A Phase 2 Clinical Trial of Axitinib and Avelumab in Patients With Recurrent/Metastatic Adenoid Cystic Carcinoma (ACC)
Phase: PHASE2
Conditions: Metastatic Adenoid Cystic Carcinoma, Progressive Disease, Recurrent Adenoid Cystic Carcinoma
Sponsor: M.D. Anderson Cancer Center

MDA Protocol: 2019-0107 
11.22.19 
MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2019-0107 
Protocol Title 
A phase 2 clinical trial of Axitinib and Avelumab in patients with 
recurrent/metastatic adenoid cystic carcinoma (ACC) 
Protocol Phase 
2 
Protocol Version 
05 
Version Date 
11.20.19 
Protocol PI 
Renata Ferrarotto, M.D. 
Department 
Thoracic Head/Neck Medical Oncology 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
Exempt 
Proprietary of MD Anderson Cancer Center 

 
 
 
 
 
 
 
 
 
 
Title: A phase 2 clinical trial of Axitinib and Avelumab in patients with recurrent/metastatic adenoid 
cystic carcinoma (ACC) 
 
Study Chair: Renata Ferrarotto MD 
Co-Chair: Yasir Elamin MD 
UT MD Anderson Cancer Center 
Department of Thoracic Head/ Neck Medical Oncology 
1515 Holcombe Blvd, Unit 0432 
Ph: 713-792-6363 
Fax: 713-792-1220 
RFerrarotto@mdanderson.org 
 
IND:  Exempt 
 
 
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Table of Contents 
1. Introduction ................................................................................................................................................ 3 
2. Study Objectives ....................................................................................................................................... 13 
3. Study Design ............................................................................................................................................. 13 
4. Study Population ....................................................................................................................................... 14 
5. Treatment Plan ......................................................................................................................................... 17 
6. Study Calendar and Procedures................................................................................................................ 33 
7. Adverse Events Collection and reporting ................................................................................................. 36 
8. Recording and Collection of Data ............................................................................................................. 42 
9. Statistical Consideration ........................................................................................................................... 42 
10. References .............................................................................................................................................. 45 
Appendix 1. Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Guidelines ......................... 46 
Appendix 2. Immune-related Response Criteria Derived From RECIST v1.1 (irRECIST) ................................. 49 
Appendix 3. ECOG Performance Status .......................................................................................................... 50 
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1. Introduction 
 
 
1.1 Background and Rationale 
 
Approximately 1,200 new cases of adenoid cystic carcinoma (ACC) occur each year in the United 
States. ACC is the second most common malignant salivary gland tumor with a recurrence rate 
following curative intent treatment of 40-50%. ACC is overall chemotherapy-refractory and there is 
no standard of care treatment for patients with recurrent/metastatic disease, highlighting the urgent 
need for effective therapy for this patient population. While the majority of patients have indolent 
metastatic disease, which eventually “accelerates”, approximately 15% have NOTCH1 activating 
mutations which drives a very aggressive disease phenotype and shorter survival. 
 
VEGF is highly expressed in ACC and its overexpression correlates with tumor aggressiveness. 
VEGFR inhibitors have shown modest activity in ACC as single agent, rendering response rates of 
approximately 5 to 10% and disease stability in a large proportion of patients. Given most metastatic 
ACC have an indolent course, the clinical benefit of disease stability is questionable if disease 
progression in a pre-specified timeframe is not documented. 
 
In a phase II single arm study including 33 ACC patients, axitinib led to objective responses in 9% 
of patients, disease stability in 75.8% (30% for more than 6 months), and 67% of patients had tumor 
shrinkage. In this study, evidence of disease progression by imaging within 6 months of study 
enrollment or worsening disease-related symptoms was required inclusion criteria. 
Immune profiling of ACC samples revealed that most tumors express PD-L2 but have few infiltrating 
immune cells. Pembrolizumab single agent is being studied in salivary gland carcinomas in a phase 
1b trial (Keynote-028) and no responses were seen in ACC. 
 
VEGF-A reduces adhesion molecule expression on endothelial cells, which results in a 
dysfunctional tumor vasculature and inhibits the infiltration of T cells and other immune cells into the 
tumor. Several studies have shown an association of tumor angiogenesis or elevated VEGF-A levels 
with reductions in tumor T cell infiltration. VEGF-A can also suppresses dendritic cell differentiation 
and activity, increases the expression of checkpoint molecules on CD8 T cells, and modulates the 
proliferation of regulatory T cells. Treatment of mouse models with VEGFRs inhibitors increases T 
cell recruitment and infiltration into tumors and can be synergistic with anti-PD1. 
 
Preliminary safety and efficacy results from an ongoing phase Ib study of axitinib plus 
pembrolizumab in treatment-naïve patients with renal cell carcinoma have been recently presented. 
Out of 52 enrolled patients, 35 (67.3%) had an objective response: 2 had complete response and 
33 had partial responses; 11 patients had stable disease. Only 10 patients tested positive for PD- 
L1. 
A phase 1b dose-finding study of avelumab and axitinib in patients with advanced renal cell 
carcinoma revealed the recommended phase 2 dose to be the standard 10 mg/Kg of avelumab 
intravenously every 2 weeks and axitinib 5 mg per oral twice a day. All 6 patients enrolled had 
clinical benefit, and five out of six (83%) achieved a partial response (PR). A phase III clinical trial 
with this combination is ongoing in metastatic renal cell carcinoma (NCT02684006). To put   these 
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results in perspective, in a large phase III trial, axitinib single agent in first line for metastatic renal 
cell carcinoma rendered an ORR of 32%. Based on this data, we believe that the combination of 
axitinib and avelumab will be well tolerated and enhance anti-tumor response of axitinib single agent 
in patients with incurable ACC who are actively progressing. Given the high unmet need, if 
promising, the results of this trial could lead to a definitive study that can establish the first standard 
of care systemic therapy for patients with recurrent/metastatic ACC. 
 
1.2 Avelumab 
 
Avelumab is a fully human anti-PD-L1 mAb of the Ig G1 isotype that is currently being investigated 
in combination with other cancer immunotherapies to enhance anti-tumor activity over that expected 
by avelumab alone in patients with locally advanced or metastatic solid tumors. Avelumab is 
expected to increase the effectiveness of anti-tumor T cells by preventing inhibition of T cell 
activation. This effect is expected to be enhanced by agents that promote anti-tumor immunity by 
complementary mechanisms such as promotion of T cell survival or removal of inhibitory myeloid 
cells. 
Avelumab selectively binds to PD-L1 and competitively blocks its interaction with programmed death 
protein-1 (PD-1). Compared with anti-PD-1 antibodies that target T-cells, avelumab targets tumor 
cells and therefore expected to have fewer side effects, including a lower risk of autoimmune-related 
safety issues, as blockade of PD-L1 leaves the programmed death-ligand 2 (PD-L2)/PD-1 pathway 
intact to promote peripheral self-tolerance. 
 
1.2.1 Avelumab Clinical Experience 
 
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono, and is being studied 
in Phase 1, 2, and 3 clinical protocols in a wide variety of cancers, including non-small cell lung 
cancer, gastric cancer, Merkel cell carcinoma (MCC), renal cell carcinoma (RCC), ovarian cancer, 
urothelial cancer, and Hodgkin’s Lymphoma, as single agent or in combination with chemotherapy, 
tyrosine kinase inhibitors (TKIs), or other immune-modulating agents. The safety profile of avelumab 
administered intravenously (IV) as single agent at a dose of 10 mg/kg every 2 weeks (Q2W) has 
been characterized primarily in 1738 adult patients from studies EMR100070-001 in various solid 
tumors (N=1650) and EMR100070-003 Part A in MCC (N=88). Study EMR100070 001 consists of 
2 parts, a dose escalation phase and a dose expansion phase, which is performed in selected tumor 
indications. As of 09 June 2016, a total of 53 patients were treated in the dose escalation phase of 
the EMR100070-001 study, with 4, 13, 15, and 21 patients treated with avelumab doses of 1, 3, 10, 
and 20 mg/kg, respectively. None of the patients treated with doses up to 10 mg/kg experienced a 
dose limiting toxicity (DLT), and the 10 mg/kg dose of avelumab was thus considered a safe and 
well tolerated dose for further investigation in the dose expansion cohorts. One DLT (a Grade 3 
immune related adverse event characterized by increased creatine kinase, myositis, and 
myocarditis) was observed in 1 patient at the dose of 20 mg/kg. The dose expansion phase of study 
EMR100070-001 included patients with NSCLC, gastric cancer, breast cancer, colorectal cancer, 
castration resistant prostate cancer, adrenocortical carcinoma, melanoma, mesothelioma, urothelial 
carcinoma, ovarian cancer, RCC, and SCCHN. Study EMR100070-003 Part A was conducted in 
patients with MCC. A summary of pooled safety data (N=1738) from the expansion phase of study 
EMR100070-001 and study EMR100070-003 is provided here. Treatment emergent adverse events 
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(TEAEs) were observed in 1697 (97.6%) patients, with 
 
