A Phase II Study of Regorafenib in Patients With Progressive, Recurrent/Metastatic Adenoid Cystic Carcinoma
Phase: PHASE2
Conditions: Adenoid Cystic Carcinoma
Sponsor: Memorial Sloan Kettering Cancer Center

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A Phase II Study of Regorafenib in Patients with Progressive, 
Recurrent/Metastatic Adenoid Cystic Carcinoma 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Alan L. Ho MD, PhD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
David G. Pfister MD 
Medicine 
Investigator(s)/Department: 
Eric Sherman, MD 
Shrujal Baxi, MD 
Sofia Haque, MD 
Vaios Hatzoglou, MD 
John Lyo, MD 
Camelia Sima, MD 
Nora Katabi, MD 
Mario Lacouture, MD 
Jahan Aghalar, MD 
Arlyn Apollo, MD 
Karen Cadoo, MD 
Philip Caron, MD, PhD 
Jasmeet Chadha Singh, MD 
Chau Dang, MD 
Avni Desai, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Diana Lake, MD 
Stuart Lichtman, MD 
Kenneth Ng, MD 
Marina Shcherba, DO 
Sarah Schweber, MD 
Steven Sugarman, MD 
Elizabeth Won, MD 
Han Xiao, MD 
Medicine 
Medicine 
Radiology 
Radiology 
Radiology 
Epidemiology/Biostatistics 
Pathology 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
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Medicine 
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Medicine 
Medicine 
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Consenting Professional(s)/Department: 
Eric Sherman, MD 
David Pfister, MD 
Alan Ho, MD, PhD 
Shrujal Baxi, MD 
Jahan Aghalar, MD 
Arlyn Apollo, MD 
Karen Cadoo, MD 
Philip Caron, MD, PhD 
Medicine 
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Jasmeet Chadha Singh, MD 
Chau Dang, MD 
Avni Desai, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Diana Lake, MD 
Stuart Lichtman, MD 
Kenneth Ng, MD 
Marina Shcherba, DO 
Sarah Schweber, MD 
Steven Sugarman, MD 
Elizabeth Won, MD 
Han Xiao, MD 
Medicine 
Medicine 
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Medicine 
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Medicine 
Medicine 
Medicine 
 
 
 
 
 
 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
 
OneMSK Sites 
Manhattan, NY 
Basking Ridge, NJ 
Rockville Centre, NY 
Commack, NY 
Westchester, NY 

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Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 5 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .......................................................... 11 
4.1 
Design ........................................................................................................................... 11 
4.2 
Intervention ................................................................................................................... 11 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS.......................................................................... 11 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................... 11 
6.1 
Subject Inclusion Criteria ............................................................................................... 12 
6.2 
Subject Exclusion Criteria .............................................................................................. 13 
7.0 
RECRUITMENT PLAN ..................................................................................................... 15 
8.0 
PRETREATMENT EVALUATION .................................................................................... 15 
9.0 
TREATMENT/INTERVENTION PLAN .............................................................................. 16 
10.0 EVALUATION DURING TREATMENT/INTERVENTION .................................................. 23 
11.0 TOXICITIES/SIDE EFFECTS ........................................................................................... 25 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...................... 32 
13.0 CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 38 
14.0 BIOSTATISTICS .............................................................................................................. 38 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
39 
15.1 Research Participant Registration ................................................................................. 39 
15.2 Randomization .............................................................................................................. 40 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 40 
16.1 Quality Assurance .......................................................................................................... 40 
16.2 Data and Safety Monitoring ........................................................................................... 40 
17.0 PROTECTION OF HUMAN SUBJECTS ........................................................................... 42 
17.1 Privacy .......................................................................................................................... 42 
17.2 Serious Adverse Event (SAE) Reporting ....................................................................... 43 
17.2.1 
 44 
18.0 INFORMED CONSENT PROCEDURES........................................................................... 45 
19.0 REFERENCES ................................................................................................................. 46 
20.0 APPENDICES .................................................................................................................. 49 

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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This is a single-arm phase II study evaluating the clinical efficacy of regorafenib in the 
treatment of patients with progressive, recurrent/metastatic adenoid cystic carcinoma 
(ACC). Any number of prior therapies for recurrent/metastatic ACC is allowed. There are 
two primary endpoints for the study: 1) proportion of patients alive at 6 months without 
disease progression by RECIST v1.1 criteria (6-month PFS), and 2) best overall response 
rate (BOR = CR+PR) documented by RECIST v1.1 criteria. The secondary endpoints are 
the safety and tolerability of regorafenib. An exploratory endpoint is analyzing tumor 
tissues for biomarkers that correlate to regorafenib clinical efficacy. Patients enrolled in 
the study will be treated with regorafenib 160 mg orally daily for 3 weeks in a 4 week 
cycle. Dose reductions and delays can be implemented according to criteria outlined in 
Section 11. RECIST v1.1 tumor assessments will be made at baseline (CT or MRI) and 
then approximately every 2 cycles (or every 8 weeks (+/- 1 week)). After 10 months, 
imaging will be done approximately every 3 cycles (or every 12 weeks (+/- 1 week)). 
Patients may remain on study until progression of disease or unacceptable toxicity. Other 
reasons patients could potentially come off study include patient non-compliance, patient 
withdrawal of consent, or physician’s clinical judgment that removal of the patient from the 
study is in his/her best interest. 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Objectives 
1) To determine the proportion of patients alive at 6 months without disease progression 
by RECIST v1.1 criteria of patients with progressive, recurrent/metastatic ACC treated 
with regorafenib. 
2) To determine the best overall response rate documented by RECIST v1.1 criteria of 
patients with progressive, recurrent/metastatic ACC treated with regorafenib. 
Secondary Objective 
To determine the safety/tolerability of regorafenib. 
Exploratory Objective 
To perform tumor tissues analyses for putative biomarkers and explore their association 
with regorafenib clinical efficacy. 
3.0 
BACKGROUND AND RATIONALE 
Recurrent/metastatic (R/M) ACC 
Adenoid cystic carcinomas (ACCs) are malignant neoplasms composed of epithelial and 
myoepithelial cells that commonly arise from both minor and major salivary glands. 
Rarely, ACC may also originate at other sites, such as the trachea, lung, and breast. 
While localized disease is potentially curable, nearly 40% of patients develop distant 
metastasis despite aggressive surgery and radiation with disease-free intervals ranging 
from 1 month to 19 years1,2. Metastatic disease is incurable and can be either indolent 
(10% of patients with distant metastases survive more than 10 years) or alternatively more 
aggressive (54% of patients with distant metastases survive less than 3 years)2. There are 
no effective therapies and the development of new treatments is urgently needed. 

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Systemic therapies tested in R/M ACC to date possess limited effectiveness 
We conducted an exhaustive review of all chemotherapy studies conducted between 1966 
and 2009 for R/M ACC which included 34 clinical trials that involved less than 500 
patients3. Most were small, single institution studies of variable methodological quality. In 
this literature, only 18 objective major responses out of 141 patients (13%) treated with 
single agent cytotoxic chemotherapy were reported. Mitoxantrone as a single agent was 
studied in the most number of patients in clinical trials of variable quality; the pooled 
response rate (an imperfect estimate of true activity) from these studies was around 
10%4,5. Ultimately, the true response rate of cytotoxic chemotherapy can only be 
concluded to be modest; the actual rate of response is difficult to ascertain across several 
different trials of variable quality. Insufficient data exists to suggest that combination 
chemotherapy improves response rates or clinical benefit over single agent treatment. 
Given the limited efficacy of cytotoxic drugs, several targeted therapies have also been 
tested. With up to 90% of ACC tumors possessing high c-kit expression and case reports 
of responses to imatinib, six studies have been reported for imatinib in ACC with 
disappointingly only 2 objective responses in 71 evaluable patients6-11. Studies with 
gefitinib, cetuximab, lapatinib, and bortezomib all have failed to yield any objective 
responses3. 
The oncogenic transcription factor c-myb is overexpressed in ACC 
In 2009, Persson et. al. confirmed the existence of a t(6;9)(q22-23;p23-24) translocation in 
ACC tumors of the breast and head/neck12 (Figure 1A). This cytogenetic alteration 
creates a gene fusion of the c-myb and NFIB transcription factors. The translocation was 
identified in all 11 tumors analyzed. The MYB-NFIB fusion characterized in that 
publication predominantly involved a breakpoint between intron 14 of MYB and intron 8 of 
NFIB. Minimally, this resulted in the loss of the last 38 amino acids on the c-myb protein 
and the addition of the last 5 amino acids of the NFIB protein to the C-terminal end of the 
truncated c-myb gene (Figure 1). This results in the loss of several microRNA binding 
sites in the 3’ UTR (“untranslated region”) of the MYB gene, leading to upregulated levels 
of c-myb expression in ACC tumors relative to non-ACC tumors at both the mRNA 
transcript and protein level12,13. c-myb overexpression presumably enhances 
transcriptional activity of c-myb, leading to the overexpression of 14 MYB target genes, 
including vascular endothelial factor A (VEGFA), KIT, fibroblast growth factor -2 (FGF2), 
and BCL212, all of which have been previously proposed to be potentially critical genes for 
therapeutic targeting in ACC. 

