Clinical trial NCT01025453
Conditions: Thyroid Cancer
Keywords: thyroid follicular cell papillary cell Hurthle cell BAY 43-9006 Temsirolimus Sorafenib 09-148
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2009-12-01; Completion date: 2018-01-16
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out what effects, good and/or bad, the combination of sorafenib and temsirolimus will have on thyroid cancer. Treatment guidelines from the National Comprehensive Cancer Network include sorafenib as a treatment option for thyroid cancer.

Temsirolimus is an intravenous medication that is FDA approved for other type of cancers. In laboratory studies, the addition of temsirolimus to sorafenib works better than sorafenib alone.

Detailed description:

Arms: arm 1: We propose a phase II study to evaluate the efficacy of the combination sorafenib with temsirolimus in patients with thyroid cancer of follicular cell origin (e.g., papillary, follicular, Hurthle cell). A maximum of 36 subjects will be evaluated during the study. Restaging scans, with evaluation of response, will be done every 2 cycles (8 weeks of treatment). Treatment will continue until clinical disease progression, unacceptable toxicity, treatment delay \> 4 weeks, or at the discretion of the treating physician or patient.
Interventions: intervention 1: Temsirolimus and Sorafenib
Intervention descriptions: intervention 1: Treatment will be with sorafenib 200 mg orally twice a day and temsirolimus 25 mg intravenous weekly. A cycle will be equivalent to 4 weeks of treatment.

Protocol documents:
Prot_SAP_000.pdf: 
MEMORIAL SLO AN-KETTERING CANCER CENTER 
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IRB PROTOCOL 
 
IRB#: 09-148 A(10) 
 
 
 
 
 
Phase II Study Evaluating t he Combination of Te msirolimus and 
Sorafenib in t he Treatment of Radioactive Iodine Refractory 
Thyroid Cancer 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
 
Principal Inves tigator/De partme nt: 
Eric Sherman MD 
Medicine 
 
Co-Principal 
Investigator(s )/De partme nt: 
James Fagin MD 
David Pfister MD 
Medicine 
Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me morial Sloan-Ke tte ring Cance r Ce nte r 
1275 York Ave . 
Ne w York, NY 10021 


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Frank Tsa i, MD 
Medicine – Commack 
Ame nde d:  05/12/15 
 
 
Inves tigator(s )/De partme nt: 
Alan Ho MD 
Robert Michae l Tuttle MD 
Shruja l Baxi, MD 
Nicole Leonhart NP 
 
Hilda Stambuk MD 
Eric Lis MD 
Sof ia Haque MD 
Sasan Karimi MD 
John Lyo, MD 
Vaios Hatzoglou, MD 
Tunc Iyr iboz, MD 
 
Rona ld Ghossein MD 
Nora Katabi MD 
Camelia Sima MD MS 
 
Michelle B oyar, MD 
Philip Caron, MD 
Nancy Mills, MD 
Stephanie Smith-Marrone, 
MD 
Carolyn Wasserhe it-Le iblic h, 
MD 
Michael Fanucchi, MD 
Arlyn Apollo, MD 
Pamela Drullins ky, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Tros o-Sandova l, MD 
Deena Atieh-Graha m, MD 
Ephra im Casper, MD 
Audrey Hamilton, MD 
Mila Gors ky, MD 
Han Xiao, MD 
Shilen Patel, MD 
Tina M. Passalaris , MD 
Asma Latif , MD 
Afsheen Iqba l, MD 
Stefan Berger, MD 
Julie Fasano, MD John 
J Fiore, MD Stuart 
Lichtman, MD Philip 
Schulma n, MD Steven 
Sugarman, MD 
Marni Sheren-Ma noff , MD 
Marisa F Siebe l 
Medicine 
Medicine 
Medicine 
Medicine 
 
Radiology 
Radiology 
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Radiology 
 
Pathology 
Pathology 
Biostatistics 
 
Medicine – Phelps 
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Medicine – Phelps 
 
Medicine – Phelps 
Medicine – Mercy 
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Medicine - Basking R idge 
Medicine - Basking R idge 
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Medicine – Commack 
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IRB#: 09-148 A(10)
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Conse nting 
Profe ss ional(s )/De partme nt: 
Eric Sherman MD 
David Pfister MD 
Alan Ho MD 
Robert Michae l Tuttle MD 
Shruja l Baxi, MD 
 
Stephanie Smith-Marrone, 
MD 
Carolyn Wasserhe it-Le iblic h, 
MD 
Philip Caron, MD 
Nancy Mills, MD 
Michael Fanucchi, MD 
Michelle B oyar, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Pamela Drullins ky, MD 
Arlyn Apollo, MD 
Tiffany Tros o-Sandova l, MD 
Ephra im Casper, MD 
Audrey Hamilton, MD 
Mila Gors ky, MD 
Han Xiao, MD 
Deena Atieh-Graha m, MD 
Tina M. Passalaris , MD 
Asma Latif , MD 
Afsheen Iqba l, MD 
Shilen Patel, MD 
Steven Sugarman, MD 
John J Fiore, MD 
Philip Schulma n, MD 
Stefan Berger, MD 
Marni Sheren-Ma noff , MD 
Julie Fasano, MD 
Marisa F Siebe l 
Frank Tsa i, MD 
Stuart Lichtman, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
 
Medicine – Phelps 
Medicine – Phelps 
Medicine – Phelps 
 
Medicine – Phelps 
Medicine – Phelps 
Medicine – Phelps 
Medicine – Mercy 
Medicine – Mercy 
Medicine – Mercy 
Medicine – Mercy 
Medicine – Mercy 
Medicine - Basking R idge 
Medicine - Basking R idge 
Medicine - Basking R idge 
Medicine - Basking R idge 
Medicine - Basking R idge 
Medicine - Basking R idge 
Medicine – Basking R idge 
Medicine - Basking R idge 
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Medicine – Commack 
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Medicine – Commack 
 
 
 
Ple ase Note : A Conse nting Profess ional mus t have comple te d the mandatory Human 
Subje cts Education and Ce rtification Program. 


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Table of Conte nts 
 
 
 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL........................................................... 0 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ............................................................ 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ..................................................................... 5 
3.0 
BACKGROUND AND RATIONALE.......................................................................... 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................. 8 
4.1 
DESIGN ........................................................................................................... 8 
4.2 
INTERVENTION ............................................................................................. 8 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS................................................................... 8 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ................................................................. 13 
6.1 
SUBJECT INCLUSION CRITERIA ............................................................... 13 
6.2 
SUBJECT EXCLUSION CRITERIA .............................................................. 14 
7.0 
RECRUITMENT PLAN ............................................................................................ 15 
8.0 
PRETREATMENT EVALUATION ........................................................................... 16 
9.0 
TREATMENT/INTERVENTION PLAN.................................................................... 16 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION...................................... 18 
11.0 
TOXICITIES/SIDE EFFECTS ................................................................................... 19 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT .............. 24 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ............................................................ 31 
14.0 
BIOSTATISTICS....................................................................................................... 31 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES ......................................................................................................... 33 
15.1 
RESEARCH PARTICIPANT REGISTRATION ............................................. 33 
16.0 
DATA  MANAGEMENT ISSUES ............................................................................. 33 
16.1 
QUALITY ASSURANCE............................................................................... 33 
16.2 
DATA AND SAFETY MONITORING........................................................... 34 
17.0 
PROTECTION OF HUMAN SUBJECTS................................................................... 34 
17.1 
PRIVACY ...................................................................................................... 35 
17.2 
SERIOUS ADVERSE EVENT (SAE) REPORTING ....................................... 35 
18.0 
INFORMED CONSENT PROCEDURES................................................................... 37 
19.0 
REFERENCE(S) ........................................................................................................ 38 
20.0 
APPENDICES ........................................................................................................... 40 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
IRB#: 09-148 A(10) 
 
Treatment options for patients w ith recurrent and/or metastatic thyr oid carcinoma not ame nable to 
curative surgery or radioactive iodine (RAI) are limited; no effective systemic therapy currently 
exists.  Doxorubic in is the only FDA-approved agent f or the treatment of RAI-refractory thyroid 
cancer, and its eff icacy is questionable. 
 
This is a proposed phase II study to eva luate the efficacy of sorafenib and tems ir olimus in 
combination, in the treatment of recurrent and/or metastatic thyr oid cancer. 
 
 
 


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2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objective : 
 Determine the objective response rate of the combination sorafenib and tems irolimus in I- 
131 refractory thyr oid cancer. 
 
Secondary Objective 
 Evaluate if the presence of BRAF mutations , w ith or without concomitant mutations in the 
PI3K AKT, mTOR pathway, predict response to therapy. 
 
Determine progression-free survival under the combination sorafenib and tems ir olimus in 
I-131 refractory thyr oid cancer. 
 Evaluate safety and tolerability for the combination sorafenib and tems ir olimus in I-131 
refractory thyr oid cancer. 
 
 
 
3.0 
B ACKGROUND AND RATIONALE 
 
3.1 Thyroid Cancer 
 
Treatment options for patients w ith recurrent and/or metastatic thyr oid carcinoma not ame nable to 
curative surgery or radioactive iodine (RAI) are limited; no effective systemic therapy currently 
exists.  Doxorubic in is the only FDA-approved agent f or the treatment of RAI-refractory thyroid 
cancer, and its eff icacy is questionable. Prior to 2005, there were no abstrac ts presented at the 
American Soc iety of C linical Onc ology annua l meeting descr ibing prospective chemotherapy 
studies for thyroid cancer.  However, dur ing the past several meetings , there have been multiple 
phase II studies evaluating targeted therapies suc h as sorafenib1,2, axitinib3 , sutinib4, gef itinib5 , and 
lena lidomide6. 
 
Thyr oid carcinomas of follic ular cell or igin are belie ved to represent a continuous and progressive 
spectrum of disease.  Two current mode ls of progression currently exist. The conventional mode l 
postulates that thyr oid carcinomas deve lop in mature follicular thyr ocytes and dedifferentiate 
through progressive genetic damage from the differentiate d thyr oid carcinomas (e.g., papillar y, 
follicular) into more high grade thyr oid carcinomas (e.g., poor ly differentiated and anaplastic). 
The alternative mode l proposes that thyroid carcinoge nesis does not result fr om transf ormation of 
mature follic ular thyr ocytes, but fr om de veloping follicula r thyr ocytes, w ith the more immature 
cells deve loping into high grade thyr oid carcinomas, and the more mature follic ular thyr ocytes 
transforming into differentiated thyr oid carcinomas. Regardless of which model is embraced, both 
models agree that there are strong genetic-pathologica l corre lations in a ll sub-types of thyr oid 
carcinomas of follicular ce ll or igin, be it one of progressive genetic damage as proposed by the 
former , or a developmenta l one as proposed by the latter. 
 
3.2 MAPK Pathway 
The RAS/RAF/MEK/ERK cascade (classical MAPK pathway) transduces growth factor - initiated 
signa ls that regulate cell proliferation and s urviva l.  In human cancer, MAPK pathway activation is 
often the result of mutations in RAS, BRAF and upstream receptor tyros ine kinases (RTK). 


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Tumors in which MAP kinase is activated by mutations upstream of BRAF (RAS, RTKs) are 
typica lly less sensitive or res istant to MEK inhibition. These data suggest that MEK inhibitors may 
be partic ular ly effective in tumors w ith BRAF mutations , and perha ps less so in some tumors w ith 
mutant RAS7,8. 
 
 
The MAPK pathway seems particular ly important in thyroid cancers. BRaf is the predominant Raf 
is ofor m seen in thyr oid follicular ce lls. BRaf has a higher affinity for MEK 1 and MEK 2 than CRaf 
or ARaf, and is more effic ient in phosphorylating MEKs than other Raf isof orms 9. BRAF 
mutations are the most common genetic abnor ma lity in pa pillary thyr oid cancers (36-69%)10-13. 
They are mutua lly exc lus ive with mutations of RAS genes and w ith mutations in the receptor 
kinase receptors RET and NTRK12, 13 . These genes encode for effectors in the MAPK signaling 
pathway, hence providing compe lling genetic evidence for the s ignif icance of MAPK 
dysregulation in thyroid tumor ige nesis.  BRAF mutations are thought to occur early in the 
development of papillar y thyroid cancers, and are found most commonly in aggress ive tumors 14. 
Studies have shown that BRAF mutations are found commonly in thyroid cancers with poor 
prognos tic features such as the tall cell varia nt of papillary thyr oid cancer (PTC), in tumors 
associated with extrathyroida l extens ion , and in anaplastic carcinomas aris ing from PTC15. 
Moreover , a recent study from our institution shows that recurrent and metastatic PTC and poor ly 
differentiated thyroid cancers (PDTC) that are radioiodine refractory and/or FD G-PET pos itive are 
markedly enr iched for BRAF mutations, often found in association w ith mutations of PIK3CA or 
AKT1 (Ricarte Filho JC et al. Cancer Research. 2009. in press). 
 