(32.4%), nausea (25.1%), diarrhea (18.9%), constipation (18.4%), decreased appetite (18.4%), 
infusion related reaction (17.1%), weight decreased (16.6%), vomiting (16.2%), anemia    (14.9%), 
abdominal pain (14.4%), cough (13.8%), pyrexia (13.6%), dyspnea (13.2%), edema peripheral 
(11.9%), back pain (11.8%), and arthralgia (10.4%). Treatment related TEAEs were observed in 
1164  (67.0%)  patients,  and  the  most  frequent (>0.5%)  were  fatigue  (17.7%),  infusion related 
reaction (17.0%), nausea (8.6%), diarrhea (7.1%), chills (6.7%), pyrexia (6.1%), decreased appetite 
(5.2%), and hypothyroidism (5.0%). A total of 177 patients (10.2%) experienced Grade ≥3 treatment 
related TEAEs, and the most frequent (≥0.5%) were fatigue (1.0%), lipase increased (1.0%), 
gamma-glutayml transferase (GGT) increased (0.6%), infusion related reaction (0.6%), and 
asparatate aminotransferase (AST) increased (0.5%). 
A total of 777 (44.7%) patients had at least 1 serious TEAE. Treatment related serious TEAEs were 
reported in 108 (6.2%) patients, with the most frequent (≥0.2%) being infusion related reaction 
(0.9%), pneumonitis (0.6%), pyrexia (0.3%), adrenal insufficiency (0.3%), and hypothyroidism, 
diarrhea, vomiting, autoimmune disorder, autoimmune hepatitis, transaminases 
increased, 
dyspnea, and colitis (0.2% each). There were 911 deaths (52.4%) in the pooled safety data set. The 
majority of deaths were due to progressive disease (42.8%). There were 59 (3.4%) deaths attributed 
to TEAEs not related to trial treatment, and 4 deaths (0.2%) attributed to a treatment related TEAE 
by the investigator and which occurred up to 30 days after the last dose of avelumab: pneumonitis 
(1 case), acute liver failure (1 case), respiratory distress (in the context of sepsis) (1 case), and 
autoimmune hepatitis with hepatic failure (1 case). In addition, 1 patient died with acute respiratory 
failure (in the context of lung cancer progression) considered related to avelumab by the investigator 
37 days after the last dose of avelumab. The cause of death was marked as “other” or “unknown” 
in 17 (1.0%) and 83 (4.8%) of cases, respectively. 
A total of 244 patients (14.0%) permanently discontinued avelumab treatment due to TEAEs, 
including 107 patients (6.2%) discontinuing because of treatment related TEAEs. The most frequent 
treatment related TEAEs leading to treatment discontinuation were infusion related reaction (1.8%), 
GGT increased (0.4%), and diarrhea, fatigue, autoimmune disorder, alanine aminotransferase (ALT 
increased), blood creatine phosphokinase (CPK) increased, lipase increased, arthralgia, and 
pneumonitis (0.2% each). 
Immune related adverse events (irAEs): in the pooled safety data (N=1738), a total of 
247 patients (14.2%) experienced irAEs, defined as adverse events requiring use of corticosteroids 
(and/or hormonal therapy for endocrinopathies), and no clear alternate etiology. The median time 
to first onset of an irAE was 11.7 weeks. The most frequent irAEs were thyroid disorders including 
hypothyroidism (5.2%), hyperthyroidism (0.4%) and thyroiditis (0.2%), immune-related rash (5.2%), 
immune-related colitis (1.5%), immune related pneumonitis (1.2%), immune-related hepatitis 
(0.9%), adrenal insufficiency (0.5%) and immune-related myositis (0.5%). In addition, irAEs reported 
in 0.1% of patients in the pooled safety dataset included: type 1 diabetes mellitus, immune-related 
nephritis/renal dysfunction, hypopituitarism, uveitis and Guillain-Barre Syndrome. The majority of 
irAEs were Grade 1 or Grade 2 in severity, with 39 (2.2%) being of Grade ≥3 severity. Fatal outcome 
was reported in 1 patient (0.1%) with immune-related pneumonitis, and 2 patients (0.1%) with 
immune-related hepatitis. Other relevant irAEs reported with avelumab outside the pooled safety 
dataset included 1 case of fatal immune-related myocarditis in study B9991002 (avelumab in 
combination with axitinib for RCC), 1 case of non-fatal immune related myocarditis in the 20 mg/kg 
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cohort of the dose escalation phase of Study EMR100070-001, and 2 patients with non-fatal graft 
versus host disease (GVHD) in study B9991007 (avelumab in patients with classical Hodgkin’s 
lymphoma). 
Infusion Related Reactions (IRRs): a total of 439 patients (25.3%) experienced at least 1 infusion 
related reaction, defined as a TEAE coded under the Preferred Terms (PTs) of infusion related 
reaction, drug hypersensitivity, hypersensitivity, anaphylactic reaction, type I hypersensitivity, chills, 
pyrexia, back pain, dyspnea, hypotension, flushing, and abdominal pain according to a predefined 
case definition. The most common PTs that met the definition for an IRR included: infusion related 
reaction (17.0%), chills (5.4%), and pyrexia (3.6%). 
Most of the events were of Grade 1 or Grade 2 severity. Grade ≥3 infusion related reactions occurred 
in 12 patients (0.7%) including 3 patients (0.2%) who experienced Grade 4 IRRs. No Grade 5 IRRs 
were reported. In most cases, the first occurrence of an IRR was related to the first infusion, with 
only 6 patients experiencing the first IRR at the fifth or later infusion. All Grade ≥ 3 IRRs occurred 
with the first (7 patients) or second (5 patients) infusion. Overall, 21.6% of patients had 1 IRR, 2.6% 
of patients had 2 IRRs, 14 patients (0.8%) had 3 IRRs, and 3 patients had > 3 IRRs. IRR recurrence 
after the fourth infusion was rare (15 patients) and all recurrent IRRs were of Grade 1 or 2 severity. 
In 35 patients (2.0%), treatment was permanently discontinued because of an infusion related 
reaction. 
Immunogenicity of Avelumab in Humans: Based on the Phase 1/1b Trial EMR 100070-001, the 
incidence of anti-drug antibodies (ADAs) was relatively low, with 1 out of 39 patients (2.6%) in the 
dose escalation cohorts and 10 out of 338 patients (2.9%) in a non-small cell lung cancer (NSCLC) 
expansion cohort. In 8 of these 10 patients, a positive signal was observed at a single time point 
and a decrease in avelumab serum exposure was observed in the 2 patients with multiple positive 
samples. From these 11 positive patients, 2 patients had symptoms on the day of the infusion 
compatible with an immune reaction (chills and fever, nausea and vomiting) and, therefore, these 
AEs could be ADA related. For the other 9 ADA-positive patients, no such AEs were recorded. 
 
1.2.2. Pharmacokinetics of Avelumab in Humans 
 
Avelumab PK and dose proportionality following the first 1-hour infusion have been characterized in 
77 Caucasian patients treated in the dose escalation and expansion cohorts of 
Study EMR 100070-001 by standard non-compartmental analysis. This analysis revealed that the 
exposure parameters of maximum plasma concentration (Cmax) and area under the curve (AUC) 
increased in a dose proportionate fashion for the 10 and 20 mg/kg doses. The half-life of avelumab 
tended to increase with dose, likely due to target mediated disposition at lower doses (1 mg/kg and 
3 mg/kg), but terminal half-life of 10 mg/kg (102 +/-28 hours) and 20 mg/kg (120 +/-42 hours) doses 
were similar, taking into account the PK variability. This likely indicates target mediated elimination 
does not increase at these two doses and target occupancy is very high. 
Target occupancy on peripheral blood CD3+ T-cells was investigated in human blood in vitro by 
flow cytometry after spiking of whole blood samples from 8 healthy volunteers with avelumab over 
a concentration of 0.003-10 µg/mL. Fifty percent (50%) receptor occupancy was observed at a drug 
concentration of 0.122 µg/mL +/- 0.042 µg/mL with a plateau indicating at least 95% receptor 
occupancy reached in all blood samples at 1 µg/mL. 
PK profiles obtained from the dose escalation phase of Trial EMR 100070-001 were utilized to 
investigate whether this concentration of at least 1 µg/mL was achieved throughout the dosing 
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interval. The median ± standard deviation trough concentration (Ctrough) at the end of the first cycle 
after administration of the 10 mg/kg dose is 21 +/-12 µg/mL (n=283). This median Ctrough increases 
during the subsequent cycles to 25 +/- 16 µg/mL (second cycle) (n=269), 27 +/-17 µg/mL (third 
cycle) (n=202), and remains between 27 and 36 µg/mL during the subsequent cycles (n=55–171). 
 
1.3 Axitinib 
 
Axitinib is an oral, potent and selective inhibitor of vascular endothelial growth factor (VEGF) 
receptors 1, 2, and 3. As of 22 September 2014, axitinib has been approved in over 65 countries for 
advanced renal cell carcinoma (RCC) after treatment with one prior systemic therapy; the actual 
indication varies from country to country. The safety and efficacy of axitinib is being evaluated in 
subjects with a variety of solid tumors, including in treatment-naïve subjects with advanced RCC. 
 
1.3.1 Axitinib clinical experience 
 
The table below summarizes the most common treatment-emergent all-causality AEs reported 
in ≥10% cancer subjects who received single agent axitinib. The majority of subjects (98%; 
1445/1474) reported at least one AE (all grade) and 73.7% (1086/1474) reported at least one grade 
≥3 AE. 
For single-agent axitinib, the most common treatment emergent all causality AEs reported from 
1474 cancer subjects were: diarrhea 55.0%, hypertension 51.0%, fatigue 47.1% , decreased 
appetite 40.0% , nausea 32.6% ,weight decreased 32.2% , dysphonia 31.1% , palmar-plantar 
erythrodysaesthesia syndrome 29.4% , hypothyroidism and vomiting 22.6% , constipation 20.3% , 
proteinuria 20.1% . The most frequent Grade ≥3 events were: hypertension 20.7%, fatigue 10.2%, 
and diarrhea 10.1%. 
 
Table. All-causality adverse events reported in ≥10% patients who received single agent axitinib 
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Table 1 
 
 
 
As of 30 June 2013, a total of 1063 subjects received axitinib in combination with other anticancer 
drug(s) including docetaxel, carboplatin/paclitaxel, gemcitabine, gemcitabine/cisplatin, paclitaxel, 
capecitabine, FOLFIRI, FOLFOX, FOLFOX plus bevacizumab, and pemetrexed/cisplatin. Of these 
1063 subjects, 381 with pancreatic cancer received axitinib plus gemcitabine in studies A4061016 
and A4061028. The other 682 subjects received axitinib in combination with various anticancer 
treatments (see Section 5.2.4.2) in studies A4061010 (breast cancer), A4061019 (solid tumor), 
A4061020 and A4061034 (colorectal cancer; CRC), A4061030, A4061038, A4061039    (NSCLC), 
and A4061055 (gastric cancer). Across all combination studies 97.1% (1044/1075) of subjects 
reported at least one AE. The most common treatment-emergent, all causality AEs reported were: 
nausea (53.1%), fatigue (49.8%), diarrhea (46.6%), decreased appetite (42.7%), hypertension 
(40.7%),  vomiting  (37.0%),  neutropenia  (32.4%),  constipation  (29.3%),  headache      (21.2%), 
abdominal pain (20.7%), asthenia (20.6%), and stomatitis (20.4%). 
 
1.3.2. Pharmacokinetics of axitinib in Humans 
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The dose proportionality of axitinib has been evaluated at steady state following multiple dosing with 
total daily doses from 2 to 40 mg. The plasma pharmacokinetics of axitinib at steady state is 
generally linear. In the first in human (FIH) Phase 1 study A4060010 in patients with solid tumors, 
the geometric mean AUC0-24 on Day 15 was 261, 458, and 971 ng.h/mL for 5 mg BID, 15 mg QD, 
and 20 mg BID dosing cohorts respectively, which represents AUC(0-24) increments of 1: 1.8 : 3.7 
for dose increments of 1 : 1.5 : 4, respectively (a proportional increase in AUC(0-24) per dose 
increment). In Phase 1 study A4061019 in patients with solid tumors, the geometric mean AUC0-24 
estimates were 47.8, 198 and 382 ng.hr/mL for 1 mg BID, 3 mg BID and 5 mg BID doses 
respectively, indicating that doses were proportional from 3 to 5 mg BID but were more than 
proportional from 1 to 3 mg BID; an explanation for this observation may be the small number of 
patients (n=3) at the 1 mg dose. 
Axitinib is rapidly absorbed with maximal plasma concentrations generally occurring within the first 
4 hours following oral administration. Axitinib is orally bioavailable; in healthy volunteers, the mean 
absolute bioavailability was 58%. 
A pilot food-effect evaluation was conducted with axitinib polymorph Form IV wet granulation tablets 
in 9 cancer patients in the FIH Phase 1 study (A4060010) which indicated that higher peak plasma 
concentrations and exposures were obtained following overnight fasting versus the fed state. A 
definitive food effect study (A4061006) was subsequently conducted in 42 healthy volunteers (with 
axitinib polymorph Form IV wet granulation tablets). The study results indicated that lower plasma 
exposures were obtained in the fed state versus overnight fasting state; Cmax and AUC0-∞ were 
reduced 39% and 23%, respectively in the fed state compared to overnight fasting. Since it was 
considered impractical for patients to be ‘overnight fasted’ around each of the 2 daily doses of 
axitinib and to avoid fluctuations in plasma exposures between morning and evening doses of the 
drug, ongoing studies at the time recommended subjects to take axitinib in the fed state. Most 
recently, a definitive food effect study (A4061053) for polymorph Form XLI (commercial formulation) 
was conducted in healthy volunteers. Overall, there were no clinically significant changes in axitinib 
plasma exposure or Cmax in the presence of food; the results indicated a mean 19% increase in 
AUC0-∞ with a high fat meal compared to overnight fasting and a mean 10% decrease in AUC0-∞ 
with a moderate fat meal compared to overnight fasting was observed. 
Metabolism of axitinib is primarily mediated by the CYP3A4 drug-metabolizing enzyme, and to a 
lesser extent by CYP1A2, CYP2C19, and UGT1A1 as determined from in vitro studies with human 
liver microsomes. Since axitinib is predominantly metabolized by CYP3A, an interaction study with 
ketoconazole, a potent CYP3A inhibitor, was conducted in 35 healthy volunteers (A4061004). There 
was a 2-fold increase in plasma exposures of axitinib in the presence of ketoconazole and a 1.5- 
fold increase in peak plasma concentration (Table 6.1-5); this indicates that the upper limit for 
elevations in plasma concentrations of axitinib following potent metabolic inhibition following a 5-mg 
dose is approximately 2-fold. 
 
