Phase II Trial of Adjuvant Crizotinib in High-Risk Uveal Melanoma Following Definitive Therapy
Phase: PHASE2
Conditions: Uveal Melanoma
Sponsor: Columbia University

Herbert Irving Comprehensive Cancer Center
Protocol
Phase II Trial of Adjuvant Crizotinib in High-Risk Uveal Melanoma Following 
Definitive Therapy
NCT02223819 

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
 
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CUMC IRB#:  AAAO8010 
 
 
TITLE:  Phase II Trial of Adjuvant Crizotinib in High-Risk Uveal Melanoma 
Following Definitive Therapy 
 
 
Coordinating Center: 
 
 
Columbia University Medical Center  
 
Principal Investigator: 
Shaheer Khan, DO 
 
161 Fort Washington Avenue 
 
 
 
New York, NY 10032 
 
Telephone: 646-317-6354 
 
Email: carvajalr@columbia.edu 
 
Co-Investigators: 
Srilaxmi Bearelly, MD 
 
sb3179@cumc.columbia.edu 
 
 
 
Gary K. Schwartz, M.D. 
 
gks2123@cumc.columbia.edu 
 
 
 
Tongalp Tezel, MD 
 
tht2115@cumc.columbia.edu 
 
 
Royce Chen, MD 
 
rc2631@cumc.columbia.edu 
 
Statistician:                                 Katherine Panageas, DrPH 
 
1275 York Avenue 
 
New York, NY 10065 
 
Telephone: 646-735-8119 
 
Email: panageak@mskcc.org 
 
Regulatory Sponsor: 
Shaheer Khan, DO 
Funding Source: 
Pfizer, Philanthropy 
Study Agent: 
Crizotinib 
IND Status: 
IND exempt   
 
 
   
Affiliate Institutions: 
 

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
 
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Site Principal Investigator and Contact Information: 
Memorial Sloan Kettering Cancer Center 
Principal Investigator: 
Alexander Shoushtari, MD 
300 East 66th Street 
 
New York, NY 10065 
Telephone: 646-888-4161 
Email: shoushta@mskcc.org 
 
Mount Sinai Comprehensive Cancer Center 
Principal Investigator: 
Phillip Bao, MD 
4300 Alton Rd Miami Beach, FL 33140-2840 
Telephone: 305-674-2397 
Email: philip.bao@msmc.com 
 
The Ohio State University 
Principal Investigator: 
Kari L. Kendra, MD, PHD  
B415 Starling Loving Hall  
320 W. 10th Ave., Columbus, OH 43210 
Telephone: (614) 293-4320 
Email: Kari.Kendra@osumc.edu 
 
 
 
 
 
 
 
 

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Protocol Signature Page 
 
I confirm that I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
ICH guidelines for good clinical practices, and the applicable federal, state, and local laws, rules, 
and regulations relating to the conduct of the protocol. I have read and understand the information 
in the Investigators’ Brochure (or Manufacturer’s Brochure) regarding the risks and potential 
benefits. I will promptly submit the protocol to the applicable IRB for review and approval. Once 
the protocol has been approved by the IRB, I understand that any modification made during the 
course of the study must first be approved by the IRB, prior to implementation except when such 
modification is made to remove an immediate hazard to the subject. I certify that I, and the study 
staff, have received the requisite training to conduct this research protocol. I agree to maintain 
adequate and accurate records in accordance with Columbia University and Herbert Irving 
Comprehensive Cancer Center policies, Federal, state and local laws and regulations. I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol. 
 
 
_________________________________                _______________ 
Signature of Principal Investigator                 Date 
 
 
 
_________________________________                 
Principal Investigator Name (Print) 
 
 
 
 
_________________________________
Instructions to Principal Investigator: Sign and Date this signature page and print your name. Return 
the original, completed and signed to the Clinical Protocol & Data Management Office. Retain a 
copy in the regulatory binder.  

 
Table of Contents 
Protocol Signature Page ...................................................................................................................3 
1. 
PROTOCOL SUMMARY AND/OR SCHEMA .................................................................2 
2. 
OBJECTIVES AND SCIENTIFIC AIMS ...........................................................................2 
3. 
BACKGROUND AND RATIONALE ................................................................................3 
3.1 
Uveal Melanoma ......................................................................................................3 
3.2 
Prognostic Features Identify Uveal Melanoma Patients at High Risk for 
Recurrence ...............................................................................................................4 
3.3 
The HGF/c-MET Pathway Plays an Essential Role in the Pathophysiology 
of Uveal Melanoma..................................................................................................6 
3.4 
Crizotinib .................................................................................................................8 
3.5 
c-MET Inhibition Impedes Uveal Melanoma Cell Migration. ................................8 
3.6 
Crizotinib Inhibits the Development and Establishment of Metastases in a 
Murine Model of Uveal Melanoma .......................................................................10 
4. 
OVERVIEW OF STUDY DESIGN/INTERVENTION ...................................................11 
4.1 
Design ....................................................................................................................11 
4.2 
Intervention ............................................................................................................12 
5. 
THERAPEUTIC/DIAGNOSTIC AGENTS ......................................................................12 
6. 
CRITERIA FOR SUBJECT ELIGIBILITY ......................................................................13 
6.1 
Subject Inclusion Criteria ......................................................................................13 
6.2 
Subject Exclusion Criteria .....................................................................................14 
7. 
RECRUITMENT PLAN ....................................................................................................15 
8. 
PRETREATMENT EVALUATION .................................................................................15 
9. 
TREATMENT/INTERVENTION PLAN .........................................................................16 
10. 
EVALUATION DURING TREATMENT/INTERVENTION .........................................16 
10.1 
Correlative Studies .................................................................................................18 
10.2 
Processing of Samples for Correlative Studies ......................................................20 
11. 
TOXICITIES/SIDE EFFECTS ..........................................................................................25 
12. 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT................28 
13. 
CRITERIA FOR REMOVAL FROM STUDY .................................................................28 
14. 
BIOSTATISTICS ..............................................................................................................29 

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15. 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES..................................................................................................................31 
15.1 
CUMC Research Participant Registration .............................................................31 
15.2 
Randomization .......................................................................................................33 
16. 
DATA MANAGEMENT ISSUES ....................................................................................33 
16.1 
DATA REPORTING / REGULATORY REQUIREMENTS ...............................33 
17. 
SERIOUS ADVERSE EVENT (SAE) REPORTING FOR CUMC .................................36 
17.1 
Definitions..............................................................................................................37 
17.2 
Reporting of Serious Adverse Events ....................................................................40 
18. 
INFORMED CONSENT PROCEDURES ........................................................................40 
REFERENCES ..............................................................................................................................42 
APPENDIX A: ...............................................................................................................................46 
PERFORMANCE STATUS CRITERIA ......................................................................................46 
APPENDIX B: ...............................................................................................................................47 
SUBSTANCES PROHIBITED DURING CRIZOTINIB ADMINISTRATION .........................47 
APPENDIX C: ...............................................................................................................................48 
PARTIAL LIST OF SUPPLEMENTS PROHIBITED DURING CRIZOTINIB THERAPY ......48 
APPENDIX D: ...............................................................................................................................49 
GUIDELINES FOR AFFILIATE INSTITUTIONS IN MULTICENTER STUDIES..................49 
 

 
1. PROTOCOL SUMMARY AND/OR SCHEMA 
 
The primary purpose of this single-arm study is to assess the relapse-free survival (RFS) 
of adjuvant crizotinib in patients with uveal melanoma who are at high-risk of recurrence 
following definitive therapy with surgery or radiotherapy.  Patients with class 2 tumors as 
defined by gene expression profiling (GEP; DecisionDx-UM, Castle Biosciences Inc, 
Friendswood, TX) who have undergone definitive therapy, who do not have evidence of 
metastatic disease, and who have adequate renal, hepatic, and hematologic function will be 
eligible for study participation. 
 
The study will be conducted in 3 phases:  
 
1. Active Therapy:  During the active therapy phase of the study, patients will receive 
48 weeks (12 four-week cycles) of crizotinib 250 mg PO BID.  Patients will be 
evaluated by routine blood work and physical examination every 4 weeks while they 
are receiving crizotinib.  Imaging studies, optimally including a chest CT scan (with or 
without contrast) and an abdominal/pelvic MRI with contrast, will be performed at 
baseline and every 12 weeks. 
 
2. Follow-Up:  During the follow-up phase of the study, patients will be seen on an every 
3 month basis until distant disease recurrence, withdrawal of consent, or study closure.  
Imaging studies, optimally including a chest CT scan (with or without contrast) and an 
abdominal/pelvic MRI with contrast, will be performed every 12 weeks until the time 
of distant disease recurrence, withdrawal of patient consent, or study closure. 
 
3. Survival Phase: Patients who have distant disease recurrence during follow-up will 
then be contacted every 3 months (+/- 2 weeks) to obtain vital status for at least 36 
months from the start of active therapy.  
Patients with tumors of 12mm basal diameter or greater and a class 2 signature have a 
median time to recurrence of 32 months (personal communication, J. William Harbour, 
MD, Bascom Palmer Eye Institute) and represent an ideal patient population for a clinical 
trial testing the efficacy of an adjuvant therapy in this disease.  We hypothesize that the 
addition of crizotinib will increase the 32 month RFS by 25%.  Thus, a 32 month RFS of 
50% would be considered not promising and a 32 month RFS of 75% or greater would be 
considered promising.  A single stage design based on a binomial probability estimate will 
be utilized with an alpha of 0.05 and a beta 0.11.  This design will require 30 patients.  At 
the end of the study, if at least 20 out of 30 patients are relapse-free at or after 32 months, 
this adjuvant treatment with crizotinib will be considered worthy of further study.  For the 
purposes of this study, distant disease relapse is defined as the development of tumor 
growth or recurrence at a site distant from the affected eye. Patients who develop recurrent 
metastatic disease at any site will be considered treatment failures. 
 
 
2. OBJECTIVES AND SCIENTIFIC AIMS 
 
• Primary   

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o To determine the 32 month rate of distant relapse in patients with uveal 
melanoma who are at high risk of recurrence following definitive therapy 
with surgery or radiation who receive adjuvant crizotinib. 
 
• Secondary 
o To determine the overall survival and disease specific survival in this patient 
population. 
o To evaluate safety and toxicity of adjuvant treatment with crizotinib. 
To describe the quality of life in patients receiving crizotinib using the 
Functional Assessment of Cancer Therapy - Melanoma (FACT-M) 
questionnaire  
 
• Correlative  
o To collect patient serum and plasma for circulating tumor DNA and 
companion normal gene expression levels 
o To investigate changes in target genes at baseline in primary tumors and at 
recurrence in metastatic samples after crizotinib therapy 
o To establish cell lines or murine xenografts of metastatic recurrences 
3. BACKGROUND AND RATIONALE 
 
3.1 
Uveal Melanoma  
 
Uveal melanoma is the most common primary intraocular malignancy in adults, and arises 
from melanocytes within the choroid plexus of the eye.1  Melanomas of the ocular and 
adnexal structures comprise approximately 5% of all melanomas and are biologically and 
prognostically distinct from cutaneous melanoma.2  In the United States, an estimated 2000 
patients are diagnosed with this disease each year.  Approximately 85% of ocular 
melanomas are uveal (iris, ciliary body, and choroid) in origin, with primary conjunctival 
and orbital melanomas being less common.2,3  Cases are nearly equally distributed between 
male and female subjects, with a median age at diagnosis of 62 years.4  The majority 
(97.8%) of cases of uveal melanoma occurs in the white population, with a white:black 
incidence ratio of 196:1.  
 
The development of metastasis in this disease is common and occurs in approximately 50% 
of patients with posterior uveal melanoma within 15 years after the initial diagnosis and 
treatment.5  Uveal melanoma is thought to be particularly resistant to systemic treatment, 
and no systemic therapy has yet been demonstrated to improve survival.6  Drugs commonly 
used to treat advanced cutaneous melanoma rarely achieve durable responses in patients 
with uveal melanoma.  Nathan et al compared the outcome between 139 patients with non-
uveal melanoma and 16 patients with uveal melanoma who were treated with DTIC, 
BCNU, cisplatin, and tamoxifen (Dartmouth regimen).7  The response rates were 33% and 
6% respectively.  In a review of the MD Anderson Cancer Center experience of 143 treated 
patients with metastatic ocular melanoma, there was only a single objective response 
observed.8  Retrospective reviews of the ECOG and SWOG experiences revealed similar 

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findings.9  Because of the lack of effective systemic treatment options, outcomes are poor 
once metastatic disease occurs, and the median survival from the time of the development 
of distant metastatic disease is 6 to 12 months.10-12  
 
Although it is clear that novel effective therapies are desperately needed for this disease, 
the development of such therapies has been hampered by the rarity of uveal melanoma.  
Indeed, over the past decade, only 8 phase II trials in uveal melanoma have been published, 
with the largest of these trials accruing only 48 patients and none demonstrating significant 
efficacy in terms of response rate, overall survival or progression-free survival (see table 1 
below). 
 
Table 1. Published phase II trials in uveal melanoma. 
 
Despite our inability to identify effective therapies for this disease thus far, our increasing 
understanding of the underlying biology of uveal melanoma has led to the identification of 
a number of novel and promising therapeutic strategies that warrant investigation.   
 
