Conditions: Metastatic Thyroid Gland Carcinoma Poorly Differentiated Thyroid Gland Carcinoma Recurrent Thyroid Gland Carcinoma Stage IV Thyroid Gland Follicular Carcinoma AJCC v7 Stage IV Thyroid Gland Papillary Carcinoma AJCC v7 Stage IVA Thyroid Gland Follicular Carcinoma AJCC v7 Stage IVA Thyroid Gland Papillary Carcinoma AJCC v7 Stage IVB Thyroid Gland Follicular Carcinoma AJCC v7 Stage IVB Thyroid Gland Papillary Carcinoma AJCC v7 Stage IVC Thyroid Gland Follicular Carcinoma AJCC v7 Stage IVC Thyroid Gland Papillary Carcinoma AJCC v7
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

Brief summary:
This phase II trial studies how well iodine I-131 works with or without selumetinib in treating patients with thyroid cancer that has returned (recurrent) or has spread from where it started to other places in the body (metastatic). Many thyroid cancers absorb iodine. Due to this, doctors often give radioactive iodine (iodine I-131) alone to treat thyroid cancer as part of standard practice. It is thought that the more thyroid tumors are able to absorb radioactive iodine, the more likely it is that the radioactive iodine will cause those tumors to shrink. Selumetinib may help radioactive iodine work better in patients whose tumors still absorb radioactive iodine. It is not yet known whether iodine I-131 is more effective with or without selumetinib in treating thyroid cancer.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine the response rate at 6 months following treatment with 131I (iodine I-131) in combination with placebo or selumetinib for radioactive iodine-avid (RAIA) recurrent and/or metastatic thyroid cancer.

SECONDARY OBJECTIVES:

I. To determine the best overall response following treatment with 131I in combination with placebo or selumetinib for RAIA recurrent and/or metastatic thyroid cancer.

II. To compare the progression-free survival of patients with RAIA recurrent and/or metastatic thyroid cancer treated with 131I in combination with placebo or selumetinib.

III. To compare serum thyroglobulin changes for patients with RAIA recurrent and/or metastatic thyroid cancer treated with 131I in combination with placebo or selumetinib.

IV. To evaluate the safety and tolerability of 131I in combination with placebo or selumetinib for patients with RAI-avid recurrent and/or metastatic thyroid cancer.

CORRELATIVE OBJECTIVE:

I. To explore the genomic and transcriptomic landscape of RAIA tumors for signatures that correlate to therapeutic benefit achieved with 131I in combination with placebo or selumetinib.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive selumetinib orally (PO) twice daily (BID) starting on week 1, day 1 and continuing through 2 days after iodine I-131 therapy has been administered. Approximately 3 weeks after beginning treatment with selumetinib, patients receive iodine I-131 PO.

ARM II: Patients receive placebo PO BID starting on week 1, day 1 and continuing through 2 days after iodine I-131 therapy has been administered. Approximately 3 weeks after beginning treatment with placebo, patients receive iodine I-131 PO.

After completion of study treatment, patients are followed up at 1 and 3 months, every 3 months for 12 months, and then every 6 months for 2 years.

Arms:
arm 1: Patients receive selumetinib PO BID starting on week 1, day 1 and continuing through 2 days after iodine I 131 therapy has been administered. Approximately 3 weeks after beginning treatment with selumetinib, patients receive iodine I-131 PO. arm 2: Patients receive placebo PO BID starting on week 1, day 1 and continuing through 2 days after iodine I-131 therapy has been administered. Approximately 3 weeks after beginning treatment with placebo, patients receive iodine I-131 PO.

Interventions: intervention 1: Iodine I-131 intervention 2: Placebo Administration intervention 3: Selumetinib
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given PO

Protocol document:
Prot_SAP_ICF_000.pdf: 
R U 2 4 1 3 0 6I  
A d de n d u m 9  
 
 
   
 
Aca de mic a n d C o m m u nit y Ca ncer Researc h U nite d ( A C C R U)  
 
R a n d o mize d D o u ble -Bli n d P h ase II St u d y of R a di o acti ve I o di ne ( R AI)  i n C o m bi n ati o n wit h Pl ace b o or 
Sel u meti ni b  f or t he Tre at me nt of R AI -A vi d Rec urre nt/ Met ast atic  T h yr oi d C a ncers   
 
F or a ny c o m m u nic at i o ns re g ar di n g t his pr ot oc ol, ple ase  c o nt act t he pr ot oc ol res o urce pers o n o n t he 
f oll o wi n g p a ge. 
 
St u d y C hairs  
 
 
 
A C C R U:  
Ala n H o, M. D.  
3 0 0 East 6 6 t h Street  
Ne w Y or k, N Y 1 0 0 6 5  
P h o ne: 2 1 2 -6 3 9 -7 2 0 2  
e-mail: h oa @ ms kcc. or g  
 
 
 
 
 
C o -c hair: 
 
2 0 0 First Street S W  
R oc hester, M N 5 5 9 0 5  
 
 
 
 
Statisticia n:  
 
 
 
Dr u g A v ail a bilit y  
Dr u g C o m p a n y S u p plie d:  Sel u meti ni b ( Astra Ze neca; I N D  0 7 4, 6 6 7 )  
 
 St u d y c o ntri b ut or(s) n ot res p o nsi ble f or patie nt care.  
 
St u d y P artici p a nts  
D ate Acti v ate d  
A C C R U Me m bers hi p  
Ma y 1, 2 0 1 5  
 
Rese arc h C o or di n ati n g Ce nter  
Aca de mic a n d C o m m u nit y Ca ncer Researc h U nite d  
2 0 0 First Street S o ut h west  
R oc hester, M N 5 5 9 0 5  
 
 
D oc u m e nt Hist or y  
(effecti ve d ate) 
Pre -acti vati o n A C C R U  
Dece m ber 5, 2 0 1 4  
Acti vati o n A C C R U  / 
A d de n d u m 1  
Ma y 1, 2 0 1 5  
A d de n d u m  2  
Se pte m ber 2 5, 2 0 1 5  
A d de n d u m 3  
Oct o ber 1 6, 2 0 1 5  
A d de n d u m 4  
Dece m ber 1 1 , 2 0 1 5 
A d de n d u m 5  
N o ve m ber 1 1, 2 0 1 6  
A d de n d u m 6  
J u ne 2 3, 2 0 1 7 
A d de n d u m 7  
A u g ust 3 1, 2 0 1 8  


 
2   
R U 2 4 1 3 0 6 I 
 
 
A d de n d u m 9  
A d de n d u m 8  
Oct o ber 3 0, 2 0 1 9  
A d de n d u m 9  
Ja nuar y 1 5, 2 0 2 1  


 
3   
R U 2 4 1 3 0 6 I 
 
 
A d de n d u m 9  
 I n de x 
 
Sc he ma  
  1. 0  
Bac k gr o u n d  
  2. 0  
G oals  
  3. 0  
Patie nt Eli gi bilit y  
  4. 0  
Test Sc he d ule  
  5. 0  
Stratificati o n Fact ors  
  6. 0  
Re gistrati o n/ Ra n d o mizat i o n Pr oce d ures 
  7. 0  
Pr ot oc ol Treat me nt  
  8. 0  
D osa ge M o dificati o n Base d o n A d verse E ve nts  
  9. 0  
A ncillar y Treat me nt/ S u p p orti ve Care  
1 0. 0  
A d verse E ve nt ( A E) Re p orti n g a n d M o nit ori n g  
1 1. 0  
Treat me nt E val uati o n Usi n g R E CI S T G ui deli ne  
1 2. 0  
Descri pti ve Fact ors  
1 3. 0  
Treat me nt/ F oll o w -u p Decisi o n at E val uati o n of Patie nt  
1 4. 0  
B o d y Fl ui d Bi os peci me ns  
1 5. 0  
Dr u g I nf or mati o n  
1 6. 0  
Statistical C o nsi derati o ns a n d Met h o d ol o g y  
1 7. 0  
Pat h ol o g y C o nsi derati o ns/ Tiss ue Bi os peci me ns  
1 8. 0  
Rec or ds a n d Data C ollecti o n Pr oce d ures  
1 9 . 0 
B u d get  
2 0. 0  
Refere nces  
 
A p pe n di x I - C o nse nt F or m  
 
A p pe n di x II–  Patie nt Me dicati o n Diar y  
 
A p pe n di x III –  T he L o w I o di ne Diet  
 
A p pe n di x I V – G ui da nce f or M a na ge me nt a n d In vesti gati o n of S el u meti ni b R elate d A d verse E ve nts  
 


 
4   
R U 2 4 1 3 0 6 I 
 
 
A d de n d u m 9  
                                                                   Sc he m a  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* O bser vati o n ti me p oi nts:  1 a n d 3 m o nt hs p ost-treat me nt, f oll o we d b y e ver y 3 m o nt hs f or 1 2 m o nt hs p ost-
treat me nt, f oll o we d b y e ver y 6 m o nt hs f or a ma xi m u m of 2 years fr o m ra n d o mizati o n.   
* * C a n be gi ve n u p t o 8 wee ks  (i.e. t he ti me o n treat me nt i ncl u di n g treat me nt i nterr u pti o ns) (see secti o n 7) 
 
 
Ge neric na me:    Sel u meti ni b  
Bra n d na me(s):  
A C C R U A b bre viati o n:   A Z D 6 2 4 4  
  
A vaila bilit y:   Astra Ze neca  
Ge neric na me:    Place b o  
 
Bra n d na me(s):  
A C C R U A b bre viati o n:   P L A C E B  
  
A vaila bilit y:   Astra Ze neca  
 
R a n d o miz ati o n  
Pl ace b o + R a di o acti ve 
I o di ne ( R AI) t her a p y 
Sel u meti ni b ( 7 5 m g P O  BI D 
x 4 wee ks) * *  + R a di o acti ve 
I o di ne ( R AI) t her a p y 
O bser v ati o n *  
E ve nt M o nit ori n g  
U n acce pt a ble a d verse e ve nts, 
alter n ati ve tre at me nt, dise ase 
pr o gressi o n, p atie nt ref us al at 
a n y ti me  
                           
                           
 
 
E ve nt M o nit ori n g  


 
5   
R U 2 4 1 3 0 6 I 
 
 
A d de n d u m 9  
1. 0  
B ac k gr o u n d   
 
Utility of 1 3 1I t her a py f or r a di oi o di ne-avi d t hyr oi d c a ncers : T he maj orit y of t h yr oi d ca ncers are 
differe ntiate d carci n o mas of f ollic ular ori gi n wit h pa pillar y t h yr oi d ca ncer ( P T C) bei n g t he m ost 
c o m m o n f oll o we d b y f ollic ular t h yr oi d ca ncer ( F T C)  ( use of t he ter m “t h yr oi d ca ncer” i n t his pr ot oc ol 
refers s pecificall y t o f ollic ular cell deri ve d t h yr oi d mali g na ncies). Metastatic disease re prese nts t he  m ost 
fre q ue nt ca use of t h yr oi d ca ncer-relate d deat h (Mazzaferri a n d Kl o os, 2 0 0 1 ). Si nce t he a bilit y t o 
tra ns p ort i o did e is retai ne d i n t h yr oi d carci n o mas of f ollic ular ori gi n  a n d is restricte d t o o nl y a fe w cell 
t y pes, ra di oacti ve i o di ne ( R AI or 1 3 1I) ca n be use d t hera pe uticall y t o deli ver t u m orici dal d oses of 
ra diati o n, eliciti n g cli nical be nefit wit h f e w si de effects a n d m o dest  l o n g-ter m t o xicit y. 
 
1 3 1I ca n be partic ularl y effecti ve f or s mall v ol u me ( < 1 c m), R AI-a vi d ( R AI A; t u m ors wit h detecta ble 
R AI u pta ke) disease wit h c o m plete re missi o n ac hie ve d i n re p orte dl y o ver 5 0 % of patie nts (D ura nte et 
al., 2 0 0 6). H o we ver, 1 3 1I efficac y  is si g nifica ntl y l o wer f or patie nts wit h lar ger, str uct urall y e vi de nt 
disease. Sa bra et al. p u blis he d  a retr os pecti ve st u d y  e val uati n g t he efficac y of first -li ne 1 3 1I t hera p y ( R AI 
a d mi nistere d f or re m na nt a blati o n a n d e vi de nce of R AI A dista nt metastasis o n p ost -a blati o n sca n)  f or 
patie nts wit h metastatic, R AI A t h yr oi d ca ncer . I n 3 6 patie nts wit h str uct ural disease, t he res p o nse rate of 
metastatic lesi o n(s)  t o i nitial R AI a blati o n t hera p y was 2 2 % (Sa bra et al., 2 0 1 3 ). T his o bser vati o n  is 
c o nsiste nt wit h t he 1 0 % t o 2 4 % res p o nse rates re p orte d i n ot her retr os pecti ve series f or si milar s u bsets 
o f patie nts (D ura nte et al., 2 0 0 6 ; Kl u b o -G wiez dzi ns ka et al., 2 0 1 1a ; Kl u b o -G wiez dzi ns ka et al., 2 0 1 1 b ; 
Tala et al., 2 0 1 1 ). 
 
1 3 1I efficac y a gai nst t h yr oi d metastases is deter mi ne d b y t he 1 3 1I acti vit y t hat ca n be s uccessf ull y 
deli vere d t o metas tatic lesi o ns (D or n et al., 2 0 0 3 ; Ma x o n et al., 1 9 9 2 ; Ma x o n et al. , 1 9 8 3; T h o mas et al., 
1 9 7 6 ). B ot h 1 3 1I u pta ke a n d rete nti o n  ca n be i m paire d b y di mi nis he d e x pressi o n of se veral t h yr oi d-
s pecific ge nes, i ncl u di n g t he s o di u m i o di de s y m p orter ( NI S; m e diates i o di de u pta ke i nt o t h yr oi d cells) 
a n d t h yr o per o xi dase ( T P O; critical f or i o di de rete nti o n). Ma n y i n vesti gat ors ha ve searc he d f or dr u gs t o 
“re-differe ntiate” metastatic t h yr oi d ca ncers t o rest ore e x pressi o n of t hese ge nes i n a n atte m pt t o 
e n ha nce 1 3 1I deli ver y a n d efficac y. U nf ort u natel y, s uc h st u dies ha ve hist oricall y re p orte d  o nl y  m o dest 
effects u p o n 1 3 1I acti o n.  
 
T hyr oi d c a ncer m ut ati o ns t h at activ ate t he M A P K p at h w ay de -differe nti ate t hyr oi d c a ncer cells : 
M ut uall y e xcl usi ve ge netic alterati o ns i n t he gr o wt h fact or rece pt or R E T , t he t hree is of or ms of R A S (N, 
H, K), a n d B R A F are prese nt i n ~ 7 0 % of P T Cs  (C o he n et al., 2 0 0 3 ; Ki m ura e t al., 2 0 0 3; K na uf a n d 
Fa gi n, 2 0 0 9 ; S oares et al., 2 0 0 3 ). T hese o nc o pr otei ns partici pate i n M A P K si g nali n g t o acti vate 
d o w nstrea m ki nases M E K a n d E R K ( R E T -> R A S -> R A F -> M E K -> E R K). T he B R A F V 6 0 0 E  m utati o n is t he 
m ost c o m m o n ge netic alterati o n i n P T C (i n v ol vi n g a b o ut 4 5 % of t u m ors)  (Ki m ura et al., 2 0 0 3 ; Ricarte -
Fil h o et al., 2 0 0 9 ). B R A F M U T t u m ors  h a ve a m ore a g gressi ve cli nical be ha vi or a n d are pr o ne t o bei n g 
R AI -refract or y (Elisei et al., 2 0 0 8 ; Lee et al., 2 0 0 7 ). Be y o n d pr o m oti n g cell ular pr oliferati o n a n d 
s ur vi val, B R A F m utati o ns i n t h yr oi d ca ncer ha ve als o bee n i m plicate d i n disr u pti n g f ollic ular cell  
differe ntiati o n, i ncl u di n g t he s u p pressi o n of ke y ge nes i n v ol ve d i n i o di d e meta b olis m (D ura nte et al., 
2 0 0 7 ; Li u et  al., 2 0 0 7 ; Riesc o -Eiza g uirre et al., 2 0 0 6 ) a n d i o di de u pta ke, s uc h as NI S (Riesc o -Eiza g u irre 
et al., 2 0 0 6 ). I n rat t h yr oi d P C C L 3 cells wit h i n d uci ble e x pressi o n of B R A F V 6 0 0 E , treat me nt wit h t he 
M E K i n hi bit or U 0 1 2 6 rest ore d e x pressi o n of NI S as well as t h yr oi d sti m ulati n g h or m o ne ( T S H) 
rece pt or a n d t h yr o gl o b uli n (Li u et al., 2 0 0 7 ). 
 
Ot her M A P K acti vati n g alterati o ns c o m m o n t o t h yr oi d ca ncer ca n als o ca use de -differe ntiati o n. R A S  
m utati o ns are f o u n d i n a p pr o xi matel y 1 0 -2 0 % of P T Cs a n d 4 0 -5 0 % of F T Cs (Ni kif or o v a n d Ni kif or o va, 
2 0 1 1 ). Rec o m bi nati o n e ve nts t hat lea d t o t he f usi o n of t he R E T t yr osi ne ki nase rece pt or wit h o ne of  
se veral part ner ge nes ( k n o w n as R E T/ P T C  rearra n ge me nts) occ ur i n 1 0 -2 0 % of P T Cs (Ni kif or o v a n d 
Ni kif or o va, 2 0 1 1 ; S oares et al., 2 0 0 3 ; Z h u et al., 2 0 0 6 ). O vere x pressi o n of eit her t he H R A S V 1 2  m uta nt or 
R E T/ P T C  i n t h yr oi d ca ncer cells s u p presses NI S e x pressi o n, w hic h ca n be rest ore d wit h M E K i n hi bit or  


 
6   
R U 2 4 1 3 0 6 I 
 
 
A d de n d u m 9  
treat me nt (De Vita et al., 2 0 0 5 ; K na uf et al., 2 0 0 3 ). He nce, ge netic alterati o ns t hat acc o u nt f or M A P K 
acti vati o n i n of t he vast maj orit y of  t h yr oi d ca ncers ca n pr o m ote M E K-d e pe n de nt NI S s u p pressi o n, 
di mi nis he d i o di de a vi dit y, a n d resista nce t o 1 3 1I t hera p y. 
 
M A P K p at h w ay i n hi biti o n c a n rest ore i o di d e i nc or p or ati o n i n a n i n viv o t hyr oi d c a ncer a ni m al m o del : 
I n a t h yr oi d ca ncer m o use m o del wit h d o x yc ycli ne ( d o x) i n d uci ble t h yr o i d e x pressi o n of B R A F V 6 0 0 E , Dr. 
Ja mes Fa gi n’s gr o u p ( Me m orial Sl oa n-Ketteri n g Ca ncer Ce nter ( M S K C C))  de m o nstrate d t hat d o x 
treat me nt res ulte d i n B R A F V 6 0 0 E  o vere x pressi o n, M A P K acti vati o n, de vel o p me nt of P T C, a n d 
s u p pressi o n of se veral t h yr oi d s pecific ge nes, i ncl u di n g NI S  (C ha kra vart y et al., 2 0 1 1 ). Wit h dra wal of 
d o x t o eli mi nate B R A F V 6 0 0 E  e x pressi o n res ulte d i n s u p pressi o n of M A P K acti vat i o n a n d re-i n d ucti o n of 
t h yr oi d ge ne e x pressi o n, s u g gesti n g t hat o nc o ge nic B R A F  i n d uce d ge ne patter ns ca n be re verse d w he n 
B R A F  acti vati o n  of M A P K si g nali n g is n ullifie d . T his ge netic pr o of of c o nce pt was reca pit ulate d wit h 
p h ar mac ol o gic i n hi biti o n of B R A F  acti vati o n: B R A F V 6 0 0 E  was i n d uce d wit h o ne wee k of d o x treat me nt 
a n d s u bse q ue ntl y mai ntai ne d w hile t he a ni mals were treate d wit h t he M E K i n hi bit or P D 0 3 2 5 9 0 1 
( P D 9 0 1) or t he selecti ve o nc o ge nic B R A F i n hi bit or P L X 4 7 2 0 ( Ple x xi k o n/ R oc he). I n hi biti o n of B R A F 
sig nali n g wit h eit her dr u g i ncrease d R AI i nc or p orati o n o ver ve hicle treat me nt , s u g gesti n g t hat i n hi biti n g 
M A P K si g nali n g wit h s mall m olec ule i n hi bit ors ca n rest ore i o di d e u pta ke i n t h yr oi d t u m ors dri ve n b y a 
M A P K acti vati n g ge netic alterati o n.  
 
Res ults of a pil ot st u dy ev al u ati n g t he i m p act of  M E K i n hi biti o n u p o n  R AI i nc or p or ati o n a n d 1 3 1I 
effic acy: We tra nslate d t hese precli nical fi n di n gs i nt o a pil ot st u d y e val uati n g t he i m pact of t he 
Astra Ze neca M E K i n hi bit or sel u meti ni b u p o n i o di de u pta ke i n patie nts wit h  R AI -refract or y t h yr oi d 
ca ncers  (H o et al., 2 0 1 3 ). A critical c o m p o ne nt of t he st u d y was t he utilizati o n of 1 2 4I P E T/ C T lesi o nal 
d osi metr y t o precisel y q ua ntif y dr u g -in d uce d c ha n ges i n i o di d e i nc or p orati o n wit hi n s pecific lesi o ns  
(Pe ntl o w et al., 1 9 9 6 ; S g o ur os et al., 2 0 0 4 ) an d pre dict t he 1 3 1I ra diati o n d ose  t hat c o ul d be deli vere d t o 
i n di vi d ual t u m ors.     
 
Eac h of t he 2 0 e val ua ble patie nts o n t he st u d y ha d R AI -refract or y disease as defi ne d b y o ne of t he 
f oll o wi n g criteria: 1) n o n-R AI -a vi d lesi o n/s o n a dia g n ostic a n d/ or p os t-t hera p y R AI sca n, 2) R AI-a vi d 
lesi o n/s t hat re mai ne d sta ble or i ncrease d i n size after R AI t hera p y, or 3) fl u or o de o x y gl uc ose ( F D G)-
a vi d lesi o n/s b y P E T s ca n. I n or der t o o pti mize i o di d e u pta ke, h u ma n rec o m bi na nt T S H (r h T S H or 
T h yr o ge n ™ fr o m Ge nz y me) was a d mi nistere d pri or t o eac h 1 2 4I P E T, w hic h was perf or me d bef ore a n d 
after treat me nt wit h sel u meti ni b  f or 4 wee ks. If t he sec o n d 1 2 4I P E T sca n pre dicte d t hat a lesi o nal 1 3 1I 
d ose of >  2, 0 0 0 c G y c o ul d be ac hie ve d, 1 3 1I was a d mi nistere d c o nc o mita ntl y wit h  selu meti ni b. Of t he 2 0 
e val ua ble patie nts, 1 2 ( 6 0 %) ha d ne w or i ncrease d 1 2 4I i nc or p orati o n after sel u meti ni b. For 8 ( 4 0 %) 
patie nts, t he sec o n d 1 2 4I P E T sca n pre dicte d t hat t he lesi o nal a bs or be d 1 3 1I ra diati o n d ose w o ul d e q ual or 
e xcee d 2, 0 0 0 c G y; t hese patie nts were c o nti n ue d o n sel u meti ni b a n d recei ve d t hera pe utic 1 3 1I. All 5 
patie nts wit h N R A S  M U T t u m ors o n  t he st u d y e xcee de d t his d osi metr y t hres h ol d a n d were treate d wit h 
1 3 1I. 
 
B y c o ntrast, 4 o ut of 9 B R A F  M U T patie nts ha d sel u meti ni b -i n d uce d i ncreases i n 1 2 4I i nc or p orati o n, b ut 
o nl y o ne ac hie ve d t he d ose t hres h ol d t o warra nt 1 3 1I treat me nt. T w o o ut of 3 R E T/ P T C  a n d 1 o ut of 3 
W T  patie nts als o ha d greater i o di d e i nc or p orati o n o n t he sec o n d 1 2 4I P E T sca n, a n d o ne of eac h of t h ose 
ge n ot y pes we nt o n t o be trea te d wit h 1 3 1I. T hese c ha n ges i n i o di de i nc or p orati o n tra nslate d t o cli nical 
be nefit as all 8 patie nts treate d wit h 1 3 1I e x perience d re d ucti o ns i n t u m or size. I n t otal, t here were 5 
c o nfir me d partial res p o nses (c P Rs) a n d 3 wit h sta ble disease ( S D). S u bsta nt ial decreases i n ser u m 
t h yr o gl o b uli n f oll o wi n g R AI t hera p y were als o ac hie ve d i n all patie nts. 
 
All e val ua ble patie nts c o m plete d t he f ull c o urse of sel u meti ni b wit h o ut d ose re d ucti o n or dela y. 
T o xicities attri b ute d t o sel u meti ni b were Gra de 1 or 2, a n d wer e c o nsiste nt wit h a d verse e ve nts re p orte d 
i n lar ger sel u meti ni b st u dies (Ha yes et al., 2 0 1 2 ; Kir k w o o d et al., 2 0 1 1 ), i ncl u di n g fati g ue ( 8 0 %), 
mac ul o pa p ular ras h ( 7 0 %), a n d ac neif or m ras h ( 2 5 %). F o urtee n ( 7 0 %) patie nts e x perie nce d Gra de 1 
ele vati o ns i n li ver tra nsa mi nases p ossi bl y relate d t o sel u meti ni b, w hic h re verte d t o baseli ne after dr u g 
disc o nti n uati o n. O ne pat ie nt w h o was treate d wit h  1 3 1I o n st u d y was dia g n ose d wit h m yel o d ys plastic 


 
7   
R U 2 4 1 3 0 6 I 
 
 
A d de n d u m 9  
s y n dr o me m ore t ha n 5 1 wee ks later; t he disease e ve nt uall y tra nsf or me d t o ac ute le u ke mia. Pri or t o 
e nr oll me nt, t his patie nt ha d recei ve d t hree c o urses of 1 3 1I (c u m ulati ve pre-st u d y dose of 9 7 6. 2 m Ci) as 
well as 8 6 4 0 c G y of e xter nal bea m ra diati o n f or pr ostate ca ncer. He nce, t his sec o n dar y mali g na nc y was 
attri b ute d t o c u m ulati ve 1 3 1I a n d e xter nal bea m ra diati o n t o xicities, a n d n ot t o sel u meti ni b.  
 
Sel u meti ni b( A R R Y 1 4 2 8 8 6; A Z D 6 2 4 4) : Sel u meti ni b is a p ote nt, selecti ve, n o nc o m petiti ve i n hi bit or of 
M E K, lice nse d f or de vel o p me nt b y Astra Ze neca P har mace uticals fr o m Arra y Bi o P har ma. Sel u meti ni b 
was disc o vere d b y Arra y Bi o p har ma a n d ha d t he desi g nati o n A R R Y 1 4 2 8 8 6. Ot her la b orat or y c o de 
na mes u se d d uri n g t he de vel o p me nt of t his m olec ule are A R 0 0 1 4 2 8 8 6 a n d A R-1 4 2 8 8 6 -X ( w here X 
refers t o a se q ue ntial l ot n u m ber). Arra y Bi o P har ma was res p o nsi ble f or t he first-i nt o-h u ma n st u d y; t he 
re mai n der of t he cli nical de vel o p me nt pr o gra m f or o nc ol o g y i n dicati ons is t he res p o nsi bilit y of 
Astra Ze neca. A Z D 6 2 4 4 has n o w bee n assi g ne d t he i nter nati o nal n o n pr o prietar y na me sel u meti ni b.  
 
Sel u meti ni b i n hi bits t he acti vit y of is olate d mit o ge n -acti vate d pr otei n ki nase ki nase ( M E K) t o 
p h os p h or ylate e xtracell ular si g nal -re gulate d ki nase ( E R K) 2 i n e nz y me assa ys, wit h a c o nce ntrati o n 
w hic h res ulte d i n 5 0 % i n hi biti o n (I C 5 0) of a p pr o xi matel y 1 0 t o 1 4 n M. I n c o ntrast, sel u meti ni b was 
i nacti ve, or o nl y mi ni mall y acti ve, a gai nst a pa nel of ot her ki nases. N-des met h yl sel u meti ni b (a 
p har mac ol o gicall y acti ve meta b olite) was i de ntifie d t o be a p pr o xi matel y 3 - t o 5-f ol d m ore acti ve t ha n 
t he sel u meti ni b pare nt c o m p o u n d. T he a mi de meta b olite is u p t o 5 0-f ol d less acti ve t ha n sel u meti ni b, 
a n d is t heref ore u nli kel y t o si g nifica ntl y c o ntri b ute  t o bi ol o gical acti vit y. 
 