1.4 Safety of Avelumab and axitinib combination 
 
The safety of Avelumab and axitinib combination was studied in the JAVELIN Renal 100 study which 
is an open-label, multicenter, dose-finding, and dose-expansion, phase 1b study, done in 14 centers 
in the USA, UK, and Japan. 55 patients were enrolled. Six were enrolled in the dose-finding phase 
of the study and 49 were enrolled into the dose-expansion cohort (ten were assigned to a 7 day 
lead-in with axitinib therapy before the first cycle of combination therapy and 39 started combination 
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therapy directly per protocol. Patients in the dose-finding cohort received a median of 32·5 avelumab 
infusions (IQR 31·0–37·0) during a median follow-up of 69.7 weeks (IQR 66.1–74.1). The median 
duration of treatment was 66.6 weeks (IQR 66.0–74.1) with axitinib and 66·0 weeks (IQR65.6–74.0) 
with avelumab. Among the six patients in the dose-finding cohort, four (67%) had a grade 3 or 4 
treatment-related adverse event (grade 3 hypertension, palmar-plantar erythrodysaesthesia, 
proteinuria, and mucosal inflammation and grade 4 increase in lipase concentration). One patient 
had a dose-limiting toxicity (grade 3 proteinuria) that led to axitinib dose reduction and resolved 
without sequelae; this patient continued treatment with avelumab at 10 mg/kg and 3 mg axitinib 
twice daily. One patient discontinued axitinib due to grade 3 palmar-plantar erythrodysaesthesia 
syndrome. This patient continued treatment with avelumab monotherapy until disease progression. 
At the end of the dose-finding phase, the maximum tolerated dose established for the combination 
was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily. There was no differences in 
antitumor activity or safety between patients in either phase who received lead-in treatment with 
axitinib and those who did not. At the cutoff of April 13, 2017, the median follow-up for all 55 patients 
was 52·1 weeks (IQR 37·4–56·1). 54 (98%) patients received avelumab and axitinib, and one 
patient received only axitinib because of an adverse event (grade 3 increase in blood creatine 
phosphokinase concentration) that arose before avelumab was started. At the time of cutoff, 
combination treatment was ongoing in 29 (53%) of 55 patients, two (4%) were receiving treatment 
with axitinib alone, and one (2%) was receiving avelumab alone. Patients received avelumab for a 
median of 37.0 weeks (IQR 14·0–50·0) and axitinib for a median of 36·0 weeks (IQR 18.1–50.1). 
Reasons for treatment discontinuation were progressive disease (n=11 for avelumab and n=14 for 
axitinib), adverse events (n=7 for avelumab and n=4 for axitinib), withdrawal of consent (n=3 for 
both treatments), death (n=2 for both treatments), and physician’s decision (n=1 for both 
treatments). All 55 patients experienced at least one adverse event during the trial, and 53 (96%) 
had one or more adverse events that were judged by the investigator to be related to avelumab or 
axitinib. The most frequent treatment-related adverse events (occurring in ≥10% of patients) 
included diarrhea, hypertension, dysphonia, fatigue, palmar-plantar erythrodysaesthesia syndrome, 
increased alanine aminotransferase concentration, rash, increased aspartate aminotransferase 
concentration, hypothyroidism, increased amylase concentration, decreased appetite, mucosal 
inflammation, infusion-related reactions, increased lipase concentration, and nausea. 32 (58%) of 
55 patients had grade 3 or worse treatment-related adverse events and one died from treatment- 
related autoimmune myocarditis (confirmed by widespread myocarditis on 
post-mortem 
histopathology; viral cause was excluded). 16 (29%) of 55 patients reported infusion-related 
reactions, most of which were grade 1 or 2; one (2%) patient had a grade 3 infusion-related reaction 
and discontinued avelumab, and one (2%) additional patient had chills unrelated to treatment. 16 
(29%) of 55 patients had infusion-related reactions with the first infusion, and one (2%) had three 
grade 2 infusion-related reactions at cycles eight, nine, and ten, but continued treatment beyond 
cycle ten until disease progression. 23 (42%) of 55 patients had immune-related adverse events; 
see appendix for adjudication criteria. The most frequent was hypothyroidism in 13 (24%) patients, 
and five (9%) had grade 3 or worse immune related events, which led to avelumab dose interruption 
in one patient (due to rash) and discontinuation of Avelumab in the other four patients. 20 (36%) of 
55 patients had serious adverse events, which were judged to be treatment related in 12 (22%). 
Serious adverse events occurring in more than one patient were increased alanine 
aminotransferase concentration (n=2, deemed to be treatment related), infusion-related   reactions 
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(n=2 related to avelumab), and presyncope, spinal cord compression, and hypoxia (all n=2, not 
related to study treatment). Ten (18%) of 55 patients discontinued one or both study drugs due to 
adverse events. Seven (13%) of 55 discontinued avelumab, with increased 
alanine 
aminotransferase concentration being the only adverse event leading to discontinuation in more 
than one patient (n=3 [6%]). Four (7%) of 55 patients discontinued axitinib (no events occurred in 
more than one patient). Six (11%) of 55 patients died before data cutoff: five (9%) due to disease 
progression (four after the end of treatment) and one (2%) due to treatment-related autoimmune 
myocarditis. 32 (58%) of 55 patients had avelumab dose delays, with duration of 7 days or longer 
in 25 (46%) of 55 patients. Four (7%) of 55 patients received less than 90% of the planned avelumab 
dose in one infusion because of adverse events: three due to infusion-related reactions (one of 
whom discontinued treatment) and one due to an electrocardiogram abnormality unrelated to study 
treatment. Axitinib was decreased at least once in 31 (56%) of 55 patients and increased at least 
once in ten (18%) of 55 patients. Axitinib dose reductions were due to adverse events in 28 (51%) 
of 55 patients, among whom the most common (in >5% of patients) were palmar-plantar 
erythrodysaesthesia syndrome (n=6), fatigue (n=5), hypertension (n=4), and proteinuria (n=3). 
 
Table. Treatment-related adverse events occurring in ≥10% of patients 
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Table 2 
 
 
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2. Study Objectives 
 
 
2.1 Primary objective 
 
Assess the objective response rate (ORR) to axitinib and avelumab combination according to 
RECIST 1.1 criteria (Appendix 1) in patients with recurrent or metastatic adenoid cystic 
carcinoma (ACC) who have evidence of disease progression within 6 months prior to study 
enrollment. 
 
2.2 Secondary objectives 
 
• 
Assess ORR to axitinib and avelumab combination according to irRECIST criteria patients with 
recurrent or metastatic adenoid cystic carcinoma (ACC) 
• 
Evaluate median progression free survival (PFS), PFS rate at 6 months after start of treatment 
• 
Evaluate median overall survival (OS), OS rate at 6 months after start of treatment 
• 
Evaluate duration of response (DoR) 
• 
Evaluate safety and toxicity 
 
2.3 Exploratory 
 
Assess molecular markers associated with response and resistance to the study combination 
using tissue and/or plasma obtained from study participants. We hypothesize that studying 
molecular characteristics of baseline tumor (such as mutational and transcriptional profile), tumor 
microenvironment (such as immune cells subsets) and serial plasma may reveal biomarkers 
associated with response to the study combination. 
 
3. Study Design 
 
 
3.1 Study Design 
 
This is a Phase II, single center open label, study to determine the safety and efficacy of axitinib 
and avelumab combination in patients with recurrent or metastatic adenoid cystic carcinoma (ACC) 
with evidence of disease progression within 6 months prior to study enrollment. 
Up to 30 patients will be treated with a combination of axitinib 5 mg orally twice a day and avelumab 
10mg/kg intravenously every two weeks. A treatment cycle will be 28 days. Treatment will continue 
until disease progression, death, unacceptable toxicity or consent withdrawal. 
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3.2 Study schema 
 
 
 
N=number; Q2W=every 2 weeks; IV=intravenously; PO= per oral; BID=twice a day; Q8W=every 8 weeks 
 
4. Study Population 
4.1 Inclusion criteria 
 
Subjects must meet all the following criteria: 
 
1. Male or female subjects aged ≥ 18 years 
2. Eastern Cooperative Oncology Group ECOG performance status 0 or 1 
3. Histologically confirmed recurrent or metastatic adenoid cystic carcinoma not amenable to 
curative intent surgery or radiotherapy 
4. Measurable disease per RECIST 1.1 
5. Evidence of disease progression within 6 months of study enrollment  
6. Previously untreated subjects and subject treated with any number of prior lines of therapy are 
eligible 
7. Adequate physiologic function defined as: Hematologic: Absolute neutrophil count (ANC) ≥ 1.5 
× 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL (may have been transfused). Hepatic: 
Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and ALT levels ≤ 2.5 × 
ULN or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic disease to the 
liver). Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula 
(or local institutional standard method) 
 
8. Must have archival tissue (Formalin-Fixed, Paraffin-Embedded (FFPE) tissue available-minimum 
of 15 unstained slides) or be willing to undergo a biopsy 
9. For patients receiving antitherapeutic coagulation, patients must be on stable anticoagulant 
regimen and INR or aPTT must be ≤ 1.5 upper limit of normal. 
10. Females of childbearing potential must not be breast feeding and must have a negative serum 
or urine pregnancy test and must agree to use highly effective contraception for a minimum of two 
weeks prior to receiving study medication until 30 days after discontinuation of the study medication. 
Acceptable methods of contraception include total and true sexual abstinence, 
hormonal 
contraceptives that are not prone to drug-drug interactions (IUS Levonorgestrel Intra Uterine System 
(Mirena), Medroxyprogesterone injections (Depo-Provera)), copper-banded intra-uterine devices, 
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and vasectomized partner. All hormonal methods of contraception should be used in combination 
with the use of a condom by their sexual male partner.  
Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral 
tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined 
as 12 months with no menses without an alternative medical cause). Women will be considered 
post-menopausal if they have been amenorrheic for the past 12 months without an alternative 
medical cause. The following age- specific requirements must also apply: Women < 50 years old: 
they would be considered post- menopausal if they have been amenorrheic for the past 12 months 
or more following cessation of exogenous hormonal treatments. The levels of Luteinizing Hormone 
(LH) and Follicle-Stimulating Hormone (FSH) must also be in the post-menopausal range (as per 
the institution). Women ≥ 50 years old: they would be considered post-menopausal if they have 
been amenorrheic for the past 12 months or more following cessation of all exogenous hormonal 
treatments, or have had radiation- induced oophorectomy with the last menses > 1 year ago, or 
have had chemotherapy-induced menopause with >1 year interval since last menses, or have 
had surgical sterilization by either bilateral oophorectomy or hysterectomy. Patients should refrain 
from donating eggs from start of dosing until 30 days after discontinuing the study medication. 
11. Non-sterilized males who are sexually active with a female partner of childbearing potential must 
use adequate contraception for the duration of the study and 30 days after the last dose of study 
medication. Adequate contraception methods include: birth control pills (e.g. combined oral 
contraceptive pill), barrier protection (e.g. condom plus spermicide, cervical/vault cap or intrauterine 
device), and abstinence. Patients should not father a child for 6 months after completion of the study 
medication. Patients should refrain from donating sperm from the start of dosing until 6 months after 
discontinuing the study medication. If male patients wish to father children they should be advised 
to arrange for freezing of sperm samples prior to the start of the study medication. 
 
12. For patients with hypertension, upon entry into study must have Blood pressure of <140/90 
 
13. Qtc <470msec. 
 
 
 
4.2 Exclusion criteria 
 
1. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, 
topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids 
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at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for 
hypersensitivity reactions (e.g., CT scan premedication) 
2. Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. 
Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring 
immunosuppressive treatment are eligible 
3. Prior organ transplantation including allogenic stem-cell transplantation 
4. Active infection requiring systemic therapy 
5. Known history of testing positive for HIV or known acquired immunodeficiency syndrome 
6. Known history of Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection  
7. Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for 
administration of inactivated vaccines 
8. Known prior severe hypersensitivity to investigational product or any component in its 
formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI 
CTCAE v4.03 Grade ≥ 3) 
9. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 
months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, 
congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac 
arrhythmia requiring medication. 
10. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however, alopecia, 
sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on 
investigator’s judgment are acceptable 
11. Inadequately controlled hypertension (defined as systolic blood pressure > 140 mmHg and/or 
diastolic blood pressure > 90 mmHg). Anti-hypertensive therapy to maintain a systolic blood 
pressure < 140 mmHg and/or diastolic blood pressure < 90 mmHg is permitted. 
12. Prior history of hypertensive crisis or hypertensive encephalopathy. 
13. Patients with a baseline EKG demonstrating a QTc > 470 ms 
14. Serious non-healing or dehiscing wound, active ulcer or untreated bone fracture 
15. Proteinuria as demonstrated by urinalysis with microscopy > 150 mg/dL or > 1 g of protein in a 
24 hour urine collection. All patients with ≥ 150mg/dL protein on urinalysis at baseline must 
undergo a 24 hour urine collection for protein. 
16. Evidence of bleeding diathesis or clinically significant coagulopathy (in the absence of 
therapeutic anticoagulation) 
17. Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel 
disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within 
the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase 
the risk associated with study participation or study treatment administration or may interfere with 
the interpretation of study results and, in the judgment of the investigator, would make the patient 
inappropriate for entry into this study. 
18. Subject with an uncontrolled seizure disorder, active neurologic disease, or active CNS 
involvement except for individuals who have previously-treated CNS metastases, 
are 
asymptomatic, and have no requirement for doses of corticosteroids (indicated to reduce brain 
edema) higher than the equivalent of 10 mg of oral prednisone a day or anti-seizure medication for 
at least 2 weeks prior to first dose of study drug. 
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19. History of ongoing malignancies or malignancies in remission < 2 years. Adequately curative 
intent treated initial stage non-melanoma skin cancers; in situ carcinoma of the cervix; breast 
carcinoma in situ; low-grade local bladder cancer; and low-risk prostate cancer undergoing active 
surveillance will be allowed. 
 