3.2 
Prognostic Features Identify Uveal Melanoma Patients at High Risk for 
Recurrence 
 
Clinical factors that relate to prognosis include location (primary melanomas of the iris 
connote a better prognosis than those arising from the choroid, and choroidal melanomas 
fare better than ciliary body melanomas),21,22 configuration of the tumor (diffuse 
configuration suggests poor prognosis),23 and size.24  Histopathologic features of 
importance include tumor cell type (spindle morphology connotes a better prognosis than 
mixed morphology, and mixed morphology fares better than epithelioid morphology),25,26 
extent of mitotic activity,27 vascular network (absent better than present),28 tumor-
infiltrating lymphocytes (absent better than present),29 and the presence of extrascleral 
extension (absent better than present).22  Nonrandom changes in chromosomes 1, 3, 6, and 
8 have been identified by FISH and CGH in uveal melanomas.30-32  Monosomy 3 and 
amplification of 8q have been identified as poor prognostic indicators.31,33  Other prognostic 
factors include high expression of HLA class I,34 c-myc,35 cyclin D1, p53 MDM2,36 and 
IGF-IR.37  
 
Investigator 
Study Treatment 
n 
Response  
Rate 
Overall  
Survival 
Progression-
Free Survival 
Homsi et al, 201013 
Docosahexaenoic acid-Paclitaxel 
22 
4%  
9.8 mos 
NR 
Penel et al, 200814 
Imatinib 
10 
0% 
10.8 mos 
NR 
Schmittel et al, 200615 
Gemcitabine/Treosulfan vs Treosulfan 
48 
2%  
NR 
2-3 mos 
O’Neill et al, 200616 
DTIC/Treosulfan 
15 
0% 
NR 
3 mos 
Schmittel et al, 200517 
Gemcitabine/Cisplatin/ Treosulfan 
17 
0% 
NR 
3 mos 
Schmidt-Hieber et al, 
200418 
Bendamustine 
14 
0% 
NR 
NR 
Bedikian et al, 200419 
Temozolomide 
14 
0% 
6.7 mos 
1.8 mos 
Kivelä et al, 200320 
Bleomycin/Vincristine/Lomustine/ 
DTIC + Interferon 
22 
0% 
NR 
1.9 mos 

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Two independent groups have identified microarray gene expression profiles (GEP) which 
accurately segregate uveal melanomas into two tumor classes by risk of metastasis.38,39  
Onken et al identified 62 genes that discriminate between tumors that have a low-risk of 
metastasis (class 1 tumors) and those that are more aggressive and are associated with a 
higher risk of metastatic death (class 2 tumors).39  The GEP assay was performed on a 
sample collected directly from the primary tumor, usually at the time of treatment.  In a 
recent study of 459 cases, the GEP assay was successful in rendering a classification in 446 
of 459 cases (97.2%).40  Among the 13 samples that failed to yield a GEP result, 5 did not 
adhere to study protocol (improper buffer, handling, or shipping). Of the 446 cases, 276 
(61.9%) were class 1 and 170 (38.1%) were class 2. Median follow-up was 17.4 months 
(mean, 18.0 months). Metastasis was detected in 3 patients (1.1%) with class 1 tumors and 
44 patients (25.9%) with class 2 tumors (log rank, P<0.0001).  
 
GEP class 2 tumors showed a significant association with other known prognostic factors, 
including increased patient age, greater tumor diameter and thickness, ciliary body 
involvement, and mixed/epithelioid cell type.  By Kaplan–Meier analysis, GEP class 2 was 
more strongly associated with metastasis than any of the other prognostic factors that were 
analyzed, including chromosome 3 status (see Figure 1 below).  By univariate Cox 
proportional hazards analysis, factors associated with metastasis included advanced patient 
age (P = 0.02), ciliary body involvement (P = 0.03), tumor diameter (P = 0.0003), tumor 
thickness (P = 0.006), tumor cell type (P = 0.04), chromosome 3 status (P = 0.0002), and 
GEP class (P<10−7).  This analysis was performed on all cases with values reported for a 
given factor, and there was no significant impact on the results when the analysis was 
restricted to those cases with complete data for all factors.  By multivariate Cox modeling, 
GEP class (P = 0.006) was the only variable that contributed independent prognostic 
information. Chromosome 3 status did not contribute additional prognostic information that 
was independent of GEP (P = 0.2).  
 
Thus, the use of GEP which is now commercially available, provides a powerful tool to 
identify those patients at highest risk of disease recurrence.  Patients with tumors of 12mm 
basal diameter or greater and a class 2 signature have a median time to recurrence of 32 
months (personal communication, J. William Harbour, MD, Bascom Palmer Eye Institute) 
and represent an ideal patient population for a clinical trial testing the efficacy of an adjuvant 
therapy in this disease. 
 
 
 
 
 
 
 
 
 
 
 
 

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Figure 1. Metastasis free survival is best predicted by GEP Class 1 versus 2. 
 
3.3 
The HGF/c-MET Pathway Plays an Essential Role in the Pathophysiology of 
Uveal Melanoma.  
 
Uveal melanomas overexpress c-MET, or HGF receptor, in 60% - 86% of cases;41,42 
however, activating mutations or genetic amplifications of c-MET do not appear to play a 
significant role in this disease.43  The lack of direct gene activation suggests that the MET 
activation in UM is mostly through an indirect mechanism.  c-MET overexpression appears 
to signify more aggressive disease and activation of the HGF/c-MET pathway in uveal 
melanoma is associated with greater cell migration capacity and inferior clinical outcomes.  
Indeed, in a series of 60 patients with resected uveal melanoma, higher levels of c-MET 
expression were found to be associated with a significantly higher risk of death from 
metastatic disease.42  
Hendrix and colleagues first reported in 1998 the expression of c-MET by the more 
invasive interconverted phenotype of uveal melanoma cell lines, and subsequently showed 
a mitogenic response to HGF by c-Met expressing cells, but not by those who failed to 

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express c-Met.44  Cell migration capacity appears to be enhanced by HGF via activation of 
phospho-AKT and the downregulation of the cell adhesion molecules e-cadherin and beta-
catenin in a dose-dependent fashion.45  Both c-MET inhibition and AKT inhibition 
independently inhibited the downregulation of adhesion molecules by HGF and completely 
abolished the migration of uveal melanoma cell lines, suggesting that activation of p-AKT 
via the HGF/c-MET axis is involved in HCF-induced uveal melanoma cell migration.45,46   
Our group evaluated the expression of cMet and its basal phosphorylation status in 6 UM 
cell lines (Figure 2A).47 All cell lines expressed cMet and pMet, however, expression was 
greater in cell lines with GNAQ or GNA11 mutations (92.1, Omm1.3, and Omm1). We 
also investigated the ability of uveal melanoma cells to secrete HGF, the ligand for cMet, 
by ELISA (Figure 2B) and observed that cell lines with GNAQ or GNA11 mutations 
secreted more HGF than the wild-type cell lines, suggesting that UM cell lines with such 
mutations may be activating cMet through an autocrine signaling mechanism.  
 
 
 
 
 
 
Interestingly, HGF and its receptor tyrosine kinase c-Met play essential roles in the 
processes of liver embryogenesis and in hepatic regeneration following injury in the adult 
state, emphasizing their role as both morphogen and mitogen for this organ.46,48  Because 
uveal melanoma metastases preferentially involve the liver, the question arises as to 
whether local factors within the hepatic environment such as HGF or IGF-1 are responsible 
Figure 2. Expression and HGF Secretion of cMet in UM cells. A, cells were grown in serum-
free media for 24 hrs and lysed for immunoblot analysis. cMet expression and phosphorylation 
is generally higher in cell lines with G-protein mutations. B, media from the plates were tested 
for the presence of HGF by ELISA. All cell lines secreted HGF but average HGF secretion of 
G-protein mutant cell lines was higher than the wild-type cell lines. 

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for the dominant pattern of metastases seen at this site, and whether inhibition of this 
pathway could decrease the risk of developing metastatic disease.49,50   
3.4 
Crizotinib 
 
Preclinical Studies. Crizotinib (PF-02341066) is a selective ATP competitive small 
molecule tyrosine kinase inhibitor of c-MET/hepatocyte growth factor receptor (HGFR) 
and ALK tyrosine kinases.  In pre-clinical studies, crizotinib inhibited cell growth of cell 
lines with either MET amplification or ALK gene rearrangement.51  In murine models, 
there was significant antitumor activity in mice with xenografts expressing activated c-
MET or the EML4-ALK gene rearrangement.51  These promising pre-clinical studies 
provided rationale for study of this agent in clinical trials. 
 
Phase I and II Clinical Trials. 
Crizotinib was initially studied as an orally available 
MET inhibitor in a phase 1 study in various solid tumors, with ALK inhibition seen as an 
off target effect (MSKCC protocol 07-157).  The maximum tolerated dose was established 
at 250mg orally given twice daily given continuously.  The EML4-ALK oncogene was 
subsequently identified in NSCLC, and upon retrospective molecular typing, two patients 
with dramatic partial responses were discovered to have the ALK gene rearrangement.  An 
expanded cohort of 82 patients with ALK+ NSCLC was given crizotinib, and had an 
overall response rate of 56%, with an additional 33% with stable disease.52  A recent update 
reported a median progression free survival of 9.2 months on crizotinib.53  Interim results 
of a phase II trial of 136 patients with advanced ALK+ NSCLC revealed that 90% of 
evaluable patients showed target lesion shrinkage.54  Based on these trials, the FDA 
recently approved crizotinib for ALK positive metastatic non-small cell lung cancer.  
 
Toxicities. 
In the phase 1 trial that established the maximum tolerated dose, the dose 
limiting toxicities included a grade 3 elevation in ALT in one patient and grade 3 fatigue 
in two patients.55  The most common adverse events were nausea, emesis, fatigue and 
diarrhea, which were primarily grade 1-2 in severity.  Nausea and emesis were independent 
of dose or duration of treatment and were effectively managed with supportive 
medications.  Treatment-related vision disturbances, observed in most patients, were grade 
1 in severity and were reversible upon discontinuation of crizotinib. The MTD was 
established at 250mg orally twice daily.  
 
3.5 
c-MET Inhibition Impedes Uveal Melanoma Cell Migration.  
 
We tested the effects of downregulation of cMet, ALK and ROS1, targets inhibited by 
crizotinib, on cell proliferation and migration of UM cell lines.47 Western blot confirmed 
decreased cMet in all the cell lines transfected with cMet siRNA (Figure 3A), with 
suppression of ALK and ROS1 observed in cell lines with positive basal expression. While 
cell viability assays demonstrated no suppression of growth by cMet knockdown (data not 
shown),22 cMet siRNA significantly inhibited cell migration (p<0.05; Figure 3B), with 
statistically non-significant inhibition of migration observed with ALK and ROS1 siRNA.  

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Next, we utilized doses of crizotinib necessary to selectively inhibit pMet but with no effect 
on cell growth. After 72 hrs of treatment, all UM cell lines showed a dose-dependent 
decrease in viability in response to crizotinib at doses >1,000 nmol/L (Figure 2C). cMet 
phosphorylation was inhibited by crizotinib starting at 25 nmol/L, whereas neither ALK 
nor ROS1 was inhibited at any of the concentrations tested with 24 hours of drug exposure 
(data not shown). When UM cells were treated with 25 nmol/L of crizotinib in a 24-hr 
migration assay, a mutation-dependent effect was observed such that only the migration of 
GNAQ and GNA11 mutant cells lines and not wild-type cell lines (C918 and Mel290), was 
decreased (Figure 2D). However, when treated with 250 nmol/L crizotinib for 24 hrs 
(conditions under which cell proliferation was still not affected), the migration of all cell 
lines was inhibited irrespective of mutational status (data not shown), suggesting that 
GNAQ and GNA11 mutant cells with higher basal activity of cMet are sensitive to lower 
concentrations of crizotinib. 
 
 
 
 
 
Figure 3. Effects of cMet Inhibition on Cell Migration. A, cells were transfected with control, 
cMet, ALK, or ROS1 siRNA. Western blot analysis of the lysates verified that all target genes 
were knocked down by their respective siRNA. B, transfected cells were seeded on Matrigel 
chambers in triplicates and allowed to migrate for 24 hours into RPMI media containing 10% 
serum. Migrated cells were then quantitated. Only cMet siRNA knockdown significantly inhibits 
cell migration. C, UM cells were plated and treated in triplicates with increasing doses of 
crizotinib for 72 hours in 96-well plates then cell viability was measured as the percentage of 
untreated controls. Crizotinib inhibited cell proliferation in a dose-dependent manner 
regardless of genotype only at higher concentrations. The IC50 range is from 750 to 2,000 
nmol/L. D, UM cells were seeded on a Matrigel chamber with 0.1% FBS in RPMI and either 
DMSO or 25 nmol/L crizotinib. Cells were then allowed to migrate for 24 hours into media 
containing 10% FBS and 50 ng/mL HGF. The migration of GNAQ-mutant UM cells was 
significantly inhibited with 25 nmol/L crizotinib but not the migration of wild-type cell lines. 

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3.6 
Crizotinib Inhibits the Development and Establishment of Metastases in a 
Murine Model of Uveal Melanoma 
 
We developed a metastatic model of UM where retro-orbital injection of 10 million 
OMM1.3 cells labeled with GFP/luciferase results in the development of hepatic metastasis 
within 6 weeks.47 Using this model, we treated mice with 50 mg/kg of crizotinib (5 
days/week) 1 week after tumor implantation for a total of 8 weeks. Imaging performed at 
week 11 demonstrated significant suppression of metastatic spread with treatment 
compared to control mice (Figures 4A and 4B) confirmed by necroscopy at week 11 
(Figure 4C). Importantly, UM tumor growth in the eye of the mice was not inhibited by 
crizotinib, which mirrors that lack of efficacy in 2 xenograft models of established UM 
tumors (data not shown). 
 

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We have demonstrated that inhibition of cMET by siRNA and crizotinib results in anti-
migratory activity in UM cell lines, and that crizotinib impedes the development of distant 
metastatic disease to the liver and other sites in a UM mouse model. Given the biological 
relevance of the HGF/cMET axis in UM combined with the preclinical data supporting the 
anti-migratory and anti-tumor activity of cMET targeting in this disease, we propose a 
phase II clinical trial to investigate our hypothesis that cMET inhibition with crizotinib 
with prevent the establishment and development of metastases in patients with high-risk 
primary uveal melanoma.  
 