3.2 mTOR 
 
The mTOR kinase is cons idered to be importa nt in cancer, as it integrates responses to grow th 
factors, particular ly those transduced via the RAF-MEK-MAPK pathway, and the phos phoinos itol- 
3-kinase (PI3K)-AKT pathways. mTOR assembles into tw o holoenzyme complexes : with Raptor, 
to for m mTORC1, and with R ictor , to f orm mTORC2. In thyr oid ce lls, mTORC1 activity is 
required for the proliferative effects of TSH in vitr o and in vivo. Unpublis hed wor k from the Fagin 
lab shows that mTORC1 is also required for the growth promoting effects of the oncopr ote ins 
RET/PTC, RAS and BRAF in rat thyroid PCCL3 cells. Rapamycin is the prototypica l mTORC1 
inhibitor, as it interferes with the association between mTOR and Raptor. R apamycin has 
signif icant growth inhibitory effects in human cell lines harbor ing endogenous mutations of these 
oncoprote ins. Further more , combine d treatment w ith MEK inhibitors and rapamyc in shows 
cooperative gr owth inhibitory effects in a subset of cell lines with BRAF mutations. 
 
Cowden’s syndrome, w hich is caused by ger mline mutations in PTEN , is associated w ith a 10% 
lifetime r isk of de veloping thyr oid cancer. The wild-type alle le is often inactivated thr ough 
epigenetic events later in tumor pr ogress ion. In addition, PTEN def ic iency in mouse mode ls is 
associated with follic ular thyroid cancer aggressiveness16. mTORC1 inhibitors are active in PTEN- 
defic ient tumors17-19. In other cancers, concomitant loss of PTEN may decrease the response to 
specif ic tyr os ine kinase inhibitors : i.e. EGFR kinase inhibitors in glioblastomas (Melinghoff IK. 
Clin Canc Res 2007). .  Hence, it is poss ible that partia l refractor iness to monotherapy w ith RAF 
or MEK inhibitors in thyr oid cancers with BRAF mutations may be accounted for in part by 
concomitant activation of PI3K-mTOR signa ling. 


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3.3 Sorafenib for the treatment of thyroid cancer 
 
Sorafenib is an ora lly active multi-tyr os ine kinase inhibitor of multiple targets, inc luding BRAF, 
VEGFR 1, and VEGFR220. It has already been appr oved by the US FDA for the treatment of renal 
cell carcinoma and hepatocellular carcinoma. A phase II study at the University of Pennsylvania 
has shown a partial response rate of 23% with stable disease present in 53% of patients w ith 
thyr oid cancer 21. Median progression-free survival was 79 weeks. No difference was se en between 
patie nts with papillary and follicular thyr oid cancer. Overall, s orafenib was felt to be an effective 
agent in the treatment of thyroid cancer. What is less clear is whether it wor ks ma inly through 
inhibiting VEGF action, the RAF-MEK-MAPK pathway, or both. Activity of sorafenib in 
mela noma is not de pendent on BRAF mutationa l status22. We do not know if this is tr ue for 
thyr oid cancer, a lthough activity was seen in follic ular and Hurthle cell thyroid cancers, which 
would not have BRAF mutations. 
 
It also needs to be noted that a phase II study w ith sorafenib at Ohio State showed only a 15% 
response rate (5 out of 33 patients)  w ith 57% stable disease rate in patie nts with papillary thyroid 
cancer who were treatment naïve23. Media n progression free survival was 16 months. No responses 
were seen in the 15 subjects (4 w ith anaplastic thyr oid cancer) who had n onpapillar y thyroid 
cancer. In the non anaplastic thyr oid cancer group, the tota l response rate was 11.5%. 
Due to this data, Nationa l Comprehens ive Cancer Network (NCCN) guide lines for the treatment of 
thyr oid cancer specif ically states that sorafenib is a n acceptable treatment for RAI-refractory 
thyr oid cancer. 
 
3.4 Combination of sorafenib and tems ir olimus 
 
Preclinica l evidence suggests syner gy when both the MAPK and PI3K-mTOR pathways are 
inhibited24. The combination of sorafenib with mTORC1 inhibitors increases cell death in 
mela nomas, where BRAF mutations are particular ly common25 , and the combination of sorafenib 
and tems irolimus is currently being eva luated in the treatment of me lanoma in a large randomized 
phase II study through the Southwest Oncology Gr oup. The doses used in this study are sorafenib 
200 mg orally tw ice a day and tems irolimus 25 mg intravenous ly weekly. Furthermore, this 
combination is be ing eva luated in the treatment of kidney cancer (by the Eastern Cooperative 
Oncology Group) and glioblastoma multif orme (North Centra l Cancer Treatment Group). In the 
phase I study eva luating this combination26, a partia l response was seen in a subject with papillary 
thyr oid cancer. 
As noted above, sorafenib is an inhibitor of multiple targets. At this time , it is unc lear whic h 
targets are meaningf ul c linica lly. Multiple phase II studies have suggested that VEGF is an 
important target in the treatment of thyr oid cancer. Despite the importa nce of the RAF-MEK- 
MAPK pathway as a target in the treatment of thyroid cancer in the laboratory, it is still unknown 
whether (1) the target is important c linically and ( 2) sorafenib exerts any c linica l effect in the 
treatment of thyroid cancer by targeting this pathway. There is little doubt from the phase II study 
at the University of Pennsylvania that sorafenib is active in tumors w ith out BRAF mutations since 
responses were seen in tumors known not to have this mutations ( i.e., Hurthle cell, f ollicular)21. It 
will be important to determine if activation of the RAF-MEK-MAPK pathway is important in 
conferring sens itivity to this drug, in or der to ref ine the des ign of future studies w ith sorafenib and 


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other agents and to determine optima l combinations. In addition, it may he lp determine whic h 
subset of thyroid cancer patients would most benef it with the combination of a RAF inhibitor 
(sorafenib) and mTORC1 inhibitors such as (tesirolimus). 
 
 
4.0 
OVERVIE W OF STUDY DESI GN/INTERVENTION 
 
4.1 
Des ign 
 
We propose a phase II study to eva luate the efficacy of the combination sorafenib w ith 
temsir olimus in patients w ith thyr oid cancer of follic ular cell or igin (e.g. , papillar y, f ollicular , 
Hurthle cell). A maximum of 36 subjects will be evaluated dur ing the study. Restaging scans, 
with evaluation of response, w ill be done every 2 cyc les (8 weeks of treatment). Treatment 
will continue until c linica l disease progress ion, unacceptable toxic ity , treatment de lay > 4 
weeks, or at the discretion of the treating phys ic ian or patient. Regardless of the duration of 
treatment, objective response rate will be based on the response within the f irst 4 cyc les of 
treatment. 
 
A secondary hypothesis w ill eva luate how the BRAF status affects response to therapy. 
Therefore, all s ubjects will be required to have tissue (archiva l is acceptable) for genetic 
testing at enrollment. 
 
 
 
4.2 
Inte rve ntion 
 
Treatment will be with sorafenib 200 mg ora lly twice a day and tems ir olimus 25 mg 
intravenous weekly. A cycle w ill be equiva lent to 4 weeks of treatment. These are the doses 
being used for SWO G protocol 0438 (a randomized phase II study in me lanoma). A phase I 
study recomme nded this dose leve l and fe lt us ing the full dos e of sorafenib (400 mg tw ice a 
day) was too toxic26. 
 
4.3 
Tumor Ge notyping 
 
In order to determine the BRAF mutational status , the DNA from the or igina l tumor and/or of 
the metastatic lesion (w hen availa ble) will be genotyped for BRAFT1799A mutation by mass 
spectrometry.  Tumor genomic DNA from a ll patients w ill be genotyped more 
comprehe ns ive ly f or all known mutations of the 3 RAS genes, PIK3CA, AKT1 by Sequenom 
mass spectrometry which has already been optimized in the Fagin lab, to investigate other 
markers potentia lly conferring respons iveness to the study agents.  The Sequenom assay 
allows a ll these genes to be screened simultaneous ly in 384 we ll plates.  Six multiplexed we lls 
are required for each tumor sample , and the entire assay can be performed in 72h, thus 
allow ing us to enroll patients based on the ir genotype (BRAF status). 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 BAY 43-9006 (sorafe nib; NSC-724772) 
 
Che mical Name : 4–{4-[3-(4-chlor o-3-tr if luoromethyl-phenyl)ure ido]- phenoxy}- 
pyr idine-2 carboxylic acid methylamide-4-methylbenzensulf onate. 


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Othe r Names: BAY 54-9085 is the tosylate salt of BAY 43-9006; sorafenib 
Class ification: Kinase inhibitor (Raf , VEGF-R, and PDGF-R) 
Mechanis m of Action: The ras/raf signaling pathway is an importa nt mediator of responses 
to growth s ignals and angiogenic factors. This pathway is often aberrantly activated in human tumors 
due to presence of activated ras, muta nt b-raf, or over expression of growth factor receptors. Sorafenib 
is a pote nt inhibitor of c-raf, and wild-type and mutant braf in vitro. Additiona lly, fur ther 
characterization of sorafenib revealed that this agent inhibits several receptor tyr os ine kinases (RTKs) 
that are involved in tumor pr ogress ion (VEGF-R, PDGF-R , Flt3, and c-KIT) and p38α , a member of 
the MAPK family. 
Molecular Formula: C12H16CIF3N4O3 X C7H8O3S 
M.W.: Sorafenib tosylate : 637 Daltons; free base: 465 Daltons 
Approximate Solubility: 0.19 mg/100 mL in 0. 1 N HCl, 453 mg/100 mL in Ethanol, and 2971 
mg/100 mL in PEG 400. 
How Supplie d: BAY 43-9006 sorafenib 200 mg is supplie d as round, biconvex, red-f ilm-coated 
tablets , debossed with the 'Bayer cross' on one s ide and '200' on the other side. The tablets conta in 
BAY 43-9006 tosylate equiva lent to 200 mg of the free base BAY 43-9006, and the exc ipients 
croscarmellose sodium, microcr ystalline cellulose , hyprome llose, sodium lauryl s ulfate, and 
magnes ium stearate. The film-coat cons ists of hyprome llose, polyethylene glycol, titanium dioxide 
and red ir on oxide. The film coating has no effect on the rate of release of the active BAY 43- 9006 
tosylate. Study Drug can be supplie d as BAY 43-9006 sorafenib 200 mg commerc ial ta blets in bottles 
of 140 tablets with a product ide ntif ication labe l affixed or as commercia l Sorafenib in bottles of 120 
tablets. 
Storage : Do not store above 25°C ( 77°F). Store in the or igina l package. 
Stability: The current shelf life is 36 months. 
Route (s ) of Adminis trat ion: Orally 
Me thod of Adminis tration: The recommended da ily dose of SORAFENIB is 200 mg ( 1 x 200 
mg tablets) taken tw ice da ily, w ithout food (at least 1 hour bef ore or 2 hours after eating). 
Pote ntial Drug Inte ractions : Sorafenib is metabolized by the P450 CYP3A enzyme and has 
been shown in preclinica l studies to inhibit multiple CYP isof or ms. Therefore, it is poss ible that 
sorafenib may interact with drugs that are metabolized by the P450 CYP is oenzymes or with drugs 
that inhibit CYP 3A. Close monitor ing is recommended for patie nts taking agents w ith narrow 
therapeutic indices and metabolized by the liver, such as warfarin, phenytoin, quinidine , 
carbamazepine , phe nobarbita l, cyclospor ine , and digoxin. Additionally, sorafenib is 97% to 99% 
prote in bound; however, no dr ug interactions have been reporte d in studies, thus far. 
 