As of 3 1 Ja n uar y 2 0 1 4, a p pr o xi matel y 1 9 4 0 patie nts wit h ca ncer ha ve recei ve d treat me nt wit h 
sel u meti ni b, i ncl u di n g a p pr o xi matel y 7 5 0 patie nts i n A Z-s p o ns ore d st u dies, 5 7 patie nts i n t he Arra y-
s p o ns ore d St u d y A R R Y-0 4 0 1, 6 2 patie nts  i n t he Merc k-s p o ns ore d St u d y D 1 5 3 2 C 0 0 0 2 8, a n d 
a p pr o xi matel y 1 0 7 0 patie nts i n i n vesti gat or - or c olla b orati ve gr o u p -s p o ns ore d st u dies. I n a d diti o n, 
a p pr o xi matel y 1 2 0 healt h y v ol u nteers ha ve bee n e x p ose d t o sel u meti ni b H y d -S ulfate.  
 
Sel u meti ni b has bee n use d  as b ot h m o n ot hera p y a n d i n c o m bi nati o n wit h ot her a nti -ca ncer a ge nts, i n a 
variet y of a d ult s oli d t u m or setti n gs (e .g ., pa ncreatic ca ncer, c ol orectal ca ncer, mela n o ma a n d N S C L C), 
a n d pe diatric ca ncer patie nts.  
 
T he f or m ulati o n ta ke n i nt o t he p hase I cli ni cal pr o gra m b y Arra y Bi o p har ma was a n e xte m p ora ne o us 
pre parati o n of a n oral s us pe nsi o n of sel u meti ni b as t he free -base i n a n a q ue o us s ol uti o n of 
s ul p h o b ut ylet her β -c ycl o de xtri n ( S B E -C D, Ca ptis ol ®), referre d t o as t he free -base s us pe nsi o n 
f or m ulati o n ( mi x an d dri n k).  
 
T he Astra Ze neca p hase II m o n ot hera p y cli nical pr o gra m als o utilize d t his f or m ulati o n. S u bse q ue nt 
f or m ulati o n de vel o p me nt res ulte d i n a ca ps ule f or m ulati o n of sel u meti ni b as t he h y dr o ge n s ul p hate salt 
( A Z D 6 2 4 4 H y d-S ulfate), w hic h will be use d i n  t his st u d y. T he ma xi m u m t olerate d d ose ( M T D) f or t he 
s us pe nsi o n f or m ulati o n was deter mi ne d t o be 1 0 0 m g t wice dail y, w hereas f or t he ca ps ule, t he M T D 
was deter mi ne d t o be 7 5 m g t wice dail y. T he e mer gi n g safet y a n d t olera bilit y pr ofile of t he ca ps ule 
f or m ulati o n is br oa dl y c o nsiste nt wit h t hat of t he s us pe nsi o n f or m ulati o n, alt h o u g h a hi g her fre q ue nc y 
of fati g ue a n d na usea has bee n re p orte d wit h t he ca ps ule f or m ulati o n c o m pare d t o t he s us pe nsi o n 
f or m ulati o n i n t he p hase II m o n ot hera p y st u dies. 
 
T w o p hase I st u dies ( D 1 5 3 2 C 0 0 0 0 5, D 1 5 3 2 C 0 0 0 2 0) were perf or me d wit h t he H y d -S ulfate f or m ulati o n. 
C o m paris o n of t he fre q ue ncies fr o m St u d y D 1 5 3 2 C 0 0 0 0 5 a n d t he A Z -s p o ns ore d p hase II m o n ot herap y 
st u dies descri be d bel o w s h o ws t hat t here are hi g her perce nta ges of patie nts re p orti n g t he m ost fre q ue nt 
A Es s uc h as fati g ue, der matitis ac neif or m, diarr hea, na usea a n d peri p heral e de ma wit h t he H y d -S ulfate 
f or m ulati o n. T his ma y be d ue t o t he hi g her plas ma e x p os ures ac hie ve d wit h t he ca ps ule f or m ulati o n, b ut 
ma y als o be i n part as a  c o nse q ue nce of t he m ore hea vil y pre -treate d patie nt p o p ulati o n i n st u d y 
D 1 5 3 2 C 0 0 0 0 5 ha vi n g l o wer t olera nces t o de vel o pi n g t o xicit y.  
 


 
8   
R U 2 4 1 3 0 6 I 
 
 
A d de n d u m 9  
T w o h u n dre d a n d si xt y ni ne ( 2 6 9) patie nts recei ve d sel u meti ni b free base s us pe nsi o n 1 0 0 m g t wice 
dail y i n 4 c o m plete d p has e II m o n ot hera p y st u dies ( D 1 5 3 2 C 0 0 0 0 3, D 1 5 3 2 C 0 0 0 0 8, D 1 5 3 2 C 0 0 0 1 1, a n d 
D 1 5 3 2 C 0 0 0 1 2).  
 
•  
Ras hes (i ncl u di n g t he preferre d ter ms der matitis ac neif or m, ras h, ras h mac ul o pa p ular, ras h mac ular, 
ras h pa p ular, ac ne, a n d f ollic ulitis) were re p orte d i n a p pr o xi matel y 7 0 % of patie nts recei vi n g 
treat me nt wit h sel u meti ni b, a n d der matitis ac neif or m was t he m ost c o m m o n A E ter m o verall ( 5 4 %). 
Ot her c o m m o nl y re p orte d A Es were diarr hea ( 4 9 %), na usea ( 3 3 %) a n d v o miti n g ( 2 4 %). A d verse 
e ve nts of peri p heral e de ma, peri or bital e de ma, a n d facial e de ma were re p orte d i n 3 1 %, 9 %, a n d 4 % 
of patie nts, res pecti vel y. T he A Es of fati g ue or ast he nia were re p orte d i n a p pr o xi matel y 3 0 % of 
patie nt s i n t his p hase II p o p ulati o n. E xerti o nal dys p nea or d ys p nea was re p orte d i n 1 3 % of patie nts 
a n d, i n i n di vi d ual st u dies, e xerti o nal  d ys p nea was re p orte d at a hi g her i nci de nce i n t he sel u meti ni b 
gr o u ps t ha n i n t he c o m parat or c he m ot hera p y gr o u ps.  
 
•  
Seri o us A Es were re p orte d i n 2 4 % of patie nts recei vi n g sel u meti ni b m o n ot hera p y. T he m ost 
fre q ue ntl y re p orte d serio us A Es were v o miti n g ( 1. 5 %), diarr hea, er ysi pelas, a n d p ul m o nar y 
e m b olis m (i n 1. 1 % patie nts eac h). Seri o us A Es of i nfecti o ns ( bacterial se psis, se psis, i nfecti o n, a n d 
bacterial art hritis) were re p orte d i n 2. 2 % of patie nts. T he m ost fre q ue ntl y relate d re p o rte d treat me nt-
relate d S A E was v o miti n g ( 3 patie nts). 
 
•  
I n St u d y D 1 5 3 2 C 0 0 0 0 3, s mall i ncreases i n bl o o d press ure were o bser ve d after 1 wee k o n 
sel u meti ni b, wit h mea n i ncreases of 7. 4 m m H g (s yst olic, S B P) a n d 5. 3 m m H g ( diast olic, D B P) at 
Wee k 8, c o m pare d wit h  mea n i ncreases of 1. 1 m m H g ( S B P) a n d 0. 5 m m H g ( D B P) i n t he 
te m oz ol o mi de c o m parat or ar m. T he A E of h y perte nsi o n was re p orte d i n 1 8 patie nts ( 6. 7 %) 
recei vi n g sel u meti ni b i n p hase II m o n ot hera p y st u dies; 6 of t hese patie nts ha d h y perte nsi o n at e ntr y 
t o t he st u d y, a n d a f urt her 5 patie nts ha d d oc u me nte d ris k fact ors f or h y perte nsi o n. 
 
•  
Re versi ble as y m pt o matic re d ucti o n i n left ve ntric ular ejecti o n fracti o n ( L V E F) t o bel o w 5 5 % has 
bee n re p orte d i n a s mall pr o p orti o n of patie nts wit h a d va nce d ca ncers i n t he m o n ot hera p y a n d 
ra n d o mize d place b o c o ntr olle d st u dies i n c o m bi nati o n wit h sta n dar d c he m ot hera pies, wit h b ot h 
f or m ulati o ns of sel u meti ni b. I n b ot h place b o-c o ntr olle d st u dies , n o patie nt treate d wit h sel u meti ni b 
ha d se vere L V E F i m pair me nt ( < 3 5 %) or s y m pt o matic h eart fail ure. E vi de nce of re versi bilit y o n 
c o nti n ui n g treat me nt wit h sel u meti ni b has bee n de m o nstrate d i n s o me patie nts. L V E F sc he d ule d 
assess me nts were o nl y i ncl u de d i n o ne p hase II st u d y ( D 1 5 3 2 C 0 0 0 0 3) a n d i n t he sel u meti ni b gr o u p 
t o e val uate a p ossi ble car diac eti ol o g y of t he peri p heral e de ma re p orte d i n earlier st u dies. T he 
me dia n c ha n ge i n L V E F at Wee k 4 was 1. 2 perce nta ge p oi nts, a n d t he i n di vi d ual c ha n ge fr o m 
baseli ne ra n ge d fr o m – 2 0 t o + 1 9 perce nta ge p oi nts. A d verse e ve nts of ejecti o n fracti o n decrea se d, 
left ve ntric ular d ysf u ncti o n, or ve ntric ular d ysf u ncti o n were re p orte d i n a t otal of 5 patie nts ( 3. 3 %) 
recei vi n g sel u meti ni b (i ncl u di n g 1 patie nt w h o ha d s witc he d fr o m te m oz ol o mi de treat me nt after 
disease pr o gressi o n) vers us 1 patie nt ( 1 %) i n t he c o m p arat or gr o u p. 
 
•  
Re vie w of cli nical la b orat or y para meters i n p hase II m o n ot hera p y st u dies i de ntifie d a tre n d t o war d 
i ncrease d ala ni ne a mi n otra nsferase ( A L T) a n d as partate a mi n otra nsferase ( A S T) le vels after starti n g 
treat me nt wit h sel u meti ni b. A n i ncrease i n ser u m p h os p hate was o bser ve d i n s o me patie nts after 
i nitiati o n of sel u meti ni b, c o m pare d wit h patie nts ra n d o mize d t o c o m parat or treat me nts. T here was a 
tre n d t o war d a s mall mea n decrease i n al b u mi n relati ve t o t he c o m parat or. N o ot her re p orts of 
sel u meti nib -relate d c ha n ges i n la b orat or y para meters were c o nsi dere d t o be of cli nical rele va nce at 
t his ti me. T here was n o e vi de nce of m yel os u p pressi o n or re nal i m pair me nt. 
 
•  
A d verse e ve nts relate d t o vis ual f u ncti o n ha ve bee n re p orte d acr oss t he pr o gra m wit h sel u me ti ni b. 
M ost ofte n t here were n o s pecific cli nical fi n di n gs re p orte d fr o m patie nts t hat u n der we nt 
o p ht hal m ol o gical e val uati o n after re p orti n g t he A E of vis ual dist ur ba nce. A Es c o nsiste nt wit h 
ce ntral ser o us reti n o pat h y ha ve bee n re p orte d i n a s mall n u m ber of patie nts recei vi n g treat me nt wit h 
sel u meti ni b, ge nerall y i n c o m bi nati o n wit h ot her a nti-ca ncer a ge nts. 


 
9   
R U 2 4 1 3 0 6 I 
 
 
A d de n d u m 9  
 
•  
T here ha ve bee n re p orts of p ne u m o nitis -t y pe e ve nts i n a s mall n u m ber of patie nts recei vi n g 
treat me nt wit h sel u meti ni b. A n ass ociati o n wit h sel u meti ni b has n ot bee n esta blis he d.  
 
•  
Wea k ness of nec k e xte ns or m uscles i n c o nj u ncti o n wit h creati ne p h os p h o ki nase ( C P K) i ncreases 
(re versi ble o n treat me nt i nterr u pti o n) ha ve bee n re p orte d i n 3 o ut of 5 4 patie nts wit h u veal 
mela n o ma recei vi n g sel u meti ni b 7 5 m g t wic e dail y i n o ne n o n -Astra Ze neca s p o ns ore d st u d y. 
I ncreases i n C P K le vels ha ve bee n rec or de d i n a s mall n u m ber of patie nts recei vi n g treat me nt wit h 
sel u meti ni b. C P K ele vati o ns are prese nt i n s o me patie nts wit h m uscle s y m pt o ms, alt h o u g h 
as y m pt o matic ele vati o n s ha ve als o bee n re p orte d. A relati o ns hi p bet wee n sel u meti ni b a n d ele vate d 
C P K le vels or m y o pat h y has n ot bee n esta blis he d.  
 
I n t he pil ot st u d y descri be d a b o ve w here 2 0 metastatic, R AI-refract or y t h yr oi d ca ncer patie nts were 
treate d wit h a 4 wee k c o urse of sel u meti ni b 7 5 m g t wice dail y  (t he H y d-S ulfate f or m ulati o n ) t o 
f oll o we d b y 1 3 1I i n a s u bset of patie nts (H o et al., 2 0 1 3 ), all e ve nts attri b ute d t o sel u meti ni b were Gra de 
1 or 2, a n d i ncl u de d fati g ue ( 8 0 %), mac ul o pa p ular ras h ( 7 0 %), ac neif or m ras h ( 2 5 %), ele vati o n i n A S T 
( 7 0 %; all Gra de 1), ele vati o n i n A L T ( 4 5 %; all Gra de 1), diarr hea ( 4 5 %), na usea ( 4 0 %), li m b e de ma 
( 3 0 %), oral m uc ositis ( 3 5 %), c o nsti pati o n ( 2 0 %), h y poal b u mi ne mia ( 1 5 %), decrease d w hite bl o o d cell 
c o u nt ( 1 5 %), face e de ma ( 1 0 %), scal p pai n ( 1 0 %), decrease d platelet c o u nt ( 1 patie nt; Gra de 1), e ye 
dis or der ( 1 patie nt; Gra de 1 c o nsisti n g of vis ual hal os a n d sli g ht bl urri ness t hat res ol ve d after t hera p y 
st op pe d), h y perte nsi o n ( 1 patie nt; Gra de 1), peri or bital e de ma ( 1 patie nt; Gra de 1), a n d v o miti n g ( 1 
patie nt, Gra de 1). O ne patie nt w h o was treate d wit h 1 3 1I was s u bse q ue ntl y dia g n ose d wit h 
m yel o d ys plastic s y n dr o me 5 1 wee ks after 
1 3 1I a d mi nistrati o n w hic h s u b se q ue ntl y e v ol ve d i nt o ac ute 
le u ke mia (t his was deter mi ne d t o be u nrelate d t o sel u meti ni b a n d li kel y relate d t o c u m ulati ve R AI 
t o xicit y as well as pre vi o us e xter nal bea m ra diati o n t hera p y).  
 
I n t he o nl y ot her st u d y t o s pecificall y i n vesti gate sel u meti ni b i n differe ntiate d t h yr oi d ca ncer patie nts 
(t he p hase II st u d y of 1 0 0 m g bi d sel u meti ni b, pre vi o us mi x-a n d-dri n k f or m ulati o n) i n 3 9 patie nts wit h 
R AI -refract or y differe ntiate d metastatic t h yr oi d ca ncer. I n t hese patie nts wit h R AI -refract or y disease, 
c o m m o n dr u g -relate d A Es i ncl u de d ras h ( 7 7 %), fati g ue ( 4 9 %), diarr hea ( 4 9 %), a n d peri p heral e de ma 
( 3 6 %). Gra de 3 a n d 4 A Es were c o nsiste nt wit h t h ose acr oss t he sel u meti ni b pr o gra m a n d als o i ncl u de d 
ras h ( 1 8 %), fati g ue ( 8 %), diarr hea ( 5 %) a n d peri p heral e de ma ( 5 %). T wel ve patie nts re q uire d d ose 
re d ucti o ns f or re p orte d A Es acr oss t he le n gt h of t he st u d y (t he d urati o n of treat me nt was greater t ha n 1 6 
wee ks f or 6 9 % of patie nts). Si x patie nts ( 1 5 %) disc o nti n ue d treat me nt d ue t o a d verse e ve nts.  
 
Sel u meti ni b is n ot m uta g e nic or clast o ge nic i n vitr o b ut pr o d uce d i ncreases i n micr o n ucleate d , i m mat ure 
er yt hr oc ytes i n m o use b o ne marr o w micr o n ucle us st u dies. I n vesti gat or y st u dies s h o w t hat t his is 
pre d o mi na ntl y via a n a ne u ge nic mec ha nis m w hic h is c o nsiste nt wit h disr u pti o n of n or mal s pi n dle 
f u ncti o n as a c o nse q ue nce of t he k n o w n p har mac ol o gical acti o n of a M E K i n hi bit or. Wit h sel u meti ni b 
H y d -S ulfate, a N O E L of 2 4 m g/ k g/ da y (f or 2 da ys) was esta blis he d f or i n d ucti o n of micr o n uclei, wit h 
plas ma e x p os ures si g nifica ntl y a b o ve t h ose  o bser ve d i n ca ncer patie nts at t he ma xi m u m t olerate d d ose 
of 7 5 m g t wice dail y. T his s u g gests t hat sel u meti ni b will ha ve little p ote ntial t o ca use a ne u ge nicit y i n 
di vi di n g cell p o p ulati o ns i n patie nts at t he pr o p ose d cli nical d ose.  
 
I n s u m mar y, sel u meti nib has bee n s h o w n t o ha ve a n acce pta ble pr ofile of si de effects, i n a n  e xte nsi ve 
safet y data base f or a c o m p o u n d at t his sta ge of de vel o p me nt. F urt her details re gar di n g t he safet y pr ofile 
of sel u meti ni b ca n be f o u n d i n t he I n vesti gat or Br oc h ure.  
 
R ati o n ale f or ev al u ati n g t he i m p act of sel u meti ni b M E K i n hi biti o n u p o n 1 3 1I effic acy i n R AI A t hyr oi d 
c a ncers : We h y p ot hesize t hat t he li mite d efficac y of 
1 3 1I al o ne f or patie nts  wit h str uct urall y e vi de nt, 
R AI A t h yr oi d ca ncer  is i n part d ue t o i ns ufficie nt lesi o nal 1 3 1I u pta ke a n d rete nti o n me diate d b y a berra nt 
M A P K pat h wa y i n hi biti o n . Pat h wa y i n hi biti o n wit h sel u meti ni b is pre dicte d t o i ncrease e x pressi o n of 
t he t h yr oi d-s pecific ge nes re q uisite t o e n ha nce 1 3 1I lesi o nal deli ver y a n d efficac y. T o test t his h y p ot hesis, 
w e will perf or m a t w o -ar m, ra n d o mize d trial i n w hic h patie nts wit h R AI A, rec urre nt/ metastatic t h yr oi d 


 
1 0   
R U 2 4 1 3 0 6 I 
 
 
A d de n d u m 9  
ca ncer are ra n d o mize d t o 1 3 1I t hera p y i n c o m bi nati o n wit h a p pr o xi matel y 4 wee ks of t hera p y wit h eit her 
place b o or sel u meti ni b. He nce, t his st u d y is a p pr o pr iate o nl y f or patie nts wit h rec urre nt/ metastatic 
t h yr oi d ca ncer f or w h o m 1 3 1I t hera p y is j u d ge d t o be i n dicate d. T he pri mar y cli nical o bjecti ve of t he 
st u d y will be t o deter mi ne t he o verall res p o nse rate at 6 m o nt hs f oll o wi n g 1 3 1I t hera p y f or eac h treat me n t 
ar m. Sec o n dar y o bjecti ves will be t o deter mi ne  t he best o verall res p o nse, pr o gressi o n -free s ur vi val 
( P F S), c ha n ges i n ser u m t h yr o gl o b uli n le vels, a n d safet y/t olera bilit y of eac h of t he treat me nt ar ms.  
 
1. 1  
Treat me nt  
 
1. 1 1  
1 3 1I i n c o m bi nati o n wit h place bo  
 
1. 1 2  
1 3 1I i n c o m bi nati o n wit h sel u meti ni b 
 
1. 2  
C orrelati ve Researc h  
 
1. 2 1  
T hera pe utic be nefit wit h 1 3 1I i n c o m bi nati o n wit h place b o or sel u meti ni b will be 
c orrelate d t o ge n o mic a n d tra nscri pt o mic bi o mar ker a nal ysis of arc hi val t u m or tiss ue 
s peci me ns. 
 
W e will e x pl ore t he ge n o mic a n d tra nscri pt o mic la n dsca pe of R AI A t u m ors f or 
si g nat ures t hat c orrelate t o t hera pe utic be nefit ac hie ve d i n patie nts wit h R AI -a vi d 
rec urre nt a n d/ or metastatic t h yr oi d ca ncer treate d wit h 1 3 1I i n c o m bi nati o n wit h 
place b o or sel u m eti ni b. E x pl orat or y a nal ysis will i ncl u de c orrelati n g res p o nse t o 
t u m or ge n ot y pes. All t u m ors will be e val uate d f or c o m m o n t h yr oi d ca ncer ge ne 
m utati o ns ( B R A F, R A S, PI K 3 C A, A K T, R E T/ P T C, P A X 8/ P P A R γ). Descri pti ve 
statistics a n d gra p hical tec h ni q ues will be use d t o s u m marize t his data b y treat me nt 
ar m. Gi ve n t he s mall sa m ple size, all t hese a nal yses will be c o nsi dere d h y p ot he sis 
ge nerati n g a n d e x pl orat or y.  
 
2. 0  
G o als  
 
2. 1  
Pri mar y  
 
2. 1 1  
T o deter mi ne t he res p o nse rate at 6 m o nt hs f oll o wi n g treat me nt  w it h 1 3 1I i n c o m bi nati o n 
wit h place b o or sel u meti ni b f or R AI A rec urre nt a n d/ or metastatic t h yr oi d ca ncer . 
 
2. 2  
Sec o n dar y  
 
2. 2 1  
T o deter mi ne t he best o verall res p o nse f oll o wi n g treat me nt wit h 1 3 1I i n c o m bi nati o n 
wit h place b o or sel u meti ni b f or R AI A rec urre nt a n d/ or metastatic t h yr oi d ca ncer.  
 
2. 2 2  
T o c o m pare t he  pr o gressi o n -free s ur vi val of patie nts wit h R AI A rec urre nt a n d/ or 
metastatic t h yr oi d ca ncer treate d wit h 
1 3 1I i n c o m bi nati o n wit h place b o or sel u meti nib.  
 
2. 2 3  
T o c o m pare ser u m t h yr o gl o b uli n c ha n ges f or patie nts wit h R AI A rec urre nt a n d/ or 
metastatic t h yr oi d ca ncer treate d wit h 
1 3 1I i n c o m bi nati o n wit h place b o or sel u meti ni b. 
 
2. 2 4  
T o e val uate t he safet y a n d t olera bilit y of 1 3 1I i n c o m bi nati o n wit h place bo or 
sel u meti ni b f or patie nts wit h R AI-a vi d rec urre nt a n d/ or metastatic t h yr oi d ca ncer.  
 
2. 3  
C orrelati ve Researc h  
 
2. 3 1  
T o e x pl ore t he ge n o mic a n d tr a nscri pt o mic la n dsca pe of R AI A  t u m ors f or si g nat ures 
t hat c orrelate t o t hera pe utic be nefit ac hie ve d wit h 1 3 1I i n c o m bi nati o n wit h place b o or 


 
1 1   
R U 2 4 1 3 0 6 I 
 
 
A d de n d u m 9  
sel u meti ni b. 
 
 
 
 
3. 0  
P atie nt Eli gi bilit y  
 
3. 1  
I ncl usi o n Criteria  
 
3. 1 1  
A ge ≥1 8 years . 
 
3. 1 2  
Dia g n osis of rec urre nt a n d/ or metastatic t h yr oi d ca ncer.  
 
3. 1 3  
Hist ol o gical or c yt ol o gical  c o nfir mati o n of t h yr oi d carci n o ma of f ollic ular ori gi n 
(i ncl u di n g pa pillar y, f ollic ular, or p o orl y differe ntiate d s u bt y pes a n d t heir res pecti ve 
varia nts) .  
 
N O T E : Me d ullar y a n d a na plastic t h yr oi d ca ncers are e xcl u de d. H urt hle cell carci n o ma s 
are e xcl u de d ( defi ne d as ha vi n g a n i n vasi ve t u m or c o m p ose d of  > 7 5 % o nc oc ytic 
( H urt hle) cells lac ki n g t he n uclear feat ures of pa pillar y carci n o ma, t u m or necr osis, a n d 
mar ke d mit otic acti vit y ). Patie nts wit h o nc oc ytic ( H urt hle cell) varia nts of pa pillar y 
t h yr oi d carci n o ma (de fi ne d as a t u m or c o m p ose d of a maj orit y of o nc oc ytic ( H urt hle) 
cells ha vi n g t he n uclear feat ures of pa pillar y carci n o ma ) are eli gi ble t o partici pate.  
 
3. 1 4  
R AI -a vi d lesi o n o n a ra di oi o di ne sca n (a dia g n ostic, p ost -t hera p y, or p ost-a blati o n 
sca ns) perf or me d ≤2 4 m o nt hs pri or t o re gistrati o n , w hic h s u g gests t hat t hera p y wit h 1 3 1I 
is j ustifia ble i n t he j u d g me nt of t he i n vesti gat or. 
 
3. 1 5  
Cli nicall y or ra di o gra p hicall y e vi de nt str uct ural disease.   Patie nts wit h meas urea ble 
disease a n d t h ose wit h o nl y n o n -meas urea ble (“ n o n -tar get”) str uct ural disease 
(acc or di n g t o m o difie d R E CI S T v 1. 1 criteria, see Secti o n 1 1. 0) are eli gi ble. 
 
 
 
N O T E 1 : M o dificati o n of t he R E CI S T v 1. 1 meas urea ble disease criteria i ncl u des a 
c ha n ge i n t he defi niti o n of w hat is c o nsi dere d a meas urea ble mali g na nt l y m p h n o de. A 
mali g na nt l y m p h n o de is c o nsi dere d meas ura ble if a n y of t he f oll o wi n g a p pl y:  
 
1) it is n ote d t o be R AI -a vi d o n ra di oacti ve i o di ne i ma gi n g ( dia g n ostic or p ost-
t hera p y w h ole b o d y sca ns acce pta ble) a n d it meas ures > 1 c m i n t he l o n g a xis,  
 
2) it is pat h ol o gicall y  pr o ve n t o be i n v ol ve d wit h t h yr oi d ca ncer ( b y c yt ol o g y or 
pat h ol o g y) a n d it meas ures > 1 c m i n t he l o n g a xis,  
 
or  
 
3) its s h ort a xis is > 1. 5 c m w he n assesse d b y C T sca n .   
 
N O T E 2 : Patie nts o nl y wit h bi oc he mical e vi de nce of disease wit h o ut str uct ural 
e vi de nce of ca ncer are n ot  eli gi ble f or t his st u d y.  
 
3. 1 6  
F or p atie nts wit h n o n -me as ure a ble, str uct ur al dise ase t he f oll o wi n g m ust a p pl y:   
 
1)  u n detecta ble t h yr o gl o b uli n a nti b o d y  
 
A N D  


 
1 2   
R U 2 4 1 3 0 6 I 
 
 
A d de n d u m 9  
 
2) a ser u m t h yr o gl o b uli n of 1 0 n g/ ml or greater i n t he c o nte xt of s u p presse d T S H ( T S H <  
0. 4 mc U/ ml) <  2 8 da ys pri or t o st u d y re gistrati o n.   
 
Use of a n y t h yr o gl o b uli n assa y is all o we d, t h o u g h all ser u m t h yr o gl o b uli n meas ure me nts 
f or st u d y p ur p oses m ust  be c o n d ucte d wit h t he sa me t h yr o gl o b uli n assa y.  
 