 
4. OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
The primary endpoint of this trial is RFS. Patients with tumors of 12mm basal diameter or 
greater and a class 2 signature have a median time to recurrence of 32 months (personal 
communication, J. William Harbour, MD, Bascom Palmer Eye Institute).  We hypothesize 
Figure 4. Inhibition of Metastasis by Crizotinib in a Metastatic UM Model. 
A, bioluminescence imaging at 7 weeks after injection of cells compared 
progression of metastasis in control- (n=10) and crizotinib-treated (n=12) mice. 
Control mice have metastasis in the abdominal region, while crizotinib inhibited 
metastasis. B, bioluminescence intensity was quantified for each mouse and the 
mean calculated for each cohort. Luciferase activity in metastatic sites was 
significantly decreased in crizotinib-treated mice compared with the vehicle 
control (p=0.03). C, necropsy showed macrometastases in the liver and lungs of 
the controls, whereas none were seen in the crizotinib-treated mice. 
Bioluminescence imaging of the liver and lungs further illustrates inhibition of 
metastasis by crizotinib.  

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that the addition of crizotinib will increase the 32 month RFS by 25%.  Thus, a 32 month 
RFS of 50% would be considered not promising and a 32 month RFS of 75% or greater 
would be considered promising.  A single stage design based on a binomial probability 
estimate will be utilized, with an alpha of 0.05 and a beta of 0.11.  This design will require 
30 patients.  At the end of the study, if at least 20 out of 30 patients are relapse free at 32 
months, this adjuvant treatment crizotinib will be considered worthy of further study.  
  
4.2 
Intervention 
 
Tumor FNA or enucleation may be performed as standard of care prior to obtaining written 
informed consent for this trial.  GEP will be determined by the DecisionDx-UM gene 
expression assay as standard of care using the FNA specimen or 5 unstained FFPE slides 
from the enucleation specimen.  Patients with class 2 tumor will be offered participation in 
this study.  Should they be interested in participation, written informed consent will be 
obtained.  Investigational studies including cMET gene expression will be performed 
subsequently by Castle Biosciences should sufficient material be available. 
 
Patients with class 2 tumors as defined by GEP that are 12mm in basal diameter or greater 
and who have undergone definitive therapy and who do not have evidence of metastatic 
disease will receive 12 four-week cycles (total of 48 weeks) of crizotinib 250 mg BID.  
Patients must have adequate renal, hepatic, and hematologic function for eligibility.     
 
Patients will be evaluated by routine bloodwork and physical examination on a monthly 
basis while they are receiving crizotinib and will subsequently be seen on an every 3 month 
basis.  Imaging studies, including a chest CT scan (with or without contrast) and an 
abdominal/pelvic MRI with contrast, will be performed every 12 weeks until the time of 
disease recurrence, withdrawal of patient consent, or study closure. 
 
5. THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Crizotinib will be taken twice daily at a dose of 250 mg BID, with each dose taken 
approximately twelve hours apart.  Crizotinib will be dosed approximately at the same 
time each day, and can be dosed without regard to meals.  If the patient forgets a dose, 
they should take it as soon as they remember unless it is less than six hours before the next 
dose.  In that case, they should be instructed to take the next dose. They should not take 
two doses at the same time to make up for a missed dose.  Medication will be dispensed 
at the beginning of each treatment cycle (28 days) and a pill diary will be used to track 
adherence.  While every effort will be made to encourage medication adherence, missed 
doses will not be treated as protocol violations unless the number of missed doses is 
greater than 25% of the total scheduled number of doses. Investigators should reference 
the current approved prescribing information.    
 
Crizotinib will be provided as capsules containing 200 or 250 mg of study medication for 
oral administration.  The 200 mg and 250 mg capsules are oval in shape.  The tablets are 
packaged in HDPE bottles and should be stored at 15 to 30°C and handled with care.  

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Crizotinib should be stored at room temperature (15-30° C).  
 
 
6. CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
1. Primary diagnosis of uveal melanoma at least 12 mm in largest basal diameter as 
clinically determined by the treating investigator.  Cytologic determination of 
diagnosis is not required. Size is based on clinical assessment (e.g. by ultrasound 
or direct ophthalmoscopy) prior to enucleation or radiation therapy. 
 
2. Definitive therapy of the primary uveal melanoma must have been performed 
within 120 days of initiating protocol therapy. 
 
3. High-risk (class 2) uveal melanoma as determined by gene expression profiling 
(GEP; DecisionDx-UM, Castle Biosciences Inc, Friendswood, TX).  
 
4. No evidence of metastatic disease.   
 
5. Age ≥18 years.   
 
6. ECOG performance status ≤ 1 (Karnofsky ≥ 70%, see Appendix A). 
 
7. Life expectancy of greater than 3 months. 
 
8. Able to swallow and retain orally-administered medication and does not have any 
clinically significant gastrointestinal abnormalities that may alter absorption such 
as malabsorption syndrome or major resection of the stomach or bowels. 
 
9. Patients must have normal organ and marrow function as defined below:   
 
• Absolute neutrophil count (ANC) >1,000 cells/mm³ 
• Platelet count >75,000/mm³ 
• Hemoglobin >9.0g/dL 
 
• AST and/or ALT <3x upper limited of normal (ULN) 
• Total bilirubin <2x ULN 
• Alkaline phosphatase <3x ULN 
 
• Serum creatinine <2x ULN or a creatinine clearance > 60mL/min 
 

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• Note:  Patients with hyperbilirubinemia clinically consistent with an inherited 
disorder of bilirubin metabolism (e.g., Gilbert syndrome) will be eligible at the 
discretion of the treating physician and/or the principal investigator. 
 
10. Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry and for the duration of study participation until 4 months after 
completion of crizotinib administration.  Women of child-bearing potential must 
have a negative serum pregnancy test within 14 days prior to study entry.  Should 
a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.  
Men treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study therapy, and 4 months 
after completion of crizotinib administration. 
 
11. Ability to understand and the willingness to sign a written informed consent 
document. 
6.2 
Subject Exclusion Criteria 
 
1. History of another malignancy except for those who have been disease-free for 3 
years, or patients with a history of completely resected non-melanoma skin cancer 
and/or patients with indolent secondary malignancies not requiring active therapy, 
are eligible.  Consult the study Principal Investigator if unsure whether second 
malignancies meet the requirements specified above. 
 
2. Any major surgery or extensive radiotherapy (except that which is required for 
definitive treatment of primary uveal melanoma), chemotherapy with delayed 
toxicity, biologic therapy, or immunotherapy within 21 days prior to initiation of 
study therapy. 
 
3. History of prior crizotinib use. 
 
4. Use of other investigational drugs within 28 days (or five half-lives, whichever is 
shorter; with a minimum of 14 days from the last dose) preceding the first dose of 
study therapy and during the study. 
 
5. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to 
drugs chemically related to crizotinib. 
 
6. Concurrent administration of crizotinib and a strong inhibitor or inducer of CYP3A 
(see Appendix B) is not permitted. Many over-the-counter and dietary supplements 
also inhibit or induce CYP3A (see Appendix C for a partial list) and thus are 
prohibited. 
 

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7. A QT interval corrected for heart rate using the Bazett’s formula QTcB ≥ 480 msec. 
 
8. Concurrent administration of crizotinib and agents that can cause QTc prolongation 
(see Appendix B) is not permitted. 
 
9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or 
Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV 
and HCV infection, which will be allowed).  HIV-positive patients on combination 
antiretroviral therapy are ineligible because of the potential for pharmacokinetic 
interactions with crizotinib.  In addition, these patients are at increased risk of lethal 
infections when treated with marrow-suppressive therapy.  
 
10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
7. RECRUITMENT PLAN 
 
A member of the patient’s treatment team, the protocol investigator or research team at 
Columbia University Medical Center or Memorial Sloan Kettering will identify potential 
research participants.  If the investigator is a part of the treatment team, s/he will screen the 
patient as to eligibility, and will discuss the study and the possibility of enrollment in the 
research study with the patient.  The preliminary screen of eligibility will be confirmation 
of the diagnosis of uveal melanoma and ascertaining the exact stage of the disease.  
Potential subjects that meet these basic criteria will be referred by their treating physician 
to the investigator/research staff of the study, whether in ophthalmology or medical 
oncology.  The patient will be approached for enrollment on the screening portion of the 
trial, which will determine risk-stratification by GEP testing. High-risk patients by GEP 
testing will then be referred to medical oncology, if not previously referred, to discuss the 
treatment portion of the protocol. The principal investigator will be available to all patients 
for further questions and information through a contact number which will be provided on 
the consent form itself. 
 
8. PRETREATMENT EVALUATION 
 
All aspects of the screening evaluation should be completed within 28 days of starting 
treatment with the exception of scans.  
 
• Documented presence of high-risk (class 2) uveal melanoma as determined 
by GEP. This may be completed at any time prior to registration. 
• Full medical history 
• Full medication list 

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• Standard baseline surveillance imaging with CT scan of the chest (with or 
without contrast) and MRI of the abdomen and pelvis with contrast up to 60 
days prior to starting treatment.  CT imaging of the abdomen and pelvic can 
be substituted for the MRI if indicated. 
• Complete vital signs (pulse, blood pressure, temperature, respiratory rate) 
as well as weight and height.  Height may be documented at any time prior 
to registration. 
• 12-lead electrocardiogram (ECG)  
• Performance status by KPS or ECOG status (see Appendix A) 
• Serum pregnancy test for women with child-bearing potential 
• Complete blood count with differential 
• Comprehensive metabolic panel (glucose, blood urea nitrogen, creatinine, 
sodium, potassium, chloride, bicarbonate, calcium, total protein, albumin, 
serum bilirubin, alkaline phosphatase, ALT, AST) 
• LDH 
• Phosphorus 
 
9. TREATMENT/INTERVENTION PLAN 
 
All patients will receive oral crizotinib 250 mg PO BID during the active therapy phase of 
the study. Dose modifications due to toxicity are described further in Section 11.0.  The 
schedule of evaluations and interventions is described in Section 10.0  
The study will be conducted in 3 phases:  
 
1. Active Therapy Phase:  During the active therapy phase of the study, patients will 
receive 48 weeks (12 four-week cycles) of crizotinib 250 mg PO BID.  Patients will be 
evaluated by routine bloodwork and physical examination every 4 weeks while they 
are receiving crizotinib.  Imaging studies, optimally including a chest CT scan (with or 
without contrast) and an abdominal/pelvic MRI with contrast, will be performed at 
baseline and every 12 weeks. 
 
2. Follow-Up Phase:  During the follow-up phase of the study, patients will be seen on 
an every 3 month basis.  Imaging studies, optimally including a chest CT scan (with or 
without contrast) and an abdominal/pelvic MRI with contrast, will be performed every 
12 weeks ± 1 week until distant disease recurrence, withdrawal of patient consent, or 
study closure.  
 
3. Survival Phase: Patients who have distant disease recurrence during follow-up will 
then be contacted every 3 months (+/-2 weeks) to obtain vital status for at least 32 
months from the start of active therapy. 
 
10. EVALUATION DURING TREATMENT/INTERVENTION 
 

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Evaluations will occur at each clinic visit, which are every 4 weeks (+/- 1 week) for 48 
weeks, and every 3 months (+/- 2 weeks) subsequently.  Surveillance imaging studies will 
be performed at baseline and every 12 weeks subsequently (+/- 1 week window).  All 
evaluations and assessments may be performed with a +/- 1 week window unless specified 
above.  The evaluations are delineated further in the study calendar (Table 4) 
 
Quality of life (QoL) will be measured using the Functional Assessment of Cancer Therapy 
- Melanoma (FACT-M) Version 4 (see Appendix D) to explore potential effect of 
treatment.  The FACT-M consists of 27 items that form four general health subscales: 
Physical Well-being (PWB), Social Well-being (SWB), Emotional Well-being (EWB), and 
Functional Well-being. In addition, the FACT-M contains 16 questions which comprise 
the Melanoma Score (MS).  The eight questions from the FACT-M related directly to the 
melanoma surgery site are excluded for this study since these questions will not be 
applicable for the patient sample.   
 
In this study, the QoL questionnaire will be administered at baseline, after 4 to 8 weeks of 
crizotinib therapy, and at the end of the 48 weeks of active treatment.  To preclude bias of 
patient responses by prior knowledge of disease status or other medical outcomes, every 
effort should be made to administer the QoL questionnaire to patients at their scheduled 
visits prior to any other assessments, treatment administration, physician/investigator 
consultation, and prior to being informed of his/her disease status.  Upon completion, the 
investigator, research nurse, or study coordinator should immediately review the 
questionnaire.  This should be done to ensure that every question has been answered and 
that there is only one response for each question.  If omissions or double responses occur, 
they should be brought to the attention of the patient. 
 