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Mitani et. al. recently published a comparative analysis of 123 salivary gland cancers (72 
primary ACC tumors, 17 ACCs metastatic to the lung and lymph nodes, and 34 salivary 
tumors of other non-ACC histologies) and 5 normal salivary gland tissue samples13. 
These authors observed that the MYB-NFIB fusion gene was present in 27.7% of primary 
ACCs, 35.2% of metastatic ACCs, and none of the non-ACC salivary cancer histologies or 
normal salivary tissues. As expected, elevated MYB expression was detected in 85% of 
fusion positive tumors at about 100-fold higher levels than non-ACC tumors. Interestingly, 
70% of fusion negative tumors also demonstrated elevated c-myb expression at an 
approximately 40-fold higher level over non-ACC tumors and just 2-fold lower than fusion- 
positive ACCs, suggesting alternate mechanisms of c-myb overexpression and supporting 
the hypothesis that c-myb plays a central role in the pathogenesis of this disease. 
c-myb is a bona fide oncogene. It was first discovered as the transforming gene co-opted 
by the Avian myeloblastosis virus (AMV) and later the MYB gene locus was identified as a 
common integration site for several avian and murine retroviruses leading to the 
development of leukemia14. It was recently reported that the MYB gene locus is involved 
with chromosomal translocations and genomic duplications associated with a new subtype 
of human T-cell acute leukemia14,15. MYB overexpression has also been described in solid 
tumors. In colon cancer, MYB overexpression has been reported in >80% of cases14 and 
when found expressed with Bcl-xl correlates with poor prognosis16. MYB overexpression 
has also been implicated in the pathogenesis of breast, melanoma, pancreatic, and 
esophageal cancers14. 
Results from two whole exome and genome sequencing projects in ACC have recently 
been reported17,18. These analyses revealed a relatively “quiet” genome with a low 
somatic mutation rate (0.31 non-silent events per megabase17) and wide mutational 
diversity. These studies verified the importance of MYB in ACC biology with one study 
confirming 57% of tumors possessed the MYB-NFIB translocation and an additional 8% 
had alterations resulting in MYB pathway dysregulation17. Mutations in chromatin- 
remodeling genes were also a prominent feature in the genetic landscape of ACCs (35%17 
and 50%18 rates of mutation in the two studies). Alterations in several other biologic 
pathways were found to occur at lower frequencies. 
Targeting c-myb activity in ACC 
Figure 1. Schematic of the t(6;9) translocation. DBD, DNA Binding Domain; TAD, Transactivation Domain; NRD, Negative 
Regulatory Domain; miR, microRNA. Adapted from Persson et. al. “Recurrent fusion of MYB and NFIB transcription factor 
genes in carcinomas of the breast and head and neck”. PNAS, 2008. 

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Devising strategies to directly block the function of a non-kinase transcription factor is a 
challenge. One approach is to inhibit the activity of critical c-myb target genes responsible 
for promoting oncogenesis. An analysis of 7 fusion positive ACC tumors confirmed that 
MYB overexpression indeed correlates to upregulation of 14 MYB transcriptional target 
genes, including the regorafenib-relevant targets VEGFA (ligand that induces 
angiogenesis by engaging VEGF receptors (VEGFRs)), FGF2 (ligand that activates a 
subset of FGF receptors (FGFRs)), and the receptor tyrosine kinase (RTK) KIT (c-kit)12. 
Regorafenib-relevant pathways and targets in ACC 
Beyond c-myb mediated activation, several lines of evidence suggest that VEGFR, c-kit, 
and FGFR pathways are potentially critical to ACC biology. 
VEGF pathway: High levels of VEGF ligand have been detected in salivary malignancies 
in general, and ACC specifically, correlating to more advanced clinicopathologic features 
(including stage, recurrence, and metastases) in several studies19-21. Multivariate 
analyses have also shown that high VEGF expression in ACC tumors is an independent 
prognostic factor for survival21. These data suggest that the VEGF pathway may be 
critical for ACC pathogenesis and/or progression for tumors that overexpress VEGF 
ligand. 
c-kit: c-kit is highly expressed in >90% of ACCs22-26. A 2004 case report described 
impressive clinical responses in two patients with c-kit positive ACC treated with 600 mg 
daily of imatinib mesylate, a small molecule inhibitor of c-kit and platelet derived growth 
factor receptor (PDGFR)27. While subsequent imatinib studies failed to show significant 
clinical activity 6-11, one requiring “strong” c-kit expression and progressive disease at 
study entry reported two responses out of 15 evaluable patients11. A recent phase II study 
of dasatinib also failed to produce RECIST responses in ACC patients, though 52% of the 
patients with progressive disease at study entry did have stable disease on drug28. These 
data indicate that c-kit targeting only has modest efficacy at best, and leaves open the 
possibility that combining c-kit inhibition with other ACC-relevant kinase targets may 
produce greater efficacy. 
FGF pathway: There is now emerging evidence that the FGF pathway is activated in 
adenoid cystic carcinomas. Immunohistochemistry revealed that FGF1, FGF2, and 
FGFR1 are expressed in ACCs, while normal salivary tissues are completely negative or 
only weakly positive for these proteins29. The recent characterization of the genetic 
landscape of ACCs revealed mutations in FGF16 ligand, FGFR2, and FGFR417,18 as well 
as a tandem duplication within FGFR2 discovered in one tumor17. Interestingly, transgenic 
mice overexpressing FGF8b develop salivary cancers, and injection of FGF ligand in a 
9,10-dimethyl-1,2-benzanthracene (DMBA) carcinogenesis mouse model for salivary 
malignancies increased the incidence of salivary cancer formation. Such data suggests 
that the FGF pathway is activated in ACC and may contribute to salivary cancer 
oncogenesis. 
Preliminary clinical efficacy data for multi-kinase inhibitors in ACC 
Evidence for both MYB-dependent and -independent mechanisms of VEGFR/c-kit/FGFR 
activation in ACC biology has raised interest in evaluating multikinase inhibitors against 

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these targets in ACC patients. Preliminarily, studies have suggested clinical activity with 
these agents. The first study conducted was a phase II trial of sunitinib (VEGFR, PDGFR, 
KIT inhibitor) in patients with progressive, recurrent/metastatic ACC30. While no 
responses were observed, 8 out of the enrolled 14 patients had stable disease for 6 
months or more, potentially meaningful given that progressive disease was required for 
enrollment30. Results from a sorafenib31 (VEGFR, PDGFR inhibitor) and a dovitinib32 
(VEGFR, PDGFR, FGFR1-3, KIT inhibitor) phase II ACC trial were reported in abstract 
form at the 2013 ASCO Annual meeting. Both agents elicited an approximately 11% 
response rate. An axitinib (VEGFR, PDGFR, c-kit inhibitor) phase II study also recently 
completed enrollment at MSKCC. The data has not yet been presented, but the study 
was a 2-stage design that met the clinical efficacy rule required for progressing to the 
second stage. These preliminary data suggest that combined VEGFR, PDGFR, c-kit 
inhibition plus or minus FGFR targeting translates to some clinical efficacy in ACC. 
Regorafenib 
Regorafenib has potent preclinical antitumor activity and long-lasting anti-angiogenic 
activity as measured by dynamic contrast enhanced (DCE) – magnetic resonance imaging 
(MRI)33. 
Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular 
kinases involved in normal cellular functions and in pathologic processes such as 
oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. In in 
vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 
and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, 
PDGFR-beta, FGFR, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, 
PTK5, and Ab1 at concentrations of regorafenib that have been achieved clinically. In in 
vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and 
inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft 
models. 
Preclinical data with regorafenib 
In vivo, regorafenib exhibited anti-angiogenic and anti-proliferative effects in human colon 
and breast xenografts as demonstrated by a reduction in microvessel area, reduced Ki-67 
staining, and reduced pERK1/2 staining in tissue sections from tumor xenografts, and 
dose-dependent inhibition of growth in multiple xenograft models (breast, colon, renal, 
NSCLC, melanoma, pancreatic, thyroid, ovarian)33. Immunohistochemical ex-vivo studies 
with a phospho–specific monoclonal anti-ERK 1 / 2 antibody demonstrated inhibition of the 
MAPK pathway five days after treatment with regorafenib in 2 of 3 tumor models examined 
(MDA-MB 231 and BxPC-3), but not in NSCLC (H460). 
In addition, all tested human tumor xenografts (MDA-MB-231, H460, BxPC-3 and Colo- 
205) demonstrated a significant reduction in new blood vessels by histomorphometry as 
detected in tumor samples using a murine CD31 antibody33. These data suggest that 
regorafenib can target the tumor cell MAPK pathway (tumor cell survival) and tumor 
vasculature in some but not all tumors. 

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Clinical experience with regorafenib 
Two phase III global randomized studies have evaluated the efficacy of regorafenib. The 
CORRECT (Patients with metastatic colorectal cancer treated with regorafenib or placebo 
after failure of standard therapy) trial is an international, multicenter, randomized, double- 
blind, placebo-controlled study that enrolled 760 patients with mCRC whose disease has 
progressed after approved standard therapies34. Metastatic colorectal cancer patients 
were randomized to regorafenib plus best supportive care (BSC) or placebo plus BSC. 
Treatment cycles consisted of 160 mg of regorafenib (or matching placebo) once daily for 
three weeks on / one week off plus BSC. The primary endpoint of this trial was overall 
survival. Secondary endpoints included progression-free survival, objective tumor 
response rate and disease control rate. The safety and tolerability of the two treatment 
groups were also compared. 
At a preplanned second interim analysis, there was a statistically significant survival 
benefit for regorafenib. The estimated hazard ratio for overall survival was 0.773 (95% 
confidence interval [CI], 0.635 to 0.941; 1-sided p = .0051). Patients treated with 
regorafenib had a median overall survival of 6.4 months, compared with 5.0 months for 
placebo — a 29% increase in survival. In addition to improved overall survival, 
progression-free survival was superior; median progression-free survival was 1.9 months 
(95% CI, 1.88 to 2.17) for regorafenib and 1.7 months (95% CI, 1.68 to 1.74) for placebo. 
The estimated hazard ratio for progression-free survival was 0.493 (95% CI, 0.418 to 
0.581; 1-sided p< .000001). There was a substantial difference in disease control rate in 
the regorafenib and placebo groups (44% vs. 15%; p<.000001). Regorafenib 
demonstrated comparable efficacy benefits across patient subgroups analyzed including 
age, number of mets, number of lines of prior therapy, and kras status. 
The most frequent grade 3+ adverse events in the regorafenib group were hand–foot skin 
reaction (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and hypertension 
(7%). The efficacy and safety from the CORRECT study supported FDA approval in 
September 2012. 
The efficacy and safety of regorafenib were examined in the Phase III GRID trial in 
patients with gastrointestinal stromal tumors (GISTs) who had exhausted all other 
treatment options35. The study involved 199 patients with metastatic and/or unresectable 
GIST that had become resistant to imatinib and sunitinib. Patients were randomized 2:1 to 
regorafenib (160 mg orally once daily on a 3 weeks on/1 week off cycle) or placebo, plus 
best supportive care. 
The results showed that treatment with regorafenib led to a statistically significant 3.9- 
month improvement in progression-free survival (PFS), compared with placebo (4.8 
months vs. 0.9 months; hazard ratio [HR] = 0.27; p <.0001). Overall survival was 
statistically similar between groups as expected due to a trial design that allowed 
crossover to regorafenib for disease progression (85% for placebo and 31% regorafenib 
randomized patients). The median survival period without tumor growth among patients 
on regorafenib was 4.8 months while for the control group on placebo it was less than a 
month. The overall disease control rate combining partial responses with durable stable 
disease for at least 12 weeks was 53% with regorafenib compared with 9% in the control 

