8322 using the Pfizer, Inc. Investigator Initiated 
Research Reportable Event Fax Cover Sheet. The Investigator-Initiated Research Serious 
Adverse Event (IIR SAE) form must be submitted to Pfizer, Inc. immediately for a death or life-
threatening event, and within 24 hours for all other types of SAEs. Any SAEs reported to Pfizer, 
Inc. should also be faxed to NCCN at 215-358-7699 or emailed via ORPReports@nccn.org. 
 
All Serious adverse Events (SAE’s) will have written report sent to:  
 
1. 
Principal Investigator of the study: Fax 647-8792 
 
2. 
Data Manager 
 
3. 
The Oncology Clinical Trials Support Unit (O-CTSU) staff will coordinate the reporting 
process between the Investigator and the IRBMED as well as other applicable reporting agencies 
(FDA, CTEP, NCCN, Pfizer, Inc.). Copies of all related correspondence and reporting 
documents will be maintained in the regulatory file. 
 
Deaths or life-threatening adverse events will be reported to the University of Michigan Medical 
Institutional Review Board (IRBMED) in accordance with the reporting policy of the IRB. 
 
 
12.12.1. Serious Adverse Event Reporting Requirements 
 
If a serious adverse event occurs, NCCN and Pfizer, Inc. are to be notified within 24 hours of 
awareness of the event by the investigator. In particular, if the serious adverse event is fatal or 
life-threatening, notification to Pfizer, Inc. must be made immediately, irrespective of the extent 
of available adverse event information. This timeframe also applies to additional new 
information (follow-up) on previously forwarded serious adverse event reports as well as to the 
initial and follow-up reporting of Exposure in Utero cases.  Pfizer, Inc. and NCCN should be 
notified via the reporting requirements stipulated in Section 12.12 (Reporting Requirements). 
Such events will be reported via submission of Pfizer, Inc. Investigator-Initiated Research 
Serious Adverse Event (IIR SAE) form, according to guidelines provided in  Pfizer, Inc. IIR 
Safety Reporting Reference Manual Version 3, and IIR SAE Form Completion Guide, or Form 
FDA 3500 A (Med Watch Form) . This will be faxed to Pfizer, Inc. U.S. Clinical Trial 
Department at 1-866-997-8322 using the Pfizer, Inc. Investigator Initiated Research Reportable 
Event Fax Cover Sheet. The Investigator-Initiated Research Serious Adverse Event (IIR SAE) 
form must be submitted to Pfizer, Inc. immediately for a death or life-threatening event, and 
within 24 hours for all other types of SAEs. Any SAEs reported to Pfizer, Inc. should also be 
faxed to NCCN at 215-358-7699 or emailed via ORPReports@nccn.org. 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
37 
 
 
In the rare event that the investigator does not become aware of the occurrence of a serious 
adverse event immediately (e.g., if an outpatient study subject initially seeks treatment 
elsewhere), the investigator is to report the event within 24 hours after learning of it and 
document the time of his/her first awareness of the adverse event. 
 
For all serious adverse events, the investigator is obligated to pursue and provide information to 
NCCN and Pfizer, Inc. in accordance with the timeframes for reporting specified above. In 
addition, an investigator may be requested by Pfizer, Inc. to obtain specific additional follow-up 
information in an expedited fashion. This information may be more detailed than that captured 
on the adverse event case report form. In general, this will include a description of the adverse 
event in sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality. Information on other possible causes of the event, such as 
concomitant medications and illnesses must be provided. In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer, Inc. or its 
designated representative. 
 
12.12.2. Non-Serious Adverse Event Reporting Requirements 
 
Non-serious adverse events are to be reported on the adverse event CRFs, which are to be 
submitted to Pfizer, Inc.. 
 
12.13. Data and Safety Monitoring 
 
12.13.1 This study will be monitored in accordance with the NCI approved University of 
Michigan Rogel Cancer Center Data and Safety Monitoring Plan. 
 
12.13.2. The study team will meet quarterly or more frequently depending on the activity of the 
protocol. During these regular meetings, the study team will discuss matters related to: 
1. safety of study participants (SAE/UaP reporting) 
2. validity and integrity of the data 
3. enrollment rate relative to expectations, characteristics of participants 
4. retention of participants, adherence to protocol (potential or real protocol deviations) 
5. data completeness 
 
12.13.3. Study team meetings will be documented by the Protocol Specific Data and Safety 
Monitoring Report (DSMR).  The data manager or designee assigned to the trial will be 
responsible for completing the report.  DSMRs will be signed by the Principal Investigator or by 
one of the co-investigators and will be kept on file in the Oncology Clinical Trials Support Unit 
(O-CTSU). 
 