 
 
 
Active Therapy 
Phase  
Follow-Up 
Phase 
Recurrence visitk 
Survival 
Phase 
 
Pre-
Study 
Every 4 Weeks for 
48 Weeks  
Every 3 
Monthsj 
 
Every 3 
Monthsl 
Crizotinib 
 
X 
 
 
 
Informed Consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical History 
X 
X 
X 
X 
 
Concurrent Meds 
X 
X 
X 
X 
 
Physical Exam 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
Weight 
X 
X 
X 
X 
 
Performance Status 
X 
X 
X 
X 
 
CBC w/ Diff, PLTs 
X 
X 
X 
X 
 
Serum/plasma 
Chemistrya 
X 
Xb 
X 
X 
 
Serum/Plasma 
Pregnancy Testc 
X 
 
 
 
 

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EKGd 
X 
X 
 
 
 
Adverse Event 
Evaluatione 
X 
X 
X 
X 
 
CT and/or MRI 
Radiographic 
Imagingf 
Xf 
Every 12 weeksf 
 
 
FACT-M 
Assessmentg 
 
X 
 
 
 
Tumor Biopsy for 
GEPh 
X 
 
 
 
 
Tumor Biopsy at 
Time of Progression 
 
 
 
X 
 
Research Blood 
Collectioni 
 
X 
X 
X 
 
Survival Phone Call 
 
 
 
 
X 
 
a:   Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
b:  Hepatic function panel (Albumin, alkaline phosphatase, total bilirubin, AST, ALT) will be obtained every 2 
weeks for first eight weeks, then every four weeks for remainder of 48-week duration. 
c: Perform only in women of child-bearing potential.   
d: A single 12-lead ECG should be performed at Screening and prior to dosing on Day 1 of each 4-week cycle 
during the treatment phase. The first treatment-phase EKG does not need to be conducted if the baseline EKG 
was conducted within 28 days of treatment start date.  Additional EKGs will be performed as clinically indicated.  
Patients with a baseline QT interval corrected for heart rate using the Bazett’s formula QTcB ≥ 480 msec are 
excluded from this trial.  
e: Adverse event evaluation should be performed during the active therapy phase and up to 30 days following 
completion of crizotinib administration.  No subsequent adverse event evaluation is required. 
f:   Surveillance imaging studies will be performed at baseline and every 12 weeks (+/- 1 week window for 
imaging studies).  Every attempt should be made to perform a CT of the chest (with or without contrast) as well 
as an MRI of the abdomen and pelvis with contrast; however, alternative imaging modalities may be performed 
upon discussion with the Principal Investigator. 
g: The FACT-M questionnaire will be administered at baseline, after 4 to 8 weeks of crizotinib therapy, at the 
end of active treatment.   
h: High-risk (class 2) uveal melanoma as determined by gene expression profiling (GEP; DecisionDx-UM, 
Castle Biosciences Inc, Friendswood, TX) may have been performed at any time prior to study initiation.  
i:   Serum will be collected from patients in 4 cell preparation (CPT) tubes with sodium heparin or ACD yellow 
top tubes (approximately 8 mL/tube) only at baseline, and 1 Streck blood collection tube (BCT) (approximately 
8 mL/tube) at baseline, at weeks 4, 8, and 12, and then every 12 weeks thereafter until 132 weeks or recurrence, 
inclusive. Standard sodium heparin or K3-EDTA tubes can substitute for CPTs or Streck BCTs if necessary. 
j:     Patients will be evaluated every 3 months (+/- 2 weeks) for follow up assessment until distant disease 
recurrence, withdrawal of patient consent, or study closure.  
k: Patients who do not withdraw consent will have a recurrence visit within 30 days of distant disease 
recurrence.  
l:      Patients will be contacted every 3 months (+/-2 weeks) for at least 32 months from the start of active therapy 
for survival data.  
 
10.1 
Correlative Studies 
 
Correlative studies of the primary tumor, peripheral blood, and metastatic samples will be 
critical to see if a biomarker and possible mechanism can be identified for those responding 

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or not responding to the therapy.   
 
10.1.1 Correlative Studies on Primary Tumor 
 
At diagnosis, an FNA of the primary tumor will be performed and sent to Castle 
Biosciences for GEP analysis via the DecisionDx-UM test per standard of care.  Patients 
who undergo enucleations may have 5 unstained formalin-fixed, paraffin-embedded slides 
sent for this test in lieu of an FNA as standard of care.  Tumor FNAs and/or enucleation 
samples performed prior to screening consent (e.g. at an outside institution) may be used 
for correlative analysis if patients have consented to Castle Bioscience’s biospecimen 
repository. 
 
Should sufficient additional sample be available at Castle Biosciences, RNA expression 
levels of genes relevant to UM biology, including, but not limited to, HGF,56,57 MYC,58 
BAP1,59,60 EGFR,57 IGF-1R,57 MITF,61 SF3B1,62,63 EIF1AX,62 DDX43,64 and STAT3,65 
as well as cMET, ROS, and ALK, all targets of crizotinib, will be assessed by Castle 
Biosciences. We will set cMET and the other analytes onto an ABI TLDA card using 
TaqMan assays.  
 
If any fresh frozen, paraffin embedded and/ or cells from tumor tissues is available in 
excess of that required for pathological diagnosis or for the analysis described above, it 
may be obtained for additional correlative studies to be performed at each of the 
participating sites.  Tumor FNAs and/or enucleation samples performed prior to screening 
consent (e.g. at an outside institution) may be used for correlative analysis if patients have 
consented to other appropriate protocols (e.g the Ohio State University Uveal Melanoma 
genetics study [IRB#06036]). 
 
10.1.2 Correlative Studies on Blood 
 
Patient serum and/or plasma for research purposes will be obtained at baseline before 
treatment on Day 1, at each on-treatment and follow-up visit, and at the off-study visit.  
 
Four cell preparation tubes with sodium heparin or ACD yellow top tubes (~8 mL/tube) 
and 1 Streck blood collection tube (BCT) or equivalent (~8 mL) will be obtained at 
baseline.  
 
While on study, 1 Streck BCT or equivalent will be obtained at Weeks 4, 8, 12, and then 
every 12 weeks thereafter until 132 weeks or recurrence, inclusive. Standard sodium 
heparin-containing and/or K3-EDTA tubes can substitute for CPTs and Streck BCT if 
necessary.  These samples will be banked for circulating tumor DNA and companion 
normal gene expression profiling studies.  
 
Samples will be spun and separated into plasma and cellular components and circulating 
cell-free (tumor) DNA and cell-associated DNA extracted.  At OSU, this will be performed 
at Dr. Abdel-Rahman’s laboratory or the Human Genetics Sample Bank core facility, and 

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all DNA samples will be logged into the study database so that they can be linked to the 
individual’s unique identifier.  Inflammatory studies to assess the role of the immune 
system in response to crizotinib therapy will be performed at OSU. KIR and HLA 
allelotyping, germline polymorphism analysis of immune modulating genes, and other 
analyses will be performed on peripheral blood DNA in Dr. Abdel-Rahman’s laboratory at 
OSU. 
 
Genotyping and sequencing will be assessed by digital PCR for tumor genes including but 
not limited to GNAQ/11, SF3B1, EIF1AX and BAP1 mutation to assess levels of 
circulating tumor DNA in response to therapy and compare to cell-associated peripheral 
blood DNA.  Although these studies will be performed in a central study laboratory, 
additional correlative studies may be performed at each of the participating sites.  
 
10.1.2 Correlative Studies on Metastatic Tumor 
 
If and when metastatic disease or recurrence is suspected, at least 3 cores and up to 5 cores 
from the patient’s biopsy specimen will be flash frozen and banked for research purposes. 
RNA expression levels of the same genes noted above (cMET, HGF, ROS, ALK, MYC 
etc) will be assessed from these specimens. Follow-up validation studies of these target 
genes (e.g. protein expression, immunohistochemistry, etc.) will be performed as required 
from analysis of GEP data. If a total of 5 cores may be safely obtained, 2 fresh cores  may 
also be utilized to establish cell lines, organoids,  and/or patient derived xenografts in 
immunocompromised mice as described below under section 10.2.3.  Inflammatory 
marker immunohistochemistry studies for all patients will be performed at OSU.  
Additional correlative studies may be performed at each of the participating sites.   
 
Every reasonable effort should be made to obtain correlates at each time point, but omitted 
correlates will not be considered protocol violations and a later time point may substitute 
for a missed time point. 
 
 
10.2 
Processing of Samples for Correlative Studies 
 
10.2.1 Plasma for cell free DNA 
 
Plasma for cell-free DNA should complete processing as soon as possible, ideally 
within 6 hours of collection for EDTA tubes or within 72 hours of collection for 
Streck BCTs. Tubes should be centrifuged at 820 x G for 10 minutes, with 
supernatant transferred to 1.5 mL Eppendorf tubes in 1 mL aliquots. A goal of 2 
mL plasma should be obtained. The sample should be centrifuged at 1600 x G for 
10 minutes at 4oC to pellet any remaining cellular debris, which should be 
discarded. The supernatant should then be labeled with subject identification 
number, date, time point (e.g. baseline, week 4), and the name of the center. These 
samples should be stored at -80oC.  Shipments will be sent to the analysis 
laboratories by batch shipments when possible.  The analyzing laboratories will be 

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notified by email (vialea@mskcc.org) the day the samples are sent.  
 
The email will contain the following information: 
 
• Subject ID 
• Subject Initials 
• Visit Name 
• Date of collection  
• Time of collection 
• Time of Freezing 
 
All samples should be directed to the address listed on the tissue sample shipment 
form. Samples should be shipped via courier so that the package is tracked 
appropriately (specifically Federal Express or UPS).    
 
Specimens will be packed in dry ice in a way to ensure they remain frozen during 
shipment and do not break. All specimens must be shipped with appropriate 
identifiers.  The samples should be shipped for morning delivery, Monday through 
Thursday for optimal processing.  DNA may isolated locally and shipped directly 
to CUMC.  At OSU circulating cell-free (tumor) DNA extracted at Dr. Abdel-
Rahman’s laboratory or the Human Genetics Sample Bank core facility at OSU.  
All DNA samples will be logged into the study database so that they can be linked 
to the individual’s unique identifier.  Date and time of collection and freezing will 
be collected. DNA will be shipped in a batch shipment to the analyzing laboratory. 
 
 
Samples will be tracked through a Microsoft Excel tracker.   
 
 
 
10.2.2 Blood for PBMC Isolation 
 
PBMC isolation will be performed at baseline only.  Please ensure an absolute 
lymphocyte count and an absolute monocyte count are collected when PBMCs are 
obtained so that PBMCs can be quantified. 
 
Invert tubes 8-10 times and store upright at ambient temperature until collection. 
Label the tubes appropriately. Isolation and freezing should be completed under 
sterile technique, preferably a biosafety cabinet, and completed within 6 hours of 
blood collection. 
 
Centrifuge for 20 minutes at 1700 x g. If after centrifugation the upper phase above 
the gel is not clear of RBCs, the tube should be centrifuged for an additional 15 
minutes. After centrifugation, the PBMCs will be found in a diffuse, whitish layer 

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above the gel or on the sides of the tube. Without disturbing the cell layer, use a 
transfer pipette to remove approximately half the upper clear plasma layer (~3 mL). 
With a clean transfer pipette, gently pipette the remaining plasma and cells up and 
down to dislodge any cells that may be resting on the gel layer, or the sides of the 
tube. Transfer the cell suspension to a 15 mL conical tube. Add room temperature 
RPMI-10 to the conical tube to a final volume of 13 mL, cap the tube tightly, and 
mix by gentle inversion. Centrifuge at 250 × g for 15 min at room temperature. The 
supernatant may be cloudy. These are platelets above the cell pellet. Decant or 
aspirate the supernatant without disturbing the cell pellet.  Flick the tube to 
resuspend cells. Repeat washing steps (RPMI-10, suspension, centrifuge, decant 
supernatant) 1-2 more times. While waiting for the 2nd (or 3rd) wash, fill an 
insulated ice pan with ice. After the 2nd (or 3rd) wash is complete, remove a small 
aliquot to record the cell count and viability, then place tube on ice.  
 
For each timepoint, collect the following parameters: 
 
i. 
Cell viability (%) before freezing 
ii. 
Total yield of PBMCs (x 106 cells/mL/vial) isolated prior to 
freezing 
 
Prepare a freezing container (e.g. Nalgene cat #5100-0001 or equivalent) Remove 
the high-density polyethylene vial holder and foam insert from the Nalgene 
Freezing Container. Do not discard the foam insert. Container must be at room 
temperature prior to use. Do not pre-chill. Add approximately 250 mL of 100% 
isopropyl alcohol to the fill line on the Freezing Container. Do not overfill. 
Carefully replace the foam insert and vial holder in the Freezing Container. 
 
To freeze the PBMCs: Important to Note: PBMC Freezing media contains DMSO, 
which is toxic to the cells if they are not frozen immediately after suspension in 
freezing media. Flick 15mL centrifuge tube containing the PBMC pellet to 
resuspend cells. Using a transfer pipette, quickly resuspend the pellet in 1 mL of 
COLD Freezing Medium. 
 
i. 
NOTE:  Prepare media per the instructions contained inside the 
media kit box. 
ii. 
Mix the cells up-and-down a few times until well mixed (no 
visible clumps). 
Immediately dispense the entire volume into the pre-labeled cryovial. Cap the vial 
tightly. Keep samples on ice until transferred to the Freezing Container. Aliquot 
PBMCs into provided labeled cryovials. A minimum of seven (7) cryovials should 
be obtained. 
 

C ol u m bi a U ni versit y Me dic al Ce nter  
Her bert I r vi n g C o m pre he nsi ve C a ncer Ce nter  
 
2 3 
Versi o n - 2 5 J A N 2 0 2 3 
 
 
 
  
 
iii. 
N O T E:  E ac h  cr y o vial  s h o ul d  c o ntai n  a  mi ni m u m  of  5 x 1 0 6 
cells/ m L/ vial  a n d  a  ma xi m u m  of  1 5 x 1 0 6  cells/ m L/ vial.    F or 
eac h cr y o vial pre pare d, please rec or d t he t otal # of P B M Cs i n 
t he cr y o vial.  
i v. 
If t here are less t ha n 3 5 milli o n cells, as ma n y cr y o vials wit h 5 
milli o n cells s h o ul d be ma de as p ossi ble. 
v.  
Place sa m ple vials i n Freezi n g C o ntai ner vial h ol der. Place t he 
li d  o n  t he  Freezi n g  C o ntai ner  a n d  place  i n  a - 7 0C/ - 8 0° C 
freezer i m me diatel y. F or eac h cr y o vial pre p are d, please rec or d 
t he date a n d ti me place d i nt o t he freezer. 
vi.  
N O T E: Lea ve u n dist ur b e d o ver ni g ht or f or a mi ni m u m of 1 2 
hrs a n d a ma xi m u m of 2 4 hrs. 
Tra nsfer  sa m ples  t o  li q ui d  nitr o ge n  st ora ge  freezer.  Rec or d  t he  ti me,  dat e,  a n d 
l ocati o n t hat t he sa m ples were place d i n li q ui d nitr o ge n st ora ge.  F or eac h cr y o vial 
pre par e d, pleas e rec or d t he date a n d ti me place d i nt o li q ui d nitr o ge n st ora ge. 
 