Adve rse Eve nts : 
Refer to current version of Sorafenib Package Insert for complete listing of adverse reactions 
for sorafenib. 
1. Hematologic: neutropenia , thr omboc ytopenia, ane mia, leukopenia 
2. Body as a whole: fatigue , f lu- like syndromes, fever , arthralgia , pa in ( including bone 
pain, joint pa in, musc le pain, mouth pa in, abdomina l pa in, tumor pa in, and headache) 
3. Cardiac: hypertension, myocardial infarction, congestive heart failure 
4. Dermatology/Sk in: hand-foot skin reaction, characterized by pa lmar and p la ntar 
erythema; rash/desquamation, hypersens itivity reactions, dr y skin, a lopecia , na il 
changes, vitiligo, pr ur itis , exfoliative dermatitis 
5. Gastrointestinal: diarrhea; pancreatitis , e levated amylase/lipase, abdomina l 


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pain/cramping, nausea, f latulence, dyspe ps ia, ascites, constipation, dehydration, 
dysphagia , muc os itis/stomatitis , vomiting, gastrointestina l perf oration 
6. Genitourinary: renal failure 
7. Hemorrhage/Bleeding: hemorrhage (inc luding gastrointestina l hemorr hage, 
respirator y tract hemorr hage, cerebra l hemorrhage , epistaxis , mouth hemorrhage , 
rectal hemorr hage, na il bed bleeding, and hematoma) 
8. Hepatic: increased bilirubin, ALT, AST, GGT, LDH, and alkaline phosphatase 
9. Infection: febrile neutropenia , infection 
10. Metabolic and Nutritional: anorexia, a lbumin, hyperglycemia, hypophosphate mia, 
decreased weight 
11. Neurologic: periphera l sensory ne uropathy, RPLS 
12. Pulmonary/Upper Respiratory: hypoxia , ple ural effus ion, pneumonitis/pulmonary 
inf iltrates, pneumothora x 
13. Other: Depression 
 
5.2 Te ms irolimus (CCI-779; Toris ol) 
 
Che mical Name : Rapamyc in 42-[2,2-bis( hydroxymethyl)pr opionate] 
 
 
 
Class ification: mTOR inhibitor. (Raf, VEGF-R , and PDGF-R) 
Mechanis m of Action: Temsirolimus (CCI-779) is a structura l analog of sir olimus (Rapamyc in®) 
that has been formulated for IV or ora l administration f or the treatment of various malignanc ies. 
Sirolimus was shown to have potent immunosuppress ive as well as antif ungal and antitumor 
properties. Its mechanis m of action results in part from binding to an intracellular cytoplasmic 
prote in, FKBP-12. The complex of s irolimus bound to FKBP -12 blocks the activity of mTOR , which 
regulates a signa ling cascade that controls gr owth factor- induced cell pr oliferation. The net effect of 
this class of compounds on ce lls is to block the G1 to S phase trans ition of the cell cycle. The activity 
of sir olimus and te ms irolimus in vitro can be bloc ked by a competitive inhibitor (ascomyc in) for 
FKBP-12 binding, suggesting that the 2 compounds have the same mechanism of action. The 
mechanism of action of tems ir olimus , that is binding to FKBP -12 and subsequent inhibition of 
growth factor- mediated mTOR signa ling, is nove l for an anticancer drug. Inasmuc h as human tumors 
are partly regulate d by growth factors, tems ir olimus is expected to inhibit pr oliferation across a broad 
range of human tumors. In addition to directly inhibiting tumor cell growth, s upportive eleme nts of 
the tumor micr oenvir onment that require gr owth factors, s uch as tumor stroma de velopment and 


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angiogenes is, may als o be inhibited by te ms irolimus. Another tumor suppressor gene frequently 
mutated in human cancer that regulates mTOR pathway is phos phatase related to tens in (PTEN). 
Loss of PTEN results in increased activation of phosphatidylinos itol-3 kinase (PI3K) and its 
downstream targets Akt and mTOR. Tumors w ith PTEN loss and or Akt activation respond well to 
temsir olimus. 
Molecular Formula: C 56H87NO16 
M.W.: 1030. 30 
Approximate Solubility at 25 oC: 514.9 mg/ mL in Etha nol (anhydrous), and 27. 3 mg/mL in PEG 
400. 
How Supplie d: 25 mg/ ml via ls 
Storage : 
 
Concentrate for Injection should be stored refrigerated (2kinase (PI3K) and its downstream targets 
Akt and mTOR. Tumors with PTEN los
 
The active pr oduct and diluent must be a llowed to warm to room te mperature for approximate ly 1 
hour before dilution. Dilution of Tems irolimus Concentrate for Injection in Diluent f or Tems irolimus 
Concentrate for Injection must be followed by f urther dilution into an infus ion bag or bottle of 0. 9% 
sodium chlor ide injection. 
The drug-diluent mixture is stable for up to 24 hours at controlled r oom temperature. The final diluted 
infus ion solution ( drug- diluent in sodium chlor ide injection) should be stored in a secured, clean 
environme nt, at room temperature , and administered w ithin 6 hours from the time that the 
concentrate-dilue nt mixture is added to the 0.9% sodium chlor ide injection. Admixtures of 
temsir olimus are stable under or dinar y f luorescent room light, but should be pr otected from excess ive 
light, such as sunlight. 
Stability: The drug- diluent mixture is stable for up to 24 hours at contr olled r oom temperature. The 
final diluted inf us ion solution (dr ug- dilue nt in sodium chlor ide injection) should be stored in a 
secured, clean environment, at room temperature, and administered w ithin 6 hours from the time that 
the concentrate-diluent mixture is adde d to the 0. 9% sodium chlor ide injection. Admixtures of 
temsir olimus are stable under or dinar y f luorescent room light, but should be pr otected from excess ive 
light, such as sunlight. 
Route (s ) of Adminis trat ion: Intravenous. D ilutions of Tems irolimus Concentrate for Injection must 
be carried out in glass or polyolef in administration devices. Infus ion bags and sets containing 
polyvinyl chlor ide should not be used to administer this pr oduct to avoid leaching of plastic izer. In 
addition, an in- 
Concentrate 
for Injectio 
Pote ntial Drug Inte ractions : The primary oxidative metabolism is via CYP3A4, indicating that 
inhibitors and inducers of CYP3A4 enzyme system may alter the metabolis m of te ms irolimus, 
although te ms irolimus does not induce CYP3A4. Te msir olimus ma y inhibit the metabolic clearance 
of substrates of CYP3A4/5 or CYP2D6 but not CYP2C9 or CYP2C8. However, a clinica l study to 
assess the ability of tems ir olimus to inhibit dispos ition of desipramine, a sensitive CYP2D6 substrate, 
was negative. This f inding indicates that the effect of temsirolimus on other agents metabolized by 
either CYP2D6 or CYP3A4/5 is expected to be low. In vitro studies showed that te ms irolimus is 
subject to P-gp- mediated eff lux; in addition, tems ir olimus inhibited the tra nsport of digoxin, a P -gp 
substrate. The clinica l re levance of these in vitr o determined P -gp data is currently unknow n. 
The drug interaction pote ntia l of tems ir olimus was evaluated in phase 1 dr ug- interaction studies. 
Coadministration of IV tems ir olimus w ith ketoconazole, a pote nt CYP3A4 inhibitor , had no 
signif icant effect on tems ir olimus Cmax and AUC but increased the major metabolite s irolimus Cmax by 


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2.2-fold and AUC by 3.1-fold compared to te ms irolimus treatment alone. Caution should be used 
when administer ing strong CYP3A4 inhibitors w ith te ms irolimus IV. For subjects with MCL, 
coadministration of CYP3A4 inhibitors w ith te ms irolimus should be avoided. Coa dministration of 
temsir olimus w ith r ifampin, a potent CYP3A4 inducer, had no s ignif icant effect on tems irolimus Cmax 
and AUC after IV administration, but decreased sirolimus Cmax by 65% and sir olimus AUC by 56% 
compared w ith tems irolimus treatment a lone. It is recommended that caution be used when 
adminis tering str ong CYP3A4 inducers with te ms irolimus. 
 
 
Adve rse Eve nts : 
Serious : 
Hypersensitivity Reactions , Hyper glycemia , Interstitia l Lung Disease, Bowe l Perforation, and Rena l 
Failure 
 
Common: 
Rash, asthenia, mucos itis, nausea, edema, and anorexia. The most common laborator y abnor ma lities 
observed w ith TORISEL are anemia , hyperglycemia, hyper lipe mia, hypertr iglyceride mia, 
lymphopenia , e levated alka line phos phatase, ele vated serum creatinine , hypophosphatemia, 
thrombocytopenia , ele vated AST, and leukope nia. 
 
 
 
Less Common but >10% : 
Pain, Pyrexia , weight loss, headaches, chest pa in, chills , diarr hea, abdomina l pa in, constipation, 
vomiting, infections , ur inar y tract infections , phar yngitis , rhinitis , back pa in, arthra lgia , dyspnea, 
cough epistaxis , prur itis, na il disor der, dry skin, acne, dys geus ia, insomnia. 
 
The follow ing se lected adverse reactions were reported less frequent ly ( <10%) : 
Gastrointestina l D isor ders – Fatal bowel perforation occurred in 1 patient ( 1%). 
Eye Disor ders - Conjunctivitis ( inc luding lacr imation disor der) occurred in 15 patients (7%). 
Immune System - Aller gic/Hypersensitivity reactions occurred in 18 patie nts (9%). 
Angioneur otic edema-type reactions ha ve been observed in some patie nts who receive d tems irolimus 
and ACE inhibitors concomitantly. 
Infections - Pneumonia occurred in 17 patients (8%); upper respiratory tract infection occurred in 
14 patients (7%). 
General D is orders and Adminis tration Site Conditions - Impa ired wound healing occurred in 
3 patients (1%). 
Respirator y, Thoracic and Mediastina l D isorders – Interstitia l lung disease occurred in 5 patients 
(2%), inc luding rare fatalities. 
Vascular - Hypertens ion occurred in 14 patients (7%); venous thromboembolism ( inc luding deep 
vein thr ombos is and pulmonary embolus) occurred in 5 patients (2%); thrombophlebitis occurred in 2 
patie nts (1%). 
 
5.2.3 Source of Te ms irolimus 
 
The supply of Te ms irolimus will come from Pfizer. All requests for dr ug need to be sent to 
Benedetta Campane lli. Contact inf or mation is : 


MEMORIAL SLO AN-KETTERING CANCER CENTER 
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IRB#: 09-148 A(10) 
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Benedetta Campane lli 
Globa l IIR Senior Assoc iate 
Pfizer , Inc. 
235 East 42 Street, MS 219/02/01 
Office 219/02/98 
New York, NY 10017 
Benedetta.Campane lli@pf izer.com 
 
6.0 
CRITERIA FOR SUB JECT ELIGIB ILITY 
 
6.1 
Subje ct Inclus ion Crite ria 
 Patients must have histopathologica lly conf irme d at MSKCC thyr oid carcinoma of 
follicular cell or igin (D-TC-FCO) , which inc ludes papillar y, follicular , Hürthle cell 
histology, or anaplastic, a long w ith the ir respective var iants. 
 Available pathology for RAF mutationa l testing (e.g., paraff in block or 5-10 unstained 
slides). It is not required that mutational testing be completed bef ore starting the c linica l 
study. 
 
 Patients must have surgica lly inoperable and/or recurrent/metastatic disease. 
 
 Patients must have a PET scan prior to the pr otocol start date and have at least one FD G- 
avid lesion that has not been remove d surgica lly or radiated (unless it has pr ogressed by 
RECIST criter ia after the completion of radiation therapy and is still FD G-avid).  FD G- 
avidity will be def ined as any focus of increased FDG uptake greater than nor mal activity 
with SUV maximum leve ls greater than or equa l to 3. PET scan can have been done at any 
time pr ior to the start of therapy, a lthough it is recommended that it be done within 3 
months pr ior to the start of therapy. 
 
 Patients must have measurable disease by RECIST criteria , def ined as at least one les ion 
that can be accurately measured in at least one dimens ion ( longest diameter to be re corded) 
as ≥ 20 mm w ith conventiona l techniques or as ≥ 10 mm w ith spira l CT scan; performed ≤ 
4 weeks of protoc ol start date. 
 
 Patients must have progressive disease defined by at least one of the follow ing occurr ing 
dur ing or after previous treatment ( inc luding RAI treatment) : 
 
o The presence of new or progress ive lesions on CT/MRI. 
 
o New lesions on bone scan or PET scan. 
 
o Ris ing thyr oglobulin level ( documente d by a minimum of three consecutive rises, 
with an interva l of > 1 week between each determination). 
 
 Prior RAI therapy is a llowed if > 3 months pr ior to initiation of therapy on this pr otoc ol 
and evidence of pr ogress ion (as defined above) has been documented in the inter im. A 
diagnostic study us ing <10 mC i of RAI is not cons idered RAI therapy. 


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 Patients may have received pr ior externa l beam radiation therapy to index les ions ≥ 4 
weeks prior to initiation of therapy on this pr otocol if there has been documented 
progress ion by RECIST cr iter ia. Prior externa l beam radiation therapy to the non- index 
les ions is allowed if ≥ 4 weeks prior to initiation of therapy on this protocol. 
 
 ECOG p 
perfor mance status 
). 
 
 Patients must have nor ma l orga n and marr ow function as defined be low : 
 
o Absolute neutrophil count ≥1,500/mcL 
 
o Platelets ≥100,000/mcL 
 
o Tota l bilir ubin  1. 5 X institutiona l ULN* 
 
o AST(SGOT)/ALT(SGPT)  2.5 X institutiona l ULN** 
 
o Creatinine  1.5 X institutiona l ULN 
 
OR 
 
Creatinine clearance ≥ 60 mL/min/1. 73 m2  for patients with creatinine leve ls above 
1.5 X institutiona l ULN [in this c ircumstance, either of a measured le vel based on a 
24 hour ur ine collection, or a calculated leve l us ing the Cockcrof t and Gault 
equation: (140 – age in years) X (weight in kg) X (0.85 if fe male)/72 X serum Cr 
may be used]. 
 
o Internationa l nor ma lized ratio (INR)   1.5 (or in range INR, usua lly between 2 and 
3, if patie nt is on a stable dose of therapeutic warfarin). 
 
*ULN = upper limit of norma l 
 
**unless liver metastasis present in which AST/ALT s hould be < 5 x ULN. 
 
 Ability to understand and the w illingness to sign a written inf orme d consent document. 
 
 Age 21 years old or older. 
 
 
 
6.2 
Subje ct Exclus ion Crite ria 
 
 Patients may not be receiving any other investigational age nts. 
 
 Patients with known histor y of active intraparenchymal brain metastas is within previous 3 
months. 
 
 Serious or non- healing wound, ulcer, or bone fracture. 