12.13.4. The University of Michigan Rogel Cancer Center Data and Safety Monitoring 
Committee (DSMC) will provide independent oversight of the safety and data integrity for this 
trial.  DSMRs and any other pertinent documents will be submitted to the DSMC for review on a 
quarterly basis unless specified more frequently by a DSMC ruling. 
 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
38 
 
12.13.5. The Principal Investigator or designee will forward all correspondence and 
recommendations generated by the DSMC to the Institutional Review Board. 
 
13. STATISTICAL METHODS 
 
13.1. Primary Objectives: 
The primary aim of this study is to compare 6-month overall survival after treatment with 
Axitinib in patients with unresectable, recurrent or metastatic head and neck cancer to historical 
rates. Based on results in the literature, we assume a 6-month mortality rate of 50% under 
current standard care in this patient population (11, 52). We will test whether survival after 
treatment with Axitinib is improved to 70% at 6-months compared to 50%.   
Overall survival will be determined from the date of treatment initiation to date of death from 
any cause. For the primary endpoint, patients that are alive at 6 months following the initiation of 
study treatment will be considered successful.  All other patients will be considered 
unsuccessful. Patients will be considered evaluable for the primary endpoint if they receive any 
dose of Axitinib. 
 
13.2. Sample size justification: 
 
We will enroll 37 additional patients for comparison of overall survival. Based on historical data, 
6 month OS in heavily pretreated patients such as those included in this study is 50%. Thirty-
seven patients will provide 80% power to detect a meaningful difference in proportion alive at 6-
months (70% vs 50% historically) with a type I error rate of 5%. For the primary endpoint of 
overall survival we anticipate no missing data and will test whether the proportion alive at 6 
months is greater than the historical rate of 50% with an upper tailed test of binomial proportion. 
Based on our prior experience at the University of Michigan, we anticipate accrual of 
approximately 4 patients every 5 months. With this rate of accrual, we can enroll 40 eligible 
patients in 50 months. With a minimum follow-up of 6 month for each patient, the study will 
complete in about 56 months.  
 
13.3. Stopping rules for futility: 
As we observed considerable evidence of activity in UMCC 2011.053, we plan no interim 
analysis for futility with data collected in the expansion cohort B. Formal analysis of efficacy 
will be performed at trial completion. 
 
13.4. Analysis plan: 
- To estimate survival rates.  
Overall and progression-free survival rates at 2, 4 and 6 months will be reported along with 95% 
confidence intervals based on the binomial distribution.  Kaplan-Meier methods will also be 
conducted to estimate these rates and the medians of PFS and overall survival (OS) of the 37 
evaluable patients, with a corresponding standard error estimate based on Greenwood’s formula 
(53).  


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
39 
 
Among this cohort of patients, progression will be determined based on Choi critieria. 
- To determine the response.  
The best overall response rate will be determined for each evaluable patient at 8 and 16 weeks 
following the start of Axitinib. The proportion of evaluable patients who have an objective 
response (complete or partial) and stable disease will be calculated, and a 95% exact binomial 
confidence interval will be determined. 
- To determine the toxicity profile of this treatment regimen.  
The proportion of treated patients experiencing any clinically significant (Grade 3 or worse) 
toxicity will be determined, with a 95% exact binomial confidence interval; specific toxicities of 
all grades will be tabulated. 
 
 
14. DATA ANALYSIS 
 
14.1. Analysis of Overall Survival 
 
Overall survival will be determined from the date of treatment initiation to date of death from 
any cause. For the primary endpoint, patients that are alive at 6 months following the initiation of 
study treatment will be considered successful.  All other patients will be considered 
unsuccessful. Patients will be considered evaluable for the primary endpoint if they receive any 
dose of Axitinib. For the primary endpoint we anticipate no missing data and will test whether 
the proportion alive at 6 months is greater than the historical rate of 50% with an upper tailed test 
of binomial proportion. 
 
 
14.2. Safety Analysis 
 
All patients receiving at least 1 dose of Axitinib under this protocol will be included in the 
safety analyses. Adverse events will be coded and grouped by body system. The incidence of 
each adverse event will be tabulated and displayed by starting dose level. Tabulations by 
maximum severity and relationship to Axitinib will also be included.  Summary patient listings 
will be provided for SAEs, adverse events resulting in discontinuation of Axitinib, and deaths 
within 28 days of drug discontinuation and possibly or probably related to Axitinib. 
 