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group. The most common grade ≥3 adverse events associated with regorafenib were 
hand-foot skin reaction (56.1%), hypertension (48.5%), and diarrhea (40.9%). The 
efficacy and safety of the GRID study data supported FDA approval February 2013. 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a single-arm phase II study of patients with progressive, recurrent/metastatic 
adenoid cystic carcinoma (R/M ACC) treated with regorafenib. There are two primary 
objectives for the study: 1) to determine the proportion of patients alive at 6 months 
without disease progression by RECIST v1.1 criteria (6-month PFS), and 2) to determine 
the best overall response rate (BOR = CR+PR) documented by RECIST v1.1 criteria. 
Thirty-eight patients will be enrolled in the study. If at least 21 patients are alive and free of 
progression at 6-month, or if at least 5 patients have a response at any time while being 
enrolled in the study, the regimen will be considered worthy of further investigation. 
Regorafenib safety and tolerability will be assessed utilizing Common Terminology Criteria 
for Adverse Events version 4.0 (CTCAE 4.0) as a secondary endpoint. An exploratory 
objective is to analyze tumor tissue in order to identify potential biomarkers that correlate 
to regorafenib clinical efficacy. 
4.2 
Intervention 
All eligible patients will receive a starting regorafenib dose of 120 mg daily taken orally for 
3 weeks in a 4-week cycle. Patients for whom regorafenib dose reduction was not 
performed or required may have their treatment dose increased to the FDA-approved 
dose of 160 mg daily orally for 3 weeks in a 4-week cycle in cycle #2 or beyond (this is not 
mandatory). RECIST v1.1 tumor assessments will be made at baseline (CT or MRI) and 
then approximately every 2 cycles (or every 8 weeks (+/- 1 week)). After 10 months, 
imaging will be done every 3 cycles (or every 12 weeks (+/- 1 week)). 
Patients may 
remain on study until progression of disease or unacceptable toxicity 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
Regorafenib (Bayer) or its major human active metabolites M-2 and M-5 inhibits the 
activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, 
FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Ab1 
at concentrations of regorafenib that have been achieved clinically. 
Regorafenib tablets will be packaged in high density polyethylene bottles with a white child 
resistant closure and induction seal. Each bottle includes 30 tablets and a 3-gram 
desiccant. The bottles will have a label affixed containing study identification, product 
identification, and quantity of tablets. Once the drug has been received it must be kept in 
a secure, dry location. Study drug must be stored in its original bottle at a temperature not 
above 25°C (77°F). The study drug must be exclusively used for the investigation 
specified in this protocol and it will only be accessible to authorized staff. 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 

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6.1 
Subject Inclusion Criteria 
• Patients must have pathologically or cytologically confirmed adenoid cystic carcinoma. 
Cancers arising from non-salivary gland primary sites are allowed. 
• Patients must have recurrent and/or metastatic disease not amenable to potentially 
curative surgery or radiotherapy. 
• At least 2 weeks must have elapsed since the end of prior systemic treatment (4 weeks for 
bevacizumab- containing regimens) or radiotherapy with resolution of all treatment-related 
toxicity to NCI CTCAE Version 4.0 grade ≤1 (or tolerable grade 2) or back to baseline 
(except for alopecia, lymphopenia, or hypothyroidism). Any number of prior therapies for 
recurrent/metastatic ACC are allowed. 
• Patients must have RECIST v1.1 measurable disease, defined as at least one lesion that 
can be accurately measured in at least one dimension (longest diameter to be recorded 
for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional 
techniques or as >10 mm with spiral CT scan. 
• Patients must have documentation of a new or progressive lesion on a radiologic imaging 
study performed within 6 months prior to study enrollment (progression of disease over 
any interval is allowed) and/or new/worsening disease related symptoms within 6 months 
prior to study enrollment. Note: This assessment will be performed by the treating 
investigator. Evidence of progression by RECIST criteria is not required. 
• Patients must have archival tissue from the primary tumor or metastases available for 
correlative studies. Either a paraffin block or twenty unstained slides are acceptable. If 
twenty slides are not available, a lesser amount may be acceptable after discussion with 
the Principal Investigator, Dr. Alan L. Ho. 
• Patients must agree to undergo biopsy of a malignant lesion. Biopsies do not need to be 
done if either the investigator or person performing the biopsy judges that no tumor is 
accessible for biopsy or that biopsy poses too great of a risk to the patient. Patients may 
also be exempt if frozen tumor tissue has been collected within 12 months of study 
enrollment that the Principal Investigator deems is appropriate/sufficient for analysis on 
this protocol. 
• Age ≥ 18 years. 
• ECOG performance status <2 (Karnofsky >60%, see Appendix A). 
• Life expectancy of at least 12 weeks (3 months) as determined by the investigator. 
• Subjects must be able to understand and be willing to sign the written informed consent 
form. A signed informed consent form must be appropriately obtained prior to the conduct 
of any trial-specific procedure. 
• Adequate bone marrow, liver and renal function as assessed by the following laboratory 
requirements: 

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o Total bilirubin ≤ 1.5 x the upper limits of normal (ULN) 
o Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) ≤ 2.5 x 
ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) 
o Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver 
involvement of their cancer) 
o Lipase ≤ 1.5 x the ULN 
o Amylase ≤ 1.5 x the ULN 
o Serum creatinine ≤ 1.5 x the ULN or calculated creatinine clearance >60 ml/min 
o Platelet count > 100,000 /mm3, hemoglobin (Hb) > 9 g/dL, absolute neutrophil 
count (ANC) >1500/mm3. Blood transfusion to meet the inclusion criteria will not 
be allowed. 
• Women of childbearing potential must have a negative serum pregnancy test performed 
within 2 weeks prior to the start of study drug. Post-menopausal women (defined as no 
menses for at least 1 year) and surgically sterilized women are not required to undergo a 
pregnancy test. 
• Subjects (men and women) of childbearing potential must agree to use adequate 
contraception beginning at the signing of the consent form until at least 3 months after the 
last dose of study drug. The definition of adequate contraception will be based on the 
judgment of the principal investigator or a designated associate. 
• Subject must be able to swallow and retain oral medication. 
6.2 
Subject Exclusion Criteria 
• Concurrent anti-cancer therapy (chemotherapy, definitive radiation therapy, surgery, 
immunotherapy, biologic therapy, or tumor embolization) other than study treatment. 
Concurrent therapy with bisphosphonates or denosumab for bone metastases is allowed. 
Palliative radiation to non-target lesions is also allowed. 
• Prior use of regorafenib. 
• Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm 
Hg [NCI-CTCAE v4.0] on repeated measurement) despite optimal medical management. 
• Concurrent use of another investigational drug or device therapy (i.e., outside of study 
treatment) during, or within 4 weeks of trial entry (signing of the informed consent form). 
• Concurrent use of strong CYP3A4 inhibitors (e.g. clarithromycin, grapefruit juice, 
itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole). 
or strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and 
St. John’s Wort). 
• Use of any herbal remedy (e.g. St. John’s wort [Hypericum perforatum]) 

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• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before 
start of study medication. 
• Active or clinically significant cardiac disease including: 
o Congestive heart failure – New York Heart Association (NYHA) > Class II. 
o Active coronary artery disease that is not medically treated. 
o Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or 
digoxin. 
o Unstable angina (anginal symptoms at rest), new-onset angina within 3 months 
before randomization, or myocardial infarction within 6 months before 
randomization. 
• Therapeutic anticoagulation with Vitamin-K antagonists (e.g., warfarin) is not allowed if the 
medication dose and/or INR/PTT are not considered stable by the treating physician. If 
the dose and/or INR/PTT are stable, therapeutic anticoagulation with Vitamin-K 
antagonists is allowed with close monitoring. Anticoagulation with heparin or heparinoids 
is allowed. 
• 
Evidence or history of bleeding diathesis or coagulopathy. 
• 
Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of 
study medication. 
• Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular 
accident (including transient ischemic attacks) deep vein thrombosis or pulmonary 
embolism within 6 months of start of study treatment. 
• Subjects with a past or current diagnosis of another malignancy that will interfere with 
conduct of the trial. Patients with past or current cancer diagnoses other than ACC are 
allowed to enroll if the investigator believes it will not interfere with trial conduct. 
• Patients with phaeochromocytoma. 
• Known history of human immunodeficiency virus (HIV) infection or current chronic or 
active hepatitis B or C infection requiring treatment with antiviral therapy. 
• Active infection that would impair the ability of the patient to receive study treatment. 
• Symptomatic metastatic brain or leptomeningeal tumors (asymptomatic or treated 
metastatic brain and leptomeningeal tumors are allowed). 
• Presence of a non-healing wound or non-healing ulcer that is not tumor related. 
• Renal failure requiring hemo-or peritoneal dialysis. 
• Patients with seizure disorder requiring medication. 

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• Interstitial lung disease with ongoing signs and symptoms at the time of informed consent. 
• History of organ allograft (including corneal transplant). 
• Known or suspected allergy or hypersensitivity to any of the study drugs, study drug 
classes, or excipients of the formulations given during the course of this trial. 
• Any malabsorption condition. 
• Women who are pregnant or breast-feeding. 
• Any condition which, in the investigator’s opinion, makes the subject unsuitable for trial 
participation. 
• Substance abuse, medical, psychological or social conditions that may interfere with the 
subject’s participation in the study or evaluation of the study results. 
7.0 
RECRUITMENT PLAN 
Potential research subjects will be identified by a member of the patient’s treatment team, 
the protocol investigator, or research team. Patient recruitment most likely will occur in the 
medical oncology clinics of the Head and Neck Disease management team. If the 
investigator is a member of the treatment team, s/he will screen their patient’s medical 
records for suitable research study participants and discuss the study and their potential 
for enrolling in the research study. Potential subjects contacted by their treating physician 
will be referred to the investigator/research staff of the study. Investigators will discuss the 
study and review/sign the informed consent documents with the patient. 
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary to the 
recruitment and enrollment process. The investigator/research staff may also review 
portions of their medical records in order to further assess eligibility. They will use the 
information provided by the patient and/or medical record to confirm that the patient is 
eligible and to contact the patient regarding study enrollment. If the patient turns out to be 
ineligible for the research study, the research staff will destroy all information collected on 
the patient during the initial conversation and medical records review. 
8.0 
PRETREATMENT EVALUATION 
Within 30 days of starting treatment, the following tests need to be done: 
• History and Physical Examination 
• Vital signs, including weight 
• Performance Status (ECOG or Karnofsky Performance Status) 
• Electrocardiogram (ECG) 
• Radiology studies (CT or MRI) for disease assessment. 