MEMORIAL SLO AN-KETTERING CANCER CENTER 
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 History of abdomina l f istula, gastrointestina l perforation, or intra -abdomina l abscess within 
28 days of treatment. 
 
 Patients with a reported history of clinica lly active diverticulos is or diverticulitis in the 
pr ior 3 years. 
 
 
Patients with clinica lly s ignif icant cardiovascular disease as defined by the follow ing: 
 
o History of CVA within past 6 months 
 
o Myocardia l infarction, CABG or unsta ble angina w ithin past 6 months 
 
o New York Heart Association grade III or greater congestive heart failure or 
Canadia n Cardiovascular Class grade III or greater angina within past 6 months 
(Appendices B&C) 
 
o Clinically s ignif icant per iphera l vascular disease within past 6 months 
 
o Pulmonary embolis m, DVT, or other thr omboe mb olic event w ithin past 6 months 
 
o Uncontr olled cor onary artery disease, angina, congestive heart failure, or 
ventr icular arrhythmia requir ing acute medica l mana gement w ithin past 6 months 
 
o History of myocardial infarct, cerebrovascular accident, or trans ient ischemic event 
within the past 6 months 
 
 Uncontr olled intercurrent illness inc luding, but not limited to, ongoing or active infection 
or psychiatr ic illness/socia l s ituations that would limit complia nce with study require ments. 
 
 While the use of Angiotens in-Converting Enzyme (ACE) inhibitors is not absolute ly 
excluded, efforts should be made to see if patients on ACE inhibitors can be taken off the 
medication or switched to another medication. 
 
 Pregnant women w ill be ineligible; breastfeeding should be discontinued if the mother is 
treated with study drugs. 
 
 The use of agents that inhibit or induce CYP3A metabolis m is not str ictly prohibited, but 
should be avoided if poss ible. Potentia l CYP3A induc ing agents inc lude carbamazepine , 
phenytoin, barbiturates, r ifabutin, r ifampic in, and St. John’s Wort. Potentia l CYP3A 
inhibitors inc lude protease inhibitors, antif unga ls, macrolide antibiotics, nefazodone , and 
selective serotonin inhibitors. 
 
 
 
7.0 
RECRUITMENT PLAN 
 
Potential research subjects will be identif ied by a member of the patient’s treatment team, the 
protocol investigator, or research team at Memor ia l Sloa n-Kettering Cancer Center (MSKCC). If 
the investigator is a member of the treatment team, s/he will scre en the ir patient’s me dical records 


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for suitable research study partic ipa nts and discuss the study and the ir potentia l f or enrolling in the 
research study. Potentia l subjects contacted by the ir treating phys ic ian w ill be referred to the 
investigator/research staff of the study. 
 
During the initia l conversation between the investigator/research staff and the patient, the patient 
may be asked to pr ovide certain hea lth infor mation that is necessary to the recruitment and 
enrollment pr ocess. The investigator/research staff may also review por tions of the ir me dical 
records at MSKCC or colla borating institution(s) in or der to further assess eligibility. They w ill 
use the inf or mation provided by the patient and/or medical record to conf ir m that the patient is 
eligible and to contact the patient regarding study enrollme nt. If the patient tur ns out to be 
ineligible for the research study and is not enrolle d, the research staff will destroy all infor mation 
collected on the patient dur ing the initia l conversation and me dical records review. 
 
 
 
8.0 
PRETREATMENT EVALUATION 
 
Within 30 days of starting treatment, the follow ing tests need to be done : 
 
History and Phys ical Exa mination 
 
Vita l s igns, inc luding blood pressure and weight 
 
Performance Status (ECOG or Karnofsky Performanc e Status) 
 
Radiology studies for disease assessment 
 
Electrocardiogra m (may be done w ithin 60 days of starting treatment) 
 
Signed Consent For m 
 
Within 14 days of starting treatment, the follow ing tests need to be done : 
 
Complete Blood Count ( including plate lets) 
 
Prothrombin Time (PT) 
 
Comprehens ive including liver function tests (SGOT, SGPT, bilirubin, a lka line 
phosphatase) 
 
Triglycer ides , cholesterol 
 
Serum thyr oid stimulating hor mone (TSH) 
 
Serum thyr oglobulin and thyroglobulin antibodies (results do not need to be back before 
the start of treatment) 
 
Pregnancy test in women of child- bearing potentia l. 
 
A PET scan is required as part of inc lus ion cr iter ia; however, it ma y be done any time pr ior to the 
start of therapy. It is recommended, but not required, that the PET scan be done within 3 months of 
starting therapy. 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 
Tre atme nt 
Note: cyc le length is 28 days. Cyc le is de layed only if both dr ugs (sorafenib and tems ir olimus) are 
held for > 1 week. Temsirolimus dose may be skipped w ithout a violation due to patient re lated 
events (such as weather, family emergency, or hospitalization). Reason for skipping a dose must 
by documented by the treating phys ic ian and appr ove d by the study PI (Sherman). 


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Agent 
Dose 
Route 
Days (+/- 2 
days) 
Interva l 
Diphenhydramine 
(or similar 
antihistamine) 
25-50 mg 
IV/PO 
Approximately 
30 minutes 
pr ior to 
temsir olimus 
infus ion 
Temsir olimus 
25 mg 
IV over 30 
minutes 
1, 8, 15, 22 
Weekly dos ing 
Sorafenib 
200 mg 
twice a day 
(tota l dose 
of 400 mg 
per day) 
Oral 
1-28 
Daily dos ing 
 
9.2 
Diary 
 
Subjects w ill be require d to complete a diary concerning the ir use of sorafenib every 28 days. 
 
 
 
9.3 
Tre atme nt Dis continuation 
In the absence of treatment de lays due to adverse event(s), treatment may continue until one 
of the follow ing criter ia applies. 
 
 Disease progression, 
 
 Intercurrent illness that prevents further adminis tration of treatment, 
 
 Unacceptable adverse event(s), as defined in Section 11, 
 
 
 Patient noncomplia nce as   determined by the judgment of the  investigator that 
would make further treatment potentia lly unsafe or make outcomes of the tr ia l 
diff icult to interpret, 
 
 Arteria l thromboembolic e vents inc luding cerebrovascular accidents , myocardia l 
infarctions , tra ns ient  isc hemic attacks, new  onset  or w orsening  of pre -existing 
angina. 
 
 Patient decides to w ithdraw from the study, or 
 
 General  or  spec if ic   changes   in  the   patie nt’s  condition  render  the   patient 
unacceptable for further treatment in the judgment of the investigator. 


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10.0  EVALUATION DURING TREATMENT/INTERVENTION 
 
Base- 
line a 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9k 
Wk 
10 
Wk 
11 
Wk 
12 
Off 
Study d 
S orafen i b (taken dail y) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Te m si roli mus 
X 
X 
X 
X 
X 
X 
X 
Xj 
X 
X 
X 
Xj 
Inf ormed consent 
X 
Obtain   pathology   specimen    f or   BRAF 
mutation testing. 
X 
History and Physical Ex am 
X 
Concurrent medsg 
X 
X--- --- --- --- --- ---- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- X 
Physical    ex am    (symptom-and    disease- 
directed) 
X 
X 
X 
X 
X 
Xi 
X 
Xi 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Xi 
X 
Xi 
X 
Blood Pressure 
X 
X 
X 
X 
X 
X 
Xi 
X 
Xi 
X 
Weight 
X 
X 
X 
X 
X 
Perf ormance status 
X 
X 
X 
X 
Triglycerides, cholesterol 
X 
X 
X 
X 
CBC w/dif f, plts 
X 
X 
X 
X 
Xi 
X 
Xi 
X 
Serum comprehensive b 
X 
X 
X 
X 
Xi 
X 
Xi 
X 
EKG 
X 
Adverse event evaluation g 
X ----- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- ---- --- --- --- -X 
X 
Radiologic Tumor measurements 
Xf 
Tumor measurements are repeat ed af ter every 2 cycles (i. e., anytime 
between the end of the 1st and the end of the 2nd cycle) while on studyh. 
Documentation must be provided f or patients removed f rom study f or 
progressive disease. 
Pregnancy test c 
X 
Serum thyroglobulin 
X 
X 
X 
PT/INR 
X 
X 
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Serum TSH 
X 
FDG-PET e 
X 
a: 
See Section 8.0 for timing prior to the start of therapy. 
b: 
Albumin,  alkaline phosphatase,  total  bilirubin,  bicarbonate,  BUN,  calcium,  chloride,  creatinine,  glucose,  ,  potassium,  total  protein, 
SGOT [AST ], SGPT [ALT ], sodium, bilirubin. 
c: 
Serum beta human chorionic gonadotropin pregnancy test (in women of childbearing potential). 
d: 
Off-study ev aluation between 4-8 weeks a fte r study termination.. In addition, follow-up for disease status (e.g. , alive with disease) should 
continue at least for 1 year a fter tr eatment is complete. T his does not requir e that th e subject be seen and/or ex amined. For  example, 
follow-up may be done through a telephone call to the subject or his treating physician. 
e: 
[18 -F] fluorod eoxyglucose (FDG)-PET . Baseline FDG-PET to be done any time prio r to the start o f ther apy. No other FDG-PET scans 
required. It is recommended, but not required, that it be done within 3 months of starting therapy. 
f: 
Baseline evaluations, including radiographic studies, are to be conducted ≤ 30 days prior to start of protocol therapy. 
g: 
Concurrent medication and adverse ev ent evaluations will only be done on days of physician visits, although they will include all data 
from between visits. 
h: 
Restaging studies may be done within 2 weeks befo re the scheduled start o f the cycle. A delay in starting the cycle wi ll not require that 
the restaging studies need to be repeated. However, a subject cannot go more than 2 cycles without restaging during the first 12 cycles of 
treatment. Aft er 12 cycles, restaging study only need to be done every 3 cycles (or up to 2 weeks befo re the 3 rd  cycle). 
i: 
After 4 cycles o f treatment ar e completed, these tests/procedur es can be eliminated. 
J: 
After 6 cycles o f treatment are completed, week 4 o f temsirolimus will be optional for the patient. 
k:    W eeks 9-12 should be repeated for all cycl es > 4 except where otherwise noted. TSH and T hyroglobulin only need to be checked eve ry 2 
cycles. 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
11.1 This study w ill utilize the CTCAE (NCI Common Ter minology Cr iteria for Adverse 
Events) Version 4. 0 for toxic ity and Ser ious Adverse Event repor ting. A copy of the CTCAE 
Version 4.0 can be dow nloade d from the CTEP home page (http://ctep.cancer.gov). Please see 
sections 5.1 and 5. 2 for list of expected toxic ities. 
 
11.2 Ge ne ral Dose Modification Ins tructions 
 
Additiona l cyc les of therapy may be administered pr ovided that the patient meets the 
follow ing cr iter ia for each cycle : 
 ANC ≥ 1,000/μ l 
 Platelets ≥ 75,000/μ l 
 Non-he matologic toxic ity recovered to ≤ Gra de 1 (or tolerable Grade 2) 
 No evidence of progressive disease 
 
11.2. 1 If multiple toxic ities are experienced, dose modif icat ions w ill be based on the toxic ity 
requir ing the largest dose reduction. 
11.2. 2 Patients who exper ience toxic ities that may be due to e ither agent, ma y have one 
agent reduced or both agents reduced depending on the nature/sever ity of the toxic ity. 
11.2. 3 Patients in whom one agent is de layed or disc ontinue d may continue to receive the 
other agent if , in the opinion of the treating phys ic ian, the patient may continue to 
benefit from treatment. 
11.2. 4 Patients requir ing dose reductions should not have the dose re -escalated wit h 
subsequent treatments. 
11.2. 5 Patients with toxic ities that are manageable with supportive therapy may not require 
dose reductions (e.g., hyper lipide mia may be treated with statins , such as Lipitor™, 
Ame nde d:  05/12/15 


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nausea/vomiting may be treated with antiemetics, diarrhea ma y be treated with 
loperamide rather than by dose reduction). 
11.2. 6 In general, patie nts will be removed from protocol treatme nt if they do not recover to 
CTC Grade 0-1 or tolerable Gra de 2 (or within 1 grade of starting va lues for pre - 
existing la borator y abnorma lities) from a treatment-re lated toxic ity w ithin 4 weeks 
(unless otherw ise specif ied be low) OR they exper ience agent-re lated toxic ities at the 
lowest allowable dose unless in the opinion of the treating phys ic ian (after obta ining 
approval fr om the PI) the patient would benef it from continuing on protocol 
treatment. 
 
 
 
11.3 Dose Re ductions 
 
Sorafe nib 
 
Agent 
Dose 
Level 
Dose 
Sorafenib 
Full Dose 
200 mg bid ( 400 mg tota l dose daily) 
-1 Level 
200 mg daily 
-2 Level 
200 mg every other day 
 
Up to two dose reductions due to unacceptable toxic ity per patient is a llowed per the table 
above. If multiple toxic ities are experienced, dose modif ications w ill be based on the toxic ity 
requir ing the largest dose reduction. 
 
NOTE: If a dose or doses are missed, the rea son(s) and the number of doses not taken s hould 
be noted and recorded in the patient’s chart. 