 
3. 1 7  
E C O G Perf or ma nce Stat us ( P S) 0, 1 or 2.  ( F or ms are a vaila ble o n t he A C C R U we b 
site) 
3. 1 8  
A ble t o s wall o w a n d retai n orall y -a d mi nistere d me dicati o n wit h n o cli nicall y si g nifica nt 
gastr oi ntesti nal a b n or malities t hat ma y alter a bs or pti o n.  
 
3. 1 9a  T he f oll o wi n g la b orat or y val ues o btai ne d   2 8  d a ys pri or t o ra n d o mizati o n: 
 
•  A bs ol ute ne utr o p hil c o u nt ( A N C) ≥1 5 0 0/ m m 3 
•  Platelet c o u nt 1 0 0, 0 0 0/ m m 3 
•  He m o gl o bi n > 9. 0 g/ d L  
•  T otal bilir u bi n ≤1. 5 x u p per li mit of n or mal ( U L N)  
•  As partate tra nsa mi nase ( A S T) 2. 5 x U L N  ( or 5 x  U L N i n prese nce of li ver 
metastases)  
•  Creati ni ne 1. 5 m g/ d L O R calculate d creati ni ne cleara nce of ≥5 0  ml/ mi n b y eit her 
t he C oc kcr oft -Ga ult f or m ula  (see bel o w) or 2 4-h o urs uri ne c ollecti o n a nal ysis  
 
 
C oc kcr oft -G a ult E q u ati o n : 
 
Cre ati ni ne cle ar a nce f or m ales =  ( 1 4 0 - a ge)( wei g ht i n k g)  
 
 
 
 
 
( 7 2)(ser u m cre ati ni ne i n m g/ d L) 
 
Cre ati ni ne cle ar a nce f or fe m ales =  ( 1 4 0 - a ge)( wei g ht i n k g)( 0. 8 5)  
 
 
 
 
 
( 7 2)(ser u m cre ati ni ne i n m g/ d L) 
 
 
3. 1 9 b  Ne gati ve  pre g na nc y test perf or me d  ≤7 da ys pri or t o re gistrati o n  f or w o me n of 
c hil d beari n g p ote ntial o nl y.  
 
3. 1 9 c Pr o vi de i nf or me d writte n c o nse nt.  
 
3. 1 9 d  Willi n g t o ret ur n t o e nr olli n g i nstit uti o n f or f oll o w -u p ( d uri n g t he Acti ve M o nit ori n g 
P hase of t he st u d y).  
 
N ote: D uri n g t he Active M o nit ori n g  P h ase of a st u dy (i.e., active tre at me nt a n d o bserv ati o n), 
p artici p a nts m ust be willi n g t o ret ur n t o t he c o nse nti n g i nstit uti o n f or f oll o w-u p.  
 
 
3. 1 9 e Willi n g t o pr o vi de  ma n dat or y  arc hi val t u m or tiss ue ( bl oc k or mi ni m u m of 3 0 u nstai ne d 
sli des fr o m a pri mar y or rec urre nt/ metastatic t h yr oi d ca ncer) f or c orrelati ve researc h 
p ur p oses (see Secti o n 1 7. 0).  N O T E:  Patie nts wit h less arc hi val t u m or tiss ue a vaila ble 
ma y still be eli gi ble f or t he st u d y after disc ussi o n  wit h A C C R U (refer t o Pr ot oc ol 
Res o urce pa ge) .  Recei pt of arc hi val t u m or tiss ue is n ot re q uire d f or st u d y re gistrati o n 
a n d i nitiati o n of t hera p y.  
 


 
1 3   
R U 2 4 1 3 0 6 I 
 
 
A d de n d u m 9  
3 .1 9 f 
Willi n g t o pr o vi de ma n dat or y  bl o o d sa m ple s f or c orrelati ve researc h p ur p oses (see 
Secti o n 1 4. 0 ). 
 
 
3. 2  
E xcl usi o n Criteria  
 
3. 2 1  
1 3 1I t hera p y < 6 m o nt hs pri or t o re gistrati o n. N ote: 1 3 1I a d mi nistere d s olel y f or dia g n ostic 
p ur p oses is n ot  c o nsi dere d 1 3 1I t hera p y. 
 
3. 2 2  
E xter nal bea m ra diati o n t hera p y < 2 8 da ys pri or t o re gistrati o n. N ote: Pre vi o us treat me nt 
wit h ra diati o n is all o we d if t he i n vesti gat or j u d ges it will n ot c o m pr o mi se patie nt safet y 
o n t he st u d y.  
 
3. 2 3  
Ha vi n g bee n treate d wit h a t otal c u m ulat i ve (lifeti me) 1 3 1I t hera pe utic acti vit y > 8 0 0 m Ci  
(e xcl u di n g 1 3 1I acti vit y a d mi nistere d f or dia g n ostic sca ns) . 
 
3. 2 4  
Treat me nt wit h c he m ot hera p y or tar gete d t hera p y (e. g. t yr osi ne ki nase i n hi bit or) < 2 8 
da ys pri or t o re gistrati o n.  
 
3. 2 5  
Pri or e x p os ure t o M E K, R A S, or R A F i n hi bit ors ( N ote: pre vi o us e x p os ure t o s orafe ni b 
is all o we d) O R hist or y of h y perse nsiti vit y t o sel u meti ni b, t h yr otr o pi n al p ha 
(T h yr o ge n ™), or a n y e xci pie nt a ge nts. 
 
3. 2 6  
U nres ol ve d t o xicit y > C T C A E gra de 2 fr o m pre vi o us a nti -ca ncer t hera p y, e xce pt f or 
al o pecia. 
 
3. 2 7  
Car diac c o n diti o ns as f oll o ws:  
 
•  U nc o ntr olle d h y perte nsi o n ( B P ≥1 5 0/ 9 5 m m H g des pite me dical t hera p y)  
•  Left ve ntric ular ejecti o n fracti o n < 5 5 % meas ure d b y ec h ocar di o gra p h y  
•  Atrial fi brillati o n wit h a ve ntric ular rate > 1 0 0 b p m o n E C G at rest  
•  S y m pt o matic heart fail ure ( N Y H A gra de II -I V) 
•  Pri or  or c urre nt car di o m y o pat h y  
•  Se vere val v ular heart disease  
•  U nc o ntr olle d a n gi na ( Ca na dia n Car di o vasc ular S ociet y gra de II -I V des pite me dical 
t hera p y) 
•  Ac ute c or o nar y s y n dr o me ≤6 m o nt hs pri or t o re gistrati o n. 
 
3. 2 8  
O p ht hal m ol o gical c o n diti o ns as f oll o ws:   
 
•  I ntra-oc ular press ure > 2 1 m m H g, or u nc o ntr olle d gla uc o ma (irres pecti ve of i ntra -
oc ular press ure)  
•  C urre nt or past hist or y of ce ntral ser o us reti n o pat h y or reti nal vei n occl usi o n  
 
3. 2 9 a S y m pt o matic or u ntreate d le pt o me ni n geal disease, brai n metastasis, or s pi nal  c or d 
c o m pressi o n. 
 
3. 2 9 b  U na ble t o f oll o w a l o w i o di ne diet or re q uiri n g me dicati o n wit h hi g h c o nte nt i n i o di de 
(e. g., a mi o dar o ne). 
 
3. 2 9c  Recei ve d i o di nate d i ntra ve n o us c o ntrast ≤2 m o nt hs of re gistrati o n. A v oi da nce of 
i o di nate d oral c o ntrast is als o preferre d  b ut n ot strictl y re q uire d f or st u d y e nr oll me nt . 
N O T E: T h ose w h o  ha ve ha d i o di nate d i ntra ve n o us c o ntrast wit hi n t his ti me  fra me ma y 
still be eli gi ble if a uri nar y i o di ne a nal ysis re veals t hat e xcess i o di ne has bee n cleare d 


 
1 4   
R U 2 4 1 3 0 6 I 
 
 
A d de n d u m 9  
( defi ne d as uri nar y i o di ne d oc u me nte d t o be < 3 0 0 mc g/ da y b y eit her a s p ot uri nar y 
i o di ne or 2 4-h o ur uri nar y i o di ne meas ure me nt).  
 
 
3. 2 9 d  A n y of t he f oll o wi n g beca use t his st u d y i n v ol ves a n i n vesti gati o nal a ge nt w h ose 
ge n ot o xic, m uta ge nic a n d terat o ge nic effects o n t he de vel o pi n g fet us a n d ne w b or n are 
u n k n o w n:  
 
•  Pre g na nt w o me n  
•  N ursi n g w o me n  
•  Me n or w o me n of c hil d beari n g p ote ntial w h o are u n willi n g t o e m pl o y a de q uate 
c o ntrace pti o n  
 
3 .2 9e  C o -m or bi d s yste mic ill nes ses or ot her se vere c o nc urre nt disease w hic h, i n t he j u d g me nt 
of t he i n vesti gat or, w o ul d ma ke t he patie nt i na p pr o priate f or e ntr y i nt o t his st u d y or 
i nterfere si g nifica ntl y wit h t he pr o per assess me nt of safet y a n d t o xicit y of t he 
prescri be d re gi me ns.  
 
3.  2 9f  I m m u n oc o m pr o mise d patie nts a n d patie nts k n o w n t o be HI V p ositi ve a n d c urre ntl y 
recei vi n g a ntiretr o viral t hera p y. N O T E: Patie nts k n o w n t o be HI V p ositi ve, b ut wit h o ut 
cli nical e vi de nce of a n i m m u n oc o m pr o mise d state, are eli gi ble f or t his trial.  
 
3. 2 9 g  U n c o ntr olle d i nterc urre nt ill ness i ncl u di n g, b ut n ot li mite d t o, o n g oi n g or acti ve 
i nfecti o n, he patitis B i nfecti o n, he patitis C i nfecti o n, s y m pt o matic c o n gesti ve heart  
fail ure, u nsta ble a n gi na pect oris, car diac arr h yt h mia, or ps yc hiatric ill ness/s ocial 
situati o ns t hat w o ul d li mit c o m plia nce wit h st u d y re q uire me nts.  
 
3.  2 9 h  Recei vi n g a n y ot her i n vesti gati o nal a ge nt w hic h w o ul d be c o nsi dere d as a treat me nt f or 
t he pri mar y ne o plas m. ( N O T E: Perf or ma nce of i n vesti gati o nal 1 2 4I P E T/ C T sca ns is 
all o we d pri or t o a n d d uri n g c o n d uct of t his st u d y.)  
 
3.  2 9i  Ot her acti ve mali g na nc y ≤2  years pri or t o re gistrati o n  t hat will i nterfere wit h c o n d uct of 
t his trial. E X C E P TI O N S: N o n-mela n otic s ki n ca ncer or carci n o ma -i n-sit u of t he cer vi x. 
N O T E: If t here is a hist or y o f pri or m ali g na nc y, patie nts  m ust n ot be recei vi n g ot her 
s pecific treat me nt (c he m ot hera p y, h or m o nal t hera p y, ra diati o n ) f or t heir ca ncer.  
 
3. 2 9j  
N ot willi n g t o disc o nti n ue use of s u p ple me ntal  vita mi n E . 
 


 
1 5   
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
 
4. 0  
Test Sc he d ule  
( Wee k desi g nati o ns ma y c ha n ge if t here are i nterr u pti o ns i n st u d y treat me nts/assess me nts)  
Tests a n d pr oce d ures  
≤2 8 d a ys 
pri or t o 
re gistr ati o n
1 2  
Pri or t o 
tre at m e nt 
i niti ati o n 
Wee k 
1  
Wee k 
2  
Wee k 
3  
Wee k 
4  
O bser v ati o n 
P h ase : 
1 m o nt h p ost -
1 3 1I t her a p y  
( +/- 1 w k)  
O bser v ati o n P h ase : 
•  3 m o nt hs p ost -1 3 1I t her a p y ( +/- 1 w k) t he n  
•  e ver y 3 m o nt hs ( ± 1 wee k)  u ntil 1 2 m o nt hs 
p ost 1 3 1I t her a p y,  
f oll o we d by  
•  e ver y 6 m o nt hs ( ± 2 wee ks) u ntil 2 ye ars ( ± 
3 m o nt hs) p ost r a n d o miz ati o n  
Sel u meti ni b or place b o 1  
 
 
X  
X  
X  
X  
 
 
A d here n ce t o l o w i o di ne 
diet 2  
 
 
 
 
X  
X  
 
 
T h yr o ge n ™3  
 
 
 
 
 
X  
 
 
A d mi nistrati o n of 
t hera p e utic 1 3 1I5  
 
 
 
 
 
X  
 
 
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
Hist or y a n d e x a m, wt, 
E C O G P S   
X  
 
X  
 
X  
 
X 1 5 
 
Hei g ht  
X  
 
 
 
 
 
 
 
P ulse a n d bl o o d press ure  
X  
 
X  
 
X  
 
 
 
A d verse e v e nt assess me nt 1 6 
X  
 
X 4 
X  
X  
X  
X 1 5 
X  
He m at ol o g y: C B C/ 
differe ntial  
X  
 
X 1 3 
 
X  
 
X 1 5 
 
C he mistr y: S G O T ( A S T), 
S G P T ( A L T), al k p h os, T. 
bili, creati ni ne, calci u m, 
p h os, gl uc ose, Na, K  
X  
 
X 1 3  
 
X  
 
X 1 5 
 
T S H, free T 4, ser u m 
t h yr o gl o b uli n, 
t h yr o gl o b uli n a nti b o d y1 8 
X  
 
 
 
 
 
X 1 5  
X  
Ra di ol o gic e v al uati o n f or 
disease assess me nt ( C T(s) 
a n d/ or M RI(s)) 6 
N O I O DI N A T E D 
C O N T R A S T I S 
A L L O W E D  
( R E Q UI R ED) 1 4  
X  
 
 
 
 
 
 
X  


 
1 6   
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
 
 
A V OI D A N C E O F 
I O DI N A T E D O R A L 
C O N T R A S T I S A L S O 
P R E F E R R E D B U T N O T 
S T RI C T L Y R E Q UI R E D 1 4 
E C G  
X  
 
 
 
 
 
 
 
Ec h ocar di o gra m 1 7  
X  
 
 
 
 
 
 
 
O p ht hal m ol o gical 
e x a mi nati o n 7  
X  
 
 
 
 
 
 
 
Pre g na n c y test (ser u m beta 
H C G) 8 
X  
 
 
 
 
X  
 
 
Ma n dat or y researc h  bl o o d 
sa m ple (see Secti o n 1 4. 0) 9, 
R  
 
X  
 
 
 
 
 
 
Ma n dat or y arc hi val tiss ue 
c ollecti o n 1 0  (see Secti o n 
1 7. 0)  
X  
 
 
 
 
 
 
 
Patie nt Me dicati o n Diar y 
(A p pe n di x II )1 1  
 
 
X  
X  
X  
X  
 
 
 
1.  
Place b o or sel u meti ni b 7 5 m g orall y t wice dail y will be starte d o n Wee k 1, Da y 1 a n d c o nti n ue d t hr o u g h 2 da ys after t hera pe utic 1 3 1I 
t hera p y has bee n a d mi nistere d. I deall y, place b o or sel u meti ni b d osi n g/treat me nt s h o ul d be mai ntai ne d f or at least 7 da ys pri or t o a n d 
t hr o u g h o ut a d mi nistrati o n of t hera pe utic 1 3 1I (t his is n ot a re q uire me nt). E xte n din g t he ti me o n place b o or sel u meti ni b (i.e. e xte n di n g 
ti me o n treat me nt a n d/ or i nstit uti n g treat me nt i nterr u pti o ns) a n d/ or resc he d uli n g/re peati n g st u d y assess me nts/ pr oce d ures/treat me nts 
(t h o u g h t hera pe utic 1 3 1I s h o ul d be a d mi nistere d o nl y o nce ) is/are all owe d t o f ulfill t he criteria disc usse d a b o ve at t he i n vesti gat or’s 
discreti o n. T he peri o d of ti me o n place b o or sel u meti ni b (i.e. e xte n di n g ti me o n treat me nt a n d/ or i nstit uti n g treat me nt i nter r u pti o ns) is 
n ot t o e xcee d 8 wee ks.  
2.  
Patie nts s h o ul d a d here t o a l o w i o di ne diet f or 5 da ys pri or t o t he start of T h yr o ge n ™-sti m ulate d a d mi nistrati o n of t hera pe utic 1 3 1I 
pr ocesses. T he l o w i o di ne diet will be c o nti n ue d t hr o u g h 1 da y after 1 3 1I is gi ve n. Please see A p pe n di x III f or details of t he l o w i o di ne 
diet.  
3.  
T h yr o ge n ™ 0. 9 m g I M will be a d mi nistere d o nce dail y f or 2 c o nsec uti ve cale n dar da ys, wit h t he last d ose gi ve n 1 cale n dar da y pri or t o 
1 3 1I i n gesti o n. 
4.  
T hese A d verse E ve nt assess me nts are mea nt t o de n ote t hat st u d y place b o or dr u g a d verse e ve nts s h o ul d be m o nit ore d t hr o u g h o ut t he 
treat me nt. N o f or mal visits are re q uire d f or t hese assess me nts, wit h t he e xce pti o n of Wee k 3 , w hic h is a ma n dat or y visit.  
5.  
Patie nts < 7 0 years of a ge will be treate d wit h 1 5 0 m Ci 1 3 1I ( +/- 5 m Ci). Patie nts > 7 0 years of a ge ca n be treate d wit h a 1 3 1I acti vit y fr o m 
1 0 0 m Ci u p t o a n d i ncl u di n g 1 5 0 m Ci ( +/ - 5 m Ci f or 1 0 0 m Ci or 1 5 0 m Ci a d mi nistere d acti vities); f or t hese patie nts, t he acti vit y t o be 


 
1 7   
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
 
a d mi nistere d m ust be deter mi ne d b y t he i n vesti gat or at t he ti me of st u d y re gistrati o n.  T h o u g h perf or mi n g w h ole bl o o d a n d b o d y 
d osi metr y t o deter mi ne ma xi m u m t olerate d acti vit y ( M T A) is N O T re q uire d, f or ce nters at w hic h t his e val uati o n is d o ne pri or t o 
t hera pe utic 1 3 1I st u d y a d mi nistrati o n ( Wee k 4), l o wer 1 3 1I acti vities t ha n w hat is rec o m men de d here ma y be a d mi nistere d if t he M T A is 
calc ulate d t o be l o wer t ha n t he l o wer li mit of w hat is all o we d per pr ot oc ol or w hat has bee n deter mi ne d t o be gi ve n (f or pati e nts > 7 0 
years of a ge). E x a m ples  (t hese are o nl y a p plica ble i n i nsta nces i n w hic h d osi metr y was perf or me d pri or t o t hera pe utic 1 3 1I 
a d mi nistrati o n): 1) P atie nts < 7 0 ye ars of a ge:  If t he d osi metr y-deter mi ne d M T A val ue is less t ha n 1 5 0 m Ci, t he n a R AI acti vit y less 
t ha n 1 5 0 m Ci ma y be a d mi nistere d; 2) P atie nts > 7 0 ye ars of a ge: If t he d osi metry -deter mi ne d M T A val ue is less t ha n t he acti vit y t hat 
was deter mi ne d t o be gi ve n at t he ti me of st u d y re gistrati o n, t he n a l o wer R AI acti vit y ma y be a d mi nistere d, e ve n acti vities less t ha n 1 0 0 
m Ci if t he M T A is bel o w t his t hres h ol d. D osi metr y ca n N O T be us e d t o j ustif y a d mi nisteri n g t hera pe utic 1 3 1I acti vities hi g her t ha n 
w hat has bee n rec o m me n de d per t his pr ot oc ol.  A d mi nistrati o n of T h yr o ge n ™ a n d/ or t hera pe utic 1 3 1I at a facilit y ot her t ha n t he 
partici pati n g site is all o we d if d oc u me ntati o n of t he dates a n d a m o u nt/acti vit y of dr u g /ra di ois ot o pe a d mi nistere d is pr o vi de d t o verif y 
a d here nce t o pr ot oc ol re q uire me nts. Perf or ma nce of p ost -t hera p y i o di ne sca ns is n ot re q uire d, b ut is all o we d per i nstit uti o nal practice. 
6.  
C T(s) WI T H O U T C O N T R A S T (refer t o f o ot n ot e 1 4) a n d/ or M RI(s) f or t u m or(s) assess me nt is/are t o be d o ne pri or t o st u d y re gistrati o n, 
a b o ut 3 m o nt hs ( +/ - 1 wee k)  after 1 3 1I t hera p y, a n d t he n e ver y 3 m o nt hs ( +/ - 1 wee k) . After 1 2 m o nt hs p ost-1 3 1I t hera p y, f oll o w u p sca ns 
are t o be d o ne e ver y 6 m o nt h s ( +/- 1 wee k) f or a ma xi m u m of 2 years ( +/ - 3 m o nt hs) fr o m st u d y ra n d o mizati o n. T he sc he d ule of 
ra di o gra p hic assess me nts ma y be altere d i n or der t o mai ntai n t he t u m or assess me nt i nter vals detaile d here i n t he e ve nt u nsc hed ule d 
assess me nts are perf or me d. E ver y eff ort m ust be ma de t o ha ve t he 6 m o nt h p ost -1 3 1I t hera p y assess me nt(s) perf or me d. 
7.  
O p ht hal m ol o gical e xa mi nati o n s h o ul d be perf or me d b y a n o p ht hal m ol o gist a n d i ncl u de best c orrecte d vis ual ac uit y, i ntra oc ular press ure 
meas ure me nt, slit -la m p f u n d usc op y. O C T sca n s h o ul d be c o nsi dere d o nl y if dee me d cli nicall y a p pr o priate. It is rec o m me n de d t hat 
patie nts wit h o n g oi n g reti nal a b n or malit y at t he ti me of disc o nti n uati o n of Sel u meti ni b or place b o s h o ul d ha ve a f oll o w -u p 
o p ht hal m ol o gical assess me nt a p pr o xi ma tel y 1 m o nt h after dr u g/ place b o disc o nti n uati o n (t he p ur p ose of t his is t o d oc u me nt re versi bilit y, 
b ut s h o ul d o nl y be c o nsi dere d if t he patie nt is fit e n o u g h t o ha ve t he assess me nt d o ne).  
8.  
F or w o me n of c hil d beari n g p ote ntial o nl y. M ust be d o ne 7 da ys pr i or t o re gistrati o n. O n t he wee k t hera pe utic 1 3 1I gi ve n, a pre g na nc y 
test will be perf or me d ≤2 da ys pri or t o a d mi nistrati o n of t he 1 3 1I. 
9.  
C ollecti o n of 1 0 ml of bl o o d (i n la ve n der t o p t u be wit h E D T A) f or researc h p ur p oses s h o ul d n ot be c ollecte d a n d s u b mitte d u nt il after  
t he patie nt is re gistere d o nt o t he st u d y, b ut pri or  t o t he i nitiati o n of place b o or sel u meti ni b t hera p y (see Secti o n 1 4. 3). 
1 0.  ≤6 0 da ys fr o m re gistrati o n. N O T E: Recei pt of arc hi val t u m or tiss ue is n ot re q uire d f or st u d y re gistrati o n a n d i nitiati o n of t hera p y.  
1 1.  T he diar y m ust be gi n t he da y t he patie nt starts ta ki n g t he me dicati o n a n d ret ur ne d t o t he treati n g i nstit uti o n after its c o m pleti o n O R  
c o m plia nce m ust be d oc u me nte d i n t he me dical rec or d b y a n y me m ber of t he care tea m.  
1 2.  “ Pre-re gistrati o n assess me nts” nee d t o be c o m plete d ≤ 2 8 da ys pri or t o st u d y re gistrati o n u nless ot her wise s pecifie d.  
1 3.  T his bl o o d w or k is t o be c o m plete d pri or t o starti n g t hera p y wit h place b o or sel u meti ni b. T hese tests d o n ot nee d t o be re pea te d if t he 
pre -re gistrati o n bl o o d w or k was perf or me d < 7 da ys pr i or t o t he i nitiati o n of place b o or sel u meti ni b. 
1 4.  I o di nate d i ntra ve n o us c o ntrast is n ot  all o we d f or ra di ol o gic e val uati o ns d o ne d uri n g scree ni n g a n d pri or t o a d mi nistrati o n of R AI. It is 
als o preferre d t hat i o di nate d oral c o ntrast (e. g. O m ni pa q ue) be a v oi de d d uri n g scree ni n g a n d pri or t o R AI (alter nati ves s uc h as bari u m or 
ot her a ge nts ma y be use d), b ut t his is n ot  a re q uire me nt. I o di nate d i ntra ve n o us a n d oral c o ntrast f or ra di ol o gic e val uati o ns i n t he 
O bser vati o n P hase is all o we d.  


 
1 8   
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
 
1 5.  T hese tests a n d as sess me nts are o nl y re q uire d f or t he 1 m o nt h p ost 1 3 1I t hera p y visit. 
1 6.  A d verse e ve nts f or sel u meti ni b will be m o nit ore d f or u p t o 3 0 da ys after disc o nti n uati o n of dr u g.  
 
 
1 7.  If a n o n g oi n g re d ucti o n i n left ve ntric ular ejecti o n fracti o n of > 1 0 % a n d t o be l o w 5 5 % at ti me of sel u meti ni b or place b o disc o nti n uati o n 
is n ote d, t he n a f oll o w-u p ec h ocar di o gra m, si n gle E C G, a n d vital si g n assess me nt s h o ul d be c o nsi dere d a p pr o xi matel y 1 m o nt h after 
dr u g/ place b o disc o nti n uati o n.  
1 8.  F or patie nts wit h n o n -meas urea ble/ n o n -tar get lesi o ns a n d l y m p h n o des, ser u m T G meas ure d i n t he c o nte xt of T S H s u p pressi o n ( T S H <  
0. 4 mc U/ ml) will be use d as part of disease res p o nse assess me nt.  F or t he pri mar y e n d p oi nt, ser u m T G m ust be assesse d wit h T S H <  0. 4 
mc U/ ml at baseli ne ( pre -treat me nt) a n d at t he 6-m o nt h assess me nt of res p o nse ( 6 m o nt hs s/ p R AI).  F or all ot her meas ure me nts of ser u m 
T G i n t hese patie nts, it is preferre d t hat t he T S H <  0. 4 mc U/ ml, b ut it is n ot a n a bs ol ute re q uire me nt.  If t he 6-m o nt h ser u m T G is 
i nitiall y meas ured i n t he c o nte xt of a T S H > 0. 4 mc U/ ml, t he n e ver y eff ort s h o ul d be ma de t o re peat t his assess me nt u ntil a ser u m T G 
val ue is o btai ne d i n t he c o nte xt of a T S H < 0. 4 mc U/ ml, e ve n if it re q uires o btai ni n g t he meas ure me nt o utsi de of t he pr ot oc ol -defi ne d +/ - 
1 wee k wi n d o w.  Ser u m T G val ues t hat ha ve t o be o btai ne d o utsi de t his pr ot oc ol -defi ne d wi n d o w t o e ns ure it is meas ure d i n t he c o nte xt 
of T S H < 0. 4 mc U/ ml will still be use d f or t he pri mar y assess me nt of res p o nse.  I M P O R T A N T: Use of a n y t h yr o gl o b uli n assa y is 
allo we d, t h o u g h all ser u m t h yr o gl o b uli n meas ure me nts f or st u d y p ur p oses m ust  be c o n d ucte d wit h t he sa me t h yr o gl o b uli n assa y.  T hese 
re q uire me nts d o n ot  a p pl y t o patie nts wit h meas urea ble disease.  
R  
“ Researc h f u n de d” (see Secti o n 1 9. 0)  
 
* N ote:  
O bserv ati o n P h as e: P art of t he Active M o nit ori n g P h ase of a st u dy. T he ti me peri o d f oll o wi n g t he active tre at me nt p h ase w he n 
t he p artici p a nt c o nti n ues t o receive cycles of ev al u ati o n i n c o m pli a nce wit h t he Test Sc he d ule a n d m ay be re q uire d t o ret ur n t o 
t he c o nse nti n g site. P artici p a nts will be re q uire d t o ret ur n t o t he c o nse nti n g site f or f oll o w -u p.  
 