20. Pregnant women are excluded from this study. Based on its mechanism of action. Avelumab 
can cause fetal harm when administered to a pregnant woman. In animal models, the PD-1/PD-L1 
signaling pathway is important in the maintenance of pregnancy through induction of maternal 
immune tolerance to fetal tissue. Human IgG1 immunoglobulins are known to cross the placenta. 
Therefore, Avelumab has the potential to be transmitted from the mother to the developing fetus. 
Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance 
to the fetus and to result in an increase in fetal loss. Therefore, potential risks of administering 
Avelumab during pregnancy include increased rates of abortion or stillbirth. Advise females of 
reproductive potential to use effective contraception during treatment with Avelumab and for at least 
one month after the last dose of avelumab. 
 
21. Lactating females: There is no information regarding the presence of Avelumab in human milk, 
the effects on the breastfed infant, or the effects on milk production. Since many drugs including 
antibodies are excreted in human milk, advise a lactating woman not to breastfeed during treatment 
and for at least one month after the last dose of Avelumab due to the potential for serious adverse 
reactions in breastfed infants. 
 
22. Prior treatment with anti-PD-1 or anti-PD-L1 
 
23. Prior treatment with VEGF or VEGFR inhibitors (e.g. lenvatinib, bevacizumab) 
 
5. Treatment Plan 
 
 
Patients will be treated with a combination of axitinib 5 mg orally twice a day and avelumab 10mg/kg 
intravenously every two weeks. A treatment cycle will be 28 days. Treatment will continue until 
disease progression, death, unacceptable toxicity or consent withdrawal. 
 
5.1 Axitinib administration 
 
Axitinib will be given at a dose of 5 mg orally twice daily. Axitinib doses will be administered 
approximately 12 hours apart with or without food and at approximately the same times each day 
on a continuous schedule. Axitinib should be swallowed whole with a glass of water. If the patient 
vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should 
be taken at the usual time. The patient will be requested to maintain a medication diary of each 
dose of medication. The medication diary will be returned to clinic staff at the end of each cycle. 
The concomitant use of potent inhibitors of CYP3A4/5 should be avoided. A comprehensive list of 
strong CYP3A4/5 inhibitors is provided here http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
Patients should avoid grapefruit products. 
Axitinib will be provided to subjects in tablets (5 mg strength). The tablets will be packaged in 
appropriate packaging material and stored at room temperature. 
Axitinib will be given on days 1 to 28 of a 28-day cycle. 
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5.2 Avelumab administration 
 
Avelumab is a sterile, clear, and colorless solution intended for intravenous (IV) administration. It is 
presented with a nominal volume of 10 mL at a concentration of 20 mg/mL in single-use glass vials 
closed with a rubber stopper and sealed with an aluminum polypropylene flip off seal. The vial is 
intended for single use only. 
Avelumab will be administered at 10 mg/kg as a 1-hour IV infusion every 2 weeks (Q2W) on Day 1 
and Day 15 of each cycle. 
Avelumab will be administered IV on an outpatient basis. Avelumab will be administered in a setting 
that allows for immediate access to an intensive care unit or equivalent environment and 
administration of therapy for anaphylaxis, such as the ability to implement immediate resuscitation 
measures. Steroids (dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy medications 
(IV antihistamines), bronchodilators, or equivalents, and oxygen should be available for immediate 
access. 
In order to mitigate infusion related reactions, premedication with Diphenhydramine 50 mg IV, 
Acetaminophen 650 mg PO and famotidine 20 mg IV 30 to 60 minutes prior avelumab infusions is 
mandatory This may be modified based on local treatment standards and guidelines, as 
appropriate. 
Following avelumab infusions, patients must be observed for 30 minutes post infusion for potential 
infusion related reactions. 
 
5.3 Safety assessment 
 
For details see section 6(study calendar and procedures) 
 
1. Blood chemistry and hematology assessments: must be performed at screening, prior to each 
avelumab dose, at end of treatment visit and at 30 days post-treatment safety follow-up. 
 
2. Urine pregnancy test for women of childbearing potential must be performed at baseline and at 
least every month during treatment. 
3. Free T4 and TSH must be performed at baseline and at least every 8 weeks during treatment 
and at end of treatment or 30 days post-treatment safety follow-up (if not performed in the previous 
8 weeks). 
4. Extended safety follow up: give the potential risk of immune-related toxicity, safety follow up will 
be performed up to 90 days after the last dose of avelumab administration. The extended follow up 
beyond 30 days after last avelumab administration may be performed either via a site visit or via a 
telephone call with subsequent site visit requested in case any concerns noted during the telephone 
call. 
 
5.4 Dose Modification 
 
For overlapping toxicities (i.e., toxicities that could be attributed to either avelumab or axitinib), the 
study PI or co-chair will guide the study co-investigators regarding management on a case by case 
basis. Decision regarding which drug should be dose reduced/held will be made according to the 
overall incidence of the adverse event with each individual drug if other factors such as onset of 
symptoms cannot help define the causative agent. In general, effort should be made to continue 
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axitinib since single agent activity has been reported with this agent in ACC. Guidance for 
management of the most common overlapping adverse events are outlined below: 
 
● Diarrhea: 
 
Grade 1-2: manage with anti-diarrheal agents (E.g., loperamide). If no improvement dose- 
reduce/hold axitinib first, if no improvement hold avelumab (management as per Table 4), if 
improvement, axitinib can be re-started. 
 
Grade ≥ 3: hold both drugs, discard an infectious agent, and treat with anti-diarrheal agents and 
steroids as per Table 4. Re-start with single agent axitinib. 
 
 
● Fatigue: 
 
Grade ≥ 2: Hold avelumab first, if no improvement dose-reduce axitinib, if improvement avelumab 
can be re-started. If only single agent can be tolerated, prioritize axitinib. 
 
 
• 
Hypertension 
• 
Hold Axitinib when unable to control blood pressure to <140/90 on greater than 4 Blood 
pressure medications from multiple classes on maximally tolerated doses. 
 
 
• 
Qtc-Hold for Qtc>500msec, for Qtc from 470-499msec, Cardiology collaborator will evaluate 
and review for drug interactions and presence of underlying structural heart disease, and 
resume when Qtc by EKG interpretation shows normal Qtc 
 
 
● Transaminitis (increase is ALT and/or AST): 
 
Grade 1-2: Hold avelumab first, if no improvement, dose-reduce/discontinue axitinib, if improvement 
avelumab can be re-started 
 
Grade ≥ 3: hold both drugs, discard an infectious agent, and treat with steroids as per Table 4. Re- 
start with single agent axitinib. 
 
Other overlapping AEs: 
 
● Decreased appetite, nausea, weight loss, vomiting, dyspnea, arthralgia, stomatitis are more 
common with axitinib, therefore, dose reductions of these agent should precede avelumab hold. 
 
● Rash, hypothyroidism, asthenia and hematologic toxicities should be initially attributed to 
avelumab and managed accordingly (Tables 3 and 4), if no improvement by avelumab hold, axitinib 
dose-reduction/discontinuation should follow. 
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5.4.1 Avelumab 
 
Every effort should be made to administer each of the investigational products at the planned dose and 
schedule. No avelumab dose modifications are permitted in this study, but the next administration of 
investigational product may be omitted based on persisting toxicity, as outlined in the next tables. 
 
Table 3. Treatment Modification for Symptoms of Infusion-Related Reactions 
 
NCI-CTCAE Grade 
Treatment Modification for Avelumab 
Grade 1 – mild 
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated. 
Decrease avelumab infusion rate by 50% and 
monitor closely for any worsening. 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(for example, antihistamines, NSAIDs, 
narcotics, IV fluids); prophylactic medications 
indicated for ≤ 24 h. 
Temporarily discontinue avelumab infusion. 
Resume infusion at 50% of previous rate 
once infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity, and 
monitor closely for any worsening. 
Grade 3 or Grade 4 – severe or 
life-threatening 
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae. 
Grade 4: Life-threatening consequences; 
urgent intervention indicated. 
Stop avelumab infusion immediately and 
disconnect infusion tubing from the subject. 
Subjects have to be withdrawn immediately 
from study drug treatment and must not 
receive any further study drug treatment. 
-If avelumab infusion rate has been decreased by 50% or interrupted due to an infusion 
reaction, it must remain decreased for the next scheduled infusion. If no infusion reaction is 
observed in the next scheduled infusion, the infusion rate may be returned to baseline at the 
subsequent infusions based on investigator’s medical judgment. 
- If hypersensitivity reaction occurs, the subject must be treated according to the best 
available medical practice. 
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse 
Event; NSAIDs = nonsteroidal anti-inflammatory drugs. 
 
 
 
 
 