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Manage me nt of Hype rte ns ion 
Toxicity  
Grade 
Action to be taken 
Hypertension  
(A) Asymptomatic and 
pers is tent SBP of > 140 
and < 170 mmHg, or 
DBP > 90 or < 110 
mmHg, or a clinically s 
ignificant increas e in 
DBP of 20 mmHg (but 
still below 110 mmHg) 
Step 1. Continue study treatment at the current dose. 
Step 2. Adjust current or initiate new antihypertens ive 
medication(s ). 
Step 3. Titrate an tih ypertens ive med icatio n (s ) during next 2 
weeks as indicated to achieve well-controlled b lood pressure 
(BP). If BP is not well-controlled within 2 weeks , cons ider 
referral to a s pecialis t and go to scenario (B). 
 
(B). Asymptomatic 
SBP ≥170 mmHg, or 
DBP ≥110 mmHg, or 
failure to achieve well- 
controlled BP within 2 
weeks in s cenario (A). 
 
 
 
 
(C). Symptomatic 
h ypertens ion or 
recurring SBP ≥170 
mmHg, or DBP ≥110 
mmHg, despite 
modification of 
antihypertens ive 
medication(s ) 
 
 
 
 
(D).  Grade 4 or 
Refractory hypertens ion 
u n resp ons ive to above 
interventions 
Step 1.Cons ider reducing or interrupting s orafenib, as clinically 
indicated. 
Step 2. Adjust current or initiate new antihypertens ive 
med icatio n (s ). 
Step 3. Titrate antihypertens ive medication(s ) during next 2 
weeks as indicated to achieve well-controlled BP. 
Step 4. If sorafenib was interrupted > 1 week, it can be resumed 
with dose-reduced by 1 level once BP is well-controlled. 
 
Step 1. Interrupt sorafenib. 
Step 2. Adjust current or in itiate new antihy pertens ive 
medication(s ). 
Step 3. Titrate an tih ypert ens ive med icatio n (s ) during next 2 
weeks as indicated to achieve well-controlled BP. Referral to a 
specialis t for further evaluation and follow-up is also 
recommended. 
Step 4. Sorafenib can be resumed with dos e-reduced by 1 level 
once BP is well-controlled if sorafenib interrupted > 1 week or at 
the investigator’s dis cretion. 
 
Seek cardiologist opinion, and permanently dis continue 
sorafenib. 
    Abbreviat ions: SBP – Syst olic Blood P ressure; DBP – Diast olic Blood Pressure 
    Blood P ressure Medicat ion suggest ions: dihydropyridine calcium -channel blockers (DHP -CCB; Norvasc 2.5mg and t itrat e up 
t o 10mg), select ive bet a blockers (BB; Toprol 12.5mg and t itrat e), , addit ionally Angiot ensin II Recept or Blockers (ARB) and 
central alpha blockers may be used in conjunct ion wit h a cardiologist . 
    If pat ient s require a delay of > 3 weeks for management of hypert ension, discont inue prot ocol therapy 
    If pat ient s require > 2 dose reduct ions, discont inue prot ocol t herapy 
    P at ient s may have up to 2 drugs (in addit ion to baseline drugs prior t o t herapy) for management of hypert ension prior t o any 
dose reduct ion in Sorafenib. 
    24-48 hour should elapse bet ween modificat ions of ant ihypert ensive therapy 
    Hypert ension should be gra ded using t he NCI CT CAEv4.0 
    If BP is elevat ed and it is felt by t he invest igat or t hat t his is secondary to an ext ernal event (e.g., pain), t he invest igator may 
(aft er document ing reason) delay adjust ing hypert ension medicat ions for up t o 2 working days and have t he blood pressure 
rechecked by a healt h care professional. 


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Dose De lays /Dose Modifications for s orafe nib 
Ad vers e Event 
Treatment Modifications 
Cardiac General 
Hypertens ion 
Refer to table in 11.3 
Dermatology/Skin 
Grade 2 & 3 
Hand /foo t s kin reaction 
Hold dose. 
Re-evalu at e at least weekly until to xicity resolves to < Grade 1 or 
tolerable Grade 2. 
Re-treat at a one dose level reduction. 
If toxicity pers ists at grade 3 or intolerable at grade 2 for > 2 weeks , 
then stop s orafenib. 
Patients with Grade 4 to xicity related to sorafenib may be removed 
from s orafenib and continue tems irolimus at the d iscretio n o f the 
treating phys ician after obtaining approval from the PI. 
Grade 3 
Rash-acne/acneiform 
Hold dose. 
 
If to xicity has not resolved to < Grade 1 or tolerable Grade 2 
within 2 weeks , d isco ntinu e sorafenib treatment. 
 
If < Grade 2, re-treat at one dose level reduction. 
 
If to xicity p ers ists > 3 weeks , remov e patient fro m both sorafenib 
and tems irolimus treatment. 
 
Patients with Grade 4 toxicities related to sorafenib may be 
removed fro m sorafenib treatment and continue tems irolimus at 
the dis cretion of the treating phys ician after obtaining approval 
from the PI. 
All other non-hematologic advers e events 
Grade 0-2 
Grade 2 toxicities that are pers is tent and intolerable (i.e., stomatitis ) 
can result in dose delays or dos e reductions to the next lower dose 
level. 
Grade 3-4 
Hold dose if poss ibly related to sorafenib. 
 
Re-evaluate until toxicity resolves to < Grade 1 (or tolerable 
Grade 2). 
 
If toxicity pers ists > 2 weeks and is felt to be poss ible, probably 
or definitely related to s orafenib, remove patient from s orafenib 
treatment and continue tems irolimus . 
 
Patients with Grade 4 toxicities related to sorafenib may be 
removed from sorafenib treatment and continue tems irolimus at 
the dis cretion of the treating phys ician after obtaining approval 
fro m the PI. 
GI Perforation 
In the event of a GI perforation, patients mus t be removed from 
protocol treatment. 
 
If toxicities are not listed in the table, dos es may be reduced or held at the dis cretion of the treating phys ician for 
the patient’s s afety ; h o wev er, th is s hou ld no t b e witho ut th e co ns en t o f th e Princip al Inves tigator (Eric Sherman), or, if 
abs ent/un av ailab le, the su rrog at e to the PI. If the PI is unavailable, the surrogate may be eith er co-PI (David Pfis 
ter or James Fagin). In addition, if there is an un fo res een event such as a surgical procedure (i.e. to oth  extraction), 
at the inves tigator’s discretion, sorafenib may be held for up to 2 weeks . 


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Te ms irolimus 
 
Agent 
Dose 
Level 
Dose 
Temsir olimus 
Full Dose 
25 mg/week 
-1 Level 
15 mg/week 
-2 Level 
10 mg/week 
 
All patie nts should be monitore d while receiving te ms irolimus infus ion and health care 
personne l must be readily availa ble to respond to hypersensitivity reactions or other 
emergencies. If the patient begins to deve lop a hypersens itivity reaction despite pretreatment 
with diphenhydramine, the infus ion should be stopped for at least 30 – 60 minutes, depe nding 
upon the sever ity of the reaction. The infus ion may be resumed by adminis tering a hista mine 
H2-receptor antagonist appr oximate ly 30 minutes before restarting the tems ir olimus inf us ion. 
Famotidine 20 mg IV or ranitidine 50 mg IV are recommended rather than c imetidine because 
of the lack of like ly metabolic /pharmacologic interactions with the for mer drugs. The rate of 
the tems irolimus infus ion may als o be slowed from 30 minutes to over an hour. 
 
In the event of toxic ity, the dose of CCI-779 (tems ir olimus) w ill be adjusted according to the 
guidelines in the table be low. If toxic it ies are not listed in t he table, doses may be reduced or 
held at the discretion of the treating phys ician f or the pat ient’s safety; however, t his should 
not be w ithout the consent of the Princ ipa l Invest igator (Er ic Sher man), or, if 
absent/una vaila ble, the surrogate to the PI. If the PI is unava ilable , the surrogate may be either 
co-PI (David Pfister or James Fagin). Dose adjustments for hematologica l toxic ity are based 
on the blood counts obta ined in preparation for the day of treatment. 
 
Patients who exper ience toxic ities due to CCI- 779 (tems irolimus) but with an unrelated or 
unlike ly re lationship to the other agent should have the ir treatment modif ied according to the 
directions in the table be low. If a dose reduction is required, the dose of CCI-779 
(temsir olimus) should be reduced, but the dose of the other agent should rema in at the current 
leve l. 
 
A dose of tems irolimus may be missed due to certain patient-re lated (e.g., family emergenc y), 
weather-related (e.g., snow stor m) , or hos pita l-re lated (e.g., holiday) events. If poss ible , 
subjects should be rescheduled to receive the tems ir olimus w ithin 2 days of the event. If not, 
the dose of tems ir olimus may be missed, but the subject should continue taking the sorafenib 
as per protocol. 


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Dose De lays /Dose Modifications for te ms irolimus 
 
Ad vers e Even t 
Treatment Modifications 
Blood/Bone Marrow 
Grade 3 
Neutrophils 
ANC 500-999 
Platelets 
50,000-75,000 
Delay tems irolimus and s orafenib until recovery to both ANC >= 1000 
and platelets > 75,000. 
Retreat at one dose level reduction for the tems irolimus if delay caus es 
more than 1 dos e of tems irolimus to be held cons ecutively. If this has 
occurred more than 1 time during the s ame cycle, als o reduce 
tems irolimus by 1 dose level. If this has occurred more than 1 time 
during the protocol, it is the investigator’s decis ion whether to reduce 
tems irolimus by 1 dose level. If tems irolimus has been decreased 1 
dose level previous ly, decrease either tems irolimus or sorafenib by 1 
dose level (investigator’s decis ion). 
If recovery requires > 2 doses of tems irolimus to be held 
consecutively, discontinue tems irolimus and continue s orafenib. 
Grade 4 
Neutrophils 
ANC <500 
Platelets 
<50,000 
Delay tems irolimus and s orafenib until recovery to < Grade 2. 
Retreat at one dose level reduction for the tems irolimus . If tems 
irolimus has been decreased 1 dos e level, decrease either tems 
irolimus or sorafenib by 1 dose level (investigator’s decis ion).If 
recovery requires > 2 weeks , d iscontinu e t ems irolimus and continue 
sorafenib. 
Pu lmo nary/ Upper Res piratory
Pneumonitis (cough, dyspnea, 
fever) 
Dis continue tems irolimus pending investigation. If d iagn os is is 
confirmed and events are cons idered at least poss ibly due to 
tems iro limu s , the patient should be removed from tems irolimus 
treatment and may con tin ue sorafenib. 
All o th er no n -h emato lo g ic advers e events 
Grade 0-2 
Grade 2 to xicities that are p ers is tent and intolerable (i.e., sto matitis ) 
can result in dose delays o r dos e reductions to the next lower dose 
level. 
Grade 3-4 
Hold dose if poss ibly related to tems iro limu s . 
 
Re-evaluate until toxicity resolves to < Grade 1 (or tolerable 
Grade 2). 
 
If to xicity p ers ists > 2 weeks and is felt to be poss ible, probably 
or definitely related to tems irolimus , remove patient from 
tems irolimus treat men t and continu e sorafenib. 
 
Patients with Grade 4 to xicities related to tems irolimus may be 
removed fro m t ems irolimus treatment and con tin ue sorafenib at 
the dis cretion of the treating phys ician. 
Grade 3: 
Hyperlipidemia 
Treat with antihyperlipidemics  and continue tems irolimus as long as 
hyperlipidemia can be main tained at < Grade 2. 
If to xicities are not listed in the table, dos es may be reduced or held at the dis cretion of the treating phys ician for 
the patient’s s afety ; h o wev er, th is s hou ld no t b e witho ut th e co ns en t o f th e Princip al Inves tigator (Eric Sherman), or, if 
abs ent/unavailable, the su rrog at e to the PI. If the PI is unavailable, the surrogate may be eith er co -PI (Dav id Pfis 
ter or James Fagin). 


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12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOM E ASSESSMENT 
 
For the purposes of this study, patients should be reevaluated for response every 2 cycles. In 
addition to a baseline scan, conf irmatory scans should a lso be obta ined 4-8 weeks follow ing 
initia l documentation of objective response. 
 
12.1     Definitions 
 
Response and pr ogress ion will be evaluated in this study us ing the new internationa l 
criter ia proposed by the Response Eva luation Cr iter ia in Solid Tumors (RECIST) 
Committee [JNCI 92(3) :205-216, 2000].  Changes in only the largest diameter 
(unidime ns ional measurement) of the tumor les ions are used in the RECIST criter ia. 
Note: Les ions are either measurable or non- measurable us ing the criter ia pr ovided 
below. The term “eva luable” in reference to measurability w ill not be used because it 
does not provide additiona l meaning or accuracy. 
 
12.1. 1  Measurable disease 
 
Measurable les ions are defined as those that can be accurately measured in at 
least one dimens ion ( longest diameter to be recorded) as ≥ 20 mm w ith 
conventional techniques (CT, MRI , x-ray) or as ≥ 10 mm with spira l CT scan. 
All tumor measurements must be recorded in millimeters (or dec ima l fractions 
of centimeters). 
 