 


 
 
 
1 9  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
5. 0  
Str atific ati o n F act ors:  
 
T his P hase 2 ra n d o mize d st u d y will c o m pare ra di oacti ve i o di ne ( R AI) i n c o m bi nati o n wit h place b o or 
sel u meti ni b f or t he treat me nt of R AI-a vi d recurre nt/ metastatic t h yr oi d ca ncers. A 1: 1 ra n d o mizati o n will 
be use d, w here t he P oc oc k -Si m o n al g orit h m ( P oc oc k SJ et al, 1 9 7 5) will be use d t o bala nce t he ar ms 
wit h res pect t o t he f oll o wi n g stratificati o n fact ors, al o n g wit h t he re gisteri n g me m bers hi p:  
 
•  
Pri or t h yr oi d ca ncer treat me nt wit h s yste mic c he m ot hera p y a n d/ or m olec ularl y tar gete d i n hi bit ors: 
Yes vs. N o  
•  
A ge ≥7 0 years : Yes vs. N o 
•  
B o ne Metastases prese nt: Yes vs. N o  
•  
Pre vi o us 1 3 1I t hera p y gi ve n f or t h yr oi d re m na nt a blati o n pri or t o t his st u d y: Yes vs. N o 
•  
Meas urea ble disease (as defi ne d b y t his pr ot oc ol): Yes or N o  
 
6. 0  
Re gistr ati o n/ R a n d o miz ati o n Pr oce d ures  
 
6. 1  
Re gistrati o n Pr oce d ures  
 
6. 1 1  
T o re gister a patie nt, access t he A C C R U we b pa ge at w w w.accr u. or g , g o t o t he 
A p plicati o n secti o n a n d clic k o n “re gistrati o n” a n d e nter t he re gistrati o n/ra n d o mizati o n 
a p plicati o n. T he re gistrati o n/ra n d o mizati o n a p plicati o n i s a vaila ble 2 4 h o urs a da y, 7 da ys 
a wee k. Bac k u p a n d/ or s yste m s u p p ort c o ntact i nf or mati o n is a vaila ble o n t he We b site. 
If u na ble t o access t he We b site, call t he Aca de mic a n d C o m m u nit y Ca ncer Researc h 
U nite d ( A C C R U) Re gistrati o n Office at 
 bet wee n t he h o urs of 8 a. m. a n d 
4: 3 0 p. m. Ce ntral Ti me ( M o n da y t hr o u g h Fri da y).  
 
Instr ucti o ns f or t he re gistrati o n/ra n d o mizati o n a p plicati o n are a vaila ble  o n t he a b o ve we b 
pa ge u n der t he St u d y Res o urces secti o n, “ A p plicati o n Trai ni n g.”   
 
Pri or t o i nitiat i o n of pr ot oc oli nter ve nti o n, t his pr ocess m ust be c o m plete d i n its e ntiret y 
a n d a n  A C C R U  s u bject I D n u m ber m ust be a vaila ble as n ote d i n t he i nstr ucti o ns. It is t he 
res p o nsi bilit y of t he i n di vi d ual a n d i nstit uti o n re gisteri n g t he patie nt t o c o nfir m t he 
pr o cess has bee n s uccessf ull y c o m plete d pri or t o release of t he st u d y a ge nt. Patie nt 
re gistrati o n via t he re gistrati o n/ra n d o mizati o n a p plicati o n ca n be c o nfir me d i n a n y of t he 
f oll o wi n g wa ys: 
 
•  
C o ntact t he A C C R U  Re gistrati o n Office 
. If t he patient was f ull y 
re gistere d, t he A C C R U Re gistrati o n Office staff ca n access t he i nf or mati o n fr o m 
t he ce ntralize d data base a n d c o nfir m re gistrati o n. 
•  
Refer t o w w w.accr u. or g; clic k o n “ Re gistrati o n, I nstallati o n & E ntr y I nstr ucti o ns.  
6. 1 2  
C orrelati ve Researc h  
 
A  ma n dat or y  c orrelati ve researc h c o m p o ne nt is part of t his st u d y, t he patie nt will be 
a ut o maticall y re gistere d o nt o t his c o m p o ne nt (see Secti o ns 3. 1 9c, 3. 1 9 d , 1 4. 1  a n d 1 7.1 ). 
 
6. 1 3  
D oc u me ntati o n of I R B a p pr o val m ust be o n file wit h A C C R U bef ore a n i n vesti ga t or 
ma y re gister a n y patie nts. A p pr o vals s h o ul d be u pl oa de d t hr o u g h t he o nli ne A C C R U 
Re g ulat or y Ma na ge me nt S yste m ( A R M S).  
 
 
I n a d diti o n t o s u b mitti n g i nitial I R B a p pr o val d oc u me nts, o n g oi n g I R B a p pr o val 


 
 
 
2 0  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
d oc u me ntati o n m ust be o n file wit h A C C R U n o less t ha n a n n uall y. A p pr o vals s h o ul d be 
u pl oa de d t hr o u g h t he o nli ne A C C R U Re g ulat or y Ma na ge me nt S yste m ( A R M S). If t he 
necessar y d oc u me ntati o n is n ot s u b mitte d i n a d va nce of atte m pti n g patie nt re gistrati o n, 
t he re gistrati o n will n ot be acce pte d a n d t he patie nt ma y n ot be e nr olle d i n t he pr ot oc ol 
u ntil t he sit uati o n is res ol ve d.  
 
S u b missi o n of a n n ual I R B a p pr o vals t o A C C R U is re q uire d u ntil t he st u d y is cl ose d 
t hr o u g h y o ur I R B. 
 
6. 1 4  
Pri or t o acce pti n g t he re gistrati o n/ra n d o mizati o n, t he re gistrati o n/ra n d o mizati o n 
a pplicati o n will verif y t he f oll o wi n g:  
 
•  
I R B a p pr o val at t he re gisteri n g i nstit uti o n 
•  
Patie nt eli gi bilit y  
•  
E xiste nce of a si g ne d c o nse nt f or m  
•  
E xiste nce of a si g ne d a ut h orizati o n f or use a n d discl os ure of pr otecte d healt h 
i nf or mati o n 
 
6. 1 5  
At t he ti me of re gistr ati o n, t he f oll o wi n g will be rec or de d:  
 
•  
Patie nt has/ has n ot gi ve n per missi o n t o st ore a n d use his/ her sa m ple(s) f or f ut ure 
researc h t o lear n a b o ut, pre ve nt, or treat ca ncer. 
•  
Patie nt has/ has n ot gi ve n per missi o n t o st ore a n d use his/ her sa m ple(s) f or f ut ure  
researc h t o lear n, pre ve nt, or treat ot her healt h pr o ble ms (f or e xa m ple: dia betes, 
Alz hei mer’s disease, or heart disease).  
•  
Patie nt has/ has n ot gi ve n per missi o n f or A C C R U  t o gi ve his/ her sa m ple(s) t o 
o utsi de researc hers.  
 
6. 1 6  
Treat me nt ca n n ot be gi n pri or t o re gistrati o n a n d m ust be gi n 7  da ys after re gistrati o n.  
 
6. 1 7  
Pretreat me nt tests/ pr oce d ures (see Secti o n 4. 0) m ust be c o m plete d wit hi n t he 
g ui deli nes s pecifie d o n t he test sc he d ule.  
 
6. 1 8  
All re q uire d baseli ne s y m pt o ms (see Secti o n 1 0. 5 ) m ust be d oc u me nte d a n d gra de d. 
 
6. 1 9  
Treat me nt o n t his pr ot oc ol m ust c o m me nce at a n A C C R U /I T O G i nstit uti o n u n der t he 
s u per visi o n of a me dical o nc ol o gist  or e n d ocri n ol o gist  f or t he a d mi nistrati o n a n d 
ma na ge me nt of place b o/sel u meti ni b t hera p y . C olla b orati o n wit h a n uclear me dici ne 
p h ysicia n will als o be necessar y t o c o or di nate t he c o n d uct a n d a d mi nistrati o n of 1 3 1I 
t hera p y. 
 
6. 2  
Ra n d o mizati o n Pr oce d ures  
 
6. 2 1  
T he fact ors defi ne d i n Secti o n 5. 0, t o get her wit h t he re gisteri n g me m bers hi p, will be 
use d as stratificati o n fact or s. 
 
6. 2 2  
After t he patie nt has bee n re gistere d i nt o t he st u d y, t he val ues of t he stratificati o n 
fact ors will be rec or de d, a n d t he patie nt will be assi g ne d t o o ne of t he f oll o wi n g 
treat me nt gr o u ps usi n g t he P oc oc k a n d Si m o n d y na mic all ocati o n pr oce d ure w hic h 
 
 bala nces t he mar gi nal distri b uti o ns of t he stratificati o n fact ors bet wee n t he treat me nt 


 
 
 
2 1  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
gr o u ps ( P oc oc k -Si m o n ref –  see bel o w). 
 
•  
Ra di oacti ve i o di ne ( R AI) pl us place b o   
•  
Ra di oacti ve i o di ne pl us sel u meti ni b  
 
6. 3  
Pr oce d ures f or D o u ble -Bli n di n g t he Treat me nt Assi g n me nt  
 
6. 3 1  
Astra Ze neca will s u p pl y sel u meti ni b or place b o t o Cli nical Researc h Ser vices, a 
di visi o n of R x Cr ossr oa ds b y Mc Kess o n f or distri b uti o n t o partici pati n g sites. N o 
bli n de d starter s u p plies will be a vaila ble f or t his st u d y. Bli n de d, patie n t-s pecific 
cli nical s u p plies will be se nt t o t he re gisteri n g i n vesti gat or at t he ti me of 
ra n d o mizati o n a n d s h o ul d arri ve wit hi n 3 -5  da ys. T his ra n d o mizati o n will be  
perf or me d b y t he A C C R U Statistical a n d Data Ce nter. T he assi g ne d A C C R U Patie nt 
I D n u m ber m ust be rec or de d b y t he re gisteri n g i nstit uti o n f or pr o per b ottle dis persi o n. 
O nce a patie nt has bee n re gistere d, A C C R U will electr o nicall y tra ns mit a cli nical 
dr u g re q uest f or t hat patie nt t o  Cli nical Researc h Ser vices, a di visi o n of R x 
Cr ossr oa ds b y Mc Kess o n . T his re q uest will be e ntere d a n d tra ns mitte d b y A C C R U 
t he da y t he patie nt is re gistere d a n d will be pr ocesse d a n d s hi p pe d b y Cli nical 
Researc h Ser vices, a di visi o n of R x Cr ossr oa ds b y Mc Kess o n t he sa me b usi ness da y if 
recei ve d bef ore 2 p m E T. If t he re quest is recei ve d after 2 p m E T, dr u g will be 
s hi p pe d t he f oll o wi n g b usi ness da y. S hi p me nts will be se nt via Fe d E x Pri orit y 
O ver ni g ht.  
 
6. 3 2  
Eac h bli n de d, patie nt -s pecific s u p pl y will be la bele d wit h: 
 
•  
T he st u d y pr ot oc ol n u m ber (i.e., A C C R U R U 2 4 1 3 0 6I)  
•  
T he p atie nt st u d y I D n u m ber  
•  
T he patie nt’s i nitials  
•  
T he n u m ber of ca ps ules  
•  
A d mi nistrati o n i nstr ucti o ns (i.e., ‘ A d mi nister as directe d per Pr ot oc ol A C C R U 
R U 2 4 1 3 0 6I’)  
•  
Dr u g I de ntificati o n (i.e., Sel u meti ni b 2 5 m g O R Place b o)  
•  
E x pirati o n Date  
•  
St ora ge i nstr ucti o ns (“ St ore at c o ntr olle d r o o m te m perat ure, 2 5° C ( 7 7° F)”)  
•  
Date dis pe nse d  
•  
I N D ca uti o n state me nt a n d/ or l ocal re g ulat or y state me nts 
•  
E mer ge nc y c o ntact i nstr ucti o ns  
 
6. 3 3  
Please see secti o n 1 5 . 1 8 f or m ore i nf or mati o n o n h o w t o re-or der m ore s u p plies, if 
nee de d.  


 
 
 
2 2  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
7. 0  
Pr ot oc ol Tre at me nt  
 
( Ple ase refer t o t he t a ble i n Secti o n 4. 0 f or sc he d ule of all pr ot oc ol tre at me nts a n d assess me nts) 
 
7. 1  
Treat me nt Sc he d ule  
 
A ge nt  
D ose Le vel  
R o ute  
Da y  
Re R x  
Sel u meti ni b or 
Place b o *  
7 5 m g  
P O  
BI D  
N o ne  
T h yr o ge n ™ 
0. 9 m g  
I M 
Dail y f or 2 da ys pri or 
t o R AI f or t hera p y 
 
R AI ( 1 3 1I) 
1 0 0 -1 5 0 m Ci * *  
P O  
O nce  
N o ne  
*  
T he t wice dail y d oses of sel u meti ni b s h o ul d be sc he d ule d 1 2 h o urs a part ( +/ - 2 h o urs). 
If a partici pa nt misses a sc he d ule d d ose b y m ore t ha n 2 h o urs, t hat d ose s h o ul d n ot be 
gi ve n a n d t he ne xt d ose a d mi nistere d at t he re g ularl y sc he d ule d ti me. It is n ot re q uire d 
t o e xte n d t he ti me o n Sel u meti ni b or place b o t o ma ke u p misse d d oses u nless 
e xte n di n g ti me (i.e. e xte n di n g ti me o n treat me nt a n d/ or i nstit uti n g treat me nt 
i nterr u pti o ns) is dee me d necessar y t o c o m pl y wit h i nstr ucti o ns detaile d bel o w. T he 
peri o d of ti me o n place b o or sel u meti ni b (i.e. t he ti me o n treat me nt i ncl u di n g 
treat me nt i nterr u pti o ns) is n ot t o e xcee d 8 wee ks. 
* *  Patie nts < 7 0 years of a ge will be treate d wit h 1 5 0 m Ci 1 3 1I ( +/- 5 m Ci). Patie nts ≥7 0 
years of a ge ca n be treate d wit h a 1 3 1I acti vit y fr o m 1 0 0 m Ci u p t o a n d i ncl u di n g 1 5 0 
m Ci ( +/ - 5 m Ci f or 1 0 0 m Ci or 1 5 0 m Ci a d mi nistere d acti vities); f or t hese patie nts, 
t he acti vit y t o be a d mi nistere d m ust be deter mi ne d b y t he i n vesti gat or at t he ti me of 
st u d y re gistrati o n. T h o u g h perf or mi n g w h ole bl o o d a n d b o d y d osi metr y t o deter mi ne 
ma xi m u m t olerate d acti vit y ( M T A) is N O T  re q uire d, f or ce nters at w hic h t his 
e val uati o n is d o ne pri or t o t hera pe utic 1 3 1I st u d y a d mi nistrati o n ( Wee k 4), l o wer 
t hera pe utic 1 3 1I acti vities t ha n w hat is rec o m me n de d here ma y  be a d mi nistere d if t he 
M T A is calc ulate d t o be l o wer t ha n t he l o wer li mit of w hat is all o we d per pr ot oc ol or 
w hat has bee n deter mi ne d t o be gi ve n (f or patie nts >  7 0 years of a ge). E x a m ples  
(t hese are a p plica ble o nl y  i n i nsta nces i n w hic h d osi metr y was perf or me d pri or t o 
t hera pe utic 1 3 1I a d mi nistrati o n): 1) P atie nts < 7 0 ye ars of a ge: If t he d osi metr y-
deter mi ne d M T A val ue is less t ha n 1 5 0 m Ci, t he n a n R AI acti vit y less t ha n 1 5 0 m Ci 
ma y be a d mi nistere d; 2) P ati e nts > 7 0 ye ars of a ge: If t he d osi metr y-deter mi ne d M T A 
val ue is less t ha n t he acti vit y t hat was deter mi ne d t o be gi ve n at t he ti me of st u d y 
re gistrati o n, t he n a l o wer R AI acti vit y ma y be a d mi nistere d, e ve n acti vities less t ha n 
1 0 0 m Ci if t he M T A is bel o w t his t hres h ol d.  D osi metr y ca n N O T  be use d t o j ustif y 
a d mi nisteri n g t hera pe utic 1 3 1I acti vities hi g her t ha n w hat has bee n rec o m me n de d per 
t his pr ot oc ol.   
 
A d mi nistrati o n of T h yr o ge n ™ a n d/ or t hera pe utic 1 3 1I at a facilit y ot her t ha n t he 
partici pati n g site is all o we d if d oc u me ntati o n of t he dates a n d a m o u nt/acti vit y of dr u g 
/ra di ois ot o pe a d mi nistere d is pr o vi de d t o verif y a d here nce t o pr ot oc ol re q uire me nts. 
Perf or ma nce of p ost -t hera p y i o di ne sca ns is n ot re q uire d, b ut is all o we d per 
i nstit uti o nal practice. 
 
 
Pl ace b o or S el u meti ni b 
 
C o nti n u o us d osi n g of place b o or sel u meti ni b  7 5 m g orall y t wice dail y will  be starte d o n Wee k 
1, Da y 1 a n d c o nti n ue d t hr o u g h 2 da ys after t hera pe utic 1 3 1I t hera p y has bee n a d mi nistere d. 


 
 
 
2 3  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
 
Bel o w are rec o m me n dati o ns t o be f oll o we d f or t hera p y wit h b ot h sel u meti ni b a n d place b o:  
 
Sel u meti ni b / place b o s h o ul d be ta ke n t wice a da y o n a n e m pt y st o mac h ( 1 h o ur bef ore or 2 h o urs 
after a meal), 1 2 h o urs  ( ± 2 h o urs) a part wit h a glass of water.  
 
•  
Patie nts s h o ul d a v oi d e xcessi ve s u n e x p os ure a n d use a de q uate s u nscree n pr otecti o n if s u n 
e x p os ure is a ntici pate d . 
•  
Patie nts s h o ul d n ot d o nate bl o o d d uri n g t he st u d y . 
•  
U nless cli nicall y i n dicate d, patie nts s h o ul d a v oi d c ha n ges t o, or t he a d diti o n of, c o nc o mita nt 
me dicati o ns, i n partic ular a n y t hat ma y affect t he meta b olis m of sel u meti ni b (e .g ., C YP 1 A 2, 
C Y P 2 C 1 9 or 3 A 4 i n hi bit ors/i n d ucers) . 
 
T he p har mac o ki netics of Sel u meti ni b were i n vesti gate d i n st u d y D 1 5 3 2 C 0 0 0 8 6, c o n d ucte d i n 
t he U K i n v ol vi n g healt h y v ol u nteers of Asia n et h nicit y ( defi ne d as bei n g b or n i n a n Asia n 
c o u ntr y, a n d e x patriate f or n ot l o n ger t ha n 5 years, a n d wit h mater nal a n d pater nal gra n d pare nts 
of Asia n et h nicit y). T he s u bjects w h o recei ve d Sel u meti ni b i n St u d y D 1 5 3 2 C 0 0 0 8 6 were of t he 
f oll o wi n g et h nicities: Ja pa nese, C hi nese, Fili pi n o, Mala y, Mala ysia n, Mal di via n, Si n ga p orea n, 
T hai, I n dia n a n d Viet na mese, a n d it is n ot k n o w n i n t hese gr o u ps w het her Sel u meti ni b e x p os ure 
will be si milar t o Wester n s u bjects or t o s u bjects of t he s pecific Asia n et h nicities i ncl u de d i n 
St u d y D 1 5 3 2 C 0 0 0 8 6.  
 
T he p har mac o k i netic fi n di n gs fr o m st u d y D 1 5 3 2 C 0 0 0 8 6 d o n ot s u p p ort e xcl u di n g s u bjects of 
Asia n et h nicit y fr o m st u dies of Sel u meti ni b. H o we ver, as it is p ossi ble t hat Asia n s u bjects ma y 
e x perie nce hi g her Sel u meti ni b plas ma e x p os ure (t ha n w o ul d be e x pecte d i n Wester n s u b jects 
recei vi n g t he sa me d ose of sel u meti ni b), t here c o ul d be a p ote ntial f or a hi g her ris k of a d verse 
e ve nts. 
 
T he n u m ber of Asia n patie nts wit h a d va nce d ca ncer w h o ha ve recei ve d treat me nt wit h 
Sel u meti ni b is ver y l o w. E mer gi n g i nf or mati o n fr o m o n g oi n g st u d y D 1 5 3 2 C 0 0 0 6 7 of Ja pa nese 
patie nts recei vi n g sel u meti ni b + d oceta xel f or sec o n d -li ne treat me nt of N S C L C s u g gests t hat 
fe brile ne utr o pe nia ma y occ ur m ore c o m m o nl y i n Ja pa nese patie nts ( 3 of 8 patie nts treate d, 
alt h o u g h c o m parati ve data i n Ja pa nese patie nt s recei vi n g d oceta xel m o n ot hera p y is n ot 
a vaila ble) t ha n mi g ht be pre dicte d fr o m st u dies c o n d ucte d i n Wester n s u bjects.  
 
Patie nts of Asia n et h nicit y are n ot e xcl u de d fr o m st u dies e val uati n g Sel u meti ni b. H o we ver, 
w he n c o nsi deri n g e nr olli n g a n i n di vi d ual of Asia n et h nicit y t o a Sel u meti ni b cli nical st u d y, 
i n vesti gat ors s h o ul d ma ke a cli nical j u d g me nt as t o w het her t he p ote ntial ris k of e x perie nci n g 
hi g her Sel u meti ni b plas ma le vels o ut wei g hs t he p ote ntial be nefit of treat me nt wit h Sel u meti ni b. 
T he Patie nt I nf o r mati o n a n d C o nse nt f or m f or st u dies of Sel u meti ni b i ncl u des i nf or mati o n o n 
t he p ossi bilit y of hi g her Sel u meti ni b plas ma le vels a n d occ urre nce of a d verse e ve nts i n Asia n 
s u bjects t ha n i n s u bjects w h o are n ot of Asia n ori gi n. I n vesti gat ors s h o ul d be a ware o f t he 
p ote ntiall y hi g her ris k of a d verse e ve nts w he n m o nit ori n g patie nts of Asia n et h nicit y recei vi n g 
treat me nt i n cli nical st u dies of Sel u meti ni b. 
 
As re pr o d ucti ve t o xic ol o g y data i n dicate t hat sel u meti ni b has a d verse effects o n e m br y of oetal 
de vel o p me nt a n d s ur vi val at d ose le vels t hat d o n ot i n d uce mater nal t o xicit y i n mice, t he 
f oll o wi n g restricti o ns a p pl y: 
 
Sel u meti ni b / place b o s h o ul d n ot be a d mi nistere d t o pre g na nt or breast-fee di n g w o me n a n d 
c o nce pti o n w hile o n treat me nt m ust be a v oi de d. Fe male patie nt s of c hil d-beari n g p ote ntial will 
be re q uire d t o use relia ble met h o ds of c o ntrace pti o n f or t he d urati o n of t he st u d y a n d u ntil 


 
 
 
2 4  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
4  wee ks after t he last d ose of Sel u meti ni b . Of n ote, patie nts ma y be re q ueste d t o mai ntai n 
c o ntrace pti o n a n d a v oi d pre g na nc y f or a l o n ger peri o d of ti me after 1 3 1I a d mi nistrati o n 
acc or di n g t o i nstit uti o nal g ui deli nes.  
 
Male patie nts wit h se x ual part ners w h o are pre g na nt or w h o c o ul d bec o me pre g na nt (i .e., 
w o me n of c hil d -beari n g p ote ntial) s h o ul d use acce pta ble met h o ds of c o ntrace pti o n f or 3 m o nt hs 
after t he last d ose  of sel u meti ni b / place b o t o a v oi d pre g na nc y a n d/ or p ote ntial a d verse effects o n 
t he de vel o pi n g e m br y o. Of n ote, patie nts ma y be re q ueste d t o mai ntai n c o ntrace pti o n a n d a v oi d 
pre g na nc y f or a l o n ger peri o d of ti me after 1 3 1I a d mi nistrati o n acc or di n g t o i nstit uti o nal 
g ui deli nes.  
 
S el u meti ni b / place b o ca ps ules c o ntai n vita mi n E i n t he f or m of D -α - T oc o p her yl p ol yet h yle ne 
gl yc ol 1 0 0 0 s ucci nate ( T P G S ), a water-s ol u ble f or m of vita mi n E w hic h acts as a f or m ulati o n  
e xci pie nt . T he ma xi m u m dail y d ose of vita mi n E t hat a st u d y s u bject ma y recei ve fr o m 
sel u meti ni b/ place b o is a p pr o xi matel y 2 6 1. 6 m g/ da y. T heref ore:  
 
Patie nts s h o ul d n ot ta ke a n y s u p ple me ntal vita mi n E. Hi g h d oses of vita mi n E ha ve bee n 
re p orte d t o ca use blee di n g a n d i nterr u pt bl o o d c oa g ulati o n pr ocesses. 
 
Sel u meti ni b/ place b o s h o ul d be a d mi nistere d wit h ca uti o n i n patie nts w h o are als o rece i vi n g 
c o nc o mita nt C o u ma di n  a ntic oa g ula nt me dicati o ns, e. g. warfari n. T hese patie nts s h o ul d ha ve 
t heir I N R m o nit ore d/a ntic oa g ulati o n assess me nts c o n d ucte d m ore fre q ue ntl y a n d t he d ose of t he 
a ntic oa g ula nt s h o ul d be a dj uste d acc or di n gl y.  
 
1 3 1I T her a p y 
Patie n ts < 7 0 years of a ge will be treate d wit h 1 5 0 m Ci 1 3 1I ( +/- 5 m Ci). Patie nts > 7 0 years of 
a ge ca n be treate d wit h 1 3 1I acti vit y fr o m 1 0 0 m Ci u p t o a n d i ncl u di n g 1 5 0 m Ci ( +/ - 5 m Ci f or 
1 0 0 m Ci or 1 5 0 m Ci a d mi nistere d acti vities); f or t hese patie nts, t he acti vit y t o be a d mi nistere d 
m ust be deter mi ne d b y t he i n vesti gat or at t he ti me of st u d y re gistrati o n.  
 
T hese 1 3 1I acti vities are wit hi n t he 1 0 0 -2 0 0 m Ci ra n ge f or e m piric  R AI treat me nt of metastatic 
t h yr oi d ca ncer rec o m me n de d b y t he 2 0 1 5 A merica n T h yr oi d Ass oc iati o n ( A T A) g ui deli nes  
( Ha u ge n et al, 2 0 1 5) All o wi n g acti vities < 1 5 0 m Ci f or patie nts > 7 0  years of a ge  as detaile d 
a b o ve  ac k n o wle d ge s t hat t he 1 3 1I ma xi m u m t olera ble acti vit y ( M T A) te n ds t o decli ne a m o n g t he 
el derl y p o p ulati o n ( T uttle et. al., 2 0 0 6); (K ul kar ni et. al, 2 0 0 6).  
 
T h o u g h perf or mi n g w h ole bl o o d a n d b o d y d osi metr y t o deter mi ne ma xi m u m t olerate d acti vit y 
( M T A) is N O T  re q uire d, f or ce nters at w hic h t his e val uati o n is d o ne ( perf or me d d uri n g t he 
st u d y or wit hi n 6 m o nt hs of st u d y e nr oll me nt), l o wer t hera pe utic  1 3 1I acti vities t ha n w hat is 
rec o m me n de d here ma y  be a d mi nistere d if t he M T A is calc ulate d t o be l o wer t ha n t he l o wer 
li mit of w hat is all o we d per pr ot oc ol (i.e. f or patie nts wit h M T A val ues < 1 5 0 m Ci f or patie nts 
< 7 0 years of a ge or < 1 0 0 m Ci f or  patie nts >  7 0 years of a ge).  D osi metr y ca n N O T  be use d t o 
j ustif y a d mi nisteri n g t hera pe utic 1 3 1I acti vities hi g her t ha n w hat has bee n rec o m me n de d per t his 
pr ot oc ol.   Perf or ma nce of p ost -t hera p y i o di ne sca ns is n ot re q uire d, b ut certai nl y all o we d per 
i nstit uti o nal practice. 
 
A d mi nistrati o n of T h yr o ge n ™ a n d/ or t hera pe utic 1 3 1I at a facilit y ot her t ha n t he partici pati n g 
site is all o we d if d oc u me ntati o n of t he dates a n d a m o u nt/acti vit y of dr u g /ra di ois ot o pe 
a d mi nistere d is pr o vi de d t o verif y a d here nce t o pr ot oc ol re q uire me nts.  
 
A n y f or m of oral 1 3 1I (e. g., ca ps ule or li q ui d) is all o we d o n t he trial. 
 


 
 
 
2 5  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
7. 2  
Patie nts ca n be i nstr ucte d i n sel u meti ni b a d mi nistrati o n tec h ni q ues a n d gra nte d  treat me nt 
i n de pe n de nce wit h n ursi n g staff a p pr o val. 
 