 
Table 4. Management of Immune-mediated Adverse Reactions 
 
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Gastrointestinal irAEs 
Severity of Diarrhea/Colitis 
(NCI-CTCAE v4.03) 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic 
Continue avelumab 
therapy 
Symptomatic treatment 
(e.g. loperamide) 
Close monitoring for worsening 
symptoms 
Educate subject to report worsening 
immediately 
If worsens: 
Treat as Grade 2, 3 or 4. 
Grade 2 
Diarrhea: 4 to 6 stools per day 
over Baseline; IV fluids indicated 
< 24 hours; not interfering with 
ADL 
Colitis: abdominal pain; blood in 
stool 
Withhold avelumab 
therapy 
Symptomatic treatment 
If improves to Grade ≤ 1: 
Resume avelumab therapy 
If persists > 5-7 days or recurs: 
Treat as Grade 3 or 4. 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools 
per day over Baseline; 
incontinence; IV fluids ≥ 24 h; 
interfering with ADL 
Colitis (Grade 3): severe 
abdominal pain, medical 
intervention indicated, peritoneal 
signs 
Grade 4: life-threatening, 
perforation 
Withhold avelumab for 
Grade 3. 
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3. 
1.0 to 2.0 mg/kg/day 
prednisone IV or 
equivalent 
Add prophylactic 
antibiotics for opportunistic 
infections 
Consider lower endoscopy 
If improves: 
Continue steroids until Grade ≤ 1, 
then taper over at least 1 month; 
resume avelumab therapy following 
steroids taper (for initial Grade 3). 
If worsens, persists > 3 to 5 days, or 
recurs after improvement: 
Add infliximab 5mg/kg (if no 
contraindication). Note: infliximab 
should not be used in cases of 
perforation or sepsis. 
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Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4.03) 
Initial Management 
Follow-up Management 
Grade 1 to 2 
Covering ≤ 30% body surface 
area 
Continue avelumab 
therapy Symptomatic 
therapy (for example, 
antihistamines, topical 
steroids) 
If persists > 1 to 2 weeks or recurs: 
Withhold avelumab therapy 
Consider skin biopsy 
Consider 0.5-1.0 mg/kg/day 
prednisone or equivalent. Once 
improving, taper steroids over at 
least 1 month, consider prophylactic 
antibiotics for opportunistic 
infections, and resume avelumab 
therapy following steroids taper. 
If worsens: 
Treat as Grade 3 to 4. 
Grade 3 to 4 
Grade 3: Covering > 30% body 
surface area; 
Grade 4: Life threatening 
consequences 
Withhold avelumab for 
Grade 3. 
Permanently discontinue 
for Grade 4 or recurrent 
Grade 3. 
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic 
antibiotics for opportunistic 
infections 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month; 
resume avelumab therapy following 
steroids taper (for initial Grade 3). 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4.03) 
Initial Management 
Follow-up Management 
Grade 1 
Radiographic changes only 
Consider withholding 
avelumab therapy 
Monitor for symptoms 
every 2 to 3 days 
Re-assess at least every 3 weeks 
If worsens: 
Treat as Grade 2 or Grade 3 to 4. 
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Consider Pulmonary and 
Infectious Disease 
consults 
Grade 2 
Mild to moderate new symptoms 
Withhold avelumab 
therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily; 
consider hospitalization 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic 
antibiotics for opportunistic 
infections 
Consider bronchoscopy, 
lung biopsy 
Re-assess every 1 to 3 days 
If improves: 
When symptoms return to Grade ≤ 
1, taper steroids over at least 1 
month, and then resume avelumab 
therapy following steroids taper 
If not improving after 2 weeks or 
worsening: 
Treat as Grade 3 to 4. 
Grade 3 to 4 
Grade 3: Severe new 
symptoms; New/worsening 
hypoxia; 
Grade 4: Life-threatening 
Permanently discontinue 
avelumab therapy. 
Hospitalize. 
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic 
antibiotics for opportunistic 
infections 
Consider bronchoscopy, 
lung biopsy 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month 
If not improving after 48 hours or 
worsening: 
Add additional immunosuppression 
(for example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or mycophenolate 
mofetil) 
Hepatic irAEs 
Grade of Liver Test Elevation 
(NCI-CTCAE v4.03) 
Initial Management 
Follow-up Management 
Grade 1 
Grade 1 AST or ALT > ULN to 
3.0 x ULN and/or Total bilirubin 
> ULN to 1.5 x ULN 
Continue avelumab 
therapy 
Continue liver function monitoring 
If worsens: 
Treat as Grade 2 or 3 to 4. 
Grade 2 
Withhold avelumab 
therapy 
If returns to Grade ≤ 1: 
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AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 3 
x ULN 
Increase frequency of 
monitoring to every 3 
days. 
Resume routine monitoring; resume 
avelumab therapy. 
If elevation persists > 5 to 7 days or 
worsens: 
Treat as Grade 3 to 4. 
Grade 3 to 4 
AST or ALT > 5 x ULN and/or 
total bilirubin > 3 x ULN 
Permanently discontinue 
avelumab therapy 
Increase frequency of 
monitoring to every 1 to 
2 days 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic 
antibiotics for opportunistic 
infections 
Consult gastroenterologist/ 
hepatologist 
Consider obtaining 
MRI/CT scan of liver and 
liver biopsy if clinically 
warranted 
If returns to Grade ≤ 1: 
Taper steroids over at least 1 month 
If does not improve in > 3 to 5 days, 
worsens or rebounds: 
Add mycophenolate mofetil 1 gram 
(g) twice daily 
If no response within an additional 3 
to 5 days, consider other 
immunosuppressants per local 
guidelines. 
Renal irAEs 
Grade of Creatinine Increased 
(NCI-CTCAE v4.03) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > ULN to 
1.5 x ULN 
Continue avelumab therapy 
Continue renal function 
monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
Creatinine increased > 1.5 and ≤ 
6 x ULN 
Withhold avelumab therapy 
Increase frequency of 
monitoring to every 3 days 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
If returns to  Grade ≤1: 
Taper steroids over at least 1 
month, and resume avelumab 
therapy following steroids taper. 
If worsens: 
Treat as Grade 4. 
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Grade 4 
Creatinine increased > 6 x ULN 
Permanently discontinue 
avelumab therapy 
Monitor creatinine daily 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
Nephrology consult 
If returns to Grade ≤1: 
Taper steroids over at least 1 
month. 
Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac signs or 
symptoms and / or new 
laboratory cardiac biomarker 
elevations (e.g. troponin, CK- 
MB, BNP) or cardiac imaging 
abnormalities suggestive of 
myocarditis. 
Withhold avelumab therapy. 
Hospitalize. 
In the presence of life 
threatening cardiac 
decompensation, consider 
transfer to a facility experienced 
in advanced heart failure and 
arrhythmia management. 
Cardiology consult to establish 
etiology and rule-out immune- 
mediated myocarditis. 
Guideline based supportive 
treatment as per cardiology 
consult.* 
Consider myocardial biopsy if 
recommended per cardiology 
consult. 
If symptoms improve and 
immune-mediated etiology is 
ruled out, re-start avelumab 
therapy. 
 
If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, and 
immune-mediated etiology is 
suspected or confirmed 
following cardiology consult, 
manage as immune-mediated 
myocarditis. 
Immune-mediated myocarditis 
Permanently discontinue 
avelumab. 
Guideline based supportive 
treatment as appropriate as per 
cardiology consult.* 
Once improving, taper steroids 
over at least 1 month. 
 
If no improvement or 
worsening, consider additional 
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1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
immunosuppressants (e.g. 
azathioprine, cyclosporine A). 
*Local guidelines, or e.g. ESC or AHA guidelines 
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue avelumab therapy 
Endocrinology consult if 
needed 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate. 
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis) 
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate. 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Withhold avelumab therapy 
Consider hospitalization 
Endocrinology consult 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate. 
Resume avelumab once 
symptoms and/or laboratory 
tests improve to Grade ≤ 1 
(with or without hormone 
replacement/suppression). 
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate. 
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Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis) 
Hypopituitarism/Hypophysiti
s (secondary 
endocrinopathies) 
If secondary thyroid and/or 
adrenal insufficiency is 
confirmed (i.e. subnormal 
serum FT4 with inappropriately 
low TSH and/or low serum 
cortisol with inappropriately low 
ACTH) : 
• 
Refer to endocrinologist for 
dynamic testing as 
indicated and measurement 
of other hormones (FSH, 
LH, GH/IGF-1, PRL, 
testosterone in men, 
estrogens in women) 
• 
Hormone 
replacement/suppressive 
therapy as appropriate 
• 
Perform pituitary MRI and 
visual field examination as 
indicated 
If hypophysitis confirmed: 
• 
Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month 
• 
Withhold avelumab if 
moderate, severe or life- 
threatening symptoms of 
hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 
mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper during 
at least 1 month. 
• 
Add prophylactic antibiotics 
for opportunistic infections. 
Resume avelumab once 
symptoms and hormone tests 
improve to Grade ≤ 1 (with or 
without hormone replacement). 
In addition, for hypophysitis 
with abnormal MRI, resume 
avelumab only once shrinkage 
of the pituitary gland on 
MRI/CT scan is documented. 
Continue hormone 
replacement/suppressio
n therapy as appropriate. 
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Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v4.03) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical 
signs or symptoms 
suggestive of a potential irAE 
Withhold avelumab therapy 
pending clinical investigation 
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider re- 
starting avelumab therapy 
If irAE is confirmed, treat as 
Grade 2 or 3 irAE. 
Grade 2 irAE or first 
occurrence of Grade 3 irAE 
Withhold avelumab therapy 
1.0 to 2.0 mg/kg/day 
prednisone  or equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as 
appropriate 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 
month and resume avelumab 
therapy following steroids 
taper. 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue 
avelumab therapy 
1.0 to 2.0 mg/kg/day 
prednisone  or equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as 
appropriate 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 
month. 
Grade 4 
Permanently discontinue 
avelumab therapy 
1.0 to 2.0 mg/kg/day 
prednisone  or equivalent 
and/or other 
immunosuppressant as needed 
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult. 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 
month 
Requirement for 10 mg per 
day or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
Permanently discontinue 
avelumab therapy 
Specialty consult 
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Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
 
 
5.4.2 Axitinib dose modification 
 
If a patient experiences a CTCAE grade 3 or higher and/or unacceptable toxicity (any grade), where 
the clinician considers the event of concern to be specifically associated with axitinib (and not 
attributable to the disease, disease-related processes for which patient is being treated, or to 
avelumab), dosing will be interrupted and supportive therapy administered as required in 
accordance with local practice/guidelines. If the toxicity resolves or reverts to ≤CTCAE grade 2 
within 3 weeks of onset, treatment with axitinib may be restarted at the same dose or a lower dose 
using the rules below for dose modifications. There will be no individual modifications to dosing 
schedule in response to toxicity, only potential dose reduction or dose interruption. If the toxicity 
does not resolve to ≤CTCAE grade 2 after 3 weeks, then the patient should be withdrawn from the 
study and observed until resolution of the toxicity. 
 
Table 5. Axitinib Dose interventions 
 
Intervention 
Axitinib dose 
Starting dose 
5 mg orally BID 
Level -1 
3 mg orally BID 
Level -2 
2 mg orally BID 
 
 
5.4.3 Axitinib induced hypertension management 
 
Patients will be asked to keep a home log of daily blood pressure and will be instructed NOT to 
take axitinib if blood pressure is > 150 x 90 mmHg with two consecutive readings and additional 
antihypertensives will be added to control BP to target and resume Axitinib 
 
Management of hypertension is as follow: 
 
Grade 1: No dose modification. 
 
Grade 2: Withhold axitinib. Start and/or optimize anti-hypertensive therapy per institutional policy. 
Patient may resume axitinib after blood pressure is <150 x 90 mmHg. 
 
Grade 3: Requires more than one antihypertensive drug or more intensive therapy than 
previously. If not controlled to 150x90 mmHg with medication, dose reduction required. 
 
Grade 4: Discontinue axitinib when on4 or > antihypertensive medications and blood pressure 
remains >150/90 or symptoms related to hypertensive urgency. 
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5.5 Investigational product supplies 
 
Avelumab and axitinib will be supplied for the study by Pfizer Global Clinical Supply, Worldwide 
Research and Development. Drug supplies will be shipped to the study site with a Drug Shipment 
and Proof of Receipt form. This form will be completed, filed, and the shipment confirmed as directed 
on the bottom of the Drug Shipment and Proof of Receipt form. The Investigator shall take 
responsibility for and shall take all steps to maintain appropriate records and ensure appropriate 
supply, storage, handling, distribution, and usage of investigational products in accordance with the 
protocol and any applicable laws and regulations. 
 
5.6 Investigational product accountability 
 
The investigative site must maintain adequate records documenting the receipt, use, loss, or other 
disposition of all investigational product supplies. Patients receiving axitinib will be required to return 
all unused study treatment at the beginning of each cycle. Pill count will be performed by research 
staff. Drug accountability will be maintained by our pharmacy team. Returned drug will be disposed 
of per MD Anderson institutional policy. 
The study drug Supporter or designee will provide guidance on the destruction of unused 
investigational products (e.g., at the site). If destruction is authorized to take place at the study site, 
the investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by Pfizer, and 
all destruction must be adequately documented. 
 