12.1. 2  Non-measurable disease 
 
All other lesions (or s ites of disease), inc luding s mall les ions ( longest 
diameter < 20 mm with conventiona l techniques or < 10 mm us ing spira l CT 
scan), are considered non- measurable disease.  Bone lesions , leptomeningeal 
disease, ascites, pleura l/pericardia l effus ions , lymphangitis cutis/pulmonis , 
inf lammator y breast disease, abdomina l masses (not followed by CT or MRI) , 
and cystic les ions are all non- measurable. 
 
12.1. 3  Target les ions 
 
All measurable les ions up to a maximum of f ive les ions per organ and 10 
les ions in total, representative of a ll involved organs , should be identif ie d as 
target les ions and recorded and measured at baseline.  Target lesions should 
be selected on the bas is of the ir s ize (les ions w ith the longest diameter) and 
their s uitability for accurate repeated measurements (either by imaging 
techniques or clinically).  A sum of the longest diameter (LD) for all target 
les ions will be calculated and reported as the baseline sum LD.  The baseline 
sum LD w ill be used as reference by which to characterize the objective tumor 
response. 


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evaluation has not yet been f ully and w ide ly validated.  The ir uses in this spec if ic 
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12.1. 4  Non-target les ions 
 
All other lesions (or s ites of disease) should be identif ied as non-target lesions 
and should a lso be recorded at baseline.  Non-target les ions inc lude 
measurable les ions that exceed the maximum numbers per organ or tota l of a ll 
involved organs as well as non-measurable lesions.  Measurements of these 
les ions are not required, but the presence or absence of each should be noted 
throughout follow-up. 
 
12.2 
Guide lines for Evaluation of Measurable D isease 
 
All measurements should be taken and recorded in metr ic notation us ing a ruler or 
calipers.  All base line eva luations should be perfor med as close ly as poss ible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identif ied and reported les ion at baseline and dur ing f ollow - up. 
Imaging-based eva luation is preferred to eva luation by c linica l examination when 
both methods ha ve been used to assess the antitumor effect of a treatment. 
 
 
Clinical les ions.  Clinica l lesions w ill only be cons idered measurable when they are 
superf icia l (e.g., s kin nodules and pa lpable lymph nodes).  In the case of skin lesions , 
documentation by color photography, inc luding a ruler to estimate the s ize of the 
les ion, is recommended. 
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable les ions when they 
are clearly def ine d and surr ounded by aerated lung.  However, CT is preferable. 
 
Conventiona l CT and MRI.  These techniques should be perfor med w ith cuts of 10 
mm or less in s lice thickness contiguous ly.  Spiral CT should be perfor med us ing a 5 
mm contiguous reconstruction a lgor ithm.  This applies to tumors of the chest, 
abdomen, and pe lvis.  Head and neck tumors and those of extremities us ually re quire 
specif ic protocols. 
 
Ultrasound (US).  When the pr imary endpoint of the study is objective response 
evaluation, US should not be used to measure tumor lesions.  It is , however, a 
poss ible a lternative to clinica l measurements of superf ic ial palpable lymph nodes , 
subcutaneous lesions , and thyr oid nodules.  US might a lso be useful to conf ir m the 
complete disappearance of superfic ia l les ions usua lly assessed by clinica l 
examination. 
 
Endoscopy, Lapar oscopy.  The utilization of these techniques for objective tumor 


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context require sophis ticated equipment and a high leve l of expertise that ma y only be 
available in some centers.  Therefore, the utilization of such techniques for objective 
tumor response should be restricted to va lidation pur poses in reference centers. 
However, such techniques may be useful to conf irm complete pathologica l response 
when biops ies are obtained. 
 
Tumor markers.  Tumor mar kers alone cannot be used to assess response.  If markers 
are initia lly above the upper nor ma l limit, they must norma lize for a patie nt to be 
cons idered in complete c linica l response.  Specif ic additional cr iter ia for standardized 
usage of prostate-specif ic antigen (PSA) and CA-125 response in support of clinical 
tria ls are being de velope d. 
 
Cytology, Histology.  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residua l lesions in 
tumor types, such as germ cell tumors , where know n residua l benign tumors can 
remain). 
 
 
The cytologica l conf ir mation of the neoplastic or igin of any effus ion that appears or 
worsens dur ing treatment w hen the measurable tumor has met criter ia for response or 
stable disease is mandator y to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and pr ogress ive disease. 
 
 
12.3 
Response Criteria 
 
12.3.1 Evaluation of target les ions 
 
Comple te Res ponse (CR): Disappearance of all target les ions 
 
Partial Res ponse (PR): 
At least a 30% decrease in the sum of the 
longest diameter (LD) of target les ions , taking 
as reference the baseline sum LD 
 
Progress ive Dise ase (PD): At least a 20% increase in the sum of the LD of 
target les ions, taking as reference the smallest 
sum LD recorded s ince the treatment started or 
the appearance of one or more new lesions 
 
Stable Dise ase (SD): 
Neither suff ic ient shr inkage to qualify for PR 
nor suff ic ient increase to qualif y for PD, taking 
as reference the smallest sum LD since the 
treatment started 
 
12.3.2 Evaluation of non- target lesions 


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Comple te Res ponse (CR): Disappearance of all non-target lesions and 
nor malization of tumor marker leve l 
 
 
 
 
 
 
Incomple te Res ponse / 
Stable Dise ase (SD): 
Persistence of one or more non-tar get les ion(s) 
and/or ma intena nce of tumor marker leve l above 
the nor ma l limits 
 
Progress ive Dise ase (PD):    Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
les ions 
 
Although a clear progress ion of “non-target” lesions only is exceptiona l, in 
such circumstances the opinion of the treating phys ic ian should preva il, and 
the progression status should be conf ir med at a later time by the review panel 
(or study chair). 
 
Note: If tumor markers are initia lly above the upper nor ma l limit , they must 
nor malize for a patient to be cons idered in complete clinical response. 
 
 
 
12.3.3 Evaluation of best overall response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progress ion/recurrence (taking as reference for 
progress ive disease the smallest measurements recorded s ince the treatment 
started).  The patient's best response assignment w ill de pend on the 
achieveme nt of both measurement and conf ir mation criteria (see Sections 
12.3. 1 and 12.4.1). 
 
 
Targe t Les ions 
Non-Targe t 
Les ions 
Ne w Les ions 
Ove rall Res ponse 
 
CR 
CR 
No 
CR 
 
CR 
 Incomple te 
res ponse /SD 
No 
PR 
 
PR                           Non-PD                          No                             PR 
SD                           Non-PD                          No                             SD 
PD                               Any                       Yes or No                       PD 


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Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Note : 
 Patients with a globa l deterioration of hea lth status requir ing disc ontinuation 
of treatment w ithout objective evidence of disease progression at that time 
should be class if ied as having “symptomatic deter ioration.”  Every effort 
should be made to document the objective progression, even after 
discontinuation of treatment. 
 In some circ umstances, it may be diff ic ult to distinguish residua l disease from 
nor mal tiss ue.  When the evaluation of complete response depe nds on this 
determination, it is recommende d that the residua l les ion be investigated (f ine 
needle aspirate) before conf ir ming the complete response status. 
 
 
 
12.4 
Conf ir mator y Measurement/D uration of Response 
 
12.4.1 Conf ir mation 
 
To be assigned a status of PR or CR, changes in tumor measurements must be 
conf irme d by repeat assessments that should be perfor med a minimum of 4 
weeks after the criteria for response are first met.  In the case of SD, follow -up 
measurements must have met the SD cr iter ia at least once after study entry at 
a minimum interva l of 6 weeks (see section 12.3.3). 
 
12.4.2 Duration of overa ll response 
 
The duration of overa ll response is measured from the time measurement 
criter ia are met for CR or PR (whichever is f irst recorded) until the first date 
that recurrent or progressive disease is objective ly doc umented (taking as 
reference for progressive disease the smallest measureme nts recorded since 
the treatment started). 
 
The duration of overa ll CR is measured from the time measurement criter ia 
are first met for CR until the f irst date that recurrent disease is objective ly 
documented. 
 
12.4.3 Duration of Stable D isease 
 
Stable disease is measured from the start of the treatment until the cr iter ia for 
progress ion are met, taking as reference the smallest measureme nts recorded 
since the treatment started. 


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12.4.4 Treatment failure 
 
All of the patients who met the eligibility criteria (w ith the exception of those 
who received no study medication) and are evalua ble should be include d in 
the ma in ana lys is of the response rate, even if there are major pr otocol 
treatment deviations.  Each patient w ill be assigned one of the follow ing 
categories : 1) complete response , 2) partia l response, 3) stable disease, 4) 
progress ive disease, 5) early death from ma ligna nt disease, 6) early death 
from toxic ity, 7) early death because of other cause, or 9) unknow n (not 
assessable, insuff ic ient data).  [Note: By arbitrary convention, categor y 9 
usua lly designates the “unknown” status of any type of data in a clinical 
database.]. Patients in response categories 4-7 should be cons idered to ha ve a 
treatment failure (disease progression) at the time of the event and as 
progress ion of disease for response rate if occurs before second restaging 
imaging.. Category 9 will c ount as disease progress ion if it occurs before a 
second restaging scan after the initiatio n of treatment unless subject is 
ineligible or ineva luable. Thus , an inc orrect treatment schedule or dr ug 
adminis tration does not result in exc lus ion from the analys is of the response 
rate. 
 
12.4.5 Definition of ine ligible/ineva luable 
 
A subject is cons idered ine ligible for ana lys is if it is found after the start of 
treatment that the subject did not meet the e ligibility cr iter ia unless a deviation 
has been approve d by the IRB or the only deviation is lack of RECIST criter ia 
les ion (see next paragraph). 
 
A subject will be c lassif ied as ineva luable for response if it is determined after 
the initiation of therapy that the subject did not have any les ions that met 
RECIST criter ia unless a new lesion appears by the end of 2 cyc les in which 
case the subject will be c lassif ie d as PD. 
 
12.5 
Progression-Free Sur viva l 
 
Progression-Free Sur viva l (PFS) is def ined as the duration of time from day 1 of 
treatment to time of disease progress ion, or death from any cause , whichever comes 
first.  For this tr ia l, the pr imar y PFS endpoint will be at the 1 year time point. 
 
12.6 
Response Review 
 
All radiologic studies perf ormed to establish RECIST baseline tumor measurements 
and for subsequent response assessment purposes will be reviewed by an institutiona l 
reference radiologist. 


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MSKCC for thyroidectomies; approximately 60% of these cases are patients with well- 
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13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
In the absence of treatment dela ys due to adverse event(s), treatment may continue until 
one of the follow ing cr iter ia applies. 
 
 Disease progression, 
 
 Intercurrent illness that prevents further adminis tration of treatment, 
 
 Unacceptable adverse event(s), 
 
 Patient noncompliance as  determined by the judgment of the investigator that 
would make f urther treatment potentia lly unsafe or make outcomes of the tr ia l 
diff icult to interpret, 
 
 
 Arteria l   thromboembolic    events    inc luding    cerebrovascular    accidents , 
myocardial infarctions, trans ient ische mic attacks, new onset or worsening of 
pre-existing angina. 
 
 Patient decides to w ithdraw from the study, or 
 
 General  or  s pecif ic  changes  in  the  patient’s  condition  render  the  patient 
unacceptable for further treatment in the judgment of the investigator. 
 
14.0 
B IOSTATISTICS 
 
14.1 Study Design/Endpoints 
 
An exact one stage Phase II design w ill be employed to assess the primary endpoint of 
radiographic response rate (partial response or complete response , by RECI ST criter ia) of the 
combination sorafenib and tems ir olimus w ithin 4 months s ince the start of therapy. A 15% 
response-rate within 4 months is cons idered not promis ing (based on previous tw o studies 
evaluating s orafenib as a single agent in the treatment of thyroid cancer, which reported 
response rates of 23% 21 and 11.5% 23) , a 34% response rate is cons idered promis ing, and the 
proba bilities of a Type I error (falsely accepting a non- promis ing therapy) and Type II error 
(falsely re jecting a promis ing therapy) are set to 0.1 and 0.1, respective ly. We will eva luate a 
tota l of 36 patients. If 9 or more of the 36 patients eva luated w ill have a response, the regimen 
will be cons idered worthy of f urther investigation. 
 
14.2 Sa mple Size/Accrual Rate 
 
Thirty-s ix patients will need to be eva luated for this tr ia l. We antic ipate 10% of the patients 
enrolled to become ine ligible/ineva luable dur ing the study, so we are prepared to accrue a 
maximum of 40 patients. There are approximate ly 200 patients per year who are referred to 


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differentiated thyroid cancer. An additiona l equiva lent number of cases are referred to the 
MSKCC departme nt of Endocr inology for recommendation of treatment options on an annua l 
basis. About 25-50% are expected to develop RAI-refractory recurrent or metastatic disease 
over the next year. In our most recent clinica l study w ith this treatment population, 21 patients 
were accrued to the study in under 5 months. From this infor mation, we antic ipate accruing a 
minimum of 3 patients per month , thereby f inis hing accrual to the clinical study w ithin 
maximum 14 months. 
 