14.3. Efficacy Analysis 
 
Efficacy analysis will include Progression-free survival (PFS), Overall response rate (ORR), 
including complete (CR) and partial response (PR), stable disease, disease control rate 
(CR+PR+stable disease) at 16 weeks, along with overall survival (OS).  
 
 
15. QUALITY CONTROL AND QUALITY ASSURANCE 
 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
40 
 
During trial conduct, Pfizer, Inc. or its agent may conduct periodic monitoring visits to ensure 
that the protocol and GCPs are being followed. The monitors may review source documents to 
confirm that the data recorded on CRFs is accurate. The investigator and institution will allow 
Pfizer, Inc. monitors or its agents and appropriate regulatory authorities direct access to source 
documents to perform this verification. 
 
The trial site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by Pfizer, Inc., and/or to 
inspection by appropriate regulatory authorities. 
 
It is important that the investigators and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
 
16. DATA HANDLING AND RECORD KEEPING 
 
16.1. Case Report Forms / Electronic Data Record 
 
As used in this protocol, the term Case Report Form (CRF) should be understood to refer to 
either a paper form or an electronic data record or both, depending on the data collection method 
used in this trial. 
 
A CRF is required and should be completed for each included subject. The completed original 
CRFs are the sole property of Pfizer, Inc. and should not be made available in any form to third 
parties, except for authorized representatives of Pfizer, Inc. or appropriate regulatory authorities, 
without written permission from Pfizer, Inc.. 
 
It is the investigator’s responsibility to ensure completion and to review and approve all CRFs. 
CRFs must be signed by the investigator or by an authorized staff member. These signatures 
serve to attest that the information contained on the CRFs is true. At all times, the investigator 
has final personal responsibility for the accuracy and authenticity of all clinical and laboratory 
data entered on the CRFs. Subject source documents are the physician’s subject records 
maintained at the trial site. In most cases, the source documents will be the hospital’s or the 
physician’s chart. In cases where the source documents are the hospital or the physician’s chart, 
the information collected on the CRFs must match those charts. 
 
In some cases, the CRF may also serve as the source document. In these cases, Pfizer, Inc. and 
the investigator must prospectively document which items will be recorded in the source 
documents and for which items the CRF will stand as the source document. 
 
16.2. Record Retention 
 
To enable evaluations and/or audits from regulatory authorities, NCCN or Pfizer, Inc., the 
investigator agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, e.g., CRFs and hospital records), all original signed informed 
consent forms, copies of all CRFs, serious adverse event forms, source documents, and detailed 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
41 
 
records of treatment disposition. The records should be retained by the investigator according to 
ICH, local regulations, or as specified in the NCCN Research Agreement, whichever is longer. 
 
If the investigator relocates, retires, or for any reason withdraws from the trial, NCCN should be 
prospectively notified. The trial records must be transferred to an acceptable designee, such as 
another investigator or another institution. The investigator must obtain NCCN’s written 
permission before disposing of any records, even if retention requirements have been 
met. 
 
17. ETHICS 
 
17.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
 
It is the responsibility of the investigator to have prospective approval of the trial protocol, 
protocol amendments, informed consent forms, and other relevant documents, e.g., 
advertisements, if applicable, from the IRB/IEC. All correspondence with the IRB/IEC should 
be retained in the Investigator File. Copies of IRB/IEC approvals should be forwarded to NCCN. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects. In that 
event, the investigator must notify the IRB/IEC and NCCN in writing within 5 working days 
after the implementation. 
 
17.2. Ethical Conduct of the Trial 
 
The trial will be performed in accordance with the protocol, International Conference on 
Harmonization Good Clinical Practice guidelines, and applicable local regulatory requirements 
and laws. 
 
17.3. Subject Information and Consent 
 
All parties will ensure protection of subject personal data and will not include subject names on 
any Pfizer, Inc. forms, reports, publications, or in any other disclosures, except where required 
by laws. In case of data transfer, Pfizer, Inc. will maintain high standards of confidentiality and 
protection of subject personal data. 
 
The informed consent form must be in compliance with ICH GCP, local regulatory requirements, 
and legal requirements. 
 
The informed consent form used in this study, and any changes made during the course of the 
study, must be prospectively approved by both the IRB/IEC and NCCN before use. 
 