5.7 Investigational product storage 
 
The Investigator, or an approved representative, e.g., pharmacist, will ensure that all investigational 
products are stored in a secured area with controlled access under required storage conditions and 
in accordance with applicable regulatory requirements. 
Site systems must be capable of measuring and documenting (for example, via a log), at a minimum, 
daily minimum and maximum temperatures for all site storage locations (as applicable, including 
frozen, refrigerated and/or room temperature products). This should be captured from the time of 
investigational product receipt throughout the study. Even for continuous monitoring systems, a log 
or site procedure that ensures active daily evaluation for excursions should be documented. The 
operation of the temperature monitoring device and storage unit (for example, refrigerator), as 
applicable, should be regularly inspected to ensure it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery. 
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible. Deviations from the storage requirements, including 
any actions taken, must be documented and reported to the study Supporter. 
Once an excursion is identified, the investigational product must be quarantined and not used until 
the study Supporter provides documentation of permission to use the investigational product. It will 
not be considered a protocol deviation if the study Supporter approves the use of the investigational 
product after the temperature excursion. Use of the investigational product prior to study Support 
approval will be considered a protocol deviation. 
Avelumab must be stored at 2 to 8 °C or 36 to 46 °F DO NOT FREEZE 
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Avelumab must be allowed to reach room temperature for a minimum of 30 minutes prior to use in 
dose preparation. The immediate administration of the prepared solution for dosing kept at room 
temperature is preferred. In case the aseptically prepared dosing solution cannot be administered 
immediately after preparation, the acceptable holding time is: not more than 24 hours under 
refrigerated conditions (2-8°C, 36-46°F) with no more than 8 of those hours at room temperature 
(15-25°C, 59-77°F), including infusion time. 
If stored under refrigerated conditions, allow each bag to equilibrate to room temperature (15-25°C, 
59-77°F), preferably for one hour before administration 
 
5.8 Preparation and administration of Avelumab 
 
• 
Avelumab infusion solutions must be prepared in 0.9% Sodium Chloride (Normal Saline) and 
the final concentration of avelumab in the infusion solutions must be between 0.016 mg/mL to 8 
mg/mL. 
• 
Total volume of final prepared solution must be 250 mL. 
• 
Parenteral investigational drug products must be inspected visually for particulate matter and 
discoloration (i.e. change in color) prior to administration, whenever the solution and container 
permit. If particulates or discoloration are observed, do not use the vial(s) and notify Pfizer. 
• 
Do not shake or freeze the vial(s). 
• 
The expiry time of final IP is 24 hours from the time the vials were removed from the refrigerator 
and allowed to reach room temperature: 24 hours under refrigerated conditions (2-80 C,36- 
460F) with no more than 8 of those hours at room temperature (15-250C, 59-770F), including 
infusion time. Dose preparation must be performed using sterile handling techniques in 
compliance with local, state, and national laws/regulations. 
• 
Avelumab MUST be administered with a low protein binding 0.2 micron PES filter. 
• 
Each vial is for single-use only. Each vial is for use in a single patient, for a single dose. 
 
 
 
5.9 Treatment duration 
 
Subjects will continue treatment until confirmed disease progression, unacceptable toxicity, refusal 
to participate further, or loss to follow-up. Patients with evidence of disease progression per RECIST 
1.1 (see appendix 1), who were still experiencing clinical benefit could be considered for 
continuation of treatment as per the investigator’s clinical judgment and after discussion between 
the investigator and study Supporter. 
 
If patients develop unacceptable toxicity attributed to one of the study treatments leading to 
discontinuation, they could continue receiving the other study treatment. 
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6. Study Calendar and Procedures 
Table 6 
 
Required 
Procedures 
Screening 
(baseline) 
During 
Treatment 
End of 
Treatment/ 
Safety 
Follow-up 
Visit7 
Long 
Term 
Follow- 
Up5 
Timing 
Within 28 days 
prior to 
treatment 
initiation 
unless 
otherwise 
specified 
Every 4 
weeks, ± 7 
days, unless 
otherwise 
specified 
30 days ± 7 
days after 
last dose of 
study 
treatment 
Consent 
X1 
Treatment 
History 
X 
Medical History 
X 
Demographics 
X 
Physical Exam 
X 
X 
X 
Vital Signs 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
ECOG PS 
X 
Axitinib dosing 
X 
Twice daily 
Avelumab 
dosing 
X 
every 2 
weeks 
Symptoms & 
Toxicities 
X 
X 
On an 
ongoing basis 
throughout 
study 
X 
Concomitant 
Medications 
X 
X 
On an 
ongoing basis 
throughout 
study 
X 
Hematology 
Profile 
X 
X 
every 2 
weeks prior to 
avelumab 
dosing 
X 
Chemistry 
Profile2, 
phosphorous2 
X 
X 
every 2 
weeks prior to 
avelumab 
dosing 
X 
GGT 
X 
aPTT and INR 
X 
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EKG 
X 
Echocardiogram 
X 
X9 
Urine analysis 
for proteinuria 
X 
X9 
Pregnancy Test 
(serum or urine) 
for all women of 
child bearing 
potential3 
X 
X9 
Radiology & 
Tumor 
Measurements 4 
X 
X 
Every 8 
weeks, ± 7 
days 
X 
Biopsy 
X 
If archived 
tissue not 
available 
Blood-based 
biomarkers 
X8 
X8 
Study Drug 
Compliance 
X 
At each clinic 
visit 
Subsequent 
Anticancer 
Therapy 
X 
Survival Status 
X 
1 Written informed consent will be given by each patient prior to undergoing protocol specific evaluation and 
prior to receiving treatment 
2 Chemistry profile includes: BUN, creatinine, sodium, potassium, carbon dioxide, magnesium, total bilirubin, 
alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total protein, and serum 
phosphorus 
3 Serum or urine pregnancy test will be obtained at baseline within 7 days prior to treatment and monthly 
during treatment in all women of child bearing age and again if clinically indicated 
4 CT scan, PET CT scan of the chest/abdomen/pelvis and/or MRI of base of skull/orbit/face as clinically indicated. 
CT scan or MRI of the brain if clinically indicated 
5 Long term follow-up will occur every 6 months by medical/clinical data review or phone contact 
6 For patients who discontinue treatment due to reasons other than disease progression, tumor assessment 
will continue as per during the treatment schedule (i.e. radiology & tumor measurements every 8 weeks +/- 7 
days). 
7 Extended safety follow up: given the potential risk of immune-related toxicity, safety follow up will be performed up 
to 90 days after the last dose of avelumab administration. The extended follow up beyond 30 days after last 
avelumab administration may be performed either via a site visit or via a telephone call with subsequent site visit 
requested in case any concerns noted during the telephone call 
8 Blood will be collected on at baseline (pre-treatment), day 7 (optional), day 15, prior to C3D1, and at 
progression (optional).Three categories of specimen will be collected: EDTA Vaccutainer (checkpoint 
markers/CAFs): 10 mL = 1 x 10 mL; Streck CF-DNA BCT (ctDNA): 10 ml = 1 x 10 mL; and Sodium 
Heparin (immunoprofiling): 60 ml = 6 x 10 mL. All blood will be collected and processed by the Thoracic 
Research Team (Dr. Tran’s laboratory) according the institutional and laboratory standard operating 
procedures (SOPs). 
9 While on treatment as clinically indicated 
6.1 Description of study assessments 
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Performance Status 
The performance status of all patients will be graded according to the ECOG PS scale. 
 
Clinical Laboratory Tests 
Clinical laboratory tests will be performed to assess eligibility for enrollment and will be 
repeated according to study calendar included in this section. Laboratory tests can be 
repeated more 
frequently, if clinically indicated. 
 
Symptoms and Toxicity Assessment 
The symptoms and adverse events of all patients will be graded at scheduled intervals according 
to the NCI CTCAE, v4.03. Patients will be monitored continuously throughout the study for 
the occurrence of adverse events. Planned medical interventions will not be considered an 
adverse event. 
 
Radiology Assessments 
CT chest (with/without abdomen/pelvis), PET-CT, and CT brain / MRI brain will be obtained 
according to Study Calendar included in this section. Response and progression will be evaluated 
in the study using the international criteria proposed by the RECIST committee, and will 
be performed by the MD Anderson radiology collaborator(s) on trial in a blind fashion. 
7. Adverse Events Collection and reporting 
 
 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. 
 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for 
subjects enrolled. 
7.1 Definitions 
 
7.1.1 Adverse events (AE) 
 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study drug, whether or not considered related to the study drug. The term AE is 
used to include both serious and non-serious adverse events. For the purposes of this clinical 
study, AEs include events which are either new or represent detectable exacerbations of pre- 
existing conditions. The term “disease progression” should not be reported as an adverse event 
term. As an example, "worsening of underlying disease" or the clinical diagnosis that is associated 
with disease progression should be reported. 
Adverse events may include, but are not limited to: 
• 
Subjective or objective symptoms provided by the patient and/or observed by the Investigator 
or study staff including laboratory abnormalities of clinical significance. 
• 
Any AEs experienced by the patient through the completion of final study procedures. 
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• 
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the underlying disease that 
were not present before the AE reporting period 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as biopsies). 
 
The following are NOT considered AEs: 
 
• 
Pre-existing condition: A pre-existing condition (documented on the medical history CRF) is 
not considered an AE unless the severity, frequency, or character of the event worsens during 
the study period. 
• 
Pre-planned or elective hospitalization: A hospitalization planned before signing the informed 
consent form is not considered an SAE, but rather a therapeutic intervention. However, if 
during the pre-planned hospitalization an event occurs, which prolongs the hospitalization or 
meets any other SAE criteria, the event will be considered an SAE. Surgeries or interventions 
that were under consideration, but not performed before enrollment in the study, will not be 
considered serious if they are performed after enrollment in the study for a condition that has 
not changed from its baseline level. Elective hospitalizations for social reasons, solely for the 
administration of chemotherapy, or due to long travel distances are also not SAEs. 
• 
Diagnostic Testing and Procedures: Testing and procedures should not to be reported as AEs 
or SAEs, but rather the cause for the test or procedure should be reported. 
• 
Asymptomatic Treatment Related Lymphocytosis: This event should also not be considered 
an AE. Patients with treatment-related lymphocytosis should remain on study treatment and 
continue with all study-related procedures. 
• 
Any adverse event clearly attributable to disease progression 
 
7.1.2 Severity criteria (Grade 1-5) 
 
Definitions found in the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE 
v4.03) will be used for grading the severity (intensity) of AEs. The CTCAE v4.03 displays Grades 
1 through 5 with unique clinical descriptions of severity for each referenced AE. Should a patient 
experience any AE not listed in the CTCAE v4.03, the following grading system should be used 
to assess severity: 
 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special treatment, 
and not interfering with the patient’s daily activities 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the patient, and which may interfere with daily activities, but are usually ameliorated 
by simple therapeutic measures 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the patient’s usual daily activity, and require systemic drug therapy or other treatment 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the patient to be in 
imminent danger of death 
• 
Grade 5 (Death related to AE) – experiences which result in patient death 
 
7.1.3 Causality (Attribution) 
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The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by 
the investigator(s) and communicated to Pfizer in accordance with the agreed process 
 
• 
Not Related: Another cause of the AE is more plausible; a temporal sequence cannot be 
established with the onset of the AE and administration of the investigational product; or, a 
causal relationship is considered biologically implausible. 
• 
Unlikely: The current knowledge or information about the AE indicates that a relationship to 
the investigational product is unlikely. 
• 
Possibly Related: There is a clinically plausible time sequence between onset of the AE and 
administration of the investigational product, but the AE could also be attributed to concurrent 
or underlying disease, or the use of other drugs or procedures. Possibly related should be 
used when the investigational product is one of several biologically plausible AE causes. 
Proprietary of MD Anderson Cancer Center 

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These AEs will be reported as related if the investigator believes it is more likely than not that 
the investigational product caused the AE. 
• 
Related: The AE is clearly related to use of the investigational product. 
 
7.1.4 Unexpected adverse events 
 
An “unexpected” AE is an AE that is not listed in the Investigator's Brochure/package insert or is 
not listed at the specificity or severity that has been observed. For example, hepatic necrosis 
would be “unexpected” (by virtue of greater severity) if the Investigator's Brochure referred only 
to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral 
vasculitis would be “unexpected” (by virtue of greater specificity) if the Investigator's 
Brochure/package insert listed only cerebral vascular accidents. "Unexpected" also refers to AEs 
that are mentioned in the Investigator's Brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the study drug under investigation. 
 
7.2 Documenting and Reporting of Adverse Events and Serious Adverse Events by Investigators 
Table7 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Possible 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Probable 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Recommended 
Adverse Event 
Recording 
Guidelines 
Phase I 
Phase II 
Phase III 
Definitive 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
 
 
 
7.2.1 Serious Adverse Events (SAE) Reporting 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
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An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
• 
Death 
• 
A life-threatening adverse drug experience – any adverse experience that places the patient, 
in the view of the initial reporter, at immediate risk of death from the adverse experience as it 
occurred. It does not include an adverse experience that, had it occurred in a more severe 
form, might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant disability/incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must be 
reported to the IRB in accordance with the institutional timeframes and procedures. 
 