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• Record of concomitant medications 
• Signed Informed Consent Form 
• Request for archival tumor tissue (if tissue is not already available at MSKCC; receipt of 
tissue is not required for study enrollment or initiation.) 
• Research tumor biopsy (this can be performed any time prior to start of study drug): 
Patients may be exempt from biopsy if either the investigator or person performing the 
biopsy judges that no tumor is accessible for biopsy or that biopsy poses too great of a 
risk to the patient. Patients may also be exempt if frozen tumor tissue has been 
collected within 12 months of study enrollment that the Principal Investigator deems is 
appropriate/sufficient for analysis on this protocol. For those undergoing research 
biopsy on protocol, radiologic guidance (CT, MRI or ultrasound guided) approaches and 
obtaining multiple cores to ensure sufficient biopsy material (at least 3 cores preferred) 
are allowed as long as it is considered reasonably safe for the patient. Tissue will be 
flash frozen in liquid nitrogen as directed by the Principal Investigator (the biopsy 
sample(s) will be placed into a cryovial, which will be submerged in a liquid nitrogen bath 
until the tissue is frozen.) Some tissue may be prepared by fixation according to 
institutional guidelines as directed by the Principal Investigator. 
• Research blood draw (this can be performed any time prior to start of study drug): 
approximately 10 mL of blood, preferably in a lavender top tube (with EDTA). 
Within 14 days of starting treatment, the following tests need to be done: 
• Complete Blood Count (including platelets) 
• Comprehensive Panel, including liver function tests (Albumin, alkaline phosphatase, 
total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total 
protein, SGOT[AST], SGPT[ALT], sodium), LDH, phosphorus 
• Coagulation studies consist of the prothrombin time (PT), partial thromboplastin time 
(PTT), and international normalized ratio (INR). These are only required for patients on 
anti-coagulation medications (heparin, low-molecular weight heparin, or coumadin). 
These do not need to be checked for patients not on these anti-coagulation medications. 
• Lipase 
• Serum pregnancy test in women of child-bearing potential. 
9.0 
TREATMENT/INTERVENTION PLAN 
9.1 Administration 
Regorafenib 120 mg daily taken orally will be administered for 3 weeks on /1 week off. 
One cycle is 28 days. Three 40-mg regorafenib tables should be taken in the morning 
with approximately 8 fluid ounces (240 mL) of water after a low-fat (<30% fat) breakfast. 
Some examples of low fat breakfasts are: 

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• Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon 
of jelly and 8 ounces (240 mL) of skim milk (approximately 319 calories and 8.2 g 
of fat). 
• One cup of cereal (i.e. Special K), 8 ounces (240 mL) of skim milk, one piece of 
toast with jam (no butter or marmalade), apple juice, and one cup of coffee or tea 
(2 g fat, 17 g protein, 93 g of carbohydrate, 520 calories. 
Patients for whom regorafenib dose reduction was not performed or required may have 
their treatment dose increased to the FDA-approved dose of 160 mg daily orally for 3 
weeks in a 4-week cycle in cycle #2 or beyond (this is not mandatory). 
If doses are missed or vomited, this must be indicated in the patient’s pill diary. Missed 
doses not directed by the investigator(s) that constitute < 20% of the mandated doses for 
a given cycle will not be considered (a) protocol violation(s). Missed or skipped doses will 
not be made up (i.e., the week/day count on therapy will continue regardless of whether 
doses have been missed or skipped). Study treatment will be administered in cycles of 4 
weeks in duration. Patients will bring their pill diaries for review at their clinic visits but it 
will not be considered a protocol violation if the patient forgets the diary. 
Patients will receive a sufficient supply of study drug to last until their next scheduled 
appointment. 
9.2 Concomitant Medications and Therapies 
All medication that is considered necessary for the subject’s welfare, and which is not 
expected to interfere with the evaluation of the study treatment, may be given at the 
discretion of the investigator. All medications (including contrast media) taken within 2 
weeks prior to the start of the study and during the study must be recorded in the subject’s 
source documentation. Specific caution should be taken when considering or 
administering a concomitant medication that is metabolized by the cytochrome enzymes 
CYP2C8, CYP2B6 and CYP2C9. Such concomitant medication should be avoided on 
protocol, if possible. 
Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of 
Stivarga decreased the mean exposure of regorafenib, increased the mean exposure of 
the active metabolite M-5, and resulted in no change in the mean exposure of the active 
metabolite M-2. Avoid concomitant use of Stivarga with strong CYP3A4 inducers (e.g. 
rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) 
Co administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160mg dose 
of Stivarga increased the mean exposure of regorafenib and decreased the mean 
exposure of the active metabolites M-2 and M-5. Avoid concomitant use of Stivarga with 
strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, 
ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole). Please refer 
to http://medicine.iupui.edu/flockhart/ for additional information regarding drug interactions 
with cytochrome P450 isoenzymes. 
Permitted concomitant therapy includes: 

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• Standard therapies for concurrent medical conditions. 
• Supportive care for any underlying illness. 
• Palliative radiation therapy is allowed if the target lesion(s) are not included within the 
radiation field and no more than 10% of the bone marrow is irradiated. 
• Granulocyte colony-stimulating factor (G-CSF) and other hematopoietic growth factors 
may be used in the management of acute toxicity, such as febrile neutropenia, when 
clinically indicated or at the investigator’s discretion. However, they may not be 
substituted for a required dose reduction. Subjects are permitted to take chronic 
erythropoietin. 
• Treatment with nonconventional therapies (such as acupuncture), and vitamin/mineral 
supplements are permitted provided that they do not interfere with the study endpoints, 
in the opinion of the investigator. 
• Bisphosphonates or denosumab. 
• Subjects who are therapeutically treated with an agent such as warfarin or heparin will 
be allowed to participate provided that their medication dose and INR/PTT are 
considered stable by the treating physician. 
9.3 
Schedule of Events (for ALL patients initiating treatment) 
9.3.1 Patients will initiate treatment with regorafenib on Week 1, Day 1. The required 
laboratory tests (detailed in Section 10) can be performed up to 7 days prior to 
initiation of treatment. It is unnecessary to repeat these laboratory tests if the 
screening assessments of the same tests were performed within 7 days prior to first 
dose of therapy. All other Week 1 evaluations (detailed in Section 10) may be 
performed up to 3 days prior to initiation of study treatment. 
9.3.2 The onset of regorafenib-induced hypertension often occurs during the first cycle of 
treatment for most patients who develop hypertension. During the first 6 weeks of 
treatment, it is strongly recommended that patients have their blood pressures 
checked even in weeks that they are not evaluated at MSKCC. There are no 
restrictions on how the blood pressure is to be obtained during those weeks, and 
can include monitoring on home blood pressure equipment, at other physician 
offices, at MSKCC, or at commercial outlets. Blood pressure values may be 
recorded in the pill diaries that will be reviewed at each MSKCC clinic visit or 
verbally reported to the study team. If the systolic blood pressure is >150 mm Hg 
and/or the diastolic blood pressure is > 90 mm Hg and/or symptoms develop that 
are perceived to be related to elevated blood pressure (for example headaches or 
visual disturbance), patients will be instructed by study staff to contact their study 
physician immediately for guidance. A re-check of the blood pressure can be 
requested at the study physician’s discretion to determine the accurate value of the 
patient’s blood pressure before protocol-dictated action(s) is/are taken in response 
to a reported blood pressure value (this applies both to recommended and protocol- 
mandated blood pressures taken at MSKCC or outside of MSKCC). The study 

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physician may at his/her discretion determine which external values likely reflect the 
true blood pressure to guide clinical decision-making. 
9.3.3 Patients for whom regorafenib dose reduction was not performed or required may 
have their treatment dose increased to the FDA-approved dose of 160 mg daily 
orally for 3 weeks in a 4-week cycle in cycle #2 or beyond (this is not mandatory). 
9.3.4 Patients will be required to complete a pill diary concerning their use of regorafenib 
every 28 days. If a patient misses a dose of regorafenib for personal reasons (i.e. 
forgetting to take medication, nausea, etc.), the missed dose should be documented 
on the patient’s pill diary (Appendix B). Missed doses not directed by the 
investigator(s) that constitute < 20% of the mandated doses for a given cycle will 
not be considered (a) protocol violation(s). Doses held at the discretion of the 
physician are never protocol violations. Missed or skipped doses will not be made 
up (i.e., the week/day count on therapy will continue regardless of whether doses 
have been missed or skipped). 
9.3.5 Evaluations during treatment will be performed according to the schedule detailed in 
Section 10. Guidelines for dose reductions are provided in Section 11. 
9.3.6 Tumor measurements with CT and/or MRI will be performed as outlined in Section 
10. 
9.3.7 Treatment may be discontinued at any time for progression of disease, 
unacceptable toxicity, patient withdrawal of consent, patient non-compliance, or 
investigator judgment. 
9.4 Correlative Studies 
Exploratory Objective: To perform tumor tissues analyses for biomarkers that correlate to 
regorafenib clinical efficacy. 
9.4.1 Background Studies/Preliminary Data: We hypothesize that ACC responses to 
regorafenib will be linked to baseline activation of the vascular endothelial growth 
factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor 
receptor (FGF), and/or c-kit (CD117) pathways via overexpression of the oncogenic 
transcription factor c-myb and/or other mechanisms outlined in Section 3.0. In order 
to evaluate this hypothesis, the studies described below will be performed upon 
both archival and research biopsy tissues, depending on the availability of funding. 
Included amongst these studies are exploratory approaches that may also suggest 
myb-independent mechanisms that may mediate drug susceptibility or resistance. 
9.4.2 Study Plan for fixed tissue: Studies evaluating c-myb protein expression, t(6;9) 
translocation status, the VEGF/PDGF/FGF/KIT pathways, and other potentially 
relevant genes/proteins will be conducted in fixed tissues. 
Expression of VEGF/PDGF/FGF/KIT pathway proteins will be evaluated by 
immunohistochemistry (IHC). c-myb expression will also be evaluated by IHC. The 
presence or absence of the t(6;9) translocation will be assessed by fluorescent in- 
situ hybridization (FISH). These studies will be performed upon collected archival 