7. 3  
F or t his pr ot oc ol, t h e patie nt m ust ret ur n t o t he c o nse nti n g A C C R U i nstit uti o n f or  e val uati o n 
d uri n g treat me nt a n d d uri n g o bser vati o n ( Acti ve M o nit ori n g P hase)  acc or di n g t o t he ta ble i n 
Secti o n 4. 0 . 
 
7. 4  
Treat me nt b y a l ocal me dical d oct or : A d mi nistrati o n of T h yr o ge n ™ a n d/ or t hera pe utic 1 3 1I at a 
facilit y ot her t ha n t he partici pati n g site is all o we d if d oc u me ntati o n of t he dates a n d 
a m o u nt/acti vit y of dr u g /ra di ois ot o pe a d mi nistere d is pr o vi de d t o verif y a d here nce t o pr ot oc ol 
re q uire me nts. 
 
7. 5  
Brea ki n g C o des i n D o u ble -Bli n de d St u dies  
 
T he treat me nt c o de ca n n ot be br o ke n e xce pt i n t he e ve nt of a n e mer ge nc y f or a n i n di vi d ual 
patie nt.  
 
I n t he e ve nt of a n e mer ge nc y, call t he A C C R U Re gistrati o n Office at 
 t o brea k 
t he c o de o n M o n da y t hr o u g h Fri da y, 8: 0 0 a. m. t o 4: 3 0 p.m. Ce ntral Ti me. If t he c o de m ust be  
br o ke n after h o urs, ass u me t he patie nt was assi g ne d t o acti ve treat me nt a n d treat acc or di n gl y. 
Place a call t o t he A C C R U Re gistrati o n Office a n d lea ve a messa ge i nf or mi n g t he m of t he nee d 
t o u n-bli n d a patie nt. Pr o vi de y o ur c o ntact i nf or mati o n s o t hat A C C R U Re gistrati o n Office 
pers o n nel ca n ret ur n t he call t he ne xt b usi ness da y.  
 
If i n t he j u d ge me nt of t he atte n di n g p h ysicia n, it w o ul d be hel pf ul f or t he f ut ure cli nical care of 
t he i n di vi d ual patie nt, t he c o de ma y be br oke n after t he patie nt has c o m plete d t he st u d y. T hat is, 
after t he patie nt has bee n f ull y e val uate d a n d all e val uati o n i nf or mati o n has bee n rec or de d b y 
t he atte n di n g p h ysicia n a n d t he patie nt (if a p pr o priate), t he A C C R U Re gistrati o n Office ma y be 
calle d t o fi n d o ut w hic h st u d y t hera p y t he patie nt was recei vi n g.  
 
 
 
 
8. 0  
D os a ge M o dific ati o n B ase d o n A d verse E ve nts  
 
F or all a d verse e ve nts re p orte d i n t his st u d y c o nsi dere d at least partl y ca usal t o t he a d mi nistrati o n of 
sel u meti ni b, t he f oll o wi n g d ose m o dificati o n g ui da nce s h o ul d be a p plie d. 
 
A L E R T : 
A D R re p orti n g m ay be re q uire d f or s o me a dverse eve nts ( See Secti o n 1 0) 
 
8. 1  
D ose Le vels ( Base d o n A d verse E ve nts i n Secti o n 8. 2)  
 
D ose 
Le vel  
Sel u meti ni b  
0  
7 5 m g P O BI D  
-1  
5 0 m g P O BI D  
D ose le vel 0 refers t o t he s tarti n g d ose. 
 
8. 2  
G ui deli nes f or D ose M o dificati o ns/I nterr u pti o ns  
 
F or a d verse e ve nts ( A Es) t hat are c o nsi dere d at least partl y d ue t o a d mi nistrati o n of sel u meti ni b 


 
 
 
2 6  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
t he f oll o wi n g d ose re d ucti o n/a dj ust me nt g ui da nce ma y be a p plie d: 
 
Treat me nt wit h sel u meti n i b/ place b o s h o ul d be te m p oraril y i nterr u pte d if o ne of t he f oll o wi n g 
a d verse e ve nts occ urs des pite o pti m al s u p p orti ve c are : 
 
•  
A n y i nt olera ble a d verse e ve nt re gar dless of gra de  
•  
A n y a d verse e ve nts ≥ C T C A E Gra de 3 ( des pite o pti mal s u p p orti ve care)  (e xce pti o n : 
patie nts wit h >  Gra de 3 l y m p h o pe nia or as y m pt o matic bi oc he mistr y la b orat or y 
a b n or malities ma y be c o nti n ue d o n st u d y treat me nt at t he sa me d ose le vel wit h o ut 
i nterr u pti o n base d u p o n i n vesti gat or j u d g me nt).  
 
O n i m pr o ve me nt of t he a d verse e ve nt t o C T C A E gra de 1 ( or t o C T C A E gra de 2 f or ras h) or 
baseli ne, sel u meti ni b ma y be restarte d at t he sa me d ose or ma y be re d uce d  as descri be d i n  
 
secti o n 8. 1 at t he discreti o n of t he i n vesti ga t or.  O ne  d ose re d ucti o n is all o we d bef ore 
per ma ne nt disc o nti n uati o n of t hera p y.  
 
•  
If a f urt her e pis o de of t he sa me A E s u bse q ue ntl y re q uires d ose i nterr u pti o n, sel u meti ni b 
ma y be restarte d at t he ne xt d ose le vel d o w n o n i m pr o ve me nt of t he A E . 
•  
If a differe nt  A E  s u bse q ue ntl y re q uires d ose i nterr u pti o n, sel u meti ni b ma y be restarte d at 
t he sa me d ose or at t he ne xt d ose le vel d o w n o n i m pr ove me nt of t he A E . 
•  
Sel u meti ni b s h o ul d n ot be re -escalate d t o a n earlier d ose le vel o n i m pr o ve me nt of a n A E.  
•  
I deall y, place b o or sel u meti ni b d osi n g/treat me nt s h o ul d be mai ntai ne d f or at least 7 da ys 
pri or t o a n d t hr o u g h o ut a d mi nistrati o n of t hera pe utic 1 3 1I; h o we ver, t his is n ot a 
re q uire me nt. If necessar y, st u d y pr oce d ures a n d/ or 1 3 1I t hera p y ma y be resc he d ule d/re peate d 
(1 3 1I t hera p y s h o ul d be a d mi nistere d o nl y o nce ) at t he discreti o n of t he i n vesti gat or t o 
ac hie ve t his.  E xte n di n g t he ti me o n place b o or sel u meti ni b  (i.e. e xte n di n g ti me o n treat me nt 
a n d/ or i nstit uti n g treat me nt i nterr u pti o ns)  a n d/ or resc he d uli n g pr ot oc ol 
assess me nts /treat me nts is all o we d i n or der t o c o m pl y wit h t his a p pr oac h at t he 
i n vesti gat or’s discreti o n. 
•  
T he peri o d of ti me o n  place b o or sel u meti ni b (i.e. e xte n di n g ti me o n treat me nt a n d/ or 
i nstit uti n g treat me nt i nterr u pti o ns) is n ot t o e xcee d 8 wee ks. 
•  
N O T E: missi n g less t ha n 7 d oses of place b o or sel u meti ni b f or reas o ns ot her t ha n t o xicit y 
will n ot be c o nsi dere d a vi olati o n of t he pr ot oc ol.  
 
9. 0  
A ncill ar y Tre at me nt/ S u p p orti ve C are  
 
All ma na ge me nt of a d verse e ve nts is left t o t he I n vesti gat or’s discreti o n. A p pe n di x I V i ncl u des 
g ui deli nes f or t he ma na ge me nt of s o me c o m m o n sel u meti ni b -relate d a d verse e ve nts. C o m plia nce wit h 
t h ose g ui deli nes is rec o m me n de d, b ut n ot re q uire d. 
 
9. 1  
A ntie metics ma y be use d at t he discreti o n of t he atte n di n g p h ysicia n.  
 
9. 2  
Bl o o d pr o d ucts a n d gr o wt h fact ors s h o ul d be utilize d as cli nicall y warra nte d a n d  f oll o wi n g 
i nstit uti o nal p olicies a n d rec o m me n dati o ns. T he use of gr o wt h fact ors s h o ul d f oll o w p u blis he d 
g ui deli nes of t he A merica n S ociet y of Cli nical O nc ol o g y U p date of Rec o m me n dati o n s f or the 
Use of W hite Bl o o d Cell Gr o wt h Fact ors: A n E vi de nce -Base d Cli nical Practice G ui deli ne. J 
Cli n O nc ol 2 0 0 6; 2 4: 3 1 8 7 -3 2 0 5 . 
 
9. 3  
Patie nts s h o ul d recei ve f ull s u p p orti ve care w hile o n t his st u d y. T his i ncl u des  bl o o d pr o d uct 
s u p p ort, a nti bi otic treat me nt, a n d treat me nt of ot her ne wl y dia g n ose d or c o nc urre nt me dical 


 
 
 
2 7  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
c o n diti o ns. All bl o o d pr o d ucts a n d c o nc o mita nt me dicati o ns s uc h as a nti diarr heals, 
a nal gesics, a n d/ or a ntie metics recei ve d fr o m t he first da y of st u d y treat me nt a d mi nistrati o n 
u ntil 3 0 da ys after t h e fi nal d ose will be rec or de d i n t he me dical rec or ds.  
 
9. 4  
Ras h : earl y i nitiati o n of treat me nt f or ras h is str o n gl y rec o m me n de d t o mi ni mize  t he d urati o n 
a n d se verit y of t he a d verse e ve nt. All patie nts s h o ul d be gi ve n e m ollie nt crea m t o ta ke h o me f or 
pr o p h y lactic use o nce  st u d y treat me nt has bee n i nitiate d (see A p pe n di x I V). 
 
9. 5  
Diarr hea : earl y i nitiati o n of treat me nt f or diarr hea is str o n gl y rec o m me n de d t o mi ni mize t he 
d urati o n a n d se verit y of t he a d verse e ve nt. Treat me nt pr o visi o n will be acc or di n g t o I n v esti gat or 
discreti o n acc or di n g t o l ocal practice a n d re g ulati o ns (see A p pe n di x I V). 
 
9. 6  
D ys p nea : ne w or w orse ni n g d ys p nea has bee n re p orte d d uri n g treat me nt wit h sel u meti ni b; 
i n vesti gati o n t o deter mi ne t he u n derl yi n g ca use is rec o m me n de d (see A p pe n di x I V). 
 
9. 7  
Re d ucti o n i n L V E F : as y m pt o matic re d ucti o ns i n L V E F ha ve bee n re p orte d i n s o me patie nts 
recei vi n g sel u meti ni b; treat me nt ma y be rec o m me n de d de pe n di n g o n t he ma g nit u de of t he 
L V E F re d ucti o n (see A p pe n di x I V). 
 
9. 8  
Vis ual dist ur ba nces : s y m pt o ms, i ncl u di n g bl urre d visi o n, occ ur c o m m o nl y d uri n g treat me nt 
wit h sel u meti ni b, a n d A Es of ce ntral ser o us reti n o pat h y a n d reti nal vei n occl usi o n ha ve bee n 
re p orte d i n st u dies of ot her M E K i n hi bit ors. I n vesti gati o n t o deter mi ne t he u n derl yi n g ca use of 
vis ual dist ur ba nce is rec o m me n de d, i ncl u di n g o p ht hal m ol o gical e xa mi nati o n. Patie nts wit h a n 
o n g oi n g reti nal a b n or malit y at t he ti me of sel u meti ni b disc o nti n uati o n s h o ul d ha ve a f oll o w-u p 
o p ht hal m ol o gical assess me nt a p pr o xi matel y 2 8 da ys after disc o nti n uati o n. T his assess me nt is 
rec o m me n de d t o d oc u me nt re versi bilit y, b ut s h o ul d be perf or me d o nl y if t he patie nt is fit 
e n o u g h t o ha ve t he assess me nt (see A p pe n di x I V). 
 
E xtra assess me nts are rec o m me n de d f or i n vesti gati o n of s pecific a d verse e ve nts t hat occ ur 
d uri n g treat me nt w it h sel u meti ni b: 
 
 
A d verse e ve nt  
Assess me nt  
Cli nic all y si g nific a nt L V E F re d ucti o n 
( b y ≥1 0 perce nt a ge p oi nts a n d t o bel o w 
5 5 %)  
Si n gle E C G  
Tr o p o ni n le vels (is of or m acc or di n g t o 
i nstit uti o n al n or m) 
C ar di o -res pir at or y A Es of n o n -o b vi o us 
c a use 
Si n gle E C G  
Tr o p o ni n le vels (is of or m acc or di n g t o 
i nstit uti o n al n or m) 
Ne w or w orse ni n g res pir at or y 
s y m pt o ms (s uc h as d ys p ne a , c o u g h) 
Si n gle E C G  
 
 
1 0. 0  
A d verse E ve nt ( A E) Re p orti n g a n d M o nit ori n g  
 
1 0. 1  
A d verse E ve nt C haracteristics  
 
C T C A E ter m ( A E descri pti o n) a n d gr a de:  T he descri pti o ns a n d gra di n g scales f o u n d i n t he 
re vise d N CI C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) versi o n 4. 0 will be 


 
 
 
2 8  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
utilize d f or A E re p orti n g. All a p pr o priate treat me nt areas s h o ul d ha ve access t o a c o p y of t he 
C T C A E versi o n 4. 0. A c o p y of t he C T C A E versi o n 4. 0 ca n be d o w nl oa de d fr o m t he C T E P we b 
site: (htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic a p plicati o ns/ctc. ht m ) 
 
1 0. 1 1  
A d verse e ve nt m o nit ori n g a n d re p orti n g is a r o uti ne part of e ver y cli nical trial. First, 
i de ntif y a n d gra de t he se verit y of t he e ve nt usi n g t he C T C A E v ersi o n 4. 0 . Ne xt, 
deter mi ne w het her t he e ve nt is e x pecte d or u ne x pecte d (see Secti o n 1 0. 2 ) a n d if t he 
a d verse e ve nt is relate d t o t he me dical treat me nt or pr oce d ure (see Secti o n 1 0. 3).  
Wit h t his i nf or mati o n, deter mi ne w het her t he e ve nt m ust be re p orte d as a n e x pe dite d 
re p ort (see Secti o n 1 0. 4). E x pe dite d re p orts are t o be c o m plete d wit hi n t he 
ti mefra mes a n d via t he mec ha nis ms s pecifie d i n Secti o ns 1 0. 4. All A Es re p orte d via 
e x pe dite d mec ha nis ms m ust als o be re p orte d via t he r o uti ne data re p orti n g 
mec ha nis ms defi ne d b y t he pr ot oc ol (see Secti o ns 1 0. 5 a n d 1 8. 0). 
 
1 0. 1 2  
Eac h C T C A E ter m i n t he c urre nt versi o n is a u ni q ue re p rese ntati o n of a s pecific e ve nt 
use d f or me dical d oc u me ntati o n a n d scie ntific a nal ysis a n d is a si n gle Me d D R A 
L o west Le vel Ter m ( L L T).  
 
N O T E:  A se vere A E, as defi ne d b y t he a b o ve gra di n g scale, is N O T  t he sa me as 
seri o us A E w hic h is defi ne d i n t he ta ble i n Secti o n 1 0. 4.  
 
1 0. 2  
E x pecte d vs. U ne x pecte d E ve nts  
 
•  
T he deter mi nati o n of w het her a n A E is e x pecte d is base d o n a ge nt -s pecific i nf or mati o n 
pr o vi de d i n Secti o n 1 5. 0 of t he pr ot oc ol.  
•  
U ne x pecte d A Es are t h ose n ot liste d i n t he a ge nt -s pecific i nf or mati o n pr o vi de d i n Secti o n 
1 5. 0 of t he pr ot oc ol.  
 
 
N O T E : “ U ne x pecte d a d verse e x perie nces” mea ns a n y a d verse e x perie nce t hat is neit her 
i de ntifie d i n nat ure, se verit y, or fre q ue nc y of ris k i n t he i nf or mati o n p r o vi de d f or I R B 
re vie w n or me nti o ne d i n t he c o nse nt f or m.  
 
1 0. 3  
Assess me nt of Attri b uti o n  
 
W he n assessi n g w het her a n a dverse eve nt is rel ate d t o a me dic al tre at me nt or pr oce d ure, t he 
f oll o wi n g attri b uti o n c ate g ories are utilize d: 
 
Defi nite - T he a d verse e ve nt is cle arly rel ate d t o t he a ge nt(s). 
Pr o ba ble - T he a d v erse e ve nt is likely rel ate d t o t he a ge nt(s). 
P ossi ble - T he a d verse e ve nt m ay be rel ate d t o t he a ge nt(s). 
U nli kel y - T he a d verse e ve nt is d o u btf ully rel ate d t o t he a ge nt(s). 
U nrelate d - T he a d verse e ve nt is cle arly N O T rel ate d t o t he a ge nt(s). 
 
E ve nts det er mi ne d t o be p ossi bl y, pr o b a bl y or defi nitel y attri b ute d t o a me dic al 
tre at me nt s u g gest t here is e vi de nce t o i n dic ate a c a us al rel ati o ns hi p bet wee n t he 
dr u g a n d t he a d verse e ve nt.  
 


 
 
 
2 9  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
1 0. 3 1  
S p e ci al Sit u ati o ns f o r E x p e dit e d R e p o rti n g   
 
E xce pti o ns t o E x pe dit e d Re p orti n g: E X P E C T E D Seri o us A d verse E ve nts  
 
A n e x pe dite d re p ort ma y n ot be re q uire d f or s pecific Gra de 1, 2 a n d 3 Seri o us 
A d verse E ve nts w here t he A E is E X P E C T E D . A n y pr ot oc ol s pecific re p orti n g 
pr oce d ures M U S T B E S P E CI FI E D B E L O W a n d will s u perse de t he sta n dar d 
E x pe dite d A d verse E ve nt Re p orti n g Re q uire me nts:  
 
S yste m Or ga n Class 
( S O C) 
A d verse e ve nt/ 
S y m pt o ms  
C T C A E Gra de at w hic h 
t he e ve nt will n ot be 
e x pe diti o usl y  re p orte d. 
Ge neral dis or ders a n d 
a d mi nistrati o n site 
c o n diti o ns 
E de ma face   
<  Gra de 3  
E d e ma tr u n k 
Fati g ue  
Fe ver  
S ki n a n d s u bc uta ne o us 
tiss ue dis or ders 
D r y sk i n 
<  Gra de 3  
Ras h ac neif or m  
Ras h mac ul o -pa p ular  
Ste ve ns -J o h ns o n 
s y n dr o me 
Res pirat or y, t h oracic 
a n d me diasti nal 
dis or ders  
D ys p nea  
<  Gra de 3  
E ye dis or ders  
Bl urre d visi o n  
<  Gra de 3  
Vasc ular dis or ders  
H y perte nsi o n  
<  Gra de 3  
I n vesti gati o ns 
Ala ni ne 
a mi n otra nsferase 
i ncrease d 
<  Gra de 3  
As partate 
a mi n otra nsferase 
i ncrease d 
Gastr oi ntesti nal 
dis or ders  
Diarr hea  
<  Gra de 3  
N a usea 
V o miti n g  
M uc ositis oral  
D r y m o ut h 
I nfecti o ns a n d  
i nfestati o ns 
Nail i nfecti o n  
<  Gra de 3  
 
 
S pecific pr ot oc ol e xce pti o ns t o e x pe dite d re p orti n g s h o ul d be re p orte d e x pe diti o usl y 
b y i n vesti gat ors O N L Y  if t he y e xcee d t he e x pecte d gra de of t he e ve nt. 
 
T hese e xce pti o ns o nl y a p pl y if t he a d verse e ve nt d oes n ot res ult i n h os pitalizati o n.  If 
t he a d verse e ve nt res ults i n h os pitalizati o n, t he n t he sta n dar d e x pe dite d a d verse 
e ve nts re p orti n g re q uire me nts m ust be f oll o we d.  
 


 
 
 
3 0  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
T he f oll o wi n g h os pitalizati o ns are n ot c o nsi dere d t o be S A Es beca use t here is  n o 
“a d verse e ve nt” ( i.e., t here is n o u nt o war d me dical occ urre nce) ass ociate d wit h t he 
h os pitalizati o n:  
 
•  
H os pitalizati o ns f or res pite care  
•  
Pla n ne d h os pitalizati o ns re q uire d b y t he pr ot oc ol  or t o a d mi nister pr ot oc ol -
directe d treat me nt ( i.e. 1 3 1I t hera p y) 
•  
H os pitalizati o n pla n ne d bef ore i nf or me d c o nse nt ( w here t he c o n diti o n re q uiri n g 
t he h os pitalizati o n has n ot c ha n ge d p ost st u d y dr u g a d mi nistrati o n) 
•  
H os pitalizati o n f or a d mi nistrati o n of st u d y dr u g or i nserti o n of access f or 
a d mi nistrati o n of st u d y dr u g  
•  
H os pi talizati o n f or r o uti ne mai nte na nce of a de vice (e. g., batter y re place me nt) 
t hat was i n place bef ore st u d y e ntr y 
 
1 0. 3 1 1  
Persiste nt or Si g nific a nt Dis a bilities/I nc a p acities  
A n y A E t hat res ults i n persiste nt or si g nifica nt i nca pacit y or  s u bsta ntial 
disr u pti o n of t he a bilit y t o c o n d uct n or mal life f u ncti o ns (f or merl y referre d 
t o as disa bilities), c o n ge nital a b n or mities or birt h defects, m ust be re p orte d 
i m me diatel y if t he y occ ur at a n y ti me f oll o wi n g treat me nt wit h a n a ge nt 
u n der a n I N D/I D E si nce t he y are c o ns i dere d t o be a seri o us A E a n d m ust be 
re p orte d t o t he s p o ns or as s pecifie d i n 2 1 C F R 3 1 2. 6 4( b). 
 
1 0. 3 1 2  
De at h  
 
•  
A n y deat h occ urri n g wit hi n 3 0 da ys of t he last d ose, re gar dless 
of attri b uti o n t o a n a ge nt/i nter ve nti o n u n der a n I N D/I D E 
re q uires e x pe dite d re p orti n g wit hi n 2 4-h o urs.  
•  
A n y deat h occ urri n g greater t ha n 3 0 da ys wit h a n attri b uti o n of 
p ossi ble, pr o ba ble, or defi nite t o a n a ge nt/i nter ve nti o n u n der a n 
I N D/I D E re q uires e x pe dite d re p orti n g wit hi n 2 4-h o urs.  
 
•  
Re p o rt a bl e c at e g o ri es of De at h   
 
•  
De at h attri b ut a b l e t o a C T C A E t er m. 
•  
De at h Ne o n at al: A dis or d er c h ar a ct eri z e d b y c ess ati o n of 
lif e d uri n g t h e first 2 8 d a ys of lif e. 
•  
De at h N O S: A c ess ati o n of lif e t h at c a n n ot b e attri b ut e d 
t o a C T C A E t er m ass o ci ate d wit h Gr a d e 5. 
•  
S u d d e n d e at h N O S: A s u d d e n ( d efi n e d as i ns t a nt or 
wit hi n o n e h o ur of t h e o ns et of s y m pt o ms) or a n 
u n o bs er v e d c ess ati o n of life t h at c a n n ot b e attri b ut e d t o a 
C T C A E t er m ass o ci at e d wit h Gr a d e 5.  
•  
De at h d u e t o pr o gr essi v e dis e as e s h o ul d b e r e p ort e d as 
G r a d e 5 “ Ne o pl as ms b e ni g n , m ali g n a nt a n d 
u ns p e cif i e d (i n cl c ysts a n d p ol y ps) –  Ot h e r 
( P r o g r essi v e Dis e as e) ” u n d er t h e s yst e m or g a n cl ass 
( S O C) of t h e s a m e n a m e. E vi d e n c e t h at t h e d e at h was a 
m a nif est ati o n of u n d erl yi n g dis e as e ( e. g., r a di ol o gi c al 
c h a n g es s u g g esti n g t u m or gr o wt h or pr o gr essi o n: cli ni c al 
d et eri or ati o n ass o ci at e d wit h a dis e as e pr o c ess) s h o ul d b e 
s u b mitt e d. 


 
 
 
3 1  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
 
1 0. 3 1 3  
Sec o n d ar y M ali g n a nc y  
 
• 
A sec o n d ary m ali g n a ncy is a ca ncer ca use d b y treat me nt f or a pre vi o us 
mali g na nc y (e. g., treat me nt wit h i n vesti gati o nal a ge nt/i nter ve nti o n, 
ra diati o n or c he m ot hera p y). A sec o n dar y mali g na nc y is n ot 
c o nsi dere d a metastasis of t he i nitial ne o plas m.  
• 
All sec o n dar y mali g na ncies t hat occ ur f oll o wi n g treat me nt wit h a n 
a ge nt u n der a n I N D/I D E t o be re p orte d. T hree o pti o ns are a vaila ble t o 
descri be t he e ve nt:  
 
o  Le u ke mia s ec o n dar y t o o nc ol o g y c he m ot hera p y (e. g., Ac ute 
M yel oct yic Le u ke mia [ A M L])  
o  M yel o d ys plastic s y n dr o me ( M D S)  
o  Treat me nt -relate d sec o n dar y mali g na nc y 
 
•  
A n y mali g na nc y p ossi bl y relate d t o ca ncer treat me nt (i ncl u di n g 
A M L/ M D S) s h o ul d als o be re p orte d via t he r o uti ne re p orti n g 
mec ha nis ms o utli ne d i n eac h pr ot oc ol.  
 
1 0. 3 1 4  
Sec o n d M ali g n a nc y  
 
• 
A sec o n d mali g na nc y is o ne u nrelate d t o t he treat me nt of a pri or 
mali g na nc y (a n d is N O T a metastasis fr o m t he i nitial mali g na nc y). 
Sec o n d mali g na ncies re q uire O N L Y r o uti ne re p orti ng.  
 




 
 
 
3 3  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
 
2.  
Use t he A C C R U pr ot oc ol n u m ber a n d t he pr ot oc ol -s pecific patie nt I D pr o vi de d 
d uri n g trial re gistrati o n o n all re p or ts. 
 
T he a b o ve e x pe dite d re p orts ( 2 4 -h o ur a n d 3 or 7 da y) m ust be s u b mitte d via t he 
A C C R U A d verse E ve nt E x pe dite d Re p ort F or m . 
 
3.  
Ma y o Cli nic Ca ncer Ce nter ( M C C C) I nstit uti o ns:  Pr o vi de c o pies, al o n g wit h t he 
U PI R T S O c o ver s heet, b y fa x 
t o t he M C C C Re g ulat or y Affairs 
U nit ( R A U) Re g ulat or y Affairs S pecialist , w h o will deter mi ne a n d c o m plete I R B 
re p orti n g. T he R A U will s u b mit t o t he A C C R U S A E C o or di nat or a n d t he 
A C C R U I N D C o or di nat or t o deter mi ne if F D A s u b missi o n is nee de d.  
 
4.  
N o n -Ma y o A C C R U Sit es : S u b mit re p orts t o A C C R U Safet y via e mail at: 
   
 
O nce A C C R U Safet y r recei ves t he re p ort viae mail , A C C R U Safet y will f or war d 
a c o p y of t he a b o ve e x pe dite d re p orts t o  the  A C C R U I N D C o or di nat or , w h o will 
n otif y t he F D A as warra nte d b y t he e ve nt a n d sti p ulate d i n t he U. S. C o de of 
Fe deral Re g ulati o ns.   
 
Re p orti n g seri o us a d verse e ve nts t o Astra Ze neca  
 
All Seri o us a d verse e ve nts t hat meet t he criteria f or re g ulat or y re p orti n g s h o ul d be 
c o pie d t o Astra Ze neca at t he sa me ti me t hat t he y are re p orte d t o re g ulat or y a ut h orities. 
T he n otificati o n t o Astra Ze neca s h o ul d i ncl u de a c o p y of t he re g ulat or y s u b missi o n a n d 
a c o ver pa ge t hat i n dicates t he f oll o wi n g:  
 
•  
“ N otificati o n fr o m a n I n vesti gat or -S p o ns ore d St u d y”  
•  
St u d y title a n d refere nce n u m ber ( prefera bl y wit h I S SI S refere nce n u m ber)  
•  
I n vesti gat or na me a n d a d dress 
•  
I N D n u m ber or e q ui vale nt 
 
N otificati o n t o Astra Ze neca s h o ul d als o i ncl u de t he ca usalit y of e ve nts i n relati o n t o all 
st u d y me dicati o ns a n d if the S A E is relate d t o disease pr o gressi o n, as deter mi ne d b y t he 
pri nci pal i n vesti gat or. T he i n vesti gat or is res p o nsi ble f or i nf or mi n g t he I R B a n d/ or t he 
Re g ulat or y A ut h orit y of t he S A E per l ocal re q uire me nts.   
 