S hi p me nts  will  be  se nt  t o  t he Sc h wartz   la b orat or y b y  batc h  s hi p me nts  w he n 
p ossi ble.    
T he  a nal yzi n g  la b orat ori es  
will  be  n otifie d  b y  e mail 
(ga 2 3 9 1 @c ol u m bia.e d u ) t he da y t he sa m ples are s e nt.   
 
T he e mail will c o ntai n t he f oll o wi n g i nf or mati o n:  
 
•  S u bject I D  
•  S u bject I nitials  
•  Visit Na me  
•  Date of c ollecti o n  
•  Ti me of c ollecti o n  
•  Ti me of Fr eezi n g  
 
All sa m ples s h o ul d be directe d t o t he a d dress liste d o n t he tiss ue sa m ple s hi p me nt 
f or m.  Sa m ples  s h o ul d  be  s hi p pe d  via  c o urier  s o  t hat  t he  pac ka ge  is  trac ke d 
a p pr o priatel y (s pecifi call y Fe d eral E x press or U P S).  S peci me ns will be pac ke d i n 
dr y ice i n a wa y  t o e ns ure t he y re mai n fr oze n d uri n g s hi p me nt a n d d o n ot brea k. 
All s peci me ns m ust be s hi p pe d wit h a p pr o priate i de ntifiers.  T he sa m ples s h o ul d 
be s hi p pe d f or m or ni n g d eli ver y, M o n da y t hr o u g h T h urs da y f or o pti mal pr o cessi n g.   
 
Sa m ples will be trac ke d t hr o u g h a Micr os oft E x cel trac ker.   
 
Fi ve micr o gra ms of t he D N A is olate d fr o m p eri p heral bl o o d fr o m P B M Cs fr o m 
eac h p atie nt will be se nt i n b ul k t o Dr. A b del -Ra h ma n’s la b orat or y f or KI R  a n d 
H L A allel ot y pi n g a n d i nfla m mat or y S N P a nal ysis.   T he D N A will be la be le d wit h 

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the appropriate identifiers and concentration and shipped via courier so that the 
package is tracked appropriately (specifically Federal Express or UPS).  The 
analyzing 
laboratories 
will 
be 
notified 
by 
email 
(mohamed.abdel-
rahman@osumc.edu) the day the samples are sent.   
 
10.2.3 Core Biopsy Specimens 
 
Tissue should be divided such that one core is placed in buffered formalin and 
paraffin embedded as standard of care for histologic diagnosis of recurrence. 
Additional core biopsy specimens, if safe to obtain, will be utilized for gene 
expression and confirmatory protein studies as well as establishment of cell lines 
and/or patient derived xenografts.  
 
Personalized tumor models consisting of cell lines, organoids, and xenografts, will 
be created by the Olive Laboratory under IRB protocol AAAR4172. Two fresh 
cores would be transferred directly from the intervention suite to media appropriate 
for establishing cell lines, organoids, and/or implantation into mice. These cores 
will then be delivered to the Olive Laboratory at the address listed below: 
 
Olive Laboratory 
Columbia University Medical Center 
1130 St. Nicholas Avenue 
ICRC Room 217A 
New York, NY 10032 
 
Tumor model creation will only be performed for study patients treated and 
followed at Columbia University Medical Center. All data and specimens shared 
with the Olive Laboratory will be fully coded unless the patient also consents to 
IRB protocol AAAR4172 which allows for the collection of clinical data including 
direct identifiers (in conjunction with the establishment of personalized models).  
 
The remaining tissue should be flash frozen in liquid nitrogen for 2 minutes or 
longer until frozen solid and then stored at -80oC or below. 
 
Shipments will be sent to the Schwartz laboratory by batch shipments when 
possible. 
The 
analyzing 
laboratories 
will 
be 
notified 
by 
email 
(ga2391@columbia.edu) the day the samples are sent.   
 
For inflammatory marker immunohistochemistry studies at OSU, five, 5 micron 
section unstained slides from fresh frozen or archival material of the metastatic liver 
tissue biopsy will be transferred in bulk shipment to the Abdel-Rahman laboratory. 
The analyzing laboratory will be notified by email (Mohamed.abdel-
rahman@osumc.edu).  Fresh-frozen tissue slides will be labeled with appropriate 
identifiers and packed in dry ice in a way which will avoid breakage. Formalin-
fixed specimens may be shipped at room temperature in containers to avoid 

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breakage. 
 
The email will contain the following information: 
 
• Subject ID 
• Subject Initials 
• Date of collection  
 
All samples should be directed to the address listed on the tissue sample shipment 
form. Samples should be shipped via courier so that the package is tracked 
appropriately (specifically Federal Express or UPS).    
 
Specimens will be packed in dry ice in a way to ensure they remain frozen during 
shipment and do not break. All specimens must be shipped with appropriate 
identifiers.  The samples should be shipped for morning delivery, Monday through 
Thursday for optimal processing.   
 
Samples will be tracked through a Microsoft Excel tracker.   
  
 
11. TOXICITIES/SIDE EFFECTS 
 
Toxicity grading will be performed in accordance with NCI CTCAE, version 4.0.  For 
safety and adverse event reporting, see section 17.0. 
 
11.1 
Dose Modification 
 
Crizotinib has been studied in multiple phase I to III trials.  Side effects of crizotinib that 
are commonly seen including nausea, vomiting, and visual changes, including floaters, 
flashes of light, double vision and blurred vision.  More uncommon side effects of 
crizotinib include fatigue, constipation, altered taste, edema, elevated transaminases, 
dizziness, and anorexia.  Rare, but serious side effects include neutropenia, anemia, renal 
dysfunction, arrhythmias, hypotension, hyponatremia, and pneumonitis.  Patients will be 
monitored closely for toxicity and the dose of crizotinib may be adjusted as suggested in 
the tables below.  Up to 2 dose reductions may be performed.  Should further intolerable 
toxicity occur despite 2 dose reductions, then treatment will be discontinued.  Investigators 
should reference the current approved prescribing information for additional dose 
modifications.  
 
Dose Level 
Dose 
0 
250 mg BID 
-1 
200 mg BID 
-2 
250 mg daily 
 
 

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Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Non-hematologic, 
general (except for 
what is noted below)* 
Continue at same 
dose level. 
Continue at same 
dose level if 
tolerable. 
Withhold dose 
until toxicity is 
grade ≤ 1, then 
resume treatment 
at same dose level, 
or the next  lowest 
dose level, at the 
discretion of the 
investigator. 
Withhold dose until 
toxicity is grade ≤ 1, 
then resume 
treatment at next  
lowest dose level. 
ALT and/or total 
bilirubin elevation 
For Both: 
Continue at same 
dose level. 
For ALT: Continue 
at same dose level 
For Bili: Withhold 
dose until toxicity 
is grade ≤ 1, 
resume treatment 
at one dose level 
reduction. If 
recurs, then 
decrease one 
additional dose 
level. If no 
recurrence after 4 
weeks, dose can 
be re-escalated as 
tolerated. 
For ALT: Withhold 
dose until toxicity 
is grade ≤ 1, 
resume treatment 
at one dose level 
reduction. If 
recurs, then 
decrease one 
additional dose 
level. If no 
recurrence after 4 
weeks, dose can 
be re-escalated as 
tolerated. 
For Bili: 
Discontinue 
treatment, do not 
re-treat. 
For ALT: Withhold 
dose until toxicity is 
grade ≤ 1, resume 
treatment at one 
dose level 
reduction. If recurs, 
then decrease one 
additional dose 
level. If no 
recurrence after 4 
weeks, dose can be 
re-escalated as 
tolerated. 
For Bili: Discontinue 
treatment, do not 
re-treat. 
Left ventricular 
systolic dysfunction 
Continue at same 
dose level. 
Continue at same 
dose level. 
Discontinue 
treatment, do not 
re-treat. 
Discontinue 
treatment, do not re-
treat. 
Prolonged QTc 
Continue at same 
dose level. 
Correct 
electrolytes, 
address 
concomitant 
medications. 
Withhold until at 
baseline. Correct 
electrolytes, 
address 
concomitant meds, 
resume treatment 
at 150mg BID. If 
recurs, discontinue 
permanently. If no 
recurrence after 4 
weeks, dose can be 
escalated to 200 
mg BID. 
Discontinue 
treatment, do not 
retreat. 
Pneumonitis (in the 
absence of other 
causes of pulmonary 
infiltrates/dysfunction) 
Withhold until at 
baseline. Resume 
treatment at same 
dose. If recurs, 
discontinue 
permanently. 
Withhold until at 
baseline. Resume 
treatment with 
dose reduction of 1 
level. If recurs, 
discontinue 
Discontinue 
treatment, do not 
re-treat. 
Discontinue 
treatment, do not re-
treat. 

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permanently. 
 
Visual disturbance** 
Continue at same 
dose level. 
Consider 
ophthalmology 
evaluation. 
Continue at same 
dose level. 
Consider 
ophthalmology 
evaluation. 
Withhold until at 
baseline. Refer for 
ophthalmology 
evaluation. 
Resume at 200 mg 
BID.  
Discontinue 
treatment, do not re-
treat. Refer for 
ophthalmology 
evaluation. 
Hematologic 
(excluding 
lymphopenia***) 
Continue at same 
dose level. 
Continue at same 
dose level. 
Withhold until 
toxicity is grade ≤ 
2. Can resume 
treatment at same 
dose or reduce 
dose at 200 mg 
BID, based on 
treating 
physician’s 
discretion. 
Withhold until 
toxicity is grade ≤ 2. 
Resume treatment at 
200 mg BID.  
*Grade 4 hyperuricemia or grade 3 hypophosphatemia without symptoms can continue with interruption at the 
discretion of investigator. Nausea, vomiting or diarrhea must persist at grade 3/4 despite maximal medical therapy, to 
require dose modification. 
** Please see text below regarding reporting requirements for visual disturbances. 
***Patients with isolated grade 3/4 lymphopenia, may continue study treatment without interruption. 
 
11.2 
Reporting Requirements for Visual Disturbances 
 
The U.S. FDA has asked Pfizer to conduct a non-interventional enhanced 
pharmacovigilance study titled “A Descriptive Study of Potential Sight Threatening/Severe 
Visual Loss Following Exposure to XALKORI” (Study A8081062). The objective of this 
study is to evaluate risk factors for, and outcomes of, PST or SVL adverse events among 
patients with cancer being treated with crizotinib. The study is due to commence on March 
31, 2016 and end on March 31, 2021. 
 
In all crizotinib-treated patients, Grade ≥2 PST (except for Visual field defect, for which 
Grade ≥3 is the standard) or SVL should be treated as Serious Adverse Events, regardless 
of relatedness to study drug. The following MEDdra preferred terms are considered 
indicative of a PST or SVL event:  Amaurosis, Amaurosis fugax, Blindness, Blindness 
cortical, Blindness day, Blindness night, Blindness transient, Blindness unilateral, 
Hemianopia, Hemianopia heteronymous, Hemianopia homonymous, Optic atrophy, Optic 
ischaemic neuropathy, Optic nerve disorder, Optic neuropathy, Quadranopia, Retinopathy, 
Sudden visual (or vision) loss, Toxic optic neuropathy, Tunnel vision, Visual cortex 
atrophy, Visual field defect, Visual pathway disorder, Retinal oedema, Retinal detachment, 
Maculopathy, Iritis, Uveitis, Visual field test abnormal. The occurrence of Grade ≥2 of any 
of these events should be treated as a SAE, except for Visual field defect, for which only 
Grade ≥3 should be treated as a SAE. Grade 2 events are considered to be PST and Grade 
≥3 events are considered to be SVL. 
 
These visual SAEs must be reported within 24 hours of you or your staff member becoming 
aware of them to the CUMC study team as outlined in Section 17 for CUMC patients and 

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in Appendix D for participating centers.  Pfizer will then be immediately notified by the 
CUMC research team. After the SAE is to Pfizer, a PST/SVL Data Capture Aid (DCA) 
which contains relevant clinical and diagnostic questions, including information from any 
ophthalmic examinations, will also be requested. Pfizer Local Drug Safety Unit will 
contact you to complete the form.  If you have any questions regarding SAE information 
for PST or SVL events, please contact the study PI, Robin Wiltshire at 
robin.wiltshire@pfizer.com, or Elizabeth Kim at elizabeth.kim@pfizer.com. 
 
 
12. CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Imaging studies will be conducted to evaluate tumor recurrence as outlined in the study 
calendar.  Additional imaging studies may be performed at the discretion of the 
investigator.  The same method(s) of tumor assessment and the same technique(s) should 
be used at each radiologic evaluation to confirm that there are no new lesions or to identify 
and follow any new lesions.  At the time of a patient’s enrollment in this study, there should 
be no current radiological evidence of disease.  Any clinical or radiographic evidence of 
recurrence is considered evidence of progression.  
 
When there is radiologic evidence of recurrence, pathologic confirmation should be 
obtained whenever possible.  Other imaging studies may be used in conjunction with the 
study mandated imaging to help the principal investigator determine whether or not there 
is true disease progression, although these scans should not replace CT imaging in terms 
of disease follow-up for this study.  If biopsy is not possible and there are indeterminate 
radiographic findings, repeat imaging studies at a 4 week interval may be performed to 
confirm recurrent disease.  
 
13. CRITERIA FOR REMOVAL FROM STUDY 
 
Patients may withdraw from the study at any time.  Patients who discontinue treatment 
early should return within 30 days of the last dose of the study drugs for a follow-up 
evaluation.  Any assessments listed for the final visit in the study calendar will be 
performed at that time. 
 