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samples and/or the fixed portions of the research biopsies obtained on this study, 
depending on the availability of tissue. Evaluation of the t(6;9) fusion breakpoint 
may also be pursued with RT-PCR cDNA amplification and sequencing if feasible, 
though the need for high yield and quality RNA to perform this analysis may 
necessitate using frozen tissues obtained from the research biopsies. 
We anticipate that all 38 patients will have archival tissue available for these 
analyses. We will explore correlations between the tumor IHC status of the target 
proteins listed above, as well as presence of the t(6;9) translocation, with clinical 
benefit from regorafenib. Please see Section14.0 for biostatistical considerations 
for these studies. 
9.4.3 Study Plan for research biopsy tissues: (to be performed in MSKCC Core facilities 
and Dr. Timothy Chan’s laboratory (MSKCC HOPP) The research biopsy samples 
will be divided for fixation and flash freezing at the discretion of the Principal 
Investigator. A member of the research team will be present at the biopsy 
procedure and transport the tissues to the MSKCC Tumor Procurement Service for 
accessioning. The tissues will then be transported by the research team to Dr. 
Chan’s Human Oncology and Pathogenesis Program (HOPP) laboratory in the 
Zuckerman Research Center for analysis and storage. These samples will be used 
to evaluate the genomic and transcriptomic landscape of the tumors with the 
exploratory goal of evaluating myb-dependent and/or -independent markers of 
regorafenib susceptibility and resistance. 
DNA and RNA will be extracted from frozen samples and/or paraffin tissue. The 
research peripheral blood sample collected on the study will be used as a control, 
matched normal sample (microdissection of normal tissue in the tumor samples 
may also be used for this purpose). 
DNA will be submitted for whole exome or whole genome sequencing (in 
collaboration with Dr. Timothy Chan’s group). It is possible that at the time these 
studies are to be conducted a customized-panel of ACC specific alterations that can 
be analyzed in a highly sensitive array based approach from fixed tissues will be 
available. In that scenario, fixed tissue from the collected archival tissue or the 
research biopsies will be used for this genomic analysis, preserving the frozen 
tissue for other assays. Hence, the specific assay that will be employed to analyze 
for genomic alterations will be dependent upon the technology available at the time 
of analysis. Comparisons of DNA between tumor and normal tissue (from the 
research blood draw) will be performed as appropriate, thus generating germline 
sequence data. There is no intention to analyze the germline data beyond utilizing 
it as a normal control for the tumor tissue analysis, and generally germline data will 
not be communicated to the patient. 
The following procedure will be followed by MSKCC investigators for the unique 
situation in which a potentially actionable incidental finding has been discovered in 
the course of research conducted on samples collected under this protocol: 

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In the event an investigator's research identifies a finding that he or she believes 
should be communicated to the subject (and/or family designee), the investigator 
shall communicate this to the OCR-IRB. The finding will be reviewed by a group 
convened by the IRB to determine whether the incidental finding should be 
discussed with the subject. In the event that group convened by the IRB determines 
that the finding should be discussed with the subject, and the subject has consented 
to be re-contacted, then the treating/consenting physician shall be contacted by the 
OCR-IRB representative and asked to refer the subject to the Clinical Genetics 
Service for further discussion of the research finding. After appropriate counseling 
and consent, the Clinical Genetics Service will request permission to confirm the 
result in a New York DOH-approved laboratory prior to communication of the 
specific result. If the patient is not available (e.g. deceased), then the surrogate 
designated on the consent will be contacted and the above will occur. 
We hypothesize that the transcription factor c-myb is a central driver of ACC 
oncogenesis, presumably through activation of an oncogenic transcriptional 
program. Several c-myb target genes have been previously identified, but a c-myb 
transcriptional signature in ACC has yet to be defined. Extracted RNA will be 
analyzed with gene expression arrays on the Affymetrix GeneChip system, or some 
other equivalent technology that may be available at the time of analysis. 
Frozen tissues from the research biopsy may be evaluated for relevant protein 
targets by Western blot or other proteomic assays that may be available at time of 
analysis. 
Assuming that only approximately 10% of patients do not qualify for the research 
biopsy, we anticipate obtaining biopsies on 34 patients. Please Section 14.0 for the 
biostatistical considerations for these studies. 
9.4.4 
Study Plan for research biopsy tissues: (to be performed in MSKCC Core facilities 
or Champions Oncology Inc.) Emerging evidence suggests that mouse patient 
derived xenografts (PDXs) models can be faithful representations of in situ human 
cancer biology, and be used to predict clinical drug efficacy in patients. ACC PDX 
models have been created by other groups, and represent the only experimental 
model system in which new therapeutic approaches and ACC biology can be 
explored pre-clinically. Patients who will undergo a research biopsy on this protocol 
and have sufficient tissue to create PDX models may be selected to have a portion 
of their biopsy submitted for this purpose. These patients will be approached to 
sign consent for IRB protocol #06-107, “Storage and Research Use of Human 
Biospecimens” and the models will be created as outlined in IRB protocol #14- 
091(PI: Dr. Elise DeStanchina) , “Establishment and Characterization of Unique 
Mouse Models Using Patient-Derived Xenografts”. These models will be 
established by the MSKCC Antitumor Assessment Core Facility, our institutional 
core facility responsible for establishing and testing xenograft mouse models. 
Alternatively, through a collaboration established with Champions Oncology, Inc., 
patient’s tumors may be collected and sent to Champions for model creation and 
conduct of experiments. Those models will be provided back to Memorial Sloan 
Kettering Cancer Center for research purposes. 

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Portions of the research biopsy may also be used to establish cell line or spheroid in 
vitro models in Memorial Sloan Kettering Cancer Center. Such efforts will help 
develop new laboratory systems to help interrogate ACC biology and develop novel 
therapeutic approaches that build upon findings from this clinical/correlative study. 

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10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
Study Calendar 
Regorafenib taken orally will be administered for 3 weeks on /1 week off. One cycle is 28 
days. The evaluations/tests scheduled for Cycles 1 through 3+ may be performed up to 3 
days prior to the start of the week designated in the table below if not otherwise specified. 
After Cycle 12 and beyond, MD visits and labs are required every odd cycles, and labs 
only during even cycles. 
 
Pre- 
Studya 
C1 
Wk 
1 
C1 
Wk 
2 
C1 
Wk 
3 
C1 
Wk 
4 
C2 
Wk 
1 
C2 
Wk 
2 
C2 
Wk 
3 
C2 
Wk 
4 
C3+ 
Wk1 
C12+ 
Even 
Wk 1 
C13+ 
Odd 
Wk 1 
Off Studyg 
Regorafenibb 
X 
X 
X 
Xb 
X 
X 
X 
X 
X 
Informed consent 
X 
Medical history 
X 
Concurrent meds 
X 
X 
X 
X 
Physical exam 
X 
Xd 
X 
X 
X 
X 
Xf 
Xf 
X 
Vital signs 
X 
Xd 
X 
X 
X 
X 
Xf 
Xf 
X 
Blood pressure 
monitoring (on non- 
clinic weeks)j 
X 
X 
Weight 
X 
Xd 
X 
X 
X 
X 
Xf 
Xf 
X 
Performance status 
X 
Xd 
X 
X 
X 
X 
Xf 
Xf 
X 
CBC w/diff, plts 
X 
Xe 
X 
X 
X 
Xf 
Xf 
Xf 
X 
Comprehensive panelc 
X 
Xe 
X 
X 
X 
Xf 
Xf 
Xf 
X 
Lipase, Amlyase blood 
test 
X 
Coagulation studiesl 
X 
X 
X 
X 
X 
Xf 
Xf 
Xf 
ECG 
X 
Beta-HCG (serum) 
Xk 
Request for archival 
tumor tissue 
X 
Research tumor 
biopsyh 
X 
Research blood draw 
X 
Adverse event 
evaluation 
X 
Xm 
X 
Tumor measurementsi 
X 
CT and/or MRI will be performed every 8 weeks (+/- 1 week) (or 
approximately every 2 cycles). After 10 months, scans will be 
performed every 12 weeks (+/- 1 week)(or approximately every 3 
cycles). Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. Objective 
responses should be confirmed with a second assessment 
performed at least 4 weeks later. Every effort should be made 
to have tumor measurements performed 6 months (+/- 1 
week) after the start of treatment, if possible, for assessment 
of the primary endpoint. 
a: See Section 8.0 for the timing of these tests/evaluations prior to the start of therapy. 
b: Patients will start the study taking regorafenib 120 mg orally daily for 3 weeks in a 4 
week cycle. Patients for whom regorafenib dose reduction was not performed or 
required may have their treatment dose increased to the FDA-approved dose of 160 
mg daily orally for 3 weeks in a 4-week cycle in cycle #2 or beyond (this is not 
mandatory). If a patient misses a dose of regorafenib for personal reasons (i.e. 
forgetting to take medication, nausea, etc.), the missed dose should be documented 
on the patient’s pill diary (Appendix B). Missed doses not directed by the 
investigator(s) that constitute < 20% of the mandated doses for a given cycle will 
not be considered (a) protocol violation(s). Doses held at the discretion of the 
physician are never protocol violations. Missed or skipped doses will not be made 
up (i.e., the week/day count on therapy will continue regardless of whether doses 