• 
Serious adverse events will be captured from the time of consent, until 30 days after the last 
dose of drug, unless the participant withdraws consent. Serious adverse events must be 
followed until clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution of the event. 
 
• Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate by 
the Principal Investigator. 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”.  
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to MDACC IRB. 
• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
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Reporting to Pfizer 
 
The investigator primary responsibilities in the safety reporting are to identify and follow-up on 
Serious Adverse Events (SAEs) experienced by participants in the study and to forward the 
information to the local regulatory authorities and Pfizer, as required by local regulations (for 
regulatory reporting) and IIR agreement (for reporting to Pfizer). 
 
The following reportable events must be submitted to Pfizer within 24 hours (or immediately for 
death or life-threatening events) using the provided Investigator-Initiated Research Serious 
Adverse Event Form (IIR SAE) with the Pfizer Reportable Events Fax Cover Sheet with each SAE 
submission. 
 
• 
Serious Adverse Events 
• 
Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse event) 
• 
Occupational exposure (even if not associated with an adverse event) 
• 
Potential drug-induced liver injury (Hy’s Law cases): These events are considered important 
medical events and should be reported as SAEs. 
• 
Detailed guidance on the safety reporting is provided in the Safety Reporting Reference 
Manual (Appendix E). 
Contact information for submission of reportable events to Pfizer: 
Fax: Pfizer U.S. Clinical Trial Department, Fax 1-866-997-8322. 
Or 
E-mail: USA.AEReporting@pfizer.com, specifying: 
PROTOCOL: 
SUBJECT: 
SITE/PI: 
SAE/ONSET: 
 
7.2.2 Assessment of adverse events 
Investigators will assess the occurrence of adverse events and serious adverse events at all 
subject evaluation time points during the study. All adverse events and serious adverse events 
whether volunteered by the subject, discovered by study personnel during questioning, detected 
through physical examination, clinically significant laboratory test, or other means, will be 
recorded. Each recorded adverse event or serious adverse event will be described by its duration 
(i.e., start and end dates), severity, regulatory seriousness criteria (if applicable), suspected 
relationship to the investigational product, and any actions taken. 
 
7.2.3 Adverse Event Reporting Period 
 
All AEs whether serious or non-serious, will be captured from the time signed and dated Informed 
Consent Form (ICF) is obtained until 30 days following the last dose of study drugs or until the 
initiation of alternative anticancer therapy. Progressive disease should NOT be reported as an 
Proprietary of MD Anderson Cancer Center 

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event term, but instead symptoms/clinical signs of disease progression may be reported. 
All Grade 3 – 5 adverse events, regardless of seriousness, severity, or presumed relationship to 
study drug, must be recorded using medical terminology in the source document. All records will 
need to capture the details of the duration and the severity of each episode, the action taken with 
respect to the study drug, investigator’s evaluation of its relationship to the study drug, and the 
event outcome. Whenever possible, diagnoses should be given when signs and symptoms are 
due to a common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion 
should be reported as "upper respiratory infection"). 
All deaths should be reported with the primary cause of death as the AE term, as death is typically 
the outcome of the event, not the event itself. 
 
7.2.4 Other events requiring reporting 
Overdose 
An overdose is defined as a subject receiving a dose of study combination in excess of that 
specified in this protocol. If the overdose results in an AE, the AE must also be recorded as an 
AE. Overdose does not automatically make an AE serious, but if the consequences of the 
overdose are serious, for example death or hospitalization, the event is serious and must be 
recorded and reported as an SAE. The investigator will use clinical judgment to treat any 
overdose. 
 
Pregnancy 
 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. 
However, should a pregnancy occur in a female study subject, consent to provide follow-up 
information regarding the outcome of the pregnancy and the health of the infant until 30 days old 
will be requested. 
A female subject must immediately inform the Investigator if she becomes pregnant from the time 
of consent to 30 days after the last dose of study combination. A male subject must immediately 
inform the Investigator if his partner becomes pregnant from the time of consent to 3 months after 
the last dose of study drug. Any female subjects receiving study drug(s) who become   pregnant 
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must immediately discontinue study drug. The Investigator should counsel the subject, discussing 
any risks of continuing the pregnancy and any possible effects on the fetus. 
Although pregnancy itself is not regarded as an adverse event, the outcome will need to be 
documented. Any pregnancy occurring in a subject or subject’s partner from the time of consent 
to 30 days after the last dose of study combination must be reported. Any occurrence of 
pregnancy must be reported per SAE reporting timelines. All pregnancies will be followed for 
outcome, which is defined as elective termination of the pregnancy, miscarriage, or delivery of 
the fetus. Pregnancies with an outcome of live birth, the newborn infant will be followed until 30 
days old by completing will need to be reported per SAE reporting timelines. Any congenital 
anomaly/birth defect noted in the infant must be reported as a serious adverse event. 
 
Paternal Exposure 
 
Pregnancy of the subject’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should if possible be followed up and documented. 
To capture information about a pregnancy from the partner of a male subject, the male subject’s 
partner consent must be obtained to collect information related to the pregnancy and outcome; 
the male subject should not be asked to provide this information. A consent form specific to this 
situation must be used. The outcome of any conception occurring from the date of the first dose 
until 6 months after dosing ends should be followed up and documented. 
 
Other Malignancies 
 
All new malignant tumors including solid tumors, skin malignancies and hematologic malignancies 
will be reported for the duration of study treatment and during any protocol-specified follow-up 
periods including post-progression follow-up for overall survival. 
 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for 
subjects enrolled. 
 
8. Recording and Collection of Data 
 
 
Case report forms 
 
Electronic case report forms will be used for this study, stored under the Data Management 
Initiative (DMI) database. All data collection and storage will be performed under the DMI 
platform. Use of concomitant medications is routinely captured in the patient’s electronic medical 
record and the information is readily available if it needs to be obtained for analysis of study 
results. As such, concomitant medications will not be captured in DMI. 
 
9. Statistical Consideration 
 
 
9.1 Definitions 
 
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All efficacy analyses will be performed in all eligible patients enrolled. Safety analyses will be 
performed on all patients who received any dose of any treatment. 
 
1. Objective Response Rate (ORR) is the percent of patients whose best response is complete 
response or partial response as determined by RECIST 1.1 criteria. 
2. irORR is the percent of patients whose best response is immune-related complete response 
(ir-CR) or immune-related partial response (ir-PR) as determined by irRECIST criteria. 
3. Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression or death, whichever occurs first. PFS rate at 6 months is the percentage of patients 
without disease progression at these time-point. 
4. Overall survival (OS) is defined as the duration of time from start of treatment to death. OS rate 
at 6 months is the percentage of alive patients at these time-point 
5. The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
9.2 Analysis plan 
This is a single-arm, phase II trial to assess the efficacy of the combination of axitinib and 
avelumab in patients with recurrent or metastatic adenoid cystic carcinoma (ACC) with disease 
progression within 6 months prior to study enrollment. The primary endpoint is the overall 
response rate by RECIST 1.1. The trial will be conducted by Simon’s 2-stage design and the 
response rate will be estimated after the second stage (Simon, 1989). 
It is assumed that the new regimen will have a target overall response rate at 6 months of 20%. 
A response rate of 5% or lower is considered a failure and the new regimen will be rejected under 
this circumstance. When the probability of accepting a “bad” regimen (i.e. ORR<=5%) is 0.05 and 
the probability of rejecting a “good” regimen (i.e. ORR >=20%) is 0.20, Simon’s Optimal design 
requires to enter 10 patients in the first stage. If no patient responds to the treatment, the trial will 
be stopped and the regimen will be declared as ineffective. If there are one or more responses, 
19 more patients will be entered in the study to reach a total of 29 evaluable patients. To ensure 
that we have 29 evaluable patients we will enroll a total of 30 patients. By the end of the study, 
the new regimen will be rejected if response rate at 6 months is less than or equal to 3/29 and will 
be accepted otherwise. The operating characteristics of the trial are given as follows. When the 
true response rate is 0.05 the probability of stopping the trial early is 60%. On the other hand, if the 
true response rate is 0.20, the probability to stop the trial early is 10.7%. The expected sample sizes 
are 17.6 and 27.0 when the true response rates are 0.05 and 0.20, respectively. 
To ensure patient safety, the toxicity monitoring will be carried out from the 7th patient using the 
stopping boundaries calculated based on the beta-binomial distribution. The target toxicity rate 
by the end of cycle 1 (4 weeks of treatment) is 30%. Toxicity is defined as: as adverse events in 
the first 4 weeks that are judged to be attributable to one agent or both in combination. Relevant 
hematological events are grade 4 anemia, grade 4 neutropenia lasting longer than7 days, febrile 
neutropenia  (absolute  neutrophil  count  <1.0  ×  10⁹/L  with  temperature  >38.3°C  on       one 
measurement or ≥38.0°C for >1 h), grade 3 or worse neutropenic infection, grade 3 or worse 
thrombocytopenia with bleeding, or grade 4 thrombocytopenia. Relevant non-hematological 
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events, including those not identified by laboratory tests, were any grade 3 or worse toxicity except 
transient (≤6 h) grade 3 flu-like symptoms or fever that could be controlled by medical 
management, transient (≤24 h) grade 3 fatigue, local reaction, or headache that resolved to grade 
1 or better, grade 3 or 4 nausea and vomiting controlled by optimum medical therapy within 72 h, 
grade 3 hypertension controlled by medical therapy, grade 3 diarrhea or grade 3 skin toxicity that 
resolved to at least grade 1 within 7 days of starting medical management (eg, 
immunosuppressants), any grade 3 or worse amylase or lipase abnormality not associated with 
symptoms or clinical manifestations of pancreatitis, and tumor flare phenomenon defined as local 
pain, irritation, or rash localized at sites of known or suspected tumors; grade 3 or 4 increases in 
alanine aminotransferase or aspartate aminotransferase concentrations concurrent with grade 2 
increase in total bilirubin concentration (liver function); non-hematological grade 3 or worse 
laboratory abnormality that needs medical intervention or led to hospital admission (excluding 
single laboratory values out of normal range judged unlikely to be related to trial treatment by the 
investigator, without clinical correlates, and that resolved to grade ≤1 within 7 days with adequate 
medical management); and any event related to the trial treatment preventing completion of at 
least 75% of doses of axitinib or two infusions of avelumab during the first cycle of combined 
therapy. The prior probability of toxicity for the regimen is modeled by a beta distribution Beta 
(0.3, 0.7). The following decision criteria will be applied: 
 
stop if Prob{ θTOX  > 0.30 | data from the trial} > 0.7 
 
Patients recruited will be monitored continuously according to the following stopping boundaries 
for toxicity. 
 
Table 8 Stopping Boundaries 
 
# Patients evaluated (inclusive) 
# Toxicities (inclusive) are 
considered too toxic 
7 
3-7 
8-10 
4-10 
11-13 
5-13 
14-16 
6-16 
17-19 
7-19 
20-22 
8-22 
23-25 
9-25 
26-28 
10-28 
29 
11-29 
30 
Always stop with this many patients 
 
The operating characteristics are summarized in the following table. 
Table 9 Operating Characteristics 
 
True Toxicity Rate 
Prob (stop the trial early) 
0.1 
0.032 
0.2 
0.225 
0.3 
0.584 
0.4 
0.876 
0.5 
0.982 
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The above stopping boundaries and operating characteristics are calculated using MultcLean 
(v.2.1.0) 
design 
software 
downloaded 
from 
http://biostatistics.mdanderson.org/SoftwareDownload. 
Summary statistics including mean, standard deviation, median, and range for the continuous variables, 
and frequency tables for categorical variables, will be provided. The response rate will be estimated 
along with its 95% confidence interval. The distribution of time-to-event endpoints including overall 
survival, progression free survival and duration of response will be estimated using the method of 
Kaplan and Meier. 
 