Other reasons for study discontinuation include, but are not limited to: 
 
• Non-compliance with the defined treatment plan 
• Investigator’s decision based on patient’s best interest 
• Withdrawal of consent 
• Severe, unexpected toxicities/side effects 
• Lost to follow-up 
• Completion of study requirements after being followed for at least 32 months for 
survival 
 

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14. BIOSTATISTICS 
 
We anticipate a total accrual period of 1 to 2 years (accrual rate of 1 to 2 patients per month 
on the treatment portion of the study) and additional follow-up after the accrual interval of 
32 months.  Prior data indicate that 40% of all uveal melanoma patients have Class II, high 
risk tumors. The median relapse free survival of this group of high-risk patients is 
approximately 32 months.  We hypothesize that the addition of crizotinib will increase the 
32-month RFS by 25%.  Thus, a 32 month relapse free rate of 50%  would be considered 
not promising and a 32 month relapse free rate of 75% or greater would be considered 
promising.  A single stage design based on a binomial probability estimate will be utilized 
with an alpha of 0.05 and a beta less than of 0.11.  This design will require 75 patients to 
be screened to treat 30 patients.  At the end of the study, if at least 20 out of 30 patients are 
free of distant relapse at 32 months, this adjuvant treatment with crizotinib will be 
considered worthy of further study. This design yields a 90% probability of a positive result 
if the relapse free rate at 32 months is at least 75% and a 95% probability of a negative 
result if the true relapse free rate is 50% at 32 months. In order to account for an estimated 
5% dropout rate, 34 patients will be accrued to this study.  The first 30 patients who relapse 
by 32 months or have been followed for 30 months will be included in the analysis.  
 
The median, 1-year, 2-year, and 3-year RFS rates will be assessed.  RFS rate will be defined 
as the percentage of patients who do not experience any new tumor growth at any site on 
the body distant from the primary site or death from any cause from the time of primary 
therapy of the uveal melanoma (date of enucleation or day of removal of the radioactive 
plaque) to the end of the relevant time point. All patients who do not withdraw consent will 
be contacted for a minimum of three years from start of study treatment for survival data. 
 
Overall survival (OS) will be defined as the time from treatment start to date of death or 
last followup and estimated using Kaplan-Meier methodology.  Disease-specific survival 
(DSS) is defined as the time from treatment start to death due to disease or last followup. 
Patients who die from other causes will be censored. 
 
The safety and tolerability of crizotinib will be determined by reported AEs, physical 
examinations, and laboratory tests. Frequencies of toxicities by grade according to NCI 
CTC will be tabulated. 
 
The FACT-M total score will be computed as sum of all 27 item scores.  Four subscale 
scores will be derived from the 27 items: 
 
• 
Physical Well-being (PWB) 
• 
Social Well-being (SWB) 
• 
Emotional Well-being (EWB) 
• 
Functional Well-being (FWB) 
From the additional 16 items of the FACT-M questionnaire, a total  Melanoma Subscale 
(MS) score will be derived in the following manner: MS = (sum of non-missing item 

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scores) multiplied by (16 divided by the number of non-missing items).  The total and 
domain score will be summarized using descriptive statistics (e.g., N, mean, SE, median, 
minimum, maximum) for each assessment time. 
 
If this clinical trial meets its efficacy endpoint, ≤10 patients will experience disease 
recurrent by 32 months.  Conservatively assuming that 20% of patients will have 
insufficient material for testing, we will have 8 matched primary/metastatic sample sets for 
comparison. More samples will be available if the recurrence rate is greater.  Given the 
potentially limited number of matched samples available, this analysis will be hypothesis 
generating for the development of future studies with larger sample sizes.  We will analyze 
each matched pair for differential gene expression and expression of each gene of interest 
in all primary and metastatic specimens will be summarized as means +/- standard errors 
of the means, with statistically significant differences between control and tumor samples 
assessed by paired t-test. 
 
 

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All patients who receive at least 1 cycle of crizotinib will be considered evaluable for the primary 
endpoint. Those who discontinue study before 1 cycle is complete will be considered replaceable. 
 
15. RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.1 
CUMC Research Participant Registration  
 
Confirm eligibility as defined in the section entitled Criteria for Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures, along with applicable institutional policies and federal regulations. 
 
Only Investigators/Research personnel properly trained and delegated to consent subjects 
for this protocol will participate in the consenting process. Furthermore, properly 
delegated/trained Physician Investigators (e.g., MD, MD PhD) are required to sign/verify 
a protocol specific Eligibility Checklist for each subject enrolled on the study, in addition 
to providing the relevant source documentation confirmation subject eligibility. 
 
All participants must be centrally registered through the Central Registration Office 
within Herbert Irving Comprehensive Cancer Center at CUMC prior to initiation of 
study treatment. 
 
Registration hours are available Monday through Friday from 9:00am – 5:00pm EST 
(excluding holidays and weekends). Same day patient registrations (and after hour 
registrations) will be accommodated on a case by case basis provided that the study team 
has expressed all time sensitive registration concerns/cases in a timely manner to the 
Central Registration Office.  
 
CPDM Central Registration Procedures: 
Within 48 hours of obtaining consent (excluding holidays and weekends), a 
completed/signed IRB approved informed consent HIPAA form, and demographics forms 
must be submitted to the CPDM Central Registration Office via an email to 
CPDMRegistration@columbia.edu or fax to 212.305.5292, with the subject line 
“AAAO8010 Pending Subject Registration Request (PHI)”.  Upon receipt, applicable 
subject information as well as a “pending eligibility” status will be entered into HICCC’s 
institutional database.  This status will remain until further source documentation is made 
available to confirm overall patient eligibility. Required materials for all pending 
registration submissions are as follows: 
 
• 
Completed/signed IRB approved/stamped Informed Consent Forms, including 
additional study ICFs (e.g., tissue, DNA, etc.), as applicable. 
• 
The completed/signed IRB approved HIPAA Authorization form 

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• 
Completed/signed CPDM ICF checklist 
• 
Completed/signed HICCC personal census form 
• 
Completed/signed CPDM Demographics Note to File 
In order to confirm eligibility status, Investigators/designees (e.g., study specific Clinical 
Research Coordinator/Research Nurse, etc.) must submit the following documentation to 
the Central Registration Office via email or fax: 
 
• 
The completed/signed study specific Eligibility Checklist  (signed by an Physician 
level Investigator) 
• 
Copies of source documentation necessary for each item to be verified on the 
CPDM specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (e.g., hematology, serum 
chemistry, pregnancy test when applicable, MRI reports, CT/bone scans, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) or other appropriate medical records capturing the consent 
process information, along with providing source documentation of any other items needed 
for screening/eligibility that are not captured in other source document forms (e.g., positive 
investigator statements of unique eligibility items not captured via other direct source 
documentation, concomitant medication lists, etc.) 
o Protocol deviation/waiver approvals (if applicable) 
• 
Please note: subject line of email or fax should include the following: “AAAO8010 
Complete Subject Registration Request (PHI)”. 
Upon receipt of the above mentioned documentation, participant eligibility information 
will be verified by a qualified Central Registration Registrar. If any questions arise during 
the review process, queries in the form of emails will be addressed to the applicable study 
team personnel for clarification prior to enrollment. .All applicable finalized 
registration/eligibility information will then be entered into HICCC’s institutional CTMS 
database by the Central Registration Registrar.  Upon completion, an official subject 
registration notification email will be sent to the PI/research team which will include 
eligibility/enrollment status, as well as subject ID information.  Protocol therapy may not 
be initiated prior to receipt of this notification from the Central Registration Office. 
 
All screen fail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration 
office in a manner analogous to the procedures noted above. Applicable source 
documentation will be required within the corresponding submissions. 
 

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15.2 
Randomization 
 
N/A 
 
 
16. DATA MANAGEMENT ISSUES 
 
16.1 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
18.0 (Adverse Events: List and Reporting Requirements).  The Data Safety Monitoring 
Plan is described in Section 16.1.3. 
 
16.1.1 Data Collection 
 
The Herbert Irving Comprehensive Cancer Center has an electronic clinical trials 
and data management system (CTMS) that will be used for data collection. CRFs 
for the study will be built into the CTMS for data entry. The system has full auditing 
capabilities which is web-based and housed on a server in a fully HIPAA compliant 
server room with restricted access and video camera monitoring.  All users must 
login with their own application username and password.  Users off campus must 
first access the Virtual Private Network with their assigned campus username and 
password and then use their application credentials.  Users are only able to see study 
information if they are indicated as study personnel in our electronic IRB system. 
Users are limited to access based on the role assigned in their corresponding 
protocol.  Subject data is entered directly into the system, which (in the case of 
Columbia subjects) confirms the correct identity of patients via an interface with 
the electronic medical patient index.  Staff with the appropriate IRB defined roles 
can run reports within the system for reporting purposes. 
 
16.1.2 Data Reporting 
 
Case Report Forms will be completed for each subject enrolled into the clinical 
study through the CTMS. It is the investigator’s responsibility for ensuring that all 
clinical and laboratory data entered on the corresponding CRFs are complete, 
accurate and authentic. 
 
16.1.3 Data and Safety Monitoring Committee 
 
The NCI-approved Data Safety and Monitoring Committee (DSMC) of the Herbert 
Irving Comprehensive Cancer Center (HICCC) will monitor every subject who 
receives treatment on this protocol for toxicity. This protocol will adhere to the 
policies of the currently approved HICCC Data and Safety Monitoring Plan 
(DSMP), which is in accordance with NCI and CUMC-IRB policy and guidelines.  
The committee is chair is appointed by the HICCC Director. The committee 

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consists of HICCC faculty and staff with expertise in oncology, research pharmacy, 
research nursing, and data management. The DSMC convenes twice a month to 
review patient safety and the conduct of the trial. The PI will submit data and safety 
monitoring reports to the DSMC at a frequency to be determined by the DSMC 
based on risk to the subjects. 
 
At the time of renewal, the study team will submit the most recent DSMC approval 
letter for safety review to the CUMC IRB. Any modifications that are required by 
the DSMC to ensure patient safety will be submitted to the IRB. All protocol 
deviations, violations, and eligibility waivers will be submitted to and approved by 
the DSMC prior to being reported to the IRB. All study data reviewed and discussed 
during these meetings will be kept confidential.  
 
For multicenter research, the principal investigator will assure that there is a 
mechanism in place to distribute the report to all participating investigators for 
submission to their local IRB.  The report will document that a review of data and 
outcomes across all centers took place on a given date.  It will summarize the 
DSMC’s review of the cumulative toxicities reported from all participating sites 
without specific disclosure by treatment arm.  It will also inform site investigators 
of the study the DSMC’s conclusion with respect to progress or need for 
modification of the protocol.   
 
16.1.4 Quality Control and Quality Assurance 
 
Independent monitoring of the clinical study for protocol and GCP compliance will 
be conducted periodically by the CPDM Compliance Core on behalf of the HICCC 
DSMC.  Additionally, the Compliance Oversight Committee of the IRB at 
Columbia University Medical Center may audit the study at any time per 
institutional policies and procedures. The investigator-sponsor and Columbia 
University Medical Center will permit direct access of the study monitors and 
appropriate regulatory authorities to the study data and to the corresponding source 
data and documents to verify the accuracy of this data. 
 
A risk-based approach will be used by the Compliance Core to determine the 
frequency, number of subject charts, and data elements to be monitored. The 
Compliance Coordinator will review the study status and summarize enrollment, 
toxicities, SAEs/UPs, dose escalation, statistical endpoints (e.g., stopping rules), 
etc. for the full DSMC membership at the regularly scheduled meetings.   
 
16.1.4 Internal On-site Monitoring: 
 
• 
Initial, recurrent, and close-out on-site monitoring visits will also be 
conducted at remote clinical sites, as appropriate/feasible. Other sites will have 
monitoring performed remotely (see below for further details). 
 

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• 
The 
Compliance 
Coordinator 
will 
communicate 
with 
the 
site 
coordinator/Site Principle Investigator to schedule the monitoring visit and 
arrange for access to study materials and documentation. 
 
• 
The assigned Compliance Coordinator will monitor IIT trials within 1 
month after the first subject is enrolled and throughout the life of the study 
to ensure that the study is being conducted in accordance with the protocol, 
GCP, applicable federal and local regulations, and per all applicable SOPs. 
The Compliance Coordinator is responsible to notify the PI and 
CRNP/CRN/CRC of upcoming monitor visits and convey what information 
and documentation will be required for the visit(s).  The Compliance 
Coordinator is responsible for verifying that informed consent is properly 
obtained, eligibility is met (via the central registration process), and all 
study procedures are conducted according to the study protocol. The 
Compliance Coordinator will also verify that the data reported in the CRF’s 
accurately reflect source documents, that all toxicities have been reported 
to date, and that all SAE’s/UPs/deviations/violations have been reported 
according to local IRB and HICCC DSMC requirements. The Compliance 
Coordinator will issue queries and ensure resolution in a timely and efficient 
manner.  The Compliance Coordinator will also monitor for applicable 
regulatory compliance and research pharmacy compliance (if applicable) 
and communicate any deficiencies as appropriate. 
 
16.1.6 Confidentiality 
 
Information about study subjects will be kept confidential and managed according 
to the requirements of the Health Insurance Portability and Accountability Act 
(HIPAA).  Those regulations require a signed subject authorization informing the 
subject of the following:  
 
• 
What protected health information (PHI) will be collected from subjects in 
this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their 
PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior 
to the revocation of subject authorization.  For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission 
to collect at least vital status (e.g., that the subject is alive) at the end of their 
scheduled study period. 

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The subject binders will be maintained with in the CPDM offices, a secured floor 
within the Herbert Irving Pavilion and only the investigator and study staff will 
have access to the file. 
 
16.1.7 Source Documents 
 
Source data is all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of 
the trial.  Source data are contained in source documents   Examples of these 
original documents, and data records include: hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject 
files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
 
16.1.8 Records Retention 
 
Records relating to a specific research activity, including research records collected 
by investigators, must be maintained for at least three years after completion of the 
research (45 CFR 46.115(b); 21 CFR 56.115(b); 21 CFR 312.62). This minimum 
retention period applies whether or not any subjects were enrolled in the study. 
 