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have been missed or skipped). 
c: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT 
[ALT], sodium. 
d: These Week 1 evaluations may be performed up to 3 days prior to the start of 
treatment. 
e: These Week 1 laboratory tests may be done up to 7 days prior to starting treatment. 
It is unnecessary to repeat these laboratory tests if the screening assessments of 
the same tests were performed within 7 days prior to the first dose of therapy. 
f:  After the completion of Cycle 2, the CBC, serum chemistry blood tests, coagulation 
studies (if required), physical examinations, vitals signs, performance status, and 
weight will be done once every cycle, preferably on week 1 of every cycle. If the 
patient cannot be seen on week 1, these evaluations may be completed up to 1 
week prior or during another week within the cycle at the discretion of the treating 
physician. 
g: Off-study evaluation will be performed within 30 days of the patient’s last dose of 
regorafenib. 
h: Patients may be exempt from biopsy if either the investigator or person performing 
the biopsy judges that no tumor is accessible for biopsy or that biopsy poses too 
great of a risk to the patient. Patients may also be exempt if frozen tumor tissue 
has been collected within 12 months of study enrollment that the Principal 
Investigator deems is appropriate/sufficient for analysis on this protocol. For those 
undergoing research biopsy on protocol, radiologic guidance (CT, MRI or 
ultrasound guided) approaches and obtaining multiple cores to ensure sufficient 
biopsy material (at least 3 cores preferred) are allowed as long as it is considered 
reasonably safe for the patient. Tissue will be flash frozen in liquid nitrogen as 
directed by the Principal Investigator (the biopsy sample(s) will be placed into a 
cryovial, which will be submerged in a liquid nitrogen bath until the tissue is frozen.) 
Some tissue may be prepared by fixation according to institutional guidelines if 
directed by the Principal Investigator. 
i:  The treating physician may reschedule radiology scans due to treatment delays at 
his or her discretion. If the patient has CT and/or MRI scans completed early for 
any reason (i.e. suspicion of disease progression), the next set of scans may be 
ordered in 8 weeks (+/- 1 week) from that assessment (or in 12 weeks (+/- 1 week) 
for patients who are on treatment for more than 10 months). Every effort should 
be made to have tumor measurements performed 6 months (+/- 1 week) after 
the start of treatment, if possible, for assessment of the primary endpoint. 
j: The onset of regorafenib-induced hypertension often occurs during the first cycle of 
treatment for most patients who develop hypertension. During the first 6 weeks of 
treatment, it is strongly recommended that patients have their blood pressures 
checked even in weeks that they are not evaluated at MSKCC. There are no 
restrictions on how the blood pressure is to be obtained during those weeks, and 
can include monitoring on home blood pressure equipment, at other physician 
offices, at MSKCC, or at commercial outlets. Blood pressure values may be 
recorded in the pill diaries that will be reviewed at each MSKCC clinic visit or or 
verbally reported to the study team. If the systolic blood pressure is >150 mm Hg 
and/or the diastolic blood pressure is >90 mm Hg and/or symptoms develop that 
are perceived to be related to elevated blood pressure (for example headaches or 
visual disturbance), patients will be instructed by study staff to contact their study 
physician immediately for guidance. A re-check of the blood pressure can be 
requested at the study physician’s discretion to determine the accurate value of the 
patient’s blood pressure before protocol-dictated action(s) is/are taken in response 
to a reported blood pressure value (this applies both to recommended and protocol- 
mandated blood pressures taken at MSKCC or outside of MSKCC). The study 
physician may at his/her discretion determine which external values likely reflect the 
true blood pressure to guide clinical decision-making. 
k. Serum pregnancy test is required within 14 days of drug treatment for all women of 
child-bearing potential. 
l. Coagulation studies consist of the prothrombin time (PT), partial thromboplastin time 
(PTT), and international normalized ratio (INR). These are only required as 
indicated on the calendar for patients on anti-coagulation medications (heparin, low- 
molecular weight heparin, or coumadin). These do not need to be checked for 
patients not on these anti-coagulation medications. 
m. During even cycles after cycle 12, adverse event will be conducted by phone 
assessment. 

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11.0 TOXICITIES/SIDE EFFECTS 
The starting dose of regorafenib is 120 mg once daily. Study medication will be administered on 
a 3 weeks on/1 week off schedule (3 weeks out of every 4). Patients for whom regorafenib dose 
reduction was not performed or required may have their treatment dose increased to the FDA- 
approved dose of 160 mg daily orally for 3 weeks in a 4-week cycle in cycle #2 or beyond (this is 
not mandatory). 
Doses will be delayed or reduced for clinically significant hematologic and non-hematologic 
toxicities that are related to protocol therapy according to the guidelines described in sections 
below. Dose modifications will follow predefined dose levels. Dose adjustments for hematologic 
toxicity are based on the blood counts obtained in preparation for the day of treatment.\ 
For patients who must undergo a procedure or surgery while on study that requires wound 
healing or involves risk for significant bleeding, regorafenib should be held 2 weeks prior to the 
scheduled surgery/procedure. The decision to resume reografenib after the surgery/procedure 
should be based on clinical judgement of adequate wound healing 
11.1 General Considerations for Managing Regorafenib-related Adverse Events 
This section contains general recommendations for the management of adverse events. Patients 
developing a regorafenib-related CTCAE Grade 1 or 2 adverse events may have their dose 
continued at the same dose level. 
Notes: The recommendations for the management of adverse events in this section are to serve 
as general guidelines; dose reductions or delays for any event of any CTCAE grade may always 
be considered for safety reasons at the discretion of the treating investigator. If a subject 
experiences more than one toxicity, dose reduction should be according to the toxicity with the 
highest grade. In the case of two or more toxicities of the same grade, the investigator may dose 
reduce according to that deemed most causally related to study treatment. 
 
 
 
The modifications of regorafenib will follow the following predefined dose levels: 
Dose level +1 
(standard starting dose) 
160 mg po qd Four 40-mg tablets of regorafenib 
Dose level 0 
120 mg po qd Three 40-mg tablets of regorafenib 
Dose level - 1 
80 mg po qd Two 40-mg tablets of regorafenib 

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Recommended dose modification for toxicities except hand-foot-skin reaction, hypertension, and ALT/AST/bilirubin for 
adverse events related to regorafenib 
NCI-CTCAE 
v4.0a 
Dose Interruptionb 
Dose 
Modificationb 
Dose for Subsequent Cycles 
Grade 0-2 
Treat on time 
No change 
No change 
Grade 3 
Delay until ≤ Grade 2c 
Reduce by 1 dose level 
If dose was reduced and toxicity remains < Grade 
2, dose re-escalation can be considered at the 
discretion of the treating investigator. If dose is re- 
escalated and toxicity (≥ Grade 3) recurs, institute 
permanent dose reduction. 
Grade 4 
Delay until ≤ Grade 2c 
Reduce by 1 dose level. 
Permanent 
discontinuation 
can be considered at 
treating investigator’s 
discretion. 
a. NCI-CTCAE = National Cancer Institute - Common Terminology Criteria for Adverse Events, version 4.0 
b. Dose modification or interruption is not required for alopecia, non-refractory hypersensitivity and asymptomatic laboratory 
abnormalities. Dose modification or interruption is not required for nausea, vomiting and diarrhea if optimal supportive 
management has not been instituted. 
c. If no recovery after a 4 week delay, treatment should be permanently discontinued unless subject is deriving clinical benefit. 

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11.2 Hand-foot skin reaction related to regorafenib 
 
Grading for Hand-Foot-Skin-Reaction 
Grade 1 
Grade 2 
Grade 3 
NCI-CTCAE v4.0 
Palmar-plantar 
erythrodysesthesia 
syndromea 
Minimal skin changes or 
dermatitis 
(e.g., erythema, edema, 
or hyperkeratosis) 
without pain 
Skin changes 
(e.g., peeling, blisters 
bleeding, edema, or 
hyperkeratosis) with 
pain 
Severe skin changes 
(e.g., peeling, 
blisters, bleeding, 
edema, or 
hyperkeratosis) with 
pain 
Further description/ 
examples of skin 
changes 
Numbness, dysesthesia 
/ paresthesia tingling, 
painless swelling, or 
erythema of the hands 
and/or feet 
Painful erythema and 
swelling of the hands 
and/or feet 
Moist desquamation, 
ulceration, blistering, 
or severe pain of the 
hands and/or feet 
Effect on activities 
Does not disrupt normal 
activities 
Limiting instrumental 
activities of daily life 
(e.g., preparing 
meals, shopping for 
groceries or clothes, 
using the telephone, 
managing money) 
Limiting self-care 
activities of daily life 
(e.g., bathing, 
dressing and 
undressing, feeding 
self, using the toilet, 
taking medications) 
and not bedridden 
a. Palmer-planter erythrodysesthesia syndrome is a disorder characterized by redness, marked 
discomfort, swelling, and tingling in the palms of hands or the soles of the feet. 
At first occurrence of HFSR, independent of grade, prompt institution of supportive measures 
such as topical emollients, low potency steroids, or urea-containing creams should be considered. 
Recommended (not mandated) prevention/management strategies for skin toxicities consistent 
with HFSR are summarized below: 
Control of calluses 
Before initiating treatment with regorafenib: 
• Check condition of hands and feet. 
• Suggest a manicure/pedicure, when indicated. 
• Recommend pumice stone use for callus or ‘rough spot’ removal. 
During regorafenib treatment: 
• Avoid pressure points. 
• Avoid items that rub, pinch or create friction. 
Use of creams 
• Non-urea based creams may be applied liberally. 
• Keratolytic creams (e.g. urea-based creams, salicylic acid 6%) may be used sparingly and 
only to affected (hyperkeratotic) areas. 
• Alpha hydroxyl acids (AHA) based creams may be applied liberally 2 times a day. 
Approximately 5% to 8% provides gentle chemical exfoliation. 
• Topical analgesics (e.g. lidocaine 2%) are to be considered for pain control. 
• Topical corticosteroids like clobetasol 0.05% can be considered for subjects with Grade 2 
or 3 HFSR. Use of any grade of HFSR is allowed. 
Tender areas should be protected as follows: 

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• Use socks/gloves to cover moisturizing creams 
• Wear well-padded footwear 
• Use insole cushions or inserts (e.g. silicon, gel) 
• Foot soaks with tepid water and Epson salts 

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Recommended dose modification for hand-foot-skin reaction related to regorafenib 
Grade of event 
(NCI-CTCAE v4.0) 
Occurrence 
Suggested Dose Modification 
Grade 1 
Any 
Maintain dose level and immediately institute supportive 
measures for symptomatic relief. 
Grade 2 
(intolerable) 
1st occurrence 
Therapy may be interrupted and restarted at the same 
dose once toxicity resolves to Grade 0-1. Alternatively, 
regorafenib may be decreased by one dose level. 
Supportive measures should be instituted immediately. 
If no improvement, interrupt therapy for a minimum of 7 
days, until toxicity resolves to Grade 0-1.b, c 
No improvement 
within 7 days or 
2nd occurrence 
Interrupt therapy until toxicity resolves to Grade 0-1.c 
When resuming treatment, treat at reduced dose level.b 
3rd occurrence 
Interrupt therapy until toxicity resolves to Grade 0-1.c 
When resuming treatment, decrease dose by one dose 
level.b, d 
4th occurrence 
Discontinue therapy. 
Grade 3 
1st occurrence 
Institute supportive measures immediately. Interrupt 
therapy for a minimum of 7 days until toxicity resolves 
to Grade 0-1.c When resuming treatment, decrease 
dose by one dose level.b, d 
2nd occurrence 
Institute supportive measures immediately. Interrupt 
therapy for a minimum of 7 days until toxicity resolves 
to Grade 0-1.c When resuming treatment, decrease 
dose by one additional dose level.b, d 
3rd occurrence 
Discontinue treatment permanently. 
a. More conservative management is allowed if judged medically appropriate by the investigator. 
b. If toxicity returns to Grade 0-1 after dose reduction, dose re-escalation is permitted at the discretion of 
the investigator if subject has completed one cycle at reduced dose without recurrence of event. 
c. If there is no recovery after a 4-week delay, treatment with regorafenib will be discontinued 
permanently. 
d. Subjects requiring > 2 dose reductions should go off protocol therapy. 
e. The maximum daily dose is 160 mg. 
 