The investigator is responsible for completing an efficacy/safety summary reportThe efficacy report will 
be reviewed by the principal investigator and/or study co-chair. For Toxicity monitoring: This will  be 
performed  after the first 7 evaluable patients per cohort, complete 1 cycle of study treatment, and 
every 3 evaluable patients thereafter. 
For Response assessment: After the first 10 patients and after 30 patients complete 6 months post- 
treatment. 
A copy of the cohort summary will be placed in the Investigator’s Regulatory Binder.  
10. References 
1. Laurie SA, Ho AL, Fury MG, Sherman E, Pfister DG. Systemic therapy in the management of 
metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic 
review. The Lancet Oncology 2011;12:815-24. 
2. Ferrarotto R, Heymach JV, Glisson BS. MYB-fusions and other potential actionable targets in 
adenoid cystic carcinoma. Current opinion in oncology 2016;28:195-200. 
3. Ferrarotto R, Mitani Y, Diao L, et al. Activating NOTCH1 Mutations Define a Distinct Subgroup 
of Patients With Adenoid Cystic Carcinoma Who Have Poor Prognosis, Propensity to Bone 
and Liver Metastasis, and Potential Responsiveness to Notch1 Inhibitors. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2017;35:352-60. 
4. Ho AL, Dunn L, Sherman EJ, et al. A phase II study of axitinib (AG-013736) in patients with 
incurable adenoid cystic carcinoma. Annals of oncology: official journal of the European 
Society for Medical Oncology 2016;27:1902-8. 
5. Sridharan V, Gjini E, Liao X, et al. Immune Profiling of Adenoid Cystic Carcinoma: PD-L2 
Expression and Associations with Tumor-Infiltrating Lymphocytes. Cancer immunology 
research 2016;4:679-87. 
6. Hughes PE, Caenepeel S, Wu LC. Targeted Therapy and Checkpoint Immunotherapy 
Combinations for the Treatment of Cancer. Trends in immunology 2016;37:462-76. 
7. Atkins M, Plimack E, Puzanov I, et al. Axitinib in combination with pembrolizumab in patients 
(pts) with advanced renal cell carcinoma (aRCC): Preliminary safety and efficacy results. 
ESMO Annual Meeting; 2016: Ann Oncol. 
8. Larkin J, Rini B, Nathan P, et al. Phase 1b dose-finding study of avelumab (anti-PD-L1) + 
axitinib in treatment-naïve patients with advanced renal cell carcinoma. ESMO Annual 
Meeting; 2016: Ann Oncol. 
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9. Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in 
patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. The 
Lancet Oncology 2013;14:1287-94. 
10. Gehan EA. The determination of the number of patients required in a preliminary and a follow- 
up trial of a new chemotherapeutic agent. Journal of chronic diseases 1961;13:346-53. 
 
Appendix 1. Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Guidelines 
Adapted from E.A. Eisenhauer, et al. New response evaluation criteria in solid tumors: Revised 
RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247.35 
 
CATEGORIZING LESIONS AT BASELINE 
 
Measurable Lesions 
 
Lesions that can be accurately measured in at least one dimension. 
Lesions with longest diameter twice the slice thickness and at least 10 mm or greater when 
assessed by CT or MRI (slice thickness 5-8 mm). 
Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 
Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT. 
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for all 
other measurable lesions. 
 
Non-measurable disease 
 
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and < 15 mm) and truly non-measurable disease such as pleural 
or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured with 
calipers, abdominal masses identified by physical exam that are not measurable by reproducible 
imaging techniques. 
 
Bone disease: Bone disease is non-measurable with the exception of soft tissue components that 
can be evaluated by CT or MRI and meet the definition of measurability at baseline. 
 
Previous local treatment: A previously irradiated lesion (or lesion subjected to other local 
treatment) is non-measurable unless it has progressed since completion of treatment. 
 
Normal sites 
 
Cystic lesions: Simple cysts should not be considered as malignant lesions and should not be 
recorded either as target or non-target disease. Cystic lesions thought to represent cystic 
metastases can be measurable lesions, if they meet the specific definition above. If non-cystic 
lesions are also present, these are preferred as target lesions. 
Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease. 
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RECORDING TUMOR ASSESSMENTS 
 
All sites of disease must be assessed at baseline. Baseline assessments should be done as close 
as possible prior to study start. For an adequate baseline assessment, all required scans must be 
done within 28 days prior to treatment/Randomization and all disease must be documented 
appropriately. If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
 
Target Lesions 
 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative 
of all involved organs, should be identified as target lesions at baseline. 
Target lesions should be selected on the basis of size (longest lesions) and suitability for accurate 
repeated measurements. Record the longest diameter for each lesion, except in the case of 
pathological lymph nodes for which the short axis should be recorded. The sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions at baseline will be 
the basis for comparison to assessments performed post-baseline. 
If two target lesions coalesce the measurement of the coalesced mass is used. If a large target 
lesion splits, the sum of the parts is used. 
Measurements for target lesions that become small should continue to be recorded. If the lesion 
is considered to have disappeared, 0 mm should be recorded; otherwise if a lesion is determined 
to be present but too small to measure, the lesion status will indicate “too small to measure and 
judged to be less than 10 mm” and 5 mm will be used in the calculation of the sum of the 
diameters. 
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should still 
be recorded. 
Non-target Disease 
All non-measurable disease is non-target. All measurable lesions not identified as target lesions 
are also included as non-target disease. Measurements are not required but rather assessments 
will be expressed as ABSENT, INDETERMINATE (i.e., Not Evaluable), 
PRESENT/NOT INCREASED, INCREASED. Multiple non-target lesions in one organ may be 
recorded as a single item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning. If a change needs to be made the case should 
be discussed with the radiologist and the Sponsor to determine if substitution is possible. If not, 
subsequent objective statuses are not evaluable. 
 
Target Disease 
Complete Response (CR): Complete disappearance of all target lesions with the exception of 
nodal disease. All target nodes must decrease to normal size (short axis 
< 10 mm). All target lesions must be assessed. 
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Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum of 
diameters of all target measurable lesions. All target lesions must be assessed. 
Stable Disease (SD): Does not qualify for CR, PR or Progression. All target lesions must be 
assessed. Stable can follow PR only in the rare case that the sum increases by less than 20% 
from the nadir (smallest sum of diameters consider baseline and all assessments prior to the time 
point under evaluation), but enough that a previously documented 30% decrease no longer holds. 
Objective Progression (PD): 20% increase in the sum of diameters of target measurable lesions 
above the smallest sum observed (over baseline if no decrease in the sum is observed during 
therapy) with a minimum absolute increase of 5 mm. 
Not evaluable (NE): Progression has not been documented, and 
one or more target lesions have not been assessed; or 
assessment methods used were inconsistent with those used at baseline; or 
one or more target lesions cannot be measured accurately (e.g., poorly visible unless due to being 
too small to measure); or 
one or more target lesions were excised or irradiated and have not reappeared or increased. 
 
Non-target Disease 
CR: Disappearance of all non-target lesions and normalization of tumor marker levels 
(if being followed). All lymph nodes must be ‘normal’ in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level (if being 
followed) above the normal limits. 
PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor burden must 
increase sufficiently to merit discontinuation of therapy. In the presence of SD or PR in target 
disease, progression due to unequivocal increase in non-target disease should be rare. 
Not evaluable (NE): Progression has not been determined, and 
one or more non-target lesion sites have not been assessed; or 
assessment methods used were inconsistent with those used at baseline; or 
one or more non-target lesions cannot be assessed (eg, poorly visible or unclear images); or one 
or more non-target lesions were excised or irradiated and have not reappeared or increased. 
 
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology. 
If repeat assessments confirm the lesion, then progression should be recorded on the date of the 
initial assessment. A lesion identified in an area not previously scanned will be considered a new 
lesion. 
 
Supplemental Investigations 
If CR determination depends on a residual lesion that decreased in size but did not disappear 
completely, it is recommended the residual lesion be investigated with biopsy or fine needle 
aspirate. If no disease is identified, objective status is CR. 
If progression determination depends on a lesion with an increase possibly due to necrosis, the 
lesion may be investigated with biopsy or fine needle aspirate to clarify status. 
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Subjective Progression 
Patients requiring discontinuation of treatment without objective evidence of disease progression 
should not be reported as PD on tumor assessment CRFs. This should be indicated on the end 
of treatment CRF as off treatment due to Global Deterioration of Health Status. Every effort should 
be made to document PD even after discontinuation of study treatment. 
 
Determination of Tumor Response by RECIST 
When both target and non-target lesions are present, individual assessments will be recorded 
separately. New lesions will also be recorded separately. Determination of tumor response at 
each assessment based on target, non-target and new lesions is summarized in the following 
table. 
 
Determination of Best Overall Response 
The best overall response is the best response recorded from the start of 
the 
treatment/randomization until disease progression/recurrence (taking as reference for 
progressive disease the smallest sum on study). For CR and PR, the patient’s best response 
assignment will depend on the achievement of both measurement and confirmation criteria. 
CR and PR must be confirmed by 2 measurements at least 4 weeks apart. In the case of SD, 
follow up measurements must have met the SD criteria at least once after start of the 
treatment/randomization at a minimum interval of 6 weeks. 
 
Appendix 2. Immune-related Response Criteria Derived From RECIST v1.1 (irRECIST) 
 
Increasing clinical experience indicates that traditional response criteria may not be sufficient to 
fully characterize activity in this new era of targeted therapies and/or biologics. This is particularly 
true for immunotherapeutic agents such as anti-CTLA4 and anti-PD-1\anti PD-L1 antibodies 
which exert the antitumor activity by augmenting activation and proliferation of T-cells, thus 
leading to tumor infiltration by T-cells and tumor regression rather than direct cytotoxic effects. 
Clinical observations of patients with advanced melanoma treated with ipilimumab, for example, 
suggested that conventional response assessment criteria such as Response Evaluation Criteria 
in Solid Tumors (RECIST) and World Health Organization (WHO) criteria are not sufficient to fully 
characterize patterns of tumor response to immunotherapy because tumors treated with 
immunotherapeutic agents may show additional response patterns that are not described in these 
conventional criteria. Furthermore, the conventional tumor assessment criteria (RECIST and 
WHO criteria) have been reported as not capturing the existence of a subset of patients who have 
an OS similar to those who have experienced CR or PR but were flagged as PD by WHO criteria. 
On these grounds, a tumor assessment system has been developed that incorporates these 
delayed or flare-type responses into the RECIST v1.1 (irRECIST). For irRECIST, with the 
exception of a complete response assessment, only target and new measurable lesions are taken 
into account. 
In contrast to RECIST v1.1, the irRECIST: 
• 
Requires confirmation of both progression and response by imaging at least 4 weeks from the 
date first documented, and 
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• 
Does not necessarily score the appearance of new lesions as progressive disease if the sum 
of lesion diameters of target lesions (minimum of 10 mm per lesion, maximum of 5 target 
lesions, maximum of 2 per organ) and measurable new lesions does not increase by ≥20%. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline and throughout the study. 
irRECIST responses are defined as follows: 
Overall immune-related complete response (irCR): Complete disappearance of all lesions 
(whether measurable or not) and no new lesions. All measurable lymph nodes also must have a 
reduction in short axis to <10 mm. 
Overall immune-related partial response (irPR): Sum of the diameters (longest for non-nodal 
lesions, shortest for nodal lesions) of target and new measurable lesions decreases ≥30%. 
Overall immune-related stable disease (irSD): Sum of the diameters (longest for non-nodal 
lesions, shortest for nodal lesions) of target and new measurable lesions does not meet criteria 
for irCR or irPR (compared to baseline), or immune-related progressive disease (irPD, compared 
to nadir). 
Overall immune-related progressive disease (irPD): Sum of the diameters (longest for non-nodal 
lesions, shortest for nodal lesions) of target and new measurable lesions increases ≥20% 
(compared to nadir), confirmed by a repeat, consecutive observation at least 4 weeks from the 
date first documented. 
New measurable lesions: Incorporated into tumor burden (ie, added to the target lesion 
measurements). A lymph node has to be ≥15 mm in short axis to be a measurable new lesion 
and its short axis measurement is included in the sum. Up to 2 new lesions per organ and up to 
5 new lesions in total can be added to the measurements. 
New non-measurable lesions: Do not define progression but preclude irCR. 
 
Appendix 3. ECOG Performance Status 
 
0 Fully active, able to carry on all pre-disease activities without restriction 
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work or office work 
2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 Dead 
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