Se n d S A E re p ort a n d acc o m pa n yi n g c o ver pa ge b y wa y of fa x t o Astr a Ze nec a’s 
desi g n ate d f a x li ne:  
. 
 
I n t he case of bli n de d trials, Astra Ze neca ma y re q uest t hat t he S p o ns or eit her pr o vi de a 
c o p y of t he ra n d o mizati o n c o de/ c o de brea k i nf or mati o n or u n bli n d t h ose S A Es w hic h 
re q uire e x pe dited re p orti n g.  
 
 


 
 
 
3 4  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
Re p orti n g pre g na nc y e ve nts t o Astra Ze neca  
 
If pre g na nc y occ urs, treat me nt wit h place b o or Sel u meti ni b s h o ul d be disc o nti n ue d, a n d 
Astra Ze neca s h o ul d be i nf or me d of t he pre g na nc y wit hi n o ne b usi ness da y of t he 
i n vesti gat or or site pers o n nel bec o mi n g a ware of t he pre g na nc y.  
 
T he o utc o me (s p o nta ne o us miscarria ge, electi ve ter mi nati o n, n or mal birt h or c o n ge nital 
a b n or malit y) of all pre g na ncies occ urri n g d uri n g treat me nt wit h place b o or Sel u meti ni b 
m ust be f oll o we d u p a n d d oc u me nte d e ve n if t he p atie nt was disc o nti n ue d fr o m t he 
st u d y. 
 
N O T E: T he Gr a de 4 or 5 N o n -A E R Re p ort a ble E ve nts/ H os pit aliz ati o n F or m is 
n ot bei n g use d f or t his st u d y.  
 
1 0. 5  
Ot her Re q uire d Re p orti n g  
 
1 0. 5 1  A d verse e ve nts t o be gra de d at eac h e val uati o n a n d pretreat me nt as s pecifie d i n t he Test 
Sc he d ule ( Secti o n 4. 0 ).  T he C T C A E v 4. 0 gra di n g s h o ul d be use d u nless a n alter nate 
gra di n g met h o d is i n dicate d i n t he ta ble bel o w: 
 
S yste m Or ga n  Class 
( S O C) 
A d verse e ve nt/  
S y m pt o ms  
Baseli ne  
Eac h  
e val uati o n 
Gra di n g scale  
(if n ot C T C A E) 
Ge ne ral dis or ders 
a n d a d mi nistrati o ns  
site c o n diti o ns 
Fati g ue  
X  
X  
 
Wei g ht l oss  
X  
X  
 
L ocalize d e de ma  
X  
X  
 
Gastr oi ntesti nal 
Dis or ders  
Diarr hea  
# of st o ols 
per da y  
X  
 
D ys p nea  
X  
X  
 
Na usea  
X  
X  
 
V o miti n g  
X  
X  
 
E ye Dis or ders  
Bl urre d visi o n  
X  
X  
 
Vasc ular dis or ders  
H y perte nsi o n  
X  
X  
 
I n vesti gati o ns 
Ala ni ne 
a mi n otra nsferase 
i ncrease 
 
As partate 
a mi n otra nsferase 
i ncrease 
X  
X  
 
S ki n a n d 
s u bc uta ne o us tiss ue 
dis or ders  
Ras h ac n eif or m  
X  
X  
 
Ras h 
mac ul o pa p ular  
X  
X  
 
 
 


 
 
 
3 5  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
1 0. 5 2  S u b mit via a p pr o priate Aca de mic a n d C o m m u nit y Ca ncer Researc h U nite d ( A C C R U)  
Case Re p ort F or ms (i.e., pa per or electr o nic, as a p plica ble) t he f oll o wi n g A Es 
e x perie nce d b y a patie nt a n d n ot s pecifie d i n Secti o n 1 0. 5 : 
 
1 0. 5 2 1  
Gra de 2 A Es dee me d p ossi bly, pr o b a bly, or defi nitely  relate d t o t he stu d y 
treat me nt or pr oce d ure. 
 
1 0. 5 2 2  
Gra de 3 a n d 4 A Es re gar dless of attri b uti o n t o t he st u d y treat me nt or 
pr oce d ure.  
 
1 0. 5 2 3  
Gra de  5 A Es ( Deat hs)  
 
1 0. 5 2 3 1  
A n y deat h wit hi n 3 0 da ys of t he patie nt’s last st u d y treat me nt 
or pr oce d ure re gar dless of attri b uti o n  t o t he st u d y treat me nt or 
pr oce d ure.  
 
1 0. 5 2 3 2  
A n y deat h m ore t ha n 3 0 da ys after t he patie nt’s last st u d y 
treat me nt or pr oce d ure t hat is felt t o be at least p ossi bl y 
treat me nt relate d m ust als o be s u b mitte d as a Gra de 5 A E, wit h 
a C T C A E t y pe a n d attri b uti o n assi g ne d.  
 
1 0. 5 3  Refer t o t he i nstr ucti o ns i n t he F or ms Pac ket ( or electr o nic data e ntr y scree ns, as 
a p plica ble) re gar di n g t he s u b missi o n of late occ urri n g A Es f oll o wi n g c o m pleti o n of t he 
Acti ve M o nit ori n g P hase (i.e., c o m plia nce wit h Test Sc he d ule i n Se cti o n 4. 0). 
 
 
1 1. 0  
Tre at me nt E v al u ati o n Usi n g R E CI S T G ui deli ne  
 
N O T E: T his st u d y uses pr ot oc ol R E CI S T v 1. 1 te m plate date d 2/ 1 6/ 2 0 1 1  wit h m o dificati o ns as detaile d 
bel o w . See t he f o ot n ote f or t he ta ble re gar di n g meas urea ble disease i n Secti o n 1 1. 4 4, as it pertai ns t o 
data c ollecti o n a n d a nal ysis.  
 
Res p o nse a n d pr o gressi o n will be e val uate d i n t his st u d y usi n g t he ne w i nter nati o nal criteria pr o p ose d 
b y t he re vise d Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) g ui deli nes ( versi o n 1. 1) 
(Eise n ha uer et al., 2 0 0 9 ) wit h s o me m o dificati o ns as detaile d bel o w . 
 
Patie nts wit h meas urea ble t u m ors a n d patie nts wit h o nl y n o n -meas urea ble t u m ors (“ n o n -tar get” disease 
o nl y) are eli gi ble f or e nr oll me nt a n d will ha ve res p o nse assesse d as detaile d bel o w (see Secti o ns 1 1. 4 3 
a n d 1 1. 4 4) . 
 
1 1. 1  
Sc he d ule of E val uati o ns: F or t he p ur p oses of t his st u d y, patie nts s h o ul d be  ree val uate d a b o ut 3 
m o nt hs ( +/ - 1 wee k) after 1 3 1I t hera p y a n d the n e ver y 3 m o nt hs ( +/ - 1 wee k).  After 1 2  m o nt hs 
p ost -treat me nt, sca ns s h o ul d be d o ne e ver y 6 m o nt hs ( +/- 2  wee k s) f or a ma xi m u m of 2 years 
( +/- 3 m o nt hs) fr o m st u d y ra n d o mizati o n.   
 
1 1. 2  
Defi niti o ns of Meas ura ble a n d N o n -Meas ura ble Disease  
 
1 1. 2 1  Meas ura ble Disease  
 
1 1. 2 1 1  
A n o n -n o dal lesi o n is c o nsi dere d meas ura ble if its l o n gest dia meter ca n be 
acc uratel y meas ure d as   ≥1. 0 c m wit h C T sca n or M RI.  


 
 
 
3 6  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
1 1. 2 1 2  
A s u perficial n o n -n o dal lesi o n is meas ura ble if its l o n gest dia meter is ≥ 1. 0 
c m i n dia meter as assesse d usi n g cali pers (e. g. s ki n n o d ules) or i ma gi n g. I n 
t he case of s ki n lesi o ns, d oc u me ntati o n b y c ol or p h ot o gra p h y, i ncl u di n g a 
r uler t o esti mate t he size of t he lesi o n, is rec o m me n de d. 
 
1 1. 2 1 3  
A mali g na nt l y m p h n o de is c o nsi dere d meas ura ble if  1) it is n ote d t o be R AI -
a vi d o n ra di oi o di ne i ma gi n g ( dia g n ostic or p ost -t hera p y w h ole b o d y sca ns 
acce pta ble) a n d it meas ures > 1 c m i n t he l o n g a xis, 2) it is pat h ol o gicall y 
pr o ve n t o be i n v ol ve d wit h t h yr oi d ca ncer ( b y c yt ol o g y or pat h ol o g y) a n d it 
meas ures > 1 c m i n t he l o n g a xis, or 3) its s h ort a xis is > 1. 5 c m w he n assesse d 
b y C T sca n ( C T sca n slice t hic k ness rec o m me n de d t o be n o greater t ha n 5 
m m).  
 
1 1. 2 1 4  
T u m or lesi o ns i n a pre vi o usl y irra diate d area are c o nsi dere d meas ura ble 
disease u n der t he f oll o wi n g c o n diti o ns: t here has bee n e vi de nce of t u m or 
pr o gressi o n i n t he irra diate d area  pri or t o st u d y re gistrati o n . 
 
1 1. 2 2  N o n -Meas u ra ble Disease 
 
1 1. 2 2 1  
All ot her lesi o ns ( or sites of disease  (e. g., visi ble p ul m o nar y n o d ules < 1 c m i n 
l o n gest dia meter)) are c o nsi dere d n o n-meas ura ble disease. B o ne lesi o ns, 
le pt o me ni n geal disease, ascites, ple ural/ pericar dial eff usi o ns, l y m p ha n gitis 
c uti s/ p ul m o nis, i nfla m mat or y breast disease, a n d a b d o mi nal masses ( n ot 
f oll o we d b y C T or M RI), are c o nsi dere d as n o n-meas ura ble as well.  
 
N ote: ‘ C ystic lesi o ns’ t h o u g ht t o re prese nt c ystic metastases ca n be  
c o nsi dere d as meas ura ble lesi o ns, if t he y meet t he defi niti o n of meas ura bilit y 
descri be d a b o ve. H o we ver, if n o n -c ystic lesi o ns are prese nt i n t he sa me 
patie nt, t hese are preferre d f or se lecti o n as tar get lesi o ns. 
 
1 1. 3  
G ui deli nes f or E val uati o n of Meas ura ble Disease  
 
1 1. 3 1  Meas ure me nt Met h o ds:  
 
•  
All meas ure me nts s h o ul d be rec or de d i n metric n otati o n (i.e., deci mal fracti o ns of 
ce nti meters) usi n g a r uler or cali pers.  
 
•  
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue m ust be use d t o c haracterize 
eac h i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w -u p.  
 
•  
I ma gi n g-base d e val uati o n is preferre d t o e val uati o n b y cli nical e xa mi nati o n w he n 
b ot h met h o ds ha ve bee n use d at t he sa me e val uati o n t o assess t he a ntit u m or effect of 
a treat me nt. 
 
1 1. 3 2  Acce pta ble M o dalities f or Meas ura ble Disease:  
 
•  
C o n ve nti o nal C T a n d M RI:  T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n 
C T sca n base d o n t he ass u m pti o n t hat C T slice t hic k ness is 5 m m or less. If C T sca ns 
ha ve slice t hic k ness greater t ha n 5 m m, t he mi ni m u m size f or a meas ura ble lesi o n 
s h o ul d be t wice t he slice t hic k ness. 
 


 
 
 
3 7  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
•  
As wit h C T, if a n M RI is perf or me d, t he tec h nical s pecificati o ns of t he sca n ni n g 
se q ue nces use d s h o ul d be o pti mize d f or t he e val uati o n of t he t y pe a n d site of 
disease. T he lesi o ns s h o ul d be meas ure d o n t he sa me p ulse se q ue nce. I deall y, t he 
same t y pe of sca n ner s h o ul d be use d a n d t he i ma ge ac q uisiti o n pr ot oc ol s h o ul d be 
f oll o we d as cl osel y as p ossi ble t o pri or sca ns. B o d y sca ns s h o ul d be perf or me d wit h 
breat h -h ol d sca n ni n g tec h ni q ues, if p ossi ble.  
 
•  
F D G -P E T: F D G -P E T sca n ni n g is all o we d t o c o m ple me nt C T sca n ni n g i n 
assess me nt of pr o gressi ve disease [ P D] a n d partic ularl y p ossi ble ' ne w' disease. A 
‘ p ositi ve’ F D G-P E T sca n ne d lesi o n is defi ne d as o ne w hic h is F D G a vi d wit h a n 
u pta ke  greater t ha n t wice t hat of t he s urr o u n di n g tiss ue o n t he atte n uati o n c orrecte d 
i ma ge; ot her wise, a n F D G-P E T sca n ne d lesi o n is c o nsi dere d ‘ ne gati ve.’ Ne w lesi o ns 
o n t he basis of F D G -P E T i ma gi n g ca n be i de ntifie d acc or di n g t o t he f oll o wi n g 
al g orit h m: 
 
a. Ne gati ve F D G -P E T at baseli ne wit h a p ositi ve F D G -P E T at f oll o w -u p is a s i g n 
of P D base d o n a ne w lesi o n.  
 
b.  N o F D G -P E T at baseli ne a n d a p ositi ve F D G -P E T at f oll o w -u p:  
 
i. 
If t he p ositi ve F D G-P E T at f oll o w -u p c orres p o n ds t o a ne w site of disease 
c o nfir me d b y C T  or M RI , t his is P D.   
 
ii. If t he p ositi ve F D G-P E T at f oll o w -u p i s n ot c o nfir me d as a ne w site of 
disease o n C T at t he sa me e val uati o n, a d diti o nal f oll o w -u p C T sca ns (i.e., 
a d diti o nal f oll o w -u p sca ns at least 4 wee ks later) are nee de d t o deter mi ne if 
t here is tr ul y pr o gressi o n occ urri n g at t hat site. I n t his sit uati o n, t he date of 
P D will be t he date of t he i nitial a b n or mal P D G -P E T sca n.   
 
iii If t he p ositi ve F D G-P E T at f oll o w -u p c orres p o n ds t o a pre -e xisti n g site of 
disease o n C T t hat is n ot pr o gressi n g o n t he basis of t he a nat o mic i ma ges, it 
is n ot classifie d as P D. 
 
1 1. 3 3  Meas ure me nt at F oll o w -u p E val uati o n:  
 
•  
C yt ol o gic a n d hist ol o gic tec h ni q ues ca n be use d t o differe ntiate bet wee n P R a n d C R 
i n rare cases (e. g., resi d ual lesi o ns i n t u m or t y pes s uc h as ger m cell t u m ors, w here 
k n o w n resi d ual be ni g n t u m ors ca n re mai n.)  
 
1 1. 4  
Meas ure me nt of Effect  
 
1 1. 4 1  
Tar get Lesi o ns & Tar get L y m p h N o des  
 
•  
Meas ura ble lesi o ns (as defi ne d i n Secti o n 1 1. 2 1) u p t o a ma xi m u m of 5 lesi o ns, 
re prese ntati ve of all i n v ol ve d or ga ns, s h o ul d be i de ntifie d as “ Tar get Lesi o ns” a n d 
rec or de d a n d meas ure d at baseli ne. T hese lesi o ns ca n be n o n -n o dal or n o dal (as 
defi ne d i n 1 1. 2 1) , w here n o m ore t ha n 2 lesi o ns are fr o m t he sa me or ga n a n d n o 
m ore t ha n 2 mali g na nt n o dal lesi o ns are selecte d.  
 
N ote:  If fe wer t ha n 5 tar get lesi o ns a n d tar get l y m p h n o des are i de ntifie d (as t here 
ofte n will be), t here is n o reas o n t o perf or m a d diti o nal st u dies be y o n d t h ose 
s pecifie d i n t he pr ot oc ol t o disc o ver ne w lesi o ns. 


 
 
 
3 8  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
 
•  
Tar get lesi o ns a n d tar get l y m p h n o des s h o ul d be selecte d o n t he basis of t heir size, 
be re prese ntati ve of all i n v ol ve d sites of disease, b ut i n a d diti o n s h o ul d be t h ose 
t hat le n d t he msel ves t o re pr o d uci ble re peate d meas ure me nts. It ma y be t he case 
t hat, o n occasi o n, t he lar gest lesi o n ( or mali g na nt l y m p h n o de) d oes n ot le n d itself 
t o re pr o d uci ble meas ure me nts i n w hic h circ u msta nce t he ne xt lar gest lesi o n ( or 
mali g na nt l y m p h n o de) w hic h ca n be meas ure d re pr o d uci bl y s h o ul d be selecte d.  
 
•  
Baseli ne S u m of Di me nsi o ns ( B S D): A s u m of t he l o n gest dia meter f or all tar get 
lesi o ns pl us t he s u m of t he l o n g or s h ort a xis of all t he tar get l y m p h n o des (if t he 
l y m p h n o de q ualifie d as a tar get lesi o n base d u p o n a l o n g a xis of > 1 c m, t he n t he 
l o n g a xis will be use d f or t he baseli ne a n d p ost-baseli ne assess me nts; if t he l y m p h 
n o de q ualifie d as a tar get lesi o n base d u p o n a s h ort a xis o f > 1. 5 c m, t he n t he s h ort 
a xis will be use d f or baseli ne a n d p ost -baseli ne assess me nts)   will be calc ulate d 
a n d re p orte d as t he baseli ne s u m of di me nsi o ns ( B S D). T he B S D will be use d as 
refere nce t o f urt her c haracterize a n y o bjecti ve t u m or res p o nse i n t he meas ur a ble 
di me nsi o n of t he disease.  
 
•  
P ost -Baseli ne S u m of t he Di me nsi o ns ( P B S D): A s u m of t he l o n gest dia meter f or 
all tar get lesi o ns pl us t he s u m of t he l o n g or s h ort a xis of all t he tar get l y m p h 
n o des (if t he l y m p h n o de q ualifie d as a tar get lesi o n based u p o n a l o n g a xis of > 1 
c m, t he n t he l o n g a xis will be use d f or p ost -baseli ne assess me nts; if t he l y m p h 
n o de q ualifie d as a tar get lesi o n base d u p o n a s h ort a xis of > 1. 5 c m, t he n t he s h ort 
a xis will be use d f or p ost -baseli ne assess me nts)  will be calc ulate d a n d re p orte d as 
t he p ost-baseli ne s u m of di me nsi o ns ( P B S D). If t he ra di ol o gist is a ble t o pr o vi de 
a n act ual meas ure f or t he tar get lesi o n ( or tar get l y m p h n o de), t hat s h o ul d be 
rec or de d, e ve n if it is bel o w 0. 5 c m. If t he tar get lesi o n ( or tar get l y m p h no de) is 
belie ve d t o be prese nt a n d is fai ntl y see n b ut t o o s mall t o meas ure, a defa ult val ue 
of 0. 5 c m s h o ul d be assi g ne d. If it is t he o pi ni o n of t he ra di ol o gist t hat t he tar get 
lesi o n or tar get l y m p h n o de has li kel y disa p peare d, t he meas ure me nt s h o ul d be 
rec or de d as 0 c m. 
 
•  
T he mi ni m u m s u m of t he di me nsi o ns ( M S D) is t he mi ni m u m of t he B S D a n d t he 
P B S D.  
 
1 1. 4 2  N o n -Tar get Lesi o ns & N o n -Tar get L y m p h N o des  
 
N o n -meas ura ble sites of disease ( Secti o n 1 1. 2 2) are classifie d as n o n - tar get lesi o ns or 
n o n -tar get l y m ph n o des a n d s h o ul d als o be rec or de d at baseli ne. T hese lesi o ns a n d 
l y m p h n o des s h o ul d be part of t he res p o nse assess me nt as detaile d i n Secti o n 1 1. 4 3 3  or  
1 1. 4 4 2 . 


 
 
 
3 9  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
 
1 1. 4 3  R E S P O N S E C RI T E RI A F O R P A TI E N T S WI T H M E A S U R E A B L E T A R G E T 
L E SI O N S/ L Y M P H N O D E S  
 
1 1. 4 3 1  All  tar get lesi o ns a n d tar get l y m p h n o des f oll o we d b y C T  or M RI m ust be 
meas ure d o n re -e val uati o n at e val uati o n ti me  p oi nt s s pecifie d i n Secti o n 1 1. 1. 
S pecificall y, a c ha n ge i n o bjecti ve stat us t o eit her a P R or C R ca n n ot be d o ne 
wit h o ut re -meas uri n g tar get l esi o ns a n d tar get l y m p h n o des.  
 
N ote: N o n -tar get lesi o ns a n d n o n-tar get l y m p h n o des s h o ul d be e val uate d at 
eac h assess me nt, es peciall y i n t he case of first res p o nse or c o nfir mati o n of 
res p o nse. I n selecte d circ u msta nces, certai n n o n-tar get or ga ns ma y be e val uate d 
less fre q ue ntl y. F or e xa m ple, b o ne sca ns ma y nee d t o be re peate d o nl y w he n 
c o m plete res p o nse is i de ntifie d i n tar get disease or w he n pr o gressi o n i n b o ne is 
s us pecte d. 
 
1 1. 4 3 2  E val uati o n of Tar get Lesi o ns  
 
•  C o m plete Res p o nse ( C R):  All of t he f oll o wi n g m ust be tr ue:  
 
a. Disa p peara nce of all tar get lesi o ns.  
 
b.  Eac h tar get l y m p h n o de m ust ha ve re d ucti o n i n s h ort a xis t o < 1. 0 c m  (if 
s h ort a xis bei n g use d f or meas ure me nt) or ha ve re d ucti o n i n l o n g a xis t o 
< 0. 7 c m (if l o n g a xis is bei n g use d f or meas ure me nt) . 
 
c. F or patie nts wit h o ut detecta ble t h yr o gl o b uli n a nti b o dies, ser u m 
t h yr o gl o b uli n o n s u p pressi o n  m ust be  meas ure d t o be < 0. 2 n g/ ml . If a 
ce nter d oes n ot ha ve a t h yr o gl o b uli n assa y t hat rea ds t o < 2 n g/ ml, t he n a 
T S H -sti m ulate d T g < 1 n g/ ml w o ul d be re q uire d t o c o nfir m c o m plete 
res p o nse. F or patie nts wit h detecta ble t h yr o gl o b uli n a nti b o dies, 
assess me nt of t h yr o gl o b uli n will n ot be necessar y f or assess me nt of 
c o m plete res p o nse.  
 
•  Partial Re s p o nse ( P R): At least a 3 0 % decrease i n P B S D (s u m of t he l o n gest 
dia meter f or all tar get lesi o ns pl us t he s u m of t he  l o n g or s h ort a xis of all t he 
tar get l y m p h n o des ( de pe n di n g o n w hic h a xis is bei n g use d f or assess me nts) 
at c urre nt e val uati o n) ta ki n g as refere nce t he B S D ( see Secti o n 1 1. 4 1).  
 
•  Pr o gressi o n ( P D):  At least o n e of t he f oll o wi n g m ust be tr ue:  
 
a. At least o ne ne w mali g na nt lesi o n, w hic h als o i ncl u des a n y l y m p h n o de 
t hat was n or mal at baseli ne ( < 1. 0 c m s h ort a xis) a n d i ncrease d t o ≥1. 0 c m 
s h ort a xis a n d is dee me d t o be mali g na nt d uri n g f oll o w -u p.  
 
b.  At least a 2 0 % i ncrease i n P B S D (s u m of t he l o n g est dia meter f or all 
tar get lesi o ns pl us t he s u m of t he l o n g or s h ort a xis of all t he tar get l y m p h 
n o des ( de pe n di n g o n w hic h a xis is bei n g use d f or assess me nts) at c urre nt 
e val uati o n) ta ki n g as refere nce t he M S D ( Secti o n 1 1. 4 1). I n a d diti o n, t he 
P B S D m ust als o de m o nstrate a n a bs ol ute i ncrease of at least 0. 5 c m fr o m 
t he M S D. 
 


 
 
 
4 0  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
c. See Secti o n 1 1. 3 2 f or details i n re gar ds t o t he re q uire me nts f or P D via 
F D G -P E T i ma gi n g.  
 
•  Sta ble Disease ( S D): Neit her s ufficie nt s hri n ka ge t o q ualif y f or P R, n or 
s ufficie nt i ncrease t o q ualif y f or P D ta ki n g as refere nce t he M S D.  
 
1 1. 4 3 3  E val uati o n of N o n -Tar get Lesi o ns & N o n -tar get L y m p h N o des 
 
•  C o m plete Res p o nse ( C R):  All of t he f oll o wi n g m ust be tr ue:  
 
a. Disa p peara nce of all n o n -tar get lesi o ns.  
 
b.  Eac h n o n -tar get l y m p h n o de m ust ha ve a re d ucti o n i n s h ort a xis t o < 1. 0 
c m. 
 
c. F or patie nts wit h o ut detecta ble t h yr o gl o b uli n a nti b o dies, sti m ulate d 
ser u m t h yr o gl o b uli n m ust be  meas ure d t o be u n detecta ble. F or patie nts 
wit h detecta ble t h yr o gl o b uli n a nti b o dies, assess me nt of t h yr o gl o b uli n  
will n ot be necessar y f or assess me nt of c o m plete res p o nse.  
 
•  N o n -C R/ N o n -P D: Persiste nce of o ne or m ore n o n -tar get lesi o ns or n o n-tar get 
l y m p h n o des. 
 
•  Pr o gres si o n ( P D): At least o ne of t he f oll o wi n g m ust be tr ue:  
 
a. At least o ne ne w mali g na nt lesi o n, w hic h  als o i ncl u des a n y l y m p h n o de 
t hat was n or mal at baseli ne ( < 1. 0 c m  s h ort a xis) a n d i ncrease d t o ≥1. 0 c m 
s h ort a xis a n d is dee me d t o be mali g na nt d uri n g f oll o w -u p.  
 
b.  U ne q ui v ocal pr o gressi o n of e xisti n g n o n -tar get lesi o ns a n d n o n-tar get 
l y m p h n o des. ( N O T E: U ne q ui v ocal pr o gressi o n s h o ul d n ot n or mall y 
tr u m p tar get lesi o n a n d tar get l y m p h n o de stat us. It m ust be 
re prese ntati ve of o verall disease stat us c ha n ge.) 
 
c. See Secti o n 1 1. 3 2 f or details i n re gar ds t o t he re q uire me nts f or P D via 
F D G -P E T i ma gi n g.  
 
 
1 1. 4 3 4  O ver all O bjecti ve St at us  f or P atie nts wit h Me as ure a ble T ar get 
Lesi o ns/ L y m p h N o des  
 
T he o veral l o bjecti ve stat us f or a n e val uati o n is deter mi ne d b y c o m bi ni n g t he 
patie nt’s stat us o n tar get lesi o ns, tar get l y m p h n o des, n o n -tar get lesi o ns, n o n-
tar get l y m p h n o des, a n d ne w disease as defi ne d i n t he f oll o wi n g ta bles. Ser u m 
t h yr o gl o b uli n meas ure me nts will n ot  be use d i n deter mi ni n g o verall res p o nse, 
e xce pt  f or desi g nati n g a c o m plete res p o nse (as detaile d i n Secti o n 1 1. 4 3 2 a n d i n 
t he ta ble bel o w): 
 
 




 
 
 
4 2  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
If a ce nter d oes n ot ha ve a t h yr o gl o b uli n assa y t hat rea ds t o <  2 
n g/ ml, t he n a T S H -sti m ulate d T G < 1 n g/ ml w o ul d be re q uire d t o 
c o nfir m c o m plete res p o nse.  F or patie nts wit h detecta ble 
t h yr o gl o b uli n a nti b o dies, assess me nt of t h yr o glo b uli n will n ot be 
necessar y f or assess me nt of c o m plete res p o nse.  
 
•  
N o n -C R/ N o n -P D: Persiste nce of o ne or m ore n o n -tar get lesi o ns or n o n-
tar get l y m p h n o des.   
  