11.3 Hypertension related to regorafenib 
Hypertension is a known AE associated with regorafenib treatment. The management of 
hypertension, including the choice of antihypertensive medication, will be performed according to 
local standards and to the usual practice of the investigator. Every effort should be made to 
control blood pressure by medical means other than study drug dose modification. 

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Management of Treatment-Emergent Hypertension related to regorafenib 
Grade 
(CTCAE v4.0) 
Antihypertensive Therapy 
Regorafenib Dosing 
1 
Prehypertension (systolic 
BP 120 - 139 mmHg or 
diastolic BP 80 - 89 
mmHg) 
None 
• Continue regorafenib 
• Consider increasing blood pressure 
(BP) monitoring 
2 
Systolic BP 140 - 159 
mmHg or diastolic BP 90 - 
99 mmHg, 
OR 
Symptomatic increase by 
> 20 mmHg (diastolic) if 
previously within normal 
limits 
• Treat with the aim to achieve 
diastolic BP ≤ 90 mm Hg: 
• If BP previously within normal 
limits, start anti-hypertensive 
monotherapy 
• If patient already on anti- 
hypertensive medication, 
titrate up the dose. 
• Continue regorafenib 
• If symptomatic, hold regorafenib until 
symptoms resolve AND diastolic BP ≤ 
90 mm Hga. When regorafenib is 
restarted, continue at the same dose 
level. 
3 
Systolic BP ≥ 160 mmHg 
or diastolic BP ≥ 100 
mmHg 
Treat with the aim to achieve 
diastolic BP ≤ 90 mm Hg: 
Start anti-hypertensive 
medication 
AND/OR 
Increase current anti- 
hypertensive medication 
AND/OR 
Add additional anti- 
hypertensive medications. 
• Hold regorafenib until diastolic BP ≤ 
90 mm Hg, and if symptomatic, until 
symptoms resolve.a 
• When regorafenib is restarted, 
continue at the same dose level. 
• If BP is not controlled with the addition 
of new or more intensive therapy, 
reduce by 1 dose level.b 
• If Grade 3 hypertension recurs despite 
dose reduction and antihypertensive 
therapy, reduce another dose level.c 
4 
Life-threatening 
consequences (eg, 
malignant hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis) 
Per institutional guidelines 
Discontinue therapy 
a. Patients requiring a delay of >4 weeks should go off protocol therapy 
b. If BP remains controlled for at least one cycle, dose re-escalation permitted per investigator’s 
discretion. 
c. Patients requiring >2 dose reductions should go off protocol therapy. 

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11.4 Liver function abnormalities related to regorafenib 
For patients with observed worsening of serum liver tests considered related to regorafenib (i.e. 
where no alternative cause is evident, such as post-hepatic cholestasis or disease progression), 
the dose modification and monitoring advice in Table 6-5 should be followed. 
Regorafenib is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in 
patients with Gilbert’s syndrome. 
 
Dose modifications/interruption for ALT and/or AST and/or bilirubin increases related to 
regorafenib 
Observed elevationsa 
1st Occurrence 
Restart 
Re-occurrence 
Baseline G0 to G1 
or 
baseline G1 to G2 
Treat on time and 
check AST, ALT and 
bilirubin 2x/week for 2 
weeks followed by 
weekly assessments 
for at least 4 weeksc. 
Continue with 
therapy with 
monitoring at the 
investigator’s 
discretion. 
Baseline G0 to G2 
Delay until < G1 and 
check AST, ALT, 
bilirubin 2x/week. 
Reduce 1 dose level and 
check AST, ALT, bilirubin 
weekly for at least 4 
weeks.a, c 
Discontinue 
Baseline any grade to 
G3 
Delay until < G1 if 
baseline was G0 OR 
until G1 if baseline 
was G1 OR until G2 if 
baseline was G2. 
Check AST, ALT, 
bilirubin 2x/week. 
If ALT or AST > 8 x 
ULN with a 
concomitant rise in 
bilirubin (of any 
degree) compared to 
previous bilirubin 
values, consider 
permanent 
discontinuation at the 
first occurrence. 
Reduce 1 dose level and 
check AST, ALT, bilirubin 
weekly assessments for 
at least 4 weeks.a, c 
Discontinue 
a: Severity Grade per NCI-CTCAE v 4.0. 
b: If ALT, AST, and bilirubin remain stable for two full cycles, dose re-escalation may be 
considered at the discretion of the investigator. After re-escalation, check ALT, AST, and 
bilirubin 2x/week for 2 weeks, then 1x/week for 4 weeks. 
“G”, abbreviation for “CTCAE v4.0 Grade”. 
c: This schedule of AST, ALT, and bilirubin monitoring need not be repeated for a given 

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12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
Please refer to Section 10 regarding the timing of tumor measurement assessments. 
 
Documentation (radiologic) must be provided for patients removed from study for 
progressive disease (not necessary if removed based on criteria for clinical progression). 
Objective responses should be confirmed with a second assessment performed at least 4 
weeks later. 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (uni 
dimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria. 
12.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with regorafenib. 
Evaluable for objective response. Only those patients who have measurable 
disease present at baseline and have received at least one dose of therapy will be 
considered evaluable for response. These patients will have their response 
classified according to the definitions stated below. (Note: Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
Evaluable Non-Target Disease Response. Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re- 
evaluated will be considered evaluable for non-target disease. The response 
assessment is based on the presence, absence, or unequivocal progression of the 
lesions. 
12.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) 
as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by 
clinical exam. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area are not 
considered measurable unless there has been demonstrated progression in the 
lesion. 
Malignant lymph nodes. To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed by CT 
dose level if already completed once. 

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scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 
mm short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non- 
measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Non-target lesions. All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of these lesions 
are not required, but the presence, absence, or in rare cases unequivocal 
progression of each should be noted throughout follow-up. 
12.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 4 weeks before the beginning of 
the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 

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Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung. However, CT is 
preferable. 
 
Conventional CT and MRI This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables involved 
in MRI, which greatly impact image quality, lesion conspicuity, and measurement. 
Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences used should be 
optimized for the evaluation of the type and site of disease. Furthermore, as with 
CT, the modality used at follow-up should be the same as was used at baseline 
and the lesions should be measured/assessed on the same pulse sequence. It is 
beyond the scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases. Ideally, the 
same type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible. 
 
Ultrasound Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next. If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, Laparoscopy The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 

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Tumor markers Tumor markers alone cannot be used to assess response. If 
markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response. Specific guidelines for both CA- 
125 response (in recurrent ovarian cancer) and PSA response (in recurrent 
prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 
3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008]. In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian 
cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions 
in tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and progressive 
disease. 
 
12.4 
Response Criteria 
12.4.1 Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non- 
target) must have reduction in short axis to <10 
mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference 
the baseline sum diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference 
the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at 
least 5 mm. (Note: the appearance of one or 
more new lesions is also considered 
progressions). 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study. 

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12.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (<10 mm 
short axis). Note: If tumor markers are initially 
above the upper normal limit, they must 
normalize for a patient to be considered in 
complete clinical response. 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits. 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, 
not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
12.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non- 
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non- 
CR/Non- 
PD/not 
evaluated 
No 
PR 
SD 
Non- 
CR/Non- 
PD/not 
evaluated 
No 
SD 
Documented at least 
once >4 wks. from 
baseline** 

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PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
 See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so 
to assign this category when no lesions can be measured is not advised 
 
12.4.4 Duration of Response 
Duration of overall response: 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). 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements. 