14.3 Ana lys is of Secondary Endpoints 
 
Progression-free surviva l cur ves will be ge nerated using Kaplan- Me ier methodology, w ith 
time or igin at the start of the treatment. Reporte d data from the phase II study at Ohio State 
suggested an appr oximate 1- year disease free surviva l rate of 47% under Sorafenib 
monotherapy. A ll patients enr olled and evaluable who receive at least one dose of the 
treatment will be inc luded in this ana lys is. With 36 eva lua ble patients , we will have 80% 
power to detect an increase of 18% in PFS at 1 year, at a leve l α = 0.1. 
 
Analys is of BRAF mutation, with or w ithout concomitant mutations in the PI3K AKT, mTOR 
pathway, will be exploratory and hypothes is generating. We will compare the two BRAF 
groups , as well as subgroups determined by conc omitant mutations , with respect to response 
rates (using logis tic regression) and to PFS (us ing Cox proportional- hazards regress ion). 
 
The safety population w ill compr ise all patients who receive at least 1 dose of study treatment. 
Safety and tolerability w ill be assessed in ter ms of AEs, laboratory data and vita l s ign data, 
which will be collected for all patients. Appr opr iate summar ies of these data will be presented. 
AEs (by CTCAE grade) will be lis ted individually by patient. The number of patients 
experie ncing each AE will be summar ized by CTCAE gra de. 
 
14.4 Evaluation of response 
 
All of the patients who met the eligibility criteria (w ith the exception of those who received no 
study medication) and are evalua ble should be inc luded in the ma in analys is of the response 
rate, even if there are major pr otoc ol treatment de viations.  Each patient w ill be assigned one 
of the follow ing categor ies : 1) complete response, 2) partia l response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxic ity, 7) 
early death because of other cause, or 9) unknow n (not assessable, ins uff icie nt data).  [Note: 
By arbitrary convention, category 9 usua lly des ignates the “unknown” status of any type of 
data in a clinica l database.]. Patients in response categor ies 4-7 should be 
cons idered to have a treatment failure (disease progress ion) at the time of the event and as 
progress ion of disease for response rate if occurs before second restaging imaging. . Category 
9 will count as disease progress ion if it occurs before a second restaging scan after the 
initiation of treatme nt unless subject is ine ligible or ineva luable. Thus , an incorrect treatment 
schedule or drug administration does not result in exc lus ion fr om the analys is of the response 
rate. 


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All conclus ions should be based on a ll eligible patients.  Subana lyses may then be performe d 
on the bas is of a subset of patients, exc luding those for whom ma jor protocol deviations have 
been identif ie d (e.g., early death due to other reasons , early discontinuation of treatment, 
major pr otoc ol violations, etc.).  However, these subanalyses may not serve as the basis for 
drawing conclus ions concerning treatment efficacy, and the reasons for excluding patients 
from the analys is should be c learly reported. 
 
 
 
 
15.0 
RES EARCH PAR TICIPANT R EGISTRA TION AND RANDO MIZA TION 
PROCED UR ES 
 
15.1 
Rese arch Participant Re gis tration 
 
Conf ir m eligibility as defined in the section entitled Cr iter ia for Patient/Subject 
Eligibility. 
 
Obtain inf orme d consent, by follow ing procedures defined in section entitled I nfor med 
Consent Procedures. 
 
During the registration process register ing individua ls will be required to complete a 
protocol spec if ic Eligibility Checklist. 
 
All partic ipants must be registered thr ough the Protoc ol Partic ipant Registration (PPR) 
Office at Memor ia l Sloan-Kettering Cancer Center. PPR is available Monday thr ough 
Fr iday from 8:30a m – 5:30pm at 646- 735-8000. The PPR fax numbers are (646) 735- 
0008 and ( 646) 735-0003. Registrations can be phoned in or faxed. The comple ted 
signature page of the writte n consent/verba l script and a completed Eligibility Checklist 
must be faxed to PPR. 
 
 
 
16.0 
DATA MANAGEMENT ISSUES 
 
A Research Study Ass istant (RSA) w ill be assigned to the study. The respons ibilities of the 
RSA include pr oject compliance, data collection, abstraction and entry, data reporting, 
regulator y monitor ing, pr oble m resolution and pr ior itization, and coor dinate the activities of 
the protocol study team. The data collected for this study will be entered into a secure 
database. Source docume ntation will be availa ble to support the computerized patie nt record. 
 
16.1 
Quality As s urance 
 
Registration reports will be generated to monitor patient’s accruals and completeness 
of registration data.  Routine data quality reports will be generated to assess miss ing 
data and incons iste ncies.  Accrual rates and extent and accuracy of evaluations and 
follow- up w ill be monitore d per iodically thr oughout the study and potential problems 
will be brought to the attention of the study team for disc ussion. 


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Random-Sample data qua lity and protocol complia nce audits may be conducted by 
the study team, at a minimum of once a year, more frequently if indicated. 
 
16.2 
Data and Safe ty Monitoring 
 
The Data and Safety Monitor ing (DSM) Pla ns at Memor ia l Sloan-Kettering Cancer 
Center were approved by the Nationa l Cancer Institute in September 2001. The plans 
address the new polic ies set forth by the NCI in the document entitled “Polic y of the 
Nationa l Cancer Institute for Data and Safety Monitor ing of C linica l Tr ia ls” which can 
be found at: htt p://cancertr ia ls.nci. nih. gov/researchers/dsm/ index.ht ml. The DSM Pla ns 
at MSKCC were established and are monitored by the Off ice of Clinica l Research. The 
MSKCC Data and Safety Monitor ing Pla ns can be found on the MSKCC Intranet at: 
http://msk web2.mskcc.org/irb/index.htm 
 
There are several different mechanis ms by whic h clinica l tr ials are monitored for data , 
safety and qua lity. There are institutiona l processes in place for quality assurance (e.g., 
protocol monitor ing, complia nce and data verif ication audits, therapeutic response, and 
staff education on c linical research QA) and departmenta l pr ocedures for qua lity control, 
plus there are two institutional committees that are responsible for monitor ing the 
activities of our c linica l tr ia ls pr ograms. The committees: Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical tr ia ls , and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinica l tr ia ls, report to the Center’s Research Counc il and 
Institutional Review Board. 
 
During the protocol deve lopment and review process, each protocol w ill be assessed for 
it’s leve l of r is k and degree of monitor ing required. Every type of pr otocol (e.g., NIH 
spons ored, in-house sponsore d, industr ia l sponsored, NCI cooperative group, etc.) will 
be addressed and the monitor ing pr ocedures will be establis hed a t the time of pr otocol 
activation. 
 
 
 
17.0    PROTECTION OF HUMAN SUB JECTS 
 
17.0.1 Risks , Be ne fits , Toxicities /s ide e ffects 
Potential r is ks to human subjects inc lude drug related toxic ity, pa in and discomfort assoc iated 
with mucos itis , sorafenib and tems irolimus, placement of IV catheters (if necessary), 
phlebotomy, and possible psychologica l discomfor t from the stresses associated with obta ining 
imaging studies (e.g., CT scan). The side effects and potentia l toxic ities of sorafenib and 
temsir olimus are describe d in Section 5. A ll efforts will be made to avoid any complication by 
complete ly reviewing patients’ symptoms , pr oviding appr opr iate ma nagement, and monitor ing 
blood tests. 
 
If an adverse medica l event occurs , the patient w ill f irst contact the pr imar y oncologist or the 
Princ ipa l Investigator. At nights and on weekends, there is an onc ology phys ic ian on call at a ll 


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times. Patients may e ither call or come directly to the ur gent care center at Memor ia l Hospita l (or 
to the ir loca l emergency r oom) to be seen. Patients suffering ser ious adverse reactions must be 
carefully f ollowed and all f ollow-up infor mation a lso recorded. 
 
 
17.0.2 Alte rnatives /options 
Patients other choices may inc lude taking part in another study or getting treatment w ithout 
being in a study. Partic ipation in this tr ia l is voluntary. 
 
Depending on the specif ic deta ils of the situation, patient options w ithout be ing in a study might 
include : 
Doxor ubic in or other cytotoxic chemotherapy 
Sorafenib 
 
At MSKCC, the standard radiation treatment outs ide of a clinica l tr ia l for patients w ith RAI 
refractory thyr oid cancer would be either doxorubic in or sorafenib. 
 
 
17.0.3 Financial Cos ts /B urde ns 
 
The patient w ill be respons ible for a ll costs related to trea tment and complications of treatment. 
Costs to the patient (third party ins urer) will inc lude the cost of sorafenib, hospita lizations , 
routine blood tests , diagnostic studies, off ice vis its , base line EK G, and doctor’s fees. 
 
17.1 
Privacy 
 
 
 
MSKCC’s Privacy Off ice may allow the use and disc los ure of protected health 
infor mation pursuant to a completed and signe d Research Author ization f orm.  The use 
and disc los ure of protected hea lth infor mation w ill be limited to the individua ls descr ibed 
in the Research Author ization form.  A Research Author ization f orm must be completed 
by the Princ ipa l Investigator and appr oved by the IRB and Privacy Board. 
 
 
17.2 
Se rious Adve rse Eve nt (SAE) Re porting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar days. 
The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronica lly to the SAE Off ice at  sae@mskcc.orgcontaining the follow ing infor mation: 
Fields populate d from t he CRDB: 
 Subject’s name (generate the report w ith only init ia ls if it will be sent outs ide of 
MSKCC) 
 Medical record number 
 Disease/histology ( if applicable) 
 Protocol number and title 
 
Data needing to be entered: 


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 The date the adverse event occurred 
 The adverse event 
 Relationship of the adverse event to the treatment (dr ug, device, or interve ntion) 
 If the AE was expected 
 The severity of the AE 
 The intervention 
 Detailed text that inc ludes the follow ing infor mation: 
o A expla nation of how the AE was handle d 
o A description of the subject's condition 
o Indication if the subject rema ins on the study 
o If an amendment will need to be made to the pr otocol and/or consent for m 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
 
17.2.1 Se rious Adve rse Eve nt Re porting to Pfize r and the NCCN 
Reporting of Ser ious Adverse Events: Within 24 hours of f irst awareness of the event (immediate ly 
if the event is fata l or life-threatening) , Principa l Investigator w ill report to Pfizer and NCCN by 
facsimile  certain Ser ious Adverse Events (“SAEs ,” as defined below) for which reporting is 
required under this provis ion (as described be low).  Such SAEs are to be reported for (1) S tudy 
subjects who are assigned or, in the case of a blinded Study, poss ibly assigned to receive the Study 
Drug or (2) individua ls otherwise exposed to the Study Drug as described be low.  Principa l 
Investigator should report SAEs as soon as they are determined to meet the def inition, even if 
complete inf or mation is not yet ava ilable. 
 
(a) 
Reporting Forms.  Princ ipal I nvestigator w ill submit reportable SAEs us ing one of the 
follow ing f orms : (1) a reporting for m approved by the loca l regulatory author ity, (2) a CIOMS for m, 
(3) a Pfizer-provided Investigator-I nitiated Research Serious Adverse Event Form, or ( 4) any other 
form pr ospective ly appr oved by Pfizer. The Reportable Eve nt Fax Cover Sheet provide d by Pf izer 
must a lso be inc luded w ith each SAE submitted (Appendix A).  Such reports sha ll be directed to 
NCCN via fax at 215- 358-7699 or e-ma iled to ORPReports@nccn.org and to the Pfizer U.S. Clinical 
Tria l Departme nt at 1-866- 997-8322: 
 
(b) 
SAE Definition.  An SAE is any adverse event, w ithout regard to caus ality, that is life-
threatening ( i.e., causes an immediate r isk of death) or that results in any of the follow ing outcomes : 
death; in- patient hospita lization or prolongation of existing hos pita lization; pers istent or signif icant 
disability or incapacity (i.e., substantia l disruption of the ability to conduct norma l life functions); or a 
congenita l anoma ly or birth defect.  Any other medica l event that, in the medica l judgment of the 
Princ ipa l Investigator , ma y jeopardize the subject or may require medical or surgica l intervention to 
prevent one of the outcomes listed above is a lso cons idered an SAE.  A planned medical or surgica l 
pr ocedure is not, in itself , an SAE. 
 
 
 
(c) 
Subset of SAEs Reportable for this Study.  Because the Study Drug used in this Study 
is a mature marketed product w ith a well-establis hed safety prof ile , only SAEs that f it into any of the 


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follow ing categor ies need to be reported to Pf izer and NCCN : (1) a death, regardless of whether it is 
cons idered re lated to treatment w ith the Study Drug, (2) a non-fatal SAE that occurs dur ing the 
reporting per iod and that is assessed by the Principa l Investigator as both related to treatment w ith 
the Study Drug and unexpected for that product, (3) an SAE assessed by the Princ ipal I nvestigator as 
related to the Study Drug that occurs after the SAE reporting per iod, or (4) an otherw ise reportable 
event as described in Section d, be low.  An event should be cons idered “re lated” to the Study Drug if 
a relations hip is at least a reasonable poss ibility, and “u nexpectedness” should be based upon a 
single safety reference document identif ied by the Principa l Investigator and documente d in 
association with the study. 
 