•  
Pr o gres si o n ( P D): At least o ne of t he f oll o wi n g m ust be tr ue:  
 
a.    At least o ne ne w mali g na nt l esi o n, w hic h als o i ncl u des a n y l y m p h 
n o de t hat was n or mal at baseli ne ( < 1. 0 c m  s h ort a xis) a n d i ncrease d 
t o ≥1. 0 c m s h ort a xis a n d is dee me d t o be mali g na nt d uri n g f oll o w -
u p.  
 
b . U ne q ui v ocal pr o gressi o n of e xisti n g n o n -tar get lesi o ns a n d n o n-
tar get l y m p h n o des. ( N O T E: U ne q ui v ocal pr o gressi o n s h o ul d n ot 
n or mall y tr u m p tar get lesi o n a n d tar get l y m p h n o de stat us. It m ust 
be re prese ntati ve of o verall disease stat us c ha n ge.)  
 
c. See Secti o n 1 1. 3 2 f or details i n re gar ds t o t he re q uire me nts f or P D 
via F D G -P E T i ma gi n g.  
 
1 1. 4 4 3  
O ver all O bjecti ve St at us f or P atie nts wit h N o n -Me as ure a ble, N o n -
T ar get Lesi o ns/ L y m p h n o des  
 
T he  o verall o bjecti ve stat us f or  a n e val uati o n is deter mi ne d b y:  
•  Str uct ural assess me nt of lesi o ns/l y m p h n o des as detaile d i n Secti o n 
1 1. 4 4 2.  
•  F or t he “ n o n-C R/ n o n -P D” str uct ural  cate g or y, meas ure me nt of t he ser u m 
T G i n t he c o nte xt of s u p presse d T S H  (a n d ne gati ve T G a nti b o d y) will be 
use d  t o deter mi ne t he  fi nal res p o nse desi g nati o n (t he e xce pti o n is f or t he 
assess me nt of c o m plete res p o nse, w hic h re q uires meas ure me nt of a 
sti m ulate d T G, see c hart bel o w).  






 
 
 
4 5  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
u p o n a c o m paris o n bet wee n t he 6 m o nt h ra di ol o gic sca n(s)/e val uati o ns a n d t he 
baseli ne, pre -treat me nt ra di ol o gic sca ns  (a n d ser u m t h yr o gl o b uli n meas ure me nts if 
a p plica ble) . 
 
1 1. 4 6  S y m pt o matic Deteri orati o n: Patie nts wit h gl o bal deteri orati o n of healt h stat us 
re q uiri n g disc o nti n uati o n of treat me nt wit h o ut o bjecti ve e vi de nce of disease 
pr o gressi o n at t hat ti me, a n d n ot eit her relate d t o s t u d y treat me nt or ot her me dical 
c o n diti o ns, s h o ul d be re p orte d as P D d ue t o “s y m pt o matic deteri orati o n.” E ver y eff ort 
s h o ul d be ma de t o d oc u me nt t he o bjecti ve pr o gressi o n e ve n after disc o nti n uati o n of 
treat me nt d ue t o s y m pt o matic deteri orati o n. A patie nt is classifie d as ha vi n g P D d ue 
t o “s y m pt o matic deteri orati o n” if a n y of t he f oll o wi n g occ ur t hat are n ot eit her relate d 
t o st u d y treat me nt or ot her me dical c o n diti o ns: 
 
•  
Wei g ht l oss > 1 0 % of b o d y wei g ht.  
•  
W orse ni n g of t u m or -relate d s y m pt o ms. 
•  
Decli ne i n perf or m a nce stat us of > 1 le vel o n E C O G scale.  
 
 
1 2. 0  
Descri pti ve F act ors   
 
1 2. 1  
N u m ber of pri or 1 3 1I treat me nts: 0 vs. 1 vs. 2 vs. 3 vs. 4 or m ore . 
 
1 2. 2  
P re vi o us c he m ot hera p y/tar gete d t hera p y f or t h yr oi d ca ncer: Yes vs. N o . 
 
1 2. 3  
P ri or R T: Yes vs. N o . 
 
1 2. 4  
T h y r oi d hist ol o g y: ( pa pillar y, f ollic ular, p o orl y differe ntiate d, a n d ot her res pecti ve varia nts). 
 
 
1 3. 0  
Tre at me nt/ F oll o w – u p Decisi o n at E v al u ati o n of P atie nt  
 
1 3. 1  
Patie nts w h o are C R, P R, or S D will c o nti n ue treat me nt/assess me nt per pr ot oc ol.  Patie nts t hat 
are n o n-P D after c o m pleti n g treat me nt will be f oll o we d d uri n g t he o bser vati o n p hase as 
o utli ne d i n Secti o n 4. 0: 1 m o nt h p ost -treat me nt, 3 m o nt hs p ost -treat me nt, f oll o we d b y e ver y 3 
m o nt hs u ntil 1 2  m o nt hs p ost -treat me nt w he n patie nts will be  f oll o we d e ver y 6 m o nt hs f or a 
ma xi m u m of 2 years  ( +/- 3 m o nt hs)  fr o m ra n d o mizati o n. 
 
1 3. 2  
Patie nts w h o de vel o p P D w hile recei vi n g t hera p y or u n der g oi n g pr ot oc ol  assess me nt  will be 
f oll o we d i n t he e ve nt m o nit ori n g p hase (see secti o n 1 8). H o we ver, it is p ossi ble t hat patients 
will ha ve P D  earl y i n t he st u d y a n d still de m o nstrate be nefit fr o m t he st u d y treat me nt later i n 
t he st u d y f or se veral reas o ns: 1) sel u meti ni b al o ne pri or t o R AI ma y n ot ha ve si g nifica nt cli nical 
efficac y, 2) T h yr o ge n ™ sti m ulati o n ca n tra nsie ntl y i ncrease t u m or size w hic h ca n be mista ke n 
f or disease pr o gressi o n; 3) t he t hera pe utic effects of R AI ca n be dela ye d; a n d 4) e vi de nce of 
pr o gressi o n ma y be e vi de nt pri or t o a d mi nistrati o n of R AI.  He nce, patie nts wit h e vi de nce of 
ra di o gra p hic, cli nical or bi oc he m ical (i.e. t h yr o gl o b uli n, if a p plica ble) P D n ote d pri or t o t he 6 -
m o nt h disease e val uati o n (i.e. t he sca ns a n d e val uati o ns perf or me d 6 m o nt hs after t hera pe utic 
1 3 1I is a d mi nistere d) ma y re mai n o n treat me nt/assess me nt at t he discreti o n of t he treati n g 
p h ysic ia n. If, i n t he o pi ni o n of t he treati n g p h ysicia n, t hese patie nts are u nli kel y t o de m o nstrate 
be nefit wit h s u bse q ue nt cli nical assess me nts, t he patie nts will be classifie d as ha vi n g P D a n d 
will be f oll o we d i n t he e ve nt m o nit ori n g p hase (see S ecti o n 1 8. 0). 


 
 
 
4 6  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
 
1 3. 3  
Patie nts w h o g o off pr ot oc ol treat me nt f or reas o ns ot her t ha n P D will g o t o t he  e ve nt -
m o nit ori n g p hase per Secti o n 1 8. 0.  
 
1 3. 4  
Patie nts w h o de vel o p C N S P D at a n y ti me s h o ul d g o t o e ve nt m o nit ori n g.  
 
T hese patie nts s h o ul d recei ve treat me nt if dee me d cli nicall y i n dicate d b y t he treati n g 
p h ysicia n(s) . 
 
1 3. 5 a A patie nt is dee me d i neli gi ble if after re gistrati o n, it is deter mi ne d t hat at t he ti me  of 
re gistrati o n, t he patie nt di d n ot satisf y eac h a n d e ver y eli gi bilit y criteria f or st u d y e ntr y. T he 
patie nt m a y c o nti n ue treat me nt off -pr ot oc ol at t he discreti o n of t he p h ysicia n as l o n g as t here 
are n o safet y c o ncer ns, a n d t he patie nt was pr o perl y re gistere d. T he patie nt will g o directl y t o 
t he e ve nt-m o nit ori n g p hase of t he st u d y ( or off st u d y, if a p plica ble).  
 
•  
If t he patie nt recei ve d treat me nt, all data u p u ntil t he p oi nt of c o nfir mati o n of i neli gi bilit y 
m ust be s u b mitte d. E ve nt m o nit ori n g will be re q uire d per Secti o n 1 8. 0 of t he pr ot oc ol.  
•  
If t he patie nt ne ver recei ve d treat me nt, o n-st u d y material m ust be s u b mitte d. E ve nt 
m o nit ori n g will be re q uire d per Secti o n 1 8. 0 of t he pr ot oc ol.  
 
1 3. 5 b  A patie nt is dee me d a maj or vi olati o n, if pr ot oc ol re q uire me nts re gar di n g  treat me nt i n c ycle 1 of 
t he i nitial t hera p y are se verel y vi olate d s uc h t hat e val uati o n of t he pri mar y  e n d p oi nt is 
si g nifica ntl y c o m pr o mise d . All data u p u ntil t he p oi nt of c o nfir mati o n of a maj or vi olati o n m ust 
be s u b mitte d. T he patie nt will g o directl y t o t he e ve nt -m o nit ori n g p hase of t he st u d y. T he 
patie nt ma y c o nti n ue treat me nt off -pr ot oc ol at t he dis creti o n of t he p h ysicia n as l o n g as t here 
are n o safet y c o ncer ns, a n d t he patie nt was pr o perl y re gistere d. E ve nt m o nit ori n g will be 
re q uire d per Secti o n 1 8. 0 of t he pr ot oc ol. 
 
1 3. 5 c A patie nt is dee me d a ca ncel if he/s he is re m o ve d fr o m t he st u d y f or a n y r eas o n  bef ore a n y 
st u d y treat me nt is gi ve n. O n-st u d y material a n d t he E n d of Acti ve Treat me nt/ Ca ncel 
N otificati o n F or m m ust be s u b mitte d. N o f urt her data s u b missi o n is necessar y.  
 
 


 
 
 
4 7  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
1 4. 0  
B o d y Fl ui d Bi os peci me ns   
 
1 4. 1  
S u m mar y Ta ble of Researc h Bl o o d/ Bl o o d Pr o d ucts t o Be C ollecte d f or T his  Pr ot oc ol  
I n dic ate if 
s peci m e n is 
m a n d at or y 
or o pti o n al  
C ollecti o n t u be 
descri pti o n 
a n d/ or a d diti ve 
(c ol or of t u be 
t o p) 
V ol u me t o 
c ollect per 
t u be ( n u m ber 
of  t u bes t o be 
c ollecte d)  
Bl o o d pr o d uct 
bei n g pr ocesse d 
a n d s u b mitt e d 
b y p artici p ati n g 
site 
Pre -
Tre at m e nt 
( pri or t o 
st arti n g pl ace b o 
or sel u meti ni b) 
A d diti o n al 
pr ocessi n g 
re q uire d at 
site after 
bl o o d dr a w ?  
St o r a ge  
/s hi p pi n g 
c o n diti o ns 1 
Ma n dat or y  
La v e n der  
1 0 ml ( 1)  
Bl o o d  
X  
N o  
Refri gerate d  
(R e q uisiti o n f or m  l ocate d o n t he A C C R U we b site .) 
 
1 4. 2  
N o kits will be re q uire d f or t his st u d y.  
 
1 4. 3  
Sa m ples s h o ul d be c ollecte d M o n da y t hr o u g h T h urs da y. H o we ver, if t he s u bject  ca n o nl y be 
see n o n Fri da y, n otif y t he Bi os peci me n Res o urce Ma na ger liste d i n t he i n t he pr ot oc ol res o urce 
pa ge of t he sa m ple, st u d y I D a n d trac ki n g n u m ber a n d Sat ur da y arra n ge me nts will be ma de t o 
sta bilize t he sa m ple o ver t he wee ke n d. D o n ot c ollect s peci me ns t he da y bef ore a fe deral 
h oli da y.  N O T E: R esearc h bl o o d sa m ples s h o ul d n ot be c ollecte d a n d s u b mitte d u ntil after  t he 
patie nt is re gistere d o nt o t he st u d y, b ut pri or  t o t he i nitiati o n of place b o/sel u meti ni b t hera p y. 
 
1 4. 3 1  
La bel t he s peci me n t u be  wit h pr ot oc ol n u m ber, A C C R U s u bject I D n u m ber, a n d ti me 
a n d date bl o o d is dra w n . 
 
1 4. 3 2  
S hi p t he E D T A t u be wit h  a pr o perl y pre pare d c ol d pac k.  
 
1 4. 3 3  
S hi p s peci me ns via Fe d E x Pri orit y O ver ni g ht ser vice.  
 
1 4. 3 4  
S hi p sa m ples t o : 
B A P Freezer  
 
 
 
 
1 4. 3 5  
B A P Recei vi n g will recei ve t he sa m ples a n d f or war d s peci me ns t o  t he A C C R U  
Researc h Base B A P S hare d Res o urce, 
. 
 
1 4. 4  
St u d y Met h o d ol o g y a n d St ora ge I nf or mati o n  
 
1 4. 4 1  
Bl o o d/ bl o o d pr o d uct sa m ples will be c ollecte d f or t he f oll o wi n g researc h :  
 
1 4. 4 1 1  
D N A extracti o n, st ora ge, a n d a nal ys is of D N A will be  perf or me d i n B A P  
usi n g sta n dar d la b orat or y pr ot oc ols.  T hese sa m ples will be use d as a 
n or mal  c o ntr ol f or t he ge n o mic a nal ysis c o n d ucte d u p o n t he arc hi val t u m or 
tiss ue a n d ma y be a nal yze d i n f ut ure p har mac o ge netic assa ys. Re mai ni n g 
D N A wil l be st ore d fr oze n at -7 0º C b y B A P, acc or di n g t o patie nt c o nse nt 
i nf or mati o n u ntil s pecific a nal yses are i de ntifie d. As pr ot oc ols are 
de vel o pe d, t he y will be prese nte d f or  A C C R U , I R B, a n d I T O G re vie w a n d 
a p pr o val.  ( T his c ollecti o n is part of a ge neral strate g y of i n vesti gati o n f or 
t he maj orit y of A C C R U/I T O G st u dies.) 
 


 
 
 
4 8  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
1 4. 4 1 2  
As part of o n g oi n g A C C R U /I T O G researc h, we will c ollect w hite bl o o d 
cells/ plas ma f or f ut ure researc h st u dies, acc or di n g t o patie nt c o nse nt 
i nf or mati o n. Sa m ples will be st ore d fr oze n at −7 0º C  b y B A P u ntil s pecific 
a nal yses are i de ntifie d. As pr ot oc ols are de vel o pe d, t he y will be prese nte d 
f or A C C R U , I T O G, a n d I R B re vie w a n d a p pr o val.  
 
1 4. 5  
Beca use t he res ults ge nerate d b y t he ge netic testi n g i ncl u de d i n t his secti o n are  n ot c urre ntl y 
a ntici pate d t o ha ve cli nical rele va nce t o t he patie nt or t heir fa mil y me m bers, t he ge netic res ults 
will n ot be discl ose d t o t he patie nts or t heir p h ysicia ns.  
 
If, at a n y ti me, ge netic res ults are o btai ne d t hat ma y ha ve cli nical rele va nce, I R B re vie w a n d 
a p pr oval will be s o u g ht re gar di n g t he m ost a p pr o priate ma n ner of discl os ure a n d w het her or n ot 
vali dati o n i n a C LI A -certifie d setti n g will be re q uire d.  S hari n g of researc h data wit h i n di vi d ual 
patie nts s h o ul d o nl y occ ur w he n data ha ve bee n vali date d b y m ulti ple  st u dies a n d testi n g has 
bee n d o ne i n C LI A -a p pr o ve d la b orat ories.  
 
 
1 5. 0  
Dr u g I nf or m ati o n  
 
I n vesti g at or Br oc h ure: T he m ost c urre nt versi o n of t he I n vesti gat or Br oc h ure will be mai ntai ne d i n t he 
st u d y f ol der o n t he A C C R U we bsite. U p date d I n vesti gat or’s Br oc h ures s h o ul d be o btai ne d fr o m t he 
st u d y f ol der as t he y bec o me a vaila ble.  
 
Eac h i n vesti gat or s h o ul d o btai n a c o p y of t he I n vesti gat or’s Br oc h ure pri or t o i nitiati o n of t he st u d y.  
 
1 5. 1  
Sel u meti ni b ( A Z D 6 2 4 4   K osel u g o ™) or sel u meti ni b-matc he d place b o  
 
1 5. 1 1  
B ac k gr o u n d : T he R A S/ R A F/ M E K/ E R K pat h wa y is a n i m p orta nt me diat or of ma n y 
cell ular pr ocesses i ncl u di n g pr oliferati o n, s ur vi val, differe ntiati o n, a p o pt osis, m otilit y 
a n d meta b olis m. T his pat h wa y is ofte n a berra ntl y acti vate d i n h u ma n t u m ors d ue t o 
t he o verex pressi o n of acti vate d K -R A S, m uta nt b -Raf, or ot her gr o wt h fact or 
rece pt ors. Sel u meti ni b is a selecti ve mit o ge n-acti vate d pr otei n ki nase ( M E K) 
i n hi bit or. B y i n hi biti n g M E K, sel u meti ni b i n hi bits E R K p h os p h or ylati o n. T h us, 
sel u meti ni b ma y i n hi bit o nc o ge nic gr o wt h si g nali n g i n t u m or cells b y tar geti n g t he 
R A S/ R A F/ M E K/ E R K pat h wa y.  
 
1 5. 1 2  F or m ul ati o n:  
 
   T he dr u g pr o d uct c o nsists of a series of plai n, H P M C  
ca ps ules c o ntai ni n g 1 0 m g ( w hite) a n d 2 5 m g ( bl ue) sel u meti ni b (e x presse d as free -
base) f or oral a d mi nis trati o n. Sel u meti ni b ca ps ules are s u p plie d i n w hite, H D P E 
b ottles wit h desicca nt, a ta m per e vi de nt i n d ucti o n seal me m bra ne a n d c hil d resista nt 
scre w cl os ure. 
 
 T he 1 0 m g ca ps ule is prese nte d as eit her a plai n w hite ca ps ule wit h a ce nter ba n d, or 
w hite t o o ff-w hite ca ps ule wit h a ce nter ba n d mar ke d wit h ‘ S E L 1 0’ pri nte d i n blac k 
i n k. 
 
 T he 2 5 m g ca ps ule is prese nte d as eit her a plai n bl ue ca ps ule wit h a ce nter ba n d, or 
bl ue ca ps ule wit h a ce nter ba n d mar ke d wit h ‘ S E L 2 5’ pri nte d i n blac k i n k.  
 
 A part fr o m t h e mar ki n gs, plai n a n d mar ke d ca ps ules are i de ntical i n all ot her as pects.  
 


 
 
 
4 9  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
 
T he ca ps ules c o ntai n sel u meti ni b H y d -S ulfate a n d Vita mi n E p ol yet h yle ne 
gl yc ol s ucci nate (als o k n o w n as T P G S - a water s ol u ble f or m of vita mi n E) Place b o 
c o m p ositi o n is c o nsiste nt w it h t he c o m p ositi o n of dr u g pr o d uct, wit h t he a bse nt dr u g 
s u bsta nce bei n g re place d b y Vita mi n E p ol yet h yle ne gl yc ol s ucci nate . T he sa me 
H P M C ca ps ule s hells are use d f or b ot h place b o a n d acti ve dr u g pr o d ucts.  
 
B ot h sel u meti ni b a n d place b o are s u p plie d i n 2 5 m g ca ps ules i n b ottles c o ntai ni n g 6 0 
ca ps ules eac h. 
 
1 5. 1 3  
Pre p ar ati o n a n d St or a ge:  St ore t he sel u meti ni b or place b o ca ps ules i n t he ori gi nal 
pac ka gi n g u ntil use at r o o m te m perat ure ( 2 0° C -2 5° C). Brief e xc ursi o ns are 
per mitte d bet wee n 1 5° C a n d 3 0° C. F o r f urt her i nf or mati o n refer t o t he 
i n vesti gati o nal pr o d uct la bel. 
 
1 5. 1 4  
A d mi nistr ati o n:  Sel u meti ni b  s h o ul d be ta ke n o n a n e m pt y st o mac h, 1 h o ur bef ore or 
2 h o urs after a meal. Ta ke ca ps ules wit h water o nl y.  
1 5. 1 5  
P h ar m ac o ki netic i nf or m ati o n :  
A bs or pti o n  - Sel u meti ni b was a bs or be d relati vel y q uic kl y acr oss all d ose 
le vels, wit h a me dia n tma x of  1 t o  1. 5 h o urs acr oss t he d ose ra n ge ( 2 5 t o 1 0 0 m g).    
Distri b uti o n  - F oll o wi n g t he pea k, sel u meti ni b c o nce ntrati o ns decli ne d m ulti -
e x p o ne ntiall y, wit h a mea n t 1/ 2 ra n gi n g fr o m 5 t o 7 h, w hic h is c o nsiste nt acr oss 
d ose le vels. C L/ F a n d V ss/ F als o re mai ne d lar gel y c o nsiste nt acr oss t he d ose 
ra n ge, wit h mea n val ues ra n gi n g fr o m 1 2 t o 2 3 L/ h a n d 8 7 t o 1 2 6 L 
res pecti vel y. Plas ma N-des met h yl sel u meti ni b c o nce ntrati o ns f oll o we d a 
si milar p har mac o ki netic pr ofile t o sel u meti ni b, alt h o u g h e x p os ure was m uc h 
l o wer, wit h Cma x  a n d A U C val ues ge nerall y < 1 5 % of pare nt, wit hi n eac h 
patie nt. T he me dia n t ma x  was ar o u n d 1. 5 hrs a n d t 1/ 2 was ar o u n d 9 t o 1 3 h o urs.  
 
Met a b olis m  -  
C yt oc hr o me  P 4 5 0 3 A 4 is t he pre d o mi na nt is of or m res p o nsi ble f or  sel u meti ni b 
o xi dati ve meta b olis m wit h C Y P 2 C 1 9, C Y P 1 A 2, C Y P 2 C 9, C Y P 2 E 1, a n d  C Y P 3 A 5 
i n v ol ve d t o a lesser e xte nt.  Its acti ve meta b olite, N-des met h yl sel u meti ni b is 
a p pr o xi matel y 3 -5 ti mes m ore p ote nt t ha n sel u meti ni b, a n d ge nerate d pri maril y b y 
C Y P 1 A 2, C Y P 2 C 1 9, C Y P 2 C 9 a n d C Y P 2 C 8 a n d meta b olize d t hr o u g h t he sa me 
r o utes as sel u meti ni b. 
S peci al P o p ul ati o ns –  Re nal i m pair me nt is e x pecte d  t o ha ve mi ni mal effect o n 
e x p os ure t o sel u meti ni b. Patie nts wit h m o derate a n d se vere he patic i m pair me nt ma y 
e x perie nce hi g her e x p os ures of a p pr o xi matel y 1. 5 -a n d 3-f ol d, res pecti vel y. It is 
rec o m me n de d t hat i n vesti gat ors ta ke t his i nf or mati o n i nt o c o nsi derati o n if patie nt 
e x perie nce m o derate or se vere he patic i m pair me nt d uri n g t h e st u d y treat me nt.   
 
1 5. 1 6  
P ote nti al Dr u g I nter acti o ns : Hi g h vita mi n E d oses ma y p ote ntiate t he a nticoa g ula nt 
acti vit y of warfari n. M o nit or P T/I N R m ore fre q ue ntl y i n patie nts recei vi n g b ot h 
sel u meti ni b a n d warfari n.  
 
T he c o nc o mita nt i nta ke of s u p ple me ntal  vita mi n E s h o ul d be a v oi de d i n all 
s u bjects recei vi n g sel u meti ni b. 
 
A v oi d c o -a d mi nisteri n g sel u meti ni b wit h me dici nal pr o d ucts t hat are str o n g 
i n hi bit ors of C Y P 3 A 4 (e g, clarit hr o m yci n, gra pefr uit j uice, oral ket oc o naz ole) 
a n d C Y P 2 C 1 9 (e g, ticl o pi di ne). If  c o-a d mi nistrati o n is u na v oi da ble, patie nts 
s h o ul d be caref ull y m o nit ore d f or A Es.  N o d ose a dj ust me nt is necessar y f or 


 
 
 
5 0  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
use of sel u meti ni b wit h m o derate C Y P 3 A 4 or C Y P 2 C 1 9 i n hi bit ors. Patie nts 
s h o ul d be caref ull y m o nit ore d f or A Es w he n c o-a d mi nistere d wit h m o derate 
C Y P 3 A 4 or C Y P 2 C 1 9 i n hi bit ors.  
 
A v oi d c o nc o mita nt use of str o n g C Y P 3 A 4 i n d ucers (e g, p he n yt oi n, rifa m pici n, 
car ba maze pi ne, St. J o h n’s W ort) or m o derate C Y P 3 A 4 i n d ucers wit h 
sel u meti ni b.   
Sel u meti ni b ma y be a n i n hi bit or of O A T 3 a n d t he p ote ntial f o r a cli nicall y 
rele va nt effect o n t he P K of c o nc o mita ntl y a d mi nistere d s u bstrates of O A T 3 
ca n n ot be e xcl u de d.  
 
Base d o n i n vitr o data a n d Si m C Y P si m ulati o ns, sel u meti ni b is c o nsi dere d 
u nli kel y t o ca use cli nicall y si g nifica nt dr u g -dr u g i nteracti o n via i n hi b iti o n or 
i n d ucti o n of C Y P e nz y mes 
 
1 5. 1 7  
K n o w n p ote nti al t o xicities : 
 
Ver y C o m m o n A d verse E ve nts, ( > 1 0 %) 
Car di o vasc ular:  Peri p heral e de ma  
Ce ntral ner v o us s yste m: Fati g ue , hea dac he 
Der mat ol o gic:  Ras h ac neif or m, ras h mac ul o -pa p ular  
E n d ocri ne & meta b olic: Cr eati ne p h os p h o ki nase ( C K) i ncrease d  
Gastr oi ntesti nal:  Diarr hea, na usea, v o miti n g , a b d o mi nal pai n, c o nsti pati o n. 
Res pirat or y: E xerti o nal d ys p nea  
 
C o m m o n A d verse E ve nts, ( 1 t o < 1 0 %) 
Car di o vasc ular: H y perte nsi o n  
Ce ntral ner v o us s yste m: Fe ver, dizzi ness, i ns o m nia, de pressi o n  
Der mat ol o gic: Dr y s ki n, pr urit us , ras h 
E n d ocri ne & meta b olic: H y p oal b u mi ne mia, h y p o ma g nese mia , 
h y per p h os p hate mia  
E ye: Peri or bital e de ma, bl urre d visi o n  
Gastr oi ntesti nal: u p per a b d o mi nal pai n, a b d o mi nal diste nsi o n, st o matitis, 
a n ore xia, decr ease d a p petite,  dr y m o ut h  
He mat ol o gic: T hr o m b oc yt o pe nia, a ne mia  
He patic: A S T i ncrease d, A L T i ncrease d  
Ne ur o m usc ular & s keletal: Bac k pai n, art hral gia, ast he nia  
Res pirat or y: D ys p nea, c o u g h  
Miscella ne o us: Al o pecia , L o w bl o o d p otassi u m  
 
R are A d verse E ve nts ( I m p ort a nt or life-t hre ate ni n g), < 1 %  
Left ve ntric ular s yst olic d ysf u ncti o n , Li ver i nj ur y/fail ure 
 
1 5. 1 8  
Dr u g pr oc ure me nt:  
Astra Ze neca will s u p pl y sel u meti ni b or place b o t o Cli nical Researc h Ser vices, a 
di visi o n of R x Cr ossr oa ds b y Mc Kess o n f or distri b uti o n t o partici pati n g sites. N o 
bli n de d starter s u p plies will be a vaila ble f or t his st u d y. Bli n de d, patie nt -s pecific 
cli nical s u p plies will be se nt t o t he re gisteri n g i n vesti gat or at t he ti me of 
ra n d o mizati o n a n d s h o ul d arri ve wit hi n 3 -5  da ys. T his ra n d o mizati o n will be 
perf or me d b y t he A C C R U Statistical a n d Data Ce nter. T he assi g ne d A C C R U Patie nt 
I D n u m ber m ust be rec or de d b y t he re gisteri n g i nstit uti o n f or pr o per b ottle dis persi o n. 
O nce a patie nt has bee n re gistere d, A C C R U will electr o nicall y tra ns mit a cli nic al 


 
 
 
5 1  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
dr u g re q uest f or t hat patie nt t o Cli nical Researc h Ser vices, a di visi o n of R x 
Cr ossr oa ds b y Mc Kess o n . T his re q uest will be e ntere d a n d tra ns mitte d b y A C C R U 
t he da y t he patie nt is re gistere d a n d will be pr ocesse d a n d s hi p pe d b y Cli nical 
Researc h Ser vices , a di visi o n of R x Cr ossr oa ds b y Mc Kess o nt he sa me b usi ness da y if 
recei ve d bef ore 2 p m E T. If t he re q uest is recei ve d after 2 p m E T, dr u g will be 
s hi p pe d t he f oll o wi n g b usi ness da y. S hi p me nts will be se nt via Fe d E x Pri orit y 
O ver ni g ht.   
 