The investigator must ensure that each study subject, or his/her legally acceptable representative, 
is fully informed about the nature and objectives of the study and possible risks associated with 
participation. The investigator, or a person designated by the investigator, will obtain written 
informed consent from each subject or the subject’s legally acceptable representative before any 
study-specific activity is performed. The investigator will retain the original of each subject’s 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
42 
 
signed consent form. 
 
17.4. Reporting of safety issues and serious breaches of the protocol or ICH GCP 
 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of Axitinib, Pfizer, 
Inc. should be informed immediately. 
 
In addition, the investigator will inform Pfizer, Inc. immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP that the investigator becomes aware of. 
 
18. COMPLETION OF TREATMENT AND FOLLOW-UP 
 
After completion of treatment on study patients will be followed for survival.  Survival 
assessment can be done by phone and will be performed once every three months (+/- 1 month) 
 
 
19. NCCN DISCONTINUATION CRITERIA 
 
Premature termination of this clinical trial may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of NCCN. In 
addition, Pfizer, Inc. retains the right to discontinue development of Axitinib at any time. 
NCCN reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. If a 
trial is prematurely terminated or discontinued, NCCN will promptly notify the investigator. 
After notification, the investigator must contact all participating patients within a 4-week time 
period. As directed by NCCN, all trial materials must be collected and all CRFs completed to the 
greatest extent possible. 
 
20. PUBLICATION OF TRIAL RESULTS 
 
20.1. Communication of Results by Pfizer, Inc. 
 
Pfizer, Inc. fulfills its commitment to publicly disclose the results of studies through posting the 
results of this study on ClinicalStudyResults.org. Pfizer, Inc. posts the results of studies that fall 
into either of the following categories: 
- Studies that Pfizer, Inc. registered on www.clinicaltrials.gov, (ClinicalTrials.gov) regardless of 
the reason for registration; OR 
- All other studies for which the results have scientific or medical importance as determined by 
Pfizer, Inc.. For studies involving a Pfizer, Inc. product, the timing of the posting depends on 
whether the Pfizer, Inc. product is approved for marketing in any country at the time the study is 
completed: 
- For studies involving products already approved in any country and for studies that do not 
involve a Pfizer, Inc. product, Pfizer, Inc. posts results within one year after study completion, 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
43 
 
defined as Last Subject Last Visit (LSLV); 
- For studies involving products that are not yet approved in any country, Pfizer, Inc. posts the 
results of already-completed studies within one year after the first regulatory approval of 
the product; 
- For studies involving products whose drug development is discontinued before approval, 
Pfizer, Inc. posts the results within one year after such discontinuation. 
Pfizer, Inc.’s posting on ClinicalStudyResults.org includes the following elements: 
- Protocol title, study phase, and indication; 
- A link to approved product labeling, if applicable; 
- The synopsis of study results; 
- Citations of known study publications; 
- Legal disclaimer. 
 
The study results synopsis posted on ClinicalStudyResults.org (called the PhRMA website 
synopsis) uses the format established by the ICH-E3 Clinical Study Report (CSR) Synopsis. 
If posting of study results to ClinicalStudyResults.org jeopardizes a planned publication of the 
study results, a Pending Full Publication notice is substituted for the synopsis until the study 
results publication has issued or two years have elapsed, whichever occurs first. Pfizer, Inc. posts 
citations only for publications that are accessible in recognized (searchable) 
publication databases.  
 
20.2. Publications by Investigators 
 
Pfizer, Inc. has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational Drug. 
However, to ensure against inadvertent disclosure of Confidential Information or unprotected 
Inventions, Investigator will provide NCCN and Pfizer, Inc. an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed. 
 
Investigator will provide manuscripts, abstracts, or the full text of any other intended disclosure 
(poster presentation, invited speaker or guest lecturer presentation, etc.) to NCCN at least 30 
days before they are submitted for publication or otherwise disclosed. If any patent action is 
required to protect intellectual property rights, Investigator agrees to delay the disclosure for a 
period not to exceed an additional 60 days. 
 
Investigator will, on request, remove any previously undisclosed Confidential Information (other 
than the study results themselves) before disclosure. 
 
For all publications relating to the study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical Considerations 
in the Conduct and Reporting of Research” of the Uniform Requirements for Manuscripts 
Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, established by 
the International Committee of Medical Journal Editors. 
 
Publication of study results is also provided for in the NCCN Research Agreement between 
NCCN and the institution. In this section entitled Publications, the defined terms shall 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
44 
 
have the meanings given to them in the NCCN Research Agreement. 


Axitinib In Head And Neck Cancer  --  Protocol For A Phase II Study 
 
45 
 
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