If the research is FDA regulated, records should be retained for at least two years 
after approval of the investigational agent by FDA; if it is not approved, records 
should be retained at least two years after the study is terminated and FDA is 
notified (note the additional requirement below for clinical research studies);  
Clinical records, including consent forms that document clinical intervention or 
clinical diagnostic procedure research-related procedures, must be retained in 
medical records by the institution for at least seven years, per CUMC and NYP 
policy which is based on state law. 
 
 
17. SERIOUS ADVERSE EVENT (SAE) REPORTING FOR CUMC 
 
Adverse  events  
 
Investigational Agent:  Include a comprehensive list of all reported adverse events and any 
potential risks (such as the toxicities seen with another agent of the same class or risks seen 
in animals administered this agent) as provided by the manufacturer. 
 
Adverse Event List(s) for Other Agent(s):  For each commercial agent, please provide a 
list of those adverse events most likely to occur on this study, and refer the reader to the 

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package insert(s) for the comprehensive list of adverse events. 
 
17.1 
Definitions 
 
Adverse Event: 
An adverse event (AE) is any untoward or unfavorable medical occurrence in a 
human subject, including abnormal sign, symptom or disease, temporally 
associated with the subject’s participation in research, whether or not considered 
related to the subject’s participation in the research. Abnormal results of diagnostic 
procedures are considered to be adverse events if the abnormality: 
 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event: 
Adverse events are classified as serious or non-serious.  A serious adverse event is 
any AE that is:  
 
• fatal 
• life-threatening 
• requires inpatient hospitalization/prolongation of existing hospitalation, 
unless:  
o routine treatment  or monitoring of the studied indication, not 
associated with any deterioration in condiction (procedures such as 
central line placements, paracentesis, pain control) 
o elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since 
the start of study drug 
o treatment on an emergency outpatient basis for an event not 
fulfilling any of the definitions of an SAE given above/below and 
not resulting in hospital administrations 
o social reasons and respite care in the absence of any deterioration in 
the patient’s general condiction 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, 
but are clearly of major clinical significance.   They may jeopardize the subject, 
and may require intervention to prevent one of the other serious outcomes noted 
above.  For example, drug overdose or abuse, a seizure that did not result in in-

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patient hospitalization or intensive treatment of bronchospasm in an emergency 
department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious events should be 
regarded as non-serious adverse events.  
 
Unanticipated Problem: 
An unanticipated problem is any incident, experience or outcome involving risks 
to subjects or others in any human subjects research that meets all of the following 
criteria: 
• Unexpected (in terms of nature, severity or frequency) given (a) the research 
procedures that are described in the IRB-approval protocol and informed consent 
document, and (b) the characteristics of the subject population being studied; 
• Related or possibly related to participation in such research (e.g., there is a 
reasonable possibility that the incident, experience or outcome may have been 
caused by the procedures involved in such research); and  
• Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic or social harm) than was 
previously known or recognized.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined 
as the period from the initiation of any study procedures (e.g., after the first dose of 
study treatment) to the end of the study treatment (e.g., last dose of study treatment) 
and/or follow-up.   
 
Baseline/Preexisting Condition 
A baseline/preexisting condition is one that is present at the start of the study. A 
preexisting condition should be recorded as an adverse event if the frequency, 
intensity, or if the character of the condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a 
preexisting condition.  At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the 
events are resolved, the subject is lost to follow-up, or the adverse event is 
otherwise explained.  At the last scheduled visit, the investigator should instruct 
each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this 
study.   
 

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Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any 
one of the following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm 
the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management (e.g., change 
of dose, discontinuation of the drug, more frequent follow-up assessments, 
further diagnostic investigation, etc.). 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization 
should be documented and reported as a serious adverse event unless specifically 
instructed otherwise in this protocol.  Any condition responsible for surgery should 
be documented as an adverse event if the condition meets the criteria for an adverse 
event.  
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for a preexisting condition.  Surgery should not be 
reported as an outcome of an adverse event if the purpose of the surgery was 
elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease 
of the study, unless it is a worsening or increase in frequency of hospital 
admissions as judged by the clinical investigator. 
 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information on 
all adverse events should be recorded immediately in the source document, and also 
in the appropriate adverse event module of the case report form (CRF).  All clearly 
related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical 
course of each event should be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause.  
Serious adverse events that are still ongoing at the end of the study period must be 
followed up to determine the final outcome.  Any serious adverse event that occurs 
after the study period and is considered to be possibly related to the study treatment 
or study participation should be recorded and reported immediately. 
 

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17.2 
Reporting of Serious Adverse Events 
 
17.2.1     IRB Notification by Sponsor-Investigator 
 
Reports of all events (including follow-up information) that meet the definition of an 
unanticipated problem posing risk to subjects or others must be submitted to the IRB within 
one week (5 business days) following the occurrence of the unanticipated problem or the 
principal investigator’s acquiring knowledge of the unanticipated problem  in accordance 
with IRB policy. Additionally, the sponsor-investigator will submit a summary of all 
Unanticipated problems that occurred since the beginning of the study at the time of 
continuing review. Copies of each report and documentation of IRB notification and receipt 
will be kept in the Regulatory binder. 
 
17.2.2 DSMC Reporting by the Sponsor Investigator 
 
Serious adverse events not constituting unanticipated problems are to be reported to the 
HICCC DSMC. Reporting should occur within 24 hours of knowledge of the SAE 
occurring at our institution or affiliate sites. 
 
17.2.3 Reporting to Drug Manufacturer by Sponsor-Investigator 
 
The Sponsor-Investigator will report to investigational agent manufacturer any serious 
adverse events within 24 hours of becoming aware of it on the Pfizer Investigator-Initiated 
Research Serious Adverse Event (IIR SAE) Form/HICCC DSMC SAE Form and 
submitting with the Pfizer-provided Reportable Events Fax Cover Sheet, so that these 
reports can be evaluated and included in the Investigator’s Brochure and for IND 
safety submissions per regulations. Reporting will occur by sending the reporting 
form along with any additional documentation sent to the regulatory authorities. 
 
If the SAE is fatal or life-threatening (i.e., causes an immediate risk of death)- regardless 
of the extent of the available information, the SAE must be reported immediately upon 
awareness.  
 
SAEs will be reported to Pfizer from the time the subject receives the first dose of study 
drug through and including 28 calendar days after last administration of the study drug. 
Any SAEs that occur after completion of the reporting time period as defined above are 
reportable to Pfizer if the Investigator suspects a causal relationship between the Pfizer 
product and the SAE.  
 
 
 
18. INFORMED CONSENT PROCEDURES 
 
This study is to be conducted in accordance with applicable government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 

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study conduct.  The decision of the IRB concerning the conduct of the study will be made in 
writing to the investigator and a copy of this decision will be obtained before commencement 
of this study.  
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in 
this study. This consent form will be submitted with the protocol for review and approval by 
the IRB for the study.  The formal consent of a subject, using the IRB-approved consent form, 
must be obtained before that subject is submitted to any study procedure.  This consent form 
must be signed by the subject or legally acceptable surrogate, as outlined in the IRB approved 
protocol, and the investigator-designated research professional obtaining the consent.  
 

 
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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: 
 
SUBSTANCES PROHIBITED DURING CRIZOTINIB ADMINISTRATION 
 
CYP3A4 Inhibitors: 
 itraconazole, ketoconazole, miconazole, voriconazole 
 amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir 
 ciprofloxacin, clarithromycin, diclofenac, doxycycline, enoxacin, imatinib, isoniazid, 
ketamine nefazodone, nicardipine, propofol, quinidine, telithromycin 
 
CYP3A4 Inducers: 
 aminoglutethimide, primidone, rifabutin, rifampin, St. John’s wort 
 carbamazepine, nevirapine, oxcarbazepine, rifapentine 
 fosphenytoin, pentobarbital, phenobarbital, phenytoin 
 
Agents with Proarrhythmic Potential 
 quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, dofetilide 
 erythromycins, clarithromycin 
 chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide 
 cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, 
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine 
 

 
APPENDIX C: 
 
PARTIAL LIST OF SUPPLEMENTS PROHIBITED DURING CRIZOTINIB 
THERAPY 
• Agaricus 
• Aloe Vera 
• Black Cohosh 
• Chrysanthemum 
• Echinacea 
• Elderberry 
• Epimedium 
• Garlic 
• Ginseng 
• Goldenseal 
• Grape Seed extract 
• Green Tea extract 
• Guggul 
• Hawthorn 
• Hoodia 
• Licorice 
• Milk Thistle 
• Mistletoe 
• Noni 
• Nigella sativa 
• Quercetin 
• Resveratrol 
• Rhodiola 
• Sho-saiko-to 
• St. John’s Wort 
• Turmeric 
• Valerian 
• Check with your doctor before taking any over the counter or other dietary 
supplements. 
 
 
 
 
 
 
 

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APPENDIX D: 
 
GUIDELINES FOR AFFILIATE INSTITUTIONS IN MULTICENTER STUDIES 
 
1. Multi-site Communication: 
The CPDM Office at CUMC provides administration, data management, and 
organizational support for the affiliate sites in the conduct of a multicenter clinical trial.  
The CPDM Office will coordinate, at minimum, regularly scheduled conference calls with 
affiliate sites.  
The following issues will be discussed, as appropriate:  
• Enrollment information  
• Cohort updates (e.g., DLTs) 
• Adverse events (e.g., new adverse events and updates on unresolved adverse events 
and new safety information) 
• Protocol violations 
• Other issues affecting the conduct of the study 
 
2. New Protocol Distribution, IRB Submission, Modifications, and Annual Renewals 
 
• Protocol specific documents are distributed to affiliate sites once CUMC IRB 
approval has been obtained.  
• The affiliate site must submit a draft of site specific revisions to protocol and/or 
consent form documents for review and approval by the sponsor-investigator prior to 
submission to the local IRB. Draft documents should be sent to the study specific 
email address. The site will be provided confirmation that they are approved to submit 
to their local IRB.  
• Protocol amendments must be approved by the affiliate site’s local IRB within 90 
days of distribution to the site by the sponsor-investigator.  
 
3. Regulatory Documents: 
Prior to Site Initiation: 
Sponsor-Investigator will ensure that proper requests are made of sites and that the 
following documentation is collected, prior to the initiation of an affiliate site.   
 
• CV of PI, Co-I’s and other research staff listed on FDA 1572 (signed and dated copy 
within 2 years) 
• Medical Licenses of PI and Co-I’s (current copy) 
• Human subjects training certificates for PI and Co-I’s 
• CLIA/Laboratory  Certifications for Local Laboratories listed on FDA 1572 
• Local Laboratory Director’s CV and License 
• Local Laboratory Reference Ranges  
• IRB roster or statement of compliance 
• FDA Form 1572, if applicable (wet ink originals required) 

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• Financial Disclosure forms for all members listed on FDA 1572 (wet ink originals 
required) 
 
Ongoing Regulatory Documentation:  Sponsor-Investigator will ensure that proper 
requests are made of sites and that the following documentation is collected throughout the 
course of the study. 
 
• IRB approval letters for all protocol modifications and all renewals 
• IRB-approved consent forms 
• Current IRB roster, if statement of compliance is not provided as part of site initiation  
• FDA Form 1572, if applicable as updates are required 
• Updated investigator and site information where relevant (e.g., CV, medical licensure 
and Financial Disclosure for new sub-investigator, local laboratory information) 
 
Regulatory documents may be sent to AAAO8010@columbia.edu or to the following 
address if wet ink originals are required: 
 
Clinical Protocol & Data Management Office 
161 Fort Washington Ave. 
Herbert Irving Pavilion 
Mezzanine Level, M-203 
New York, NY 10032 
 
4. Site activation 
Columbia University will schedule a site initiation visit once IRB approval has been 
submitted from the affiliate site.  
 
5. Central Registration Procedures- Affiliate Institution Research Participant 
Registration Process:  
All Affiliate Institutions must register subjects with the coordinating center (CUMC) prior 
to any administration of study drug/intervention/local institution registration.  Please see 
instructions below: 
 
1. Within 48 hours of obtaining consent (excluding holidays and weekends), the 
Affiliate Institution CRN and/or CRC is required to submit the following 
documents to the coordinating center’s designee (CUMC’s study specific Clinical 
Research Coordinator or Clinical Research Nurse).  The coordinating center’s 
designee will review the documents for accurateness, and subsequently submit the 
documents to the CPDM Central Registration Office via email at 
AAAO8010@columbia.edu (or via fax at 212.305.5292), with a request to register 
the patient “pending eligibility.” The title of the email should read, “AAAO8010 
Pending Subject Registration Request (PHI)”.  The following documents should be 
submitted with the pending registration request, as applicable: 
 

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a. Redacted Completed/signed IRB approved/stamped Informed Consent 
Forms, including additional study ICFs (e.g., tissue, DNA, etc.), as 
applicable 
b. Redacted Signed HIPAA (or institutional equivalent) 
c. MCT CPDM Velos Note to File form  
 
2. The Affiliate Institution’s investigator/research nurse/data manager/coordinator must 
contact the coordinating center’s designee (CUMC’s study specific Clinical Research 
Coordinator or Clinical Research Nurse) via telephone or email to communicate the 
following: 
• Notify of pending registration request  
• Confirm method of registration request submission (email or fax) 
• Communicate expected time-line of registration request submission (e.g., same 
day, next day, within the hour, etc.) 
 
3. To complete registration, the Affiliate Institution’s investigator/research nurse/data 
manager/coordinator should then submit the following documents to the CUMC study 
specific designee: 
• A signed Affiliate Site Eligibility Checklist (signed by the investigator) 
• Copies of redacted source documentation necessary for each item to be verified on 
the CUMC specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (e.g., hematology, 
serum chemistry, pregnancy test when applicable, MRI reports, CT/bone 
scans, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) capturing the consent process information, along with 
providing source documentation of any other items needed for 
screening/eligibility that are not captured in other source document forms. 
(e.g., positive investigator statements of unique eligibility items not 
captured via other direct source documentation, concomitant medication 
lists, etc.) 
o Protocol deviation/waiver approvals (if applicable) 
• Please note: subject line of email or fax should include the following: “AAAO8010 
Complete Subject Registration Request (PHI)”. 
 