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12.4.5 6-month Progression-Free Survival 
Proportion of patients alive and free of progression at 6 months. 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
• 
Disease progression on treatment with regorafenib 
• 
Patients may be removed from the study for protocol non-compliance. 
• 
If at any time the patient develops unacceptable toxicity he/she will be removed from 
study. 
• 
Participants can be removed from the study at any time if the study doctor feels that it is in 
their best interest to do so. 
• 
Patients may withdraw consent from the study at any time. 
14.0 
BIOSTATISTICS 
Two co-primary objectives will be evaluated: best overall response rate (BOR; CR+PR by 
RECIST v1.1 observed at any time between start of treatment and patient’s removal from 
the study) and 6-month PFS (proportion of patients alive and progression-free at 6 
months). If either one of these objectives is met, the treatment would be considered 
worthy of further investigation. 
Our recent literature review of all systemic chemotherapy studies reported for R/M ACC 
patients from 1966 to 2009 revealed that these were generally small studies of variable, 
poor methodological quality from which definitive conclusions regarding the efficacy of 
chemotherapy are difficult to establish3. Objective responses with cytotoxic chemotherapy 
were infrequent, and in 10 studies evaluating different targeted agents (imatinib, gefitinib, 
cetuximab, lapatinib, bortezomib) involving 157 ACC patients, only 2 objective responses 
were reported (in response to high dose imatinib). Notably, there is no data addressing 
potential efficacy of systemic therapy beyond the first line setting in R/M ACC3. Therefore, 
we will adopt a null hypothesis of BOR of 5% and an expected BOR of 20% as the 
alternative hypothesis. In order to demonstrate that the BOR in the studied population is 
>5% with a one-sided type I error of 5% and power of 90%, at least 5 responses need to 
be observed among 38 patients enrolled. 
Among all published phase II single-agent trials performed in recurrent/metastatic ACC, 
we identified six studies involving 106 patients that reported a 6-month progression-free 
survival (PFS) with single-agent therapy (imatinib7, cetuximab36, gemcitabine37, 
paclitaxel38, lapatinib39, and sunitinib30). The mean 6-month PFS from these studies was 
40.1%. Three of these studies did not require evidence of radiographic or clinical disease 
progression for study entry7,36,38 ; of the remaining three studies, two required evidence of 
RECIST progression or clinical deterioration within 6 months30,39 and the other study 
required symptomatic and/or progressive disease by undefined criteria37. Based on these 
studies, we will adopt a null hypothesis for 6-month PFS of 40% and an expected 6-month 
PFS of 65% as the alternative hypothesis. In order demonstrate that 6-month PFS in the 

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studied population is > 40% with a one-sided type I error of 5% and power of 90%, at least 
21 of the 38 patients enrolled need to be alive and free of progression at the 6-month time 
point (exact binomial design). 
Assuming that 6-month PFS and BOR are independent, the overall type 1 error is <0.1. 
The type 1 error decreases very slightly if PFS and BOR are positively correlated. 
Patients who receive at least one dose of medication will be included in the evaluation of 
the primary objectives. Patients who do not have a recorded CR or PR and are removed 
from the study without a final radiologic evaluation will be classified as non-responders for 
BOR evaluation. If patients discontinue the study before the 6-mo PFS evaluation without 
evidence of progression, every effort will be made to bring them in for a 6-mo radiologic 
evaluation. If this is not possible, the patients will be classified as progressors for the 
purpose of the 6-month PFS evaluation. 
The secondary endpoint is the evaluation of safety/tolerability of regorafenib. 
Safety will be assessed in terms of AEs, laboratory data and vital sign data, which will be 
collected for all patients. Appropriate summaries of these data will be presented. AE will 
be listed individually per patient according to CTCAE version 4.0, and the number of 
patients experiencing each AE will be summarized. The safety population will comprise all 
patients who receive at least one dose of study treatment. 
Due to the limited sample size, the analyses investigating the association between 
correlative markers and response to therapy will be exploratory. Levels of c-kit, VEGF, 
VEGFR, PDGF, PDGFR, in archival tumor tissue will be quantified by 
immunohistochemistry (IHC) and their association with objective response to regorafenib 
will be investigated using the non-parametric Wilcoxon rank-sum test. Similarly, 
association between c-myb (strong staining, 2+ vs other) or t(6;9) translocation and 
response will be tested using Fisher’s exact test. 
We will investigate, in an exploratory fashion, whether gene alterations that we detect are 
associated with response. Further, we will use linear models for microarray data (LIMMA), 
which performs moderated t-tests by discounting changes in low expressing genes with 
low variance, to identify genes who are differentially expressed between responders and 
non-responders. Multiplicity correction will be undertaken by controlling the false discovery 
rate. 
We anticipate an accrual rate of approximately 2-3 patients/month; therefore we expect 
accrual to be completed within 15 months. 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 

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During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the 
PPR Electronic Registration System (http://ppr/). The completed signature page of the 
written consent/RA or verbal script/RA, a completed Eligibility Checklist and other relevant 
documents must be uploaded via the PPR Electronic Registration System. 
15.2 
Randomization 
Not applicable 
16.0 
DATA MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of 
the RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinating the activities 
of the protocol study team. 
 
The data collected for this study will be entered into the secure Clinical Research 
Database (CRDB). Source documentation will be available to support the computerized 
patient record. 
 
Whole exome or genome sequencing data will be deidentified; samples will be labelled 
with patient study IDs to preserve links to clinical data. The deidentified genomic data will 
be stored to a protected server that is specifically set aside for clinical trial data. 
 
 
16.1 
Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to 
assess missing data and inconsistencies. Accrual rates and extent and accuracy of 
evaluations and follow-up will be monitored periodically throughout the study 
period and potential problems will be brought to the attention of the study team for 
discussion and action. 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1.. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research. The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://smskpsps9/dept/ocr/OCR%20Website%20Documents/Clinical%20Research%20Qu 
ality%20Assurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20P 
lan.pdf 

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There are several different mechanisms by which clinical trials are monitored for data, 
safety and quality. There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and 
staff education on clinical research QA) and departmental procedures for quality control, 
plus there are two institutional committees that are responsible for monitoring the activities 
of our clinical trials programs. The committees: Data and Safety Monitoring Committee 
(DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring Board 
(DSMB) for Phase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board. 
 
During the protocol development and review process, each protocol is assessed for the 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH 
sponsored, in house sponsored, industrial sponsored, NCI cooperative group, etc.) will be 
addressed and the monitoring procedures will be established at the time of protocol 
activation. 

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17.0 
PROTECTION OF HUMAN SUBJECTS 
Inclusion of Children in Research 
 
This protocol/project does not include children because the number of children is limited and 
because the majority is already accessed by a nationwide pediatric cancer research network. 
This statement is based on exclusion 4b of the NIH Policy and Guidelines on the Inclusion of 
Children as Participants in Research Involving Human Subjects. 
 
Risks, Benefits, Toxicities/side effects 
 
Potential risks to human subjects include drug related toxicity, placement of IV catheters, 
phlebotomy, and possible psychological discomfort from the stresses associated with 
obtaining imaging studies (e.g., CT scan, PET scan). All efforts will be made to avoid any 
complication by completely reviewing patients’ symptoms, providing appropriate 
management, and monitoring blood tests. 
If an adverse medical event occurs, the patient will first contact the primary oncologist or the 
Principal Investigator. At nights and on weekends, there is an oncology physician on call at 
all times. Patients may either call or come directly to the urgent care center at Memorial 
Hospital (or to their local emergency room) to be seen. Patients suffering serious adverse 
reactions must be carefully followed and all follow-up information also recorded. 
Alternatives/options 
 
Participation in this trial is voluntary. Depending on the specific details of the situation, patient 
options without being in a study might include: 
 
• Other palliative chemotherapy off study. 
• Participation in a different clinical trial 
• Best supportive care 
Financial Costs/Burdens 
The patient will be responsible for all costs related to treatment and complications of 
treatment. Costs to the patient (third party insurer) will include hospitalizations, routine blood 
tests and diagnostic studies, office visits, baseline EKG, and doctor’s fees. Patients will not 
be charged the cost of analysis for the research correlates. The patient also will not be 
charged for the subsequent research analysis of these specimens. Regorafenib is provided 
by Bayer and therefore is not billable to research participants. 
17.1 
Privacy 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
It is also stated in the consent and Research Authorization that research data (e.g. genomic 
sequence) may be placed into databases monitored by the National Institutes of Health, and 

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may be made accessible to investigators approved by the U.S. government. It is difficult to 
identify genotype/phenotype specifics since multiple diseases are studied under the auspices 
of this protocol and therefore, the requirements for submission of genotype/phenotype data 
into the NIH GWAS Repository (or any other public database) will be followed as per the 
MSKCC IRB GWAS SOP-503. 
17.2 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is 
required for 30-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious 
Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org. All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org. All other reports should be sent to sae@mskcc.org. 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 

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Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
The PI’s signature and the date it was signed are required on the completed report. 
 
 
17.2.1 SAE reporting for the Drug Supplier 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f): 
a. Results in death. 
b. Is life-threatening. 
The term ‘life-threatening’ in the definition refers to an event in which the patient was at 
risk of death at the time of the event, it does not refer to an event which hypothetically 
might have caused death if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization. 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if at 
least one of the following exceptions is met: 
- The admission results in a hospital stay of less than 12 hours. 
- The admission is pre-planned. (i.e. elective or scheduled surgery arranged prior to the 
start of the study) 
- The admission is not associated with an AE. (e.g. social hospitalization for purposes of 
respite care). 
However, it should be noted that invasive treatment during any hospitalization may fulfill the 
criterion of ‘medically important’ and as such may be reportable as an SAE dependent on 
clinical judgment. In addition, where local regulatory authorities specifically require a more 
stringent definition, the local regulation takes precedence. 

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d. Results in persistent or significant disability / incapacity. Disability means a substantial 
disruption of a person’s ability to conduct normal life’s functions. 
e. Is a congenital anomaly / birth defect. 
f. Is another medically important serious event as judged by the investigator. 
Each serious adverse event must be followed up until resolution or stabilization, by 
submission of updated reports to the designated person. An isolated laboratory abnormality 
that is assigned grade 4, according to CTC definition, is not reportable as an SAE; unless the 
investigator assesses that the event meets standard ICH criteria for an SAE. CTC grade 4 
baseline laboratory abnormalities that are part of the disease profile should not be reported 
as an SAE, specifically when they are allowed or not excluded by the protocol 
inclusion/exclusion criteria. 
When required, and according to local law and regulations, serious adverse events must be 
reported to the Ethics Committee and Regulatory Authorities. 
All serious adverse events should be reported to Bayer within 24 hours. In the event of such 
an event, the investigator should refer to the Pharmacovigilance section of the contract for 
reporting procedures. 
The Investigator may report serious adverse drug reactions (SADRs) using: 
A MedWatch form available at http://www.fda.gov/medwatch/ 
All reports shall be sent electronically to: 
Electronic Mailbox: 
DrugSafety.GPV.US@bayer.com 
Facsimile: 
(973) 709-2185 
Address: 
Global Pharmacovigilance - USA 
Mail only: 
Bayer HealthCare Pharmaceuticals Inc. 
P.O. Box 1000 
Montville, NJ 07045-1000 
Address: 
340 Changebridge Road 
FDX or UPS only 
Pine Brook, NJ 07058 
 
Reports for all Bayer products can also be phoned in via our Clinical Communications 
Dept: 
 
Phone: 
1-888-842-2937 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 

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form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
19.0 
REFERENCES 
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20.0 
APPENDICES 

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APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 

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APPENDIX B: Pill Diary