(d) 
Exposure Dur ing Pregnancy, Exposure Dur ing Lactation, Occupationa l Exposure, and 
Lack Of Effect.  Even though there may not be an associated SAE, exposure to the Study Drug dur 
ing pre gnancy, exposure to the Study Drug dur ing lactation, and occupationa l exposure to the Study 
Drug are reportable, and lack of effect of the Study Drug may a lso be reportable.  These 
requirements are further expla ined in the training mater ia l pr ovided by Pfizer (see Pfizer -Provided 
Training, below).  As used in this Agreement, the term SAE w ill be understood to include exposure 
dur ing pre gnancy, exposure dur ing lactation , occupational expos ure, and reportable insta nces of lack 
of effect. 
 
(e) 
SAE Reporting Period.  The SAEs that are subject to this reporting provis ion are those 
that occur from after the first dose of the Study Drug thr ough 28 da ys after discontinuation of the 
Study Drug, or longer if so specif ie d in the Protoc ol.  In addition, if Princ ipa l Investigator becomes 
aware of an SAE occurring any time after the administration of the last dose of the Study Drug, Princ 
ipal I nvestigator should report that SAE to Pfizer and NCCN if the Princ ipa l Investigator suspects a 
causal relations hip between the Study Drug and the SAE. 
 
(f) 
Follow-Up Inf ormation.  Institution w ill assist Pf izer in investigating any SAE and 
will provide any f ollow- up infor mation reasonably requested by Pf izer. 
 
(g) 
Regulator y Reporting.  Reporting an SAE to Pfizer and NCCN does not relie ve 
Institution of respons ibility f or reporting it to appr opr iate regulatory author ities, if such reporting is 
required. 
 
(h) 
Pfizer-Provided Tra ining.  Pfizer will make availa ble training mater ia l that pr ovides 
infor mation about the SAE repor ting require ments for IIR studies.  Principa l Investigator w ill review 
this mater ia l and share it w ith any Study staff engaged in the reporting of SAEs. 
 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specif ie d procedures are carried out, consenting pr ofessiona ls w ill 
expla in full deta ils of the pr otoc ol and study procedures as well as the risks involved to 
partic ipants pr ior to the ir inc lus ion in the study. Partic ipants will a lso be infor med that 
they are free to withdraw from the study at any time. All partic ipants must sign an 


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IRB/PB-approved consent for m indicating the ir consent to partic ipate. This consent form 
meets the requirements of the Code of Federa l Regulations and the Institutiona l Review 
Board/Privacy Board of this Center. The consent for m w ill inc lude the follow ing: 
 
1.   The nature and objectives, potentia l ris ks and benef its of the intended study. 
2.   The length of study and the like ly f ollow-up required. 
3.   Alternatives to the pr oposed study. (This w ill inc lude ava ilable standard and 
investigationa l therapies. In addition, patients w ill be offered an option of 
supportive care for therapeutic studies.) 
4.   The name of the investigator(s) respons ible for the protocol. 
5.   The right of the partic ipant to accept or refuse study interventions/interactions and 
to withdraw from partic ipation at any time. 
 
Before any protocol-spec if ic procedures can be carried out, the consenting profess iona l 
will f ully expla in the aspects of patient pr ivacy concerning research specif ic infor mation. 
 
In addition to s igning the IRB Infor med Consent, all patients must agree to the Research 
Author ization compone nt of the inf or med consent f orm. 
 
Each partic ipant and consenting pr ofessiona l w ill s ign the consent form. The participant 
must receive a copy of the s igned inf ormed consent for m. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19.0 
REFERENCE(S) 
 
1. 
Brose MS, Ne llore A, Paziana K, et al: A phase II study of sorafenib in metastatic 
thyr oid carcinoma. J Clin O ncol (Meeting Abstracts) 26:6026- , 2008 
2. 
Ahmed M, Barbachano Y , R iddell A M, et al: Pre liminary results of an open 
labe lled phase 2 study eva luating the safety and efficacy of sorafenib in metastatic adva nced 
thyr oid cancer. J Clin Oncol ( Meeting Abstracts) 26:6060-, 2008 


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3. 
Cohen EE, Vokes EE, Rosen LS, et al: A phase II study of axitinib (AG- 013736 
[AG]) in patients (pts) with advanced thyr oid cancers. J Clin Oncol ( Meeting Abstracts) 
25:6008- , 2007 
4. 
Cohen EE, Needles BM, Culle n KJ, et al: Phase 2 study of sunitinib in refractory 
thyr oid cancer. J Clin Oncol ( Meeting Abstracts) 26:6025-, 2008 
5. 
Pennell NA, Danie ls GH , Haddad RI , et al: A phase II study of gef itinib in 
patie nts with adva nced thyr oid cancer. J Clin Onc ol (Meeting A bstracts) 25:6020- , 2007 
6. 
Ain KB, Lee C, Holbr ook KM, et a l: Phase II study of lena lidomide in distantly 
metastatic , rapidly pr ogress ive, and radioiodine -unrespons ive thyroid carcinomas: preliminary 
results. J Clin Oncol ( Meeting Abstracts) 26:6027-, 2008 
7. 
Ouyang B , Knauf JA, Smith EP, et al: I nhibitors of Raf kinase activity block 
growth of thyroid cancer cells w ith RET/PTC or BRAF mutations in vitr o and in vivo. C lin 
Cancer Res 12:1785-93, 2006 
8.         Ball DW, J in N, Rosen DM, et al: Se lective Growth Inhibition in BRAF Mutant 
Thyr oid Cancer by the Mitogen-Activated Prote in K inase Kinase 1/2 Inhibitor AZD6244. J 
Clin Endocr inol Metab 92:4712- 4718, 2007 
9. 
Peyssonnaux C , Eyche ne A: The Raf/MEK/ERK pathway: new concepts of 
activation. B iol Ce ll 93:53- 62, 2001 
10. 
Cohen Y, Xing M, Mambo E, et al: BRAF mutation in papillar y thyroid 
carcinoma. J Natl Cancer Inst 95:625- 7, 2003 
11. 
Fukushima T, Suzuki S, Mashiko M, et al: BRAF mutations in papillary 
carcinomas of the thyroid. Oncogene 22:6455-7, 2003 
12. 
Kimura ET, Nikif orova MN, Zhu Z, et a l: H igh preva lence of BRAF mutations in 
thyr oid cancer: genetic evidence for constitutive activation of the RET/PTC -RAS-BRAF 
signa ling pathway in papillary thyroid carcinoma. Cancer Res 63:1454- 7, 2003 
13. 
Soares P, Trovisco V, Roc ha AS, et al: BRAF mutations and RET/PTC 
rearrangements are alternative events in the etiopathogenes is of PTC. Oncogene 22:4578-80, 
2003 
14. 
Fagin JA : Genetics of pa pillary thyr oid cancer initiation: implications for therapy. 
Trans Am Clin C limatol Assoc 116:259-69; discuss ion 269- 71, 2005 
15. 
Nikifor ova MN, K imura ET, Ga ndhi M, et al: BRAF mutations in thyr oid tumors 
are restricted to papillary carcinomas and anaplastic or poor ly differentiated carcinomas 
aris ing from papillar y carcinomas. J Clin Endocr inol Metab 88:5399- 404, 2003 
16. 
Guigon CJ, Zhao L, Willingham MC , et al: PTEN defic ienc y accelerates tumour 
progress ion in a mouse mode l of thyr oid cancer. Oncogene, 2008 
17. 
Cloughesy TF, Yos himoto K, Nghiemphu P, et al: Antitumor activity of 
rapamyc in in a Phase I tria l for patients w ith recurrent PTEN-defic ient glioblastoma. PLoS 
Med 5:e8, 2008 
18. 
Hu X, Pandolf i PP, Li Y, et al: mTOR promotes surviva l and astrocytic 
characteristics induced by Pten/AKT signa ling in glioblastoma. Neoplasia 7:356-68, 2005 
19.       Wu L, B ir le DC, Tannoc k IF: Effects of the Mammalia n Target of Rapamycin 
Inhibitor CCI- 779 Used Alone or w ith C hemotherapy on Human Prostate Cancer Cells and 
Xenografts. Cancer Res 65:2825-2831, 2005 
20. 
Wilhe lm SM, Carter C, Tang L, et al: BAY 43- 9006 Exhibits Broad Spectrum 


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Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyros ine 
Kinases Involve d in Tumor Progression and Angiogenes is. Cancer Res 64:7099- 7109, 2004 
21. 
Gupta-Abrams on V, Tr oxe l AB , Nellore A, et al: Phase II trial of s orafenib in 
advanced thyroid cancer. J Clin Oncol 26:4714-9, 2008 
22. 
Flaherty KT: Chemotherapy and targeted therapy combinations in advanced 
mela noma. Clin Cancer Res 12:2366s- 2370s , 2006 
23. 
Kloos RT, Ringe l MD , Knopp MV, et al: Phase II Tria l of Sorafenib in Metastatic 
Thyr oid Cancer. J Clin O ncol:JCO.2008. 18.2717, 2009 
24. 
Molhoek KR , Brautigan DL, Slingluff CL, Jr.: Synergis tic inhibition of human 
mela noma proliferation by combination treatment w ith B-Raf inhibitor BAY43-9006 and 
mTOR inhibitor Rapamyc in. J Trans l Med 3:39, 2005 
25. 
Lasithiotakis K G, Sinnber g TW, Sc hittek B , et al: Combined I nhibition of MAPK 
and mTOR Signa ling I nhibits Gr owth, Induces Cell Death, and Abr ogates Invas ive Growth of 
Melanoma Ce lls. J Invest Dermatol 128:2013- 2023, 2008 
26. 
Patnaik A, R icart A, Cooper J, et al: A phase I, phar macokinetic and 
pharmacodynamic study of sorafenib (S) , a multi-targeted kinase inhibitor in combination 
with tems irolimus (T), an mTOR inhibitor in patients w ith advanced solid ma lignanc ies. J 
Clin Oncol (Meeting Abstracts) 25:3512- , 2007 
 
 
 
20.0 
APPENDICES 
 
Appendix A : SAE Fax Cover Sheet 
Appendix B : Canadian Cardiovascular Society C lassif ication System 
Appendix C : New York Heart Association C lass if ications 
Appendix D : Sample Pill D iary 


MEMORIAL SLO AN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 09-148 A(10)
Ame nde d:  05/12/15 
- 41 – 
 
 
APPENDIX A 
SAE FAX COVER SHEET 
 
 


MEMORIAL SLO AN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 09-148 A(10)
Ame nde d:  05/12/15 
- 42 – 
 
 
 
APPENDIX B 
Grading of angina pector is by the Canadia n Cardiovascular Soc iety class if ication system 
 
 
Class 
Description 
__  
 
 
Class I 
Ordinary phys ical activity does not 
cause angina, s uch as walking, climbing 
s tairs . Angina [occurs ] with 
s tre nuous, rapid, or prolonge d exe rtion at 
work or re cre ation. 
 
Class II Slight limitation of ordinary activity. 
Angina occurs on walking or climbing 
s tairs rapidly, walking uphill, 
walking or s tair climbing afte r me als , 
or in cold, or in wind, or unde r 
e motional s tress , or only during the fe w 
hours afte r awake ning. Walking more than two 
blocks on the leve l and climbing more than 
one flight of ordinary s tairs at a normal 
pace and in normal condition. 
 
Class III  Marke d limitations of ordinary phys ical 
activity. Angina occurs on walking one 
to two blocks on the le vel and climbing one 
flight of s tairs in normal conditions and 
at a normal pace . 
 
Class IV Inabilit y to carry on any phys ical activity 
without dis comfort -- angina s ymptoms may be 
present at res t. 
 
Re fe re nce : Campe au L. Grading of angina pe ctoris [lette r]. Circulation, 54:522 -523, 1976. 


MEMORIAL SLO AN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 09-148 A(10)
Ame nde d:  05/12/15 
- 43 – 
 
 
APPENDIX C 
New York Heart Association Class if ications 
 
Clinical Evaluation of Functional Capacity of Patie nts with 
He art Dise ase in Re lation to Ordinary Physical Activity 
 
 
 
Class 
Cardiac Symptoms 
Limitations 
Nee d for 
Additional 
Res t* 
Phys ical Ability 
to work** 
I 
None 
None 
None 
Full time 
II 
Only mode rate 
Slight 
Us ually only 
s light or 
occas ional 
Us ually full 
time 
III 
De fine d, with 
less than 
ordinary activity 
Marke d 
Us ually 
mode rate 
Us ually part 
time 
IV 
May be prese nt 
eve n at res t, 
and any activity 
incre ases 
dis comfort 
Extre me 
Marke d 
Unable to work 
 
 
* 
To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician. 
 
** 
At accustomed occupation or usual tasks. 
 
 
Reference:  Bruce, R. A.: Mod. Concepts Cardiovasc. Dis. 25:321, 1956.  (Modified from New York 
Heart Association, 1953). 


Amended:  05/12/15 
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IRB PROTOCOL 
 
 
APPENDIXD 
Sample Pill DiaJY 
 
 
IRB#:09-148 A(10) 
 
 
 
IRB Protocol:09-148 
 
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