4. Upon receipt of the above mentioned documents, the designated study specific 
Clinical Research Coordinator will review all documents and verify patient eligibility.  
If any questions arise during the review process, queries in the form of emails will be 
addressed to the applicable affiliate site study team personnel for clarification prior to 
enrollment.  Upon verification, the CUMC study specific designee will then forward 
all documents to the CPDM Central Registration Office for central registration (as 
described above). The CPDM Central Registration Registrar will review all applicable 
documents and communicate to the CUMC study specific designee in order to clarify 
any items.  The CUMC study specific designee will communicate with the applicable 
site study team personnel for additional clarifications necessary prior to enrollment. 

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5. Upon receipt of the subject registration notification email, the CUMC study specific 
designee will forward the notification email (which will include the study specific 
patient ID) to the affiliate site’s Principal Investigator, Consenting Professional, and 
applicable research personnel.  This notification should be filed in the patient research 
binder accordingly. Protocol therapy may not be initiated prior to receipt of this 
notification from the coordinating center. 
 
6. All screenfail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration 
Office in a manner analogous to the procedures noted above. Applicable source 
documentation will be required within the corresponding submissions. 
 
6. Protocol Deviation/Subject Waiver request for Affiliate Sites: 
The Affiliate site MUST submit a prospective deviation request to the CUMC lead PI for 
review and submission to the HICCC DSMC and CUMC IRB. Approvals must be obtained 
from all entities prior to implementation at the Affiliate site.  If a prospective protocol 
deviation request is submitted for review (from an Affiliate site), the PI/site memo(s), 
HICCC DSMC approval(s) and correspondence and CUMC IRB eligibility deviation 
approval letter(s) should be forwarded to the Affiliate site for documentation. The Affiliate 
site is also required to obtain prospective local IRB approval as per institutional 
policies/procedures prior to implementing the proposed deviation and registering/enrolling 
the subject via CUMC Central Registration. All documents and determinations must be 
clearly documented in the study subject’s medical record, research chart and regulatory 
binder, as described. 
 
7. Guidelines for Affiliate Site Monitoring  
 
On-Site MCT Monitoring:  
 
1. Initial, recurrent, and close-out on-site monitoring visits will also be conducted at 
Affiliate sites, as appropriate/feasible. Other sites will have monitoring performed 
remotely (see below for further details). 
 
a. The study Monitoring Visit Log will be completed and signed by the monitor 
and the PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
 
2. The Compliance Coordinator will communicate with the Affiliate site coordinator/Site 
Principle Investigator to schedule the monitoring visit and arrange for access to study 
materials and documentation. 
 
3. The Compliance Coordinator will monitor IIT trials within 1 month after the first 
subject is enrolled at the Affiliate site and throughout the life of the study to ensure that 
the study is being conducted in accordance with the protocol, GCP, applicable federal 
and local regulations, and per all applicable SOPs. The Compliance Coordinator is 

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responsible to notify the participating site PI and CRNP/CRN/CRC of upcoming 
monitor visits and convey what information and documentation will be required for the 
visit(s).  The Compliance Coordinator is responsible for verifying that informed 
consent is properly obtained, eligibility is met (via the central registration process), and 
all study procedures are conducted according to the study protocol. The Compliance 
Coordinator will also verify that the data reported in the CRF’s accurately reflect source 
documents, that all toxicities have been reported to date, and that all 
SAE’s/UPs/deviations/violations have been reported according to Coordinating Center, 
local IRB and HICCC DSMC requirements. The Compliance Coordinator will issue 
queries and ensure resolution in a timely and efficient manner.  The Compliance 
Coordinator will also monitor for applicable regulatory compliance and research 
pharmacy compliance (if applicable) and communicate any deficiencies as appropriate. 
 
4. An SIV (or) teleconference will be scheduled and conducted prior to study drug being 
made available (if applicable) and before any subjects are enrolled on a study at the 
Affiliate site. 
 
MCT Remote Monitoring:  
 
1. When necessary (due to logistical constraints), Affiliate sites will be monitored 
remotely by a designated Compliance Coordinator. Sites will be informed of this 
remote monitoring process on a site by site basis. 
 
2. Affiliate sites will be monitored by the Compliance Coordinator on both a regulatory 
level, as well as a clinical data/source documentation review level. 
 
3. Redacted source documents (applicable to supporting the protocol specific CRF data 
requirements) will be sent to the designated Compliance Coordinator via fax or secure 
email for all subjects enrolled at Affiliate sites. Timelines for submission procedures 
will be defined on a case by case basis.   
 
4. The Compliance Coordinator will review all submitted redacted source documents 
against the data entered on the protocol specific CRFs. The Compliance Coordinator 
will issue queries when/if necessary. 
 
5. The Affiliate site research staff will respond to queries within 30 days. If queries remain 
outstanding, the Compliance Coordinator will send a delinquent query reminder for the 
outstanding items. 
 
6. The remote monitoring procedures will include review of applicable redacted source 
documentation and supporting applicable documents to determine compliance 
regarding: 
 
a. Informed consent procedures 
b. Eligibility criteria 
c. Protocol specific treatment compliance 

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d. Protocol specific toxicity/outcome documentation/compliance 
e. Protocol specific schedule of events (e.g., baseline visits, pre-treatment, on 
study, follow-up) 
f. Participating site IRB documents (e.g., IRB amendment approvals, annual 
renewals, SAE/UP submissions, violation/deviation submissions, INDSR 
submissions, etc). 
g. Required specimen submissions (e.g., tissue specimens, research blood 
specimens, etc.) 
h. Pharmacy accountability records 
i. Adherence to the CRF submission timeframes to CUMC (within the protocol 
specified timeframes) 
 
7. Affiliate site remote monitoring reports will be sent to the lead PI, HICCC DSMC, and 
Affiliate sites after each remote monitoring review. Reports will include information 
regarding data submission timeliness/accuracy, protocol adherence items, query 
resolution status, regulatory status, and overall Affiliate site performance. These 
reports will be generated by the Compliance Coordinator and reviewed with the 
Compliance Core Manager prior to dissemination. 
 
8. Dose Level Determinations: 
 
The sponsor-investigator will review enrollment for each dose level cohort during the 
regularly scheduled conference call with the affiliate sites.  
 
The dose level for newly enrolled subjects will be determined by the study statistician upon 
notification that a subject has signed informed consent to participate in the study. The 
assigned dose level for any subject to begin study treatment will be communicated to the 
affiliate site along with the determination by Central Registration that the subject is eligible 
for enrollment in the study.  
 
If a Dose Limiting Toxicity (DLT) is identified in a subject, the affiliate site must notify 
the sponsor-investigator via email at the study specific email address within 1 business day 
of identification. The lead site will communicate that a DLT has been experienced within 
1 business day.  
 
9. Adverse event reporting 
Sponsor reporting: Notifying participating investigators at affiliate sites of adverse 
events 
 
It is the responsibility of the study sponsor to notify all affiliate sites, in a written IND 
safety report, of any adverse event associated with the use of the drug that is both serious 
and unexpected, as well as any finding from tests in laboratory animals that suggest a 
significant risk for human subjects.  Additionally, sponsors are also required to identify in 
IND safety reports all previous reports concerning similar adverse events and to analyze 
the significance of the current event in light of the previous reports. 

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Serious Adverse Event Reporting 
 
Each participating investigator is required to abide by the reporting requirements set by 
Columbia University Medical Center. The study must be conducted in compliance with 
FDA regulations, local safety reporting requirements, and reporting requirements of the 
principal investigator. 
 
Participating investigators must report each serious adverse event to the Columbia 
University Medical Center Overall Principal Investigator within 24 hours of learning of the 
occurrence using the SAE Report Form. In the event that the participating investigator does 
not become aware of the serious adverse event immediately (e.g., participant sought 
treatment elsewhere), the participating investigator is to report the event within 24 hours 
after learning of it and document the time of his or her first awareness of the adverse event. 
Report serious adverse events by telephone, email or facsimile to: 
 
Richard Carvajal, M.D. 
177 Fort Washington Avenue 
Suite 6-435 
New York, NY 10032 
AAAO8010@columbia.edu  
 
Within the following 24-48 hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether 
the event has resolved or continues, if and how the event was treated, and whether the 
participant will continue or discontinue study participation. 
 
Follow-up information is sent to the same person to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow- up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, 
or progression of the original event should be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event 
has resolved or continues, if and how it was treated, and whether the subject continued or 
withdrew from study participation or if study drug was interrupted or discontinued. 
 
If the SAE is not previously documented in the Investigator’s Brochure for the study 
drug (new occurrence) and is thought to be related to the investigational agent, the 
sponsor-investigator may urgently require further information from the investigator for 
reporting to Health Authorities. 
 
Non-Serious Adverse Event Reporting 
 
Non-serious adverse events will be reported to the Columbia University Medical Center 
Overall Principal Investigator on the toxicity Case Report Forms. 
 
Reporting to the Institutional Review Board (IRB) and the Data and Safety 

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Monitoring Committee: 
 
All Unanticipated Problems (UPs) will be reported to the CUMC IRB. SAEs not 
constituting UPs will reported to the HICCC DSMC.   
 
Each affiliate site will be responsible for safety reporting to their local IRB.  Investigators 
are responsible for complying with their local IRB’s reporting requirements, though must 
submit the required reports to their IRB no later than 7 calendar days following the 
occurrence of the UP or the Principal’s Investigator’s acquiring knowledge of the UP.  
Copies of each report and documentation of IRB notification and receipt must be included 
in the regulatory binder. 
 
Expected AEs must be reported at the time of continuing review of a protocol. 
 
Guidelines for Processing IND Safety Reports  
 
The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical 
studies to notify the FDA and all participating investigators of any serious and unexpected 
adverse experiences that are possibly related to the investigational agent. The CUMC 
Principal Investigator will review all applicable IND Safety Reports and has the 
responsibly for forwarding the IND Safety Reports to the Affiliate Institutions. The 
Affiliate Institution investigators are to review, send a copy to their IRB according to their 
local IRB’s policies and procedures, and file a copy with their regulatory documents. All 
Affiliate site INDSR submissions, along with IRB acknowledgment (per local policies and 
procedures) are to be forwarded to CUMC for placement within the trial master file. 
 
Reporting to Hospital Risk Management 
 
Affiliate Site investigators will report to their local Risk Management Office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
 
10.  Confidentiality 
Each affiliate site will be assigned a site number. Each subject that signs consent should be 
assigned a unique code number consisting of site number followed by a number with each 
new subject being assigned the next sequential number (e.g., 04-10). All sites will be 
required to enter their data in the Velos eResearch, the Clinical Trial Management System 
used for all Cancer-related clinical research at CUMC. All users must login with their own 
application username and password.  Users off campus must first access the Virtual Private 
Network with their assigned campus username and password and then use their application 
credentials.   
 
Subject confidentiality must be maintained according to HIPAA regulations and GCP 
recommendations.  
 
Except when required by law, study information shared with persons and organizations 

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outside of Columbia University Medical Center must not identify the patient by name, 
social security number, address, telephone number, or any other direct personal identifier. 
If the results of this research project are published or presented at a scientific or medical 
meeting, the patient not be identified. Otherwise, all results will be kept confidential and 
will not be divulged (except as required by law) without permission.  
 
11. Data Reporting Plan 
Columbia University Medical Center (CUMC) is deeply committed to research integrity 
and strong credibility when it comes to the discovery of new treatment concepts, 
implementation of new clinical research techniques, and acceptance of its researcher's 
findings by the medical establishment. In accord with these ethics, CUMC encourages and 
supports its investigators in the sharing of final research data and/or details of newly 
developed clinical treatments. 
 
CUMC's policies that pertain to patient data sharing conform to CUMC IRB rules, local 
and state laws, and HIPAA privacy regulations. The primary reason for this is to protect 
the privacy of patients who participate in clinical trials. The data can be made available for 
continuing review by federal agencies upon request and for ongoing study safety reviews 
by the Principal Investigator, Statistician, Data Safety and Monitoring Board (DSMC), and, 
in other instances, the CUMC IRB. 
 
Data collected during the course of this clinical trial will primarily be shared with other 
investigators and University staff, the IRB, FDA, and other reporting agencies, and/or 
transferred to other collaborators.  Prior to transfer, the data collected must comply with, 
and must be limited by, the CUMC's guidelines for Protecting the Rights and Privacy of 
Human Subjects.   
 
12. Data Acquisition and Submission 
Informed consent, including HIPPA authorization, must be obtained on all subjects prior 
to their participation. Always keep the original signed and dated consent form, with the 
redacted source documents and eligibility checklist. Velos eResearch will be used as the 
electronic clinical trials and data management system. Affiliate sites will enter data directly 
into Velos eResearch via customized case report forms for the study. The research staff 
will generate reports from Velos eResearch to ensure timely submission of data by affiliate 
sites. This resource allows for the timely analysis of particular data sets for safety analysis. 
 
13. Record Keeping and Record Retention 
 
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the 
disposition of the drug when the study ends.   
 
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 

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individual administered the investigational drug or employed as a control in the 
investigation. Case histories include the case report forms and supporting data including, 
for example, signed and dated consent forms and medical records including, for example, 
progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The 
case history for each individual shall document that informed consent was obtained prior 
to participation in the study. 
 
Study documentation includes all CRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, CHR correspondence and approval, signed 
patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 
years following the date a marketing application is approved for the drug for the indication 
for which it is being investigated; or, if no application is to be filed or if the application is 
not approved for such indication, until 2 years after the investigation is discontinued and 
FDA is notified.