If a d diti o nal s u p plies are nee de d, c o ntact a me m ber of t he Cli nical Researc h Ser vices 
tea m:  
  
Cli nical Researc h Ser vices, a di visi o n of R x Cr ossr oa ds b y Mc Kess o n  
Cli nical Researc h Ser vices  
 
 
 
O ut d ate d or re m ai ni n g dr u g is t o be destr oye d o n -site as per pr oce d ures i n pl ace at 
e ac h i nstit uti o n. 
 
1 5. 1 9  
N ursi n g G ui deli nes  
 
1 5. 1 9 1  
Me dicati o n s h o ul d be ta ke n o n a n e m pt y st o mac h wit h n o f o o d or dri n k 
ot her t ha n water f or 1 h o ur bef ore a n d 2 h o urs after d osi n g.  
 
1 5. 1 9 2  
Gastr oi ntesti nal si de effects were t he m ost c o m m o nl y re p orte d si de effects 
wit h t his a ge nt (i ncl u di n g na usea, diarr hea, c o nsti pati o n, d ys pe psia a n d 
v o miti n g). Ma na ge s y m pt o maticall y a n d assess f or effecti ve ness of 
i nter ve nti o n. 
 
1 5. 1 9 3  
Patie nts e x perie nce d ac neif or m ras h. I nstr uct patie nt t o re p ort t his ras h a n d 
ma na ge s y m pt o maticall y.  
 
1 5. 1 9 4  D ys p nea has bee n re p orte d. I nstr uct patie nt t o re p ort a n y s h ort ness of breat h t o 
t he st u d y tea m. Rarel y i nterstitial l u n g disease has bee n see n wit h a ge nt.  
 
1 5. 1 9 5  
H y perte nsi o n has bee n see n. Assess bl o o d press ure acc or di n g t o st u d y 
re q uire me nts. 
 
1 5. 1 9 6  
I nstr uct patie nts t o re p ort a n y li m b s welli n g ( us uall y le gs) t o t he st u d y 
tea m. Rarel y L V E F d ysf u ncti o n has bee n see n.  
 
1 5. 1 9 7  
M o nit or L F T’s.  
 
1 5. 1 9 8  
M o nit or C B C w/ di ff. I nstr uct patie nts t o re p ort a n y u n us ual br uisi n g or 
blee di n g t o t he st u d y tea m.  
 
1 5. 1 9 9 a Patie nts ma y e x perie nce i ncrease d fati g ue. I nstr uct patie nts i n e ner g y 
c o nser vi n g lifest yle.  
 
1 5. 1 9 9 b  War n patie nts of p ossi ble al o pecia.  
 
1 5. 1 9 9 c I nstr uct patie nts t o re p ort a n y bl urre d visi o n or peri or bital e de ma t o t he 


 
 
 
5 2  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
st u d y tea m. 
1 5. 1 9 9 d    Assess patie nt’s c o nc o mita nt me dicati o ns as t here are n u mer o us dr u g t o 
dr u g i nteracti o ns.  
 
1 5. 2  
T h yr o ge n ™ (r h T S H, t h yr otr o pi n alfa f or i njecti o n) 
 
Effecti ve c o n d uct of R AI t hera p y re q uires sti m ulati o n b y T S H i n or der t o ma xi mize  R AI u pta ke 
b y  t h yr oi d cells. Rec o m bi na nt h u ma n T S H (r h T S H or T h yr o ge n ™) will be use d t o sti m ulate 
i o di de u pta ke acc or di n g t o t he ma n ufact urer’s rec o m me n dati o n ( 0. 9 m g i ntra -m usc ular i njecti o n 
f or 2 da y s pri or t o t he R AI a d mi nistrati o n  acc or di n g t o t he Secti o n 4. 0 ). T his all o ws patie nts t o 
a v oi d t he h y p ot h yr oi dis m state, si nce t he y ca n mai ntai n t heir r o uti ne  t h yr oi d h or m o ne 
s u p ple me ntati o n. Patie nts or cli nicia ns c h o osi n g wit h dra wal of t h yr oi d  h or m o ne tr eat me nt f or 
t his p ur p ose will be i neli gi ble f or t his st u d y.  
 
1 5. 2 1  
Dr u g pr oc ure me nt:  C o m mercial s u p plies. P har macies or cli nics s hall o btai n 
s u p plies fr o m n or mal c o m mercial s u p pl y c hai n or w h olesaler.  
 
1 5. 3  
Ra di oacti ve i o di ne ( R AI)  
 
1 5. 3 1  
T hera pe utic R AI  d ose ( 1 3 1I) 
 
Patie nts < 7 0 years of a ge will be treate d wit h 1 5 0 m Ci 1 3 1I ( +/- 5 m Ci). Patie nts > 7 0 
years of a ge ca n be treate d wit h a 1 3 1I acti vit y fr o m 1 0 0 m Ci u p t o a n d i ncl u di n g 1 5 0 
m Ci ( +/ - 5 m Ci f or 1 0 0 m Ci or 1 5 0 m Ci a d mi nistere d acti vities); f or t h ese patie nts, 
t he acti vit y t o be a d mi nistere d m ust be deter mi ne d b y t he i n vesti gat or at t he ti me of 
st u d y re gistrati o n. 
 
T h o u g h perf or mi n g w h ole bl o o d a n d b o d y d osi metr y t o deter mi ne ma xi m u m 
t olerate d acti vit y ( M T A) is N O T  re q uire d, f or ce nters at w hic h t his e val uati o n is d o ne 
pri or t o t hera pe utic 1 3 1I st u d y a d mi nistrati o n ( Wee k 4), l o wer 1 3 1I acti vities t ha n w hat 
is rec o m me n de d here ma y  be a d mi nistere d if t he M T A is calc ulate d t o be l o wer t ha n 
t he l o wer li mit of w hat is all o we d per pr ot oc ol or w hat has bee n deter mi ne d t o be 
gi ve n  (f or patie nts > 7 0 years of a ge).  E x a m ples (t hese are a p plica ble o nl y i n 
i nsta nces i n w hic h d osi metr y was perf or me d pri or t o t hera pe utic 1 3 1I a d mi nistrati o n): 
1) P atie nts < 7 0 ye ars of a ge: If t he d osi metr y-deter mi ne d M T A val ue is l ess t ha n 1 5 0 
m Ci, t he n a R AI acti vit y less t ha n 1 5 0 m Ci ma y be a d mi nistere d; 2) P atie nts > 7 0 
ye ars of a ge: If t he d osi metr y-deter mi ne d M T A val ue is less t ha n t he acti vit y t hat was 
deter mi ne d t o be gi ve n at t he ti me of st u d y re gistrati o n, t he n a l o wer R AI a cti vit y 
ma y be a d mi nistere d, e ve n acti vities less t ha n 1 0 0 m Ci if t he M T A is bel o w t his 
t hres h ol d. D osi metr y ca n N O T  be use d t o j ustif y a d mi nisteri n g t hera pe utic 1 3 1I 
acti vities hi g her t ha n w hat has bee n rec o m me n de d per t his pr ot oc ol.  
 
A d mi nistrati o n of T h yr o ge n ™ a n d/ or t hera pe utic 1 3 1I at a facilit y ot her t ha n t he 
partici pati n g site is all o we d if d oc u me ntati o n of t he dates a n d a m o u nt/acti vit y of dr u g 
/ra di ois ot o pe a d mi nistere d is pr o vi de d t o verif y a d here nce t o pr ot oc ol re q uire me nts. 
 
A n y f or m of oral 1 3 1I (e. g., ca ps ule or li q ui d) is all o we d. 
 
1 5. 3 2  
Dr u g pr oc ure me nt: C o m mercial s u p plies. P har macies or cli nics s hall o btai n s u p plies 
fr o m n or mal c o m mercial s u p pl y c hai n or w h olesaler.  
 
1 6. 0  
St atistic al C o nsi der ati o ns a n d Met h o d ol o g y  


 
 
 
5 3  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
 
1 6. 1  
St u d y O ver vie w  
 
T h is ra n d o mize d, d o u ble-bli n d  P hase II trial will c o m pare t he res p o nse rate at 6 m o nt hs after 
t hera p y wit h 1 3 1I i n c o m bi nati o n wit h place b o or sel u meti ni b f or t he treat me nt of patie nts wit h 
R AI A  rec urre nt a n d/ or metastatic t h yr oi d ca ncer. Hist orical res p o nse  rate t o a si n gle d ose of 
R AI ca n be diffic ult t o esti mate fr o m retr os pecti ve data t hat i ncl u de heter o ge neit y wit h re gar ds 
t o t he e xte nt of disease treate d, R AI d oses a d mi nistere d, patie nt pre parati o n, res p o nse 
assess me nts etc. N o net heless, a  retr os pecti ve a nal ysis has de m o nstrate d t hat t he  res p o nse rate 
f or first-li ne 1 3 1I t hera p y al o ne f or rec urre nt/ metastatic R AI A t h yr oi d ca ncer wit h meas ura ble 
disease is ge nerall y ar o u n d 2 0 % (Sa bra et al., 2 0 1 3 ). We esti mate t hat patie nts wit h n o n -
meas urea ble disease a n d wit h t he ser u m t h yr o gl o b uli n criteria descri be d i n t his pr ot oc ol will 
ha ve a res p o nse rate of a p pr o xi matel y 5 0 %.  A ntici pati n g t hat 4 0 % of t he patie nts accr ue d wi ll 
ha ve meas urea ble disease a n d 6 0 % wit h n o n -meas urea ble disease o nl y (re q uiri n g ser u m T G 
meas ure me nts t o be use d i n res p o nse assess me nt), t he pre dicte d res p o nse rate f or t his 
p o p ulati o n w o ul d be 4 0 %. It is h o pe d t hat t he c o m bi nati o n of sel u meti ni b a n d 1 3 1I ca n i ncrease 
t he res p o nse rate t o 6 5 % .  
 
T his  trial will als o c o m pare t he best o verall res p o nse rate, pr o gressi o n -free s ur vi val ( P F S), 
c ha n ges i n ser u m t h yr o gl o b uli n le vels  a n d a d verse e ve nt rates  bet wee n t he t w o treat me nt ar ms. 
I n a d diti o n, we will e x pl ore t he ge n o mic a n d tra nscri pt o mic la n dsca pe of R AI A t u m ors f or 
si g nat ures t hat c orrelate t o t hera pe utic be nefit ac hie ve d i n patie nts wit h R AI -a vi d rec urre nt 
a n d/ or metastatic t h yr oi d ca ncer treate d wit h 1 3 1I i n c o m bi nati o n wit h place b o or sel u meti ni b. 
 
1 6 . 2 
Pri mar y E n d p oi nt  
 
T he pri mar y e n d p oi n t f or t his st u d y will c o m pare t he res p o nse rate wit h 1 3 1I i n c o m bi nati o n wit h 
place b o or sel u meti ni b f or t he treat me nt of patie nts wit h R AI A  rec urre nt a n d/ or metastatic 
t h yr oi d ca ncer at t he 6 -m o nt h ti me p oi nt  (“ 6-m o nt h ti me p oi nt” refers t o t he assess me nts 
desi g nate d t o occ ur a p pr o xi matel y 6 m o nt hs after 1 3 1I t hera p y i n c o m bi nati o n wit h place b o or 
sel u meti ni b has bee n a d mi nistere d , w hic h ma y be 6 m o nt hs +/- 1  wee k fr o m  t he ti me 
t hera pe utic R AI is a d mi nistere d. F or patie nts wit h n o n -meas urea ble disease, T G val ues o btai ne d 
o utsi de t his wi n d o w ma y be all o we d if re peat meas ure me nts were re q uire d t o e ns ure t he t his 
val ue was o btai ne d i n t he c o nte xt of a T S H <  0. 4 .). 
 
A patie nt will be classifie d as a res p o n der if t he y ha ve a partial or c o m plete res p o nse at t he 6-
m o nt h ti me p oi nt w he n c o m pare d t o t he baseli ne, pre -st u d y ra di ol o gic sca n(s) acc or di n g t o t he 
criteria o utli ne d i n Secti o n 1 1. 0  (c o nfir mati o n of res p o nse is n ot re q uire d) . T he pr o p orti o n of 
patie nts wit h a res p o ns e will be calc ulate d a n d c o m pare d bet wee n t he 2 ar ms usi n g a C hi -s q uare 
or Fis her’s E xact test.  All eli gi ble patie nts w h o are ra n d o mize d a n d be gi n treat me nt will be 
e val ua ble f or t he pri mar y e n d p oi nt.  
 
It is p ossi ble t hat patie nts will ha ve cli nical, ra di ol o gic, or bi oc he mical e vi de nce of disease 
pr o gressi o n earl y i n t he st u d y a n d still de m o nstrate be nefit fr o m t he st u d y treat me nt later i n t he 
st u d y f or se veral reas o ns: 1) sel u meti ni b al o ne pri or t o R AI ma y n ot ha ve si g nifica nt cli nical 
efficac y, 2) T h yr o ge n ™ sti m ulati o n ca n tra nsie ntl y i ncrease t u m or size w hic h ca n be mista ke n 
f or disease pr o gressi o n; 3) t he t hera pe utic effects of R AI ca n be dela ye d; a n d 4) e vi de nce of 
pr o gressi o n ma y be e vi de nt pri or t o a d mi nistrati o n of R AI. He nce, patie nts wit h e vi de nce of 
ra di o gra p hic or cli nical P D n ote d pri or t o t he 6 -m o nt h  ti me p oi nt assess me nt ma y re mai n o n 
st u d y a n d c o nti n ue t o recei ve treat me nt a n d/ or be e val uate d f or res p o nse at t he discreti o n of t he 
treati n g p h ysicia n. T he fi nal o bjecti ve res p o nse assess me nt  at 6 m o nt hs f or t hese patie nts will 
be base d u p o n a c o m paris o n bet wee n t he 6 -m o nt h ra di ol o gic sca n(s) (a n d ser u m t h yr o gl o b uli n, 


 
 
 
5 4  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
if a p plica ble) a n d t he baseli ne, pre -st u d y ra di ol o gic sca ns (a n d ser u m t h yr o gl o b uli n, if 
a p plica ble). H o we ver, if i n t he o pi ni o n of t he treati n g p h ysicia n t hese patie nts are u nli kel y t o 
de m o nstrate be nefit at t he 6 -m o nt h ti me p oi nt, t he patie nts will be c o nsi dere d t o ha ve ha d a 
pr o gressi o n/ deat h e ve nt, cate g orize d as n o n -res p o n ders, a n d ta ke n off t he st u d y. 
 
Patie nts w h o recei ve a d diti o nal treat me nt f or t heir t h yr oi d ca ncer o utsi de of t his pr ot oc ol pri or 
t o t he 6-m o nt h ti me p oi nt (e xce pt f or t h yr oi d h or m o ne T S H s u p pressi o n, palliati ve ra diati o n t o 
a n o n-tar get lesi o n, or t hera p y t o pre ve nt pat h ol o gic fract ures ca use d b y b o ne metastases (e. g. 
z ole dr o nic aci d a n d de n os u ma b)) will be c o nsi dere d n o n -res p o n ders. 
 
Fi n al A n al ysis f or Pri m ar y E n d p oi nt : T he pri mar y g oal is t o c o m pare 1 3 1I i n c o m bi nati o n 
wit h place b o or sel u meti ni b w here t he alter nati ve h y p ot hesis is t hat sel u meti ni b a n d 1 3 1I has a n 
i m pr o ve d c o nfir me d res p o nse rate c o m pare d t o  place b o pl us 1 3 1I. T we nt y -ei g ht  e val ua ble 
patie nts will be e nr olle d t o eac h ar m, f or 5 6 e val ua ble patie nts , t otal. Wit h t his sa m ple size, we 
will be a ble t o detect a si g nifica nt differe nce bet wee n a res p o nse rate of 4 0 % i n t he c o ntr ol 
gr o u p vs. 6 5 % i n t he e x peri me ntal gr o u p  ( o d ds rati o f or res p o nse of 2. 7 8 6, wit h 1-si de d t y pe I 
err or = 0. 1 5 a n d p o wer = 8 0 % ). All patie nts w h o meet t he eli gi bilit y criteria, si g n t he c o nse nt 
f or m, are ra n d o mize d, a n d start treat me nt will be e val ua ble.  
 
1 6. 3  
Sec o n dar y E n d p oi nts  
 
T he f oll o wi n g e n d p oi nts will be c o m pare d bet wee n t he 2 ar ms: best o verall res p o nse , 6- m o nt h 
pr o gressi o n -free s ur vi val, c ha n ge s i n ser u m t h yr o gl o b uli n le vels, a n d a d verse e ve nt rates 
bet wee n t he 2 treat me nt  ar ms. All patie nts w h o meet t he eli gi bilit y criteria, si g n t he c o nse nt 
f or m, are ra n d o mize d, a n d start a n y treat me nt will be c o nsi dere d e val ua ble f or t he e n d p oi nts 
bel o w.  
 
Best o ver all res p o nse : T he best o verall res p o nse will be c o m pare d bet wee n t he t w o acc or di n g 
t o t he criteria o utli ne d i n Secti o n 1 1. 0. T his c o m paris o n will be d o ne usi n g a c hi -s q uare test. F or 
a patie nt t o be classifie d as a res p o nse, t he y nee d a partial or c o m plete res p o nse t hat is 
c o nfir me d at least 4 wee ks later a n yti me d uri n g t he st u d y.  
 
Pr o gressi o n -Free S ur vi v al : Pr o gressi o n -free s ur vi val ( P F S) is defi ne d as t he ti me fr o m st u d y 
e ntr y t o t he first of eit her disease pr o gressi o n or deat h fr o m a n y ca use, w here disease 
pr o gressi o n will be deter mi ne d base d o n criteria o utli ne d i n Secti o n 1 1 . 0. P F S will be esti mate d 
usi n g t he Ka pla n -Meier met h o d, w here t he l o g -ra n k test will be use d t o c o m pare t he 2 treat me nt 
ar ms. E vi de nce of pr o gressi o n n ote d  fr o m t he ti me of re gistrati o n t o wit hi n 6 m o nt hs after 1 3 1I 
t hera p y ma y be disre gar de d as a pr o gressi o n e ve nt if t he treati n g p h ysicia n feels it is reas o na ble 
acc or di n g t o t he rati o nale detaile d i n Secti o n 1 6. 2 . T he res p o nse assess me nt at 6 m o nt hs f or 
t hese patie nts will be base d u p o n a c o m paris o n bet wee n t he 6-m o nt h  ra di ol o gic sca n(s) a n d t he 
baseli ne,  pre -st u d y ra di ol o gic sca ns. I n a d diti o n, t he 6-m o nt h P F S rate will als o be c o m pare d 
bet wee n t he ar ms.  
 
Ser u m T h yr o gl o b uli n Le vels : C ha n ges i n t h yr o gl o b uli n will be assesse d. T he  Wilc o x o n Ra n k -
S u m test will be use d t o c o m pare t he c ha n ge s i n t h yr o gl o b uli n (pre -R AI a n d p ost -R AI) bet wee n 
t he t w o treat me nt ar ms. ( T his a nal ysis will n ot be p ossi ble f or patie nts wit h detecta ble 
t h yr o gl o b uli n a nti b o dies.) 
 
A d verse e ve nts : T he ma xi m u m gra de f or eac h t y pe of a d verse e ve nt will be s u m marize d usi n g 
C T C A E versi o n 4. 0. T he fre q ue nc y a n d perce nta ge of gra de 3 + a d verse e ve nts will be 
c o m pare d bet wee n t he 2 treat me nt ar ms. C o m paris o ns bet wee n ar ms will be ma de b y usi n g 
eit her t he C hi -s q uare or Fis her’s E xact test. 


 
 
 
5 5  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
 
1 6. 4  
Tra nslati o nal St u dies  
 
W e will e x pl ore t he ge n o mic a n d  tra nscri pt o mic la n dsca pe of R AI A t u m ors f or si g nat ures t hat 
c orrelate t o t hera pe utic be nefit ac hie ve d i n patie nts wit h R AI -a vi d rec urre nt a n d/ or metastatic 
t h yr oi d ca ncer treate d wit h 1 3 1I i n c o m bi nati o n wit h place b o or sel u meti ni b. E x pl orat or y 
a nal ysis will i ncl u de c orrelati n g res p o nse t o t u m or ge n ot y pes. All t u m ors will be e val uate d f or 
c o m m o n t h yr oi d ca ncer ge ne m utati o ns ( B R A F, R A S, PI K 3 C A, A K T, R E T/ P T C, 
P A X 8/ P P A R γ). Descri pti ve statistics a n d gra p hical tec h ni q ues will be use d t o s u m marize t his 
data b y  treat me nt ar m.  Gi ve n t he s mall sa m ple size, all t hese a nal yses will be c o nsi dere d 
h y p ot hesis ge nerati n g a n d e x pl orat or y.  
 
1 6. 5  
T otal Sa m ple Size  
 
A ma xi m u m of 5 6 e val ua ble patie nts ( 2 8  per ar m) will be accr ue d o nt o t his ra n d o mize d p hase II 
st u d y u nless the st u d y is cl ose d earl y f or e xcessi ve t o xicit y. We a nti ci pate accr ui n g a n 
a d diti o nal 5 % of patie nts t o acc o u nt f or i neli gi bilit y, ca ncellati o n, maj or treat me nt vi olati o n, or 
ot her reas o ns. T heref ore, ma xi m u m accr ual is 6 0 patie nts ( 3 0  per ar m).  
 
 
1 6. 6  
E x p ecte d Accr ual a n d Accr ual D urati o n  
 
T he e x pecte d accr ual rate is a b o ut 3  patie nts per m o nt h f or t he A C C R U gr o u p . Wit h t his accr ual 
rate, we e x pect t o fi nis h accr ual wit hi n a b o ut 2 0  m o nt hs, ass u mi n g we accr ue 6 0 t otal patie nts.  
 
1 6. 7  
A ntici pate d ti me t o st u d y c o m pleti o n  
 
We a ntici pate t hat t he st u d y will ta ke a p pr o xi matel y 3 years t o c o m plete . T his all o ws a 6 m o nt h 
f oll o w-u p f or t he fi nal patie nt e nr olle d, al o n g wit h data e ntr y, data clea n -u p, a n d a nal ysis.  
1 6. 8  
Data & Safet y M o nit ori n g  
 
T he pri nci pal i n ve sti gat or(s) a n d t he st u d y statisticia n will re vie w t he st u d y at  least t wice a year 
t o i de ntif y accr ual, a d verse e ve nt, a n d a n y e n d p oi nt pr o ble ms t hat mi g ht be de vel o pi n g. T he 
trial is m o nit ore d c o nti n uall y b y t he st u d y tea m w h o are n otifie d of e ver y gra de 4 a n d 5 e ve nt i n 
real ti me. T he Ma y o Cli nic Ca ncer Ce nter ( M C C C) Data Safet y M o nit ori n g B oar d ( D S M B) is 
res p o nsi ble f or re vie wi n g accr ual a n d safet y data f or t his trial at least t wice a year, base d o n 
re p orts pr o vi de d b y t he M C C C Statistical Office.  
 
T he st o p pi n g r ule s pecifie d bel o w is base d o n t he k n o wle d ge a vaila ble at st u d y de vel o p me nt. 
We n ote t hat t he A d verse E ve nt St o p pi n g R ule ma y be a dj uste d i n t he e ve nt of eit her ( 1) t he 
st u d y re-o pe ni n g t o accr ual after a n y te m p orar y s us pe nsi o n or ( 2) at a n y ti m e d uri n g t he 
c o n d uct of t he trial a n d i n c o nsi derati o n of ne wl y ac q uire d i nf or mati o n re gar di n g t he a d verse 
e ve nt pr ofile of t he treat me nt(s) u n der i n vesti gati o n. T he st u d y tea m ma y als o c h o ose t o 
s us pe n d accr ual beca use of u ne x pecte d a d verse e ve nt pr ofiles  t hat ha ve n ot cr osse d t he 
s pecifie d r ule bel o w. 
 
Accr ual will be te m p oraril y s us pe n de d t o t his st u d y if at a n y ti me we o bser ve e ve nts c o nsi dere d 
at least p ossi bl y relate d t o st u d y treat me nt (i.e., a n a d verse e ve nt wit h attri b ute s pecifie d as 
" p ossi ble", "pr o ba ble", or " defi nite") t hat satisf y a n y of t he f oll o wi n g criteria f or eac h ar m 
se paratel y: 
 


 
 
 
5 6  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
•  
If at a n y ti me, 6 of t he i nitial 2 0 treate d patie nts or 3 0 % or m ore of all patie nts (i.e. w he n 
accr ual is greater t ha n 2 0 patie nts) ha ve e x perie nce d a gra de 4 n o n -he mat ol o gic a d verse 
e ve nt. 
•  
If at a n y ti me, 2 of t he i nitial 2 0 treate d patie nts  or 1 0 % or m ore of all patie nts (i.e. w he n 
accr ual is greater t ha n 2 0 patie nts)  ha ve e x perie nc e d a gra de 5 a d verse e ve nt ( n o n -
pr o gressi ve disease).  
•  
I n a d diti o n, eac h gra de 5 eve nt will be re vie we d o n a case b y case basis i n a real ti me 
fas hi o n t o deter mi ne w het her st u d y accr ual s h o ul d be s us pe n de d. We ma y s us pe n d accr ual 
after j ust 1 gra de 5 A E, if nee de d , f or patie nt safet y. 
 
1 6. 9 a Accr ual M o nit ori n g St o p pi n g R ule  
 
Gi ve n t he e x pecte d accr ual rate is ar o u n d 4  patie nts per m o nt h, it is e x pecte d t hat t he st u d y will 
ta ke ar o u n d 2 5 m o nt hs t o f ull y accr ue. We pla n t o m o nit or t he accr ual c o nti n uall y a n d if we 
o nl y e n d u p accr ui n g 1 0  patie nts or less i n t he first year (after st u d y acti vati o n), we will 
c o nsi der st o p pi n g t he trial f or sl o w accr ual . 
 
1 6. 9 b  Pri mar y E n d p oi nt C o m pleti o n Ti me Esti mati o n ( F or cli nicaltrails. g o v re p orti n g):  
 
T he pri mar y e n d p oi nt is a c o m paris o n of t he c o nfir me d res p o nse rate  bet wee n t he 2 treat me nt 
ar ms, as disc usse d i n detail i n secti o n 1 6. 2. T he fi nal a nal ysis is e x pecte d t o ta ke place ar o u n d 
3 6  m o nt hs after t he st u d y be gi ns, s o we e x pect t he pri mar y e n d p oi nt c o m pleti o n ti me t o be 
ar o u n d 3 6  m o nt hs after st u d y acti vati o n.  
 
1 6. 9c  I ncl usi o n of W o me n a n d Mi n orities 
 
T his st u d y will be a vaila ble t o all eli gi ble patie nts, re gar dless of race, ge n der, or et h nic ori gi n. 
T here is n o i nf or mati o n c urre ntl y a vaila ble re gar di n g differe ntial effects of t his re gi me n i n 
s u bsets defi ne d b y race, ge n der, or et h nicit y, a n d t here is n o reas o n t o e x pect s uc h differe nces t o 
e xist. Base d o n pri or st u dies i n v ol vi n g si milar d isease sites, we e x pect a b o ut 2 5% of patie nts 
will be classifie d as  mi n orities b y race a n d a b o ut 5 5 % of patie nts t o be w o me n. E x pecte d sizes 
of racial b y ge n der s u bse ts are s h o w n i n t he f oll o wi n g ta ble: 
 
Accr u al T ar gets  
Et h nic C ate g or y  
Se x/ Ge n der  
Fe m ales  
M ales  
T ot al  
His pa nic or Lati n o  
 6  
5  
1 1  
N ot His pa nic or Lati n o  
2 7  
2 2  
4 9  
Et h nic C ate g or y: T ot al of all s u bjects  
3 3  
2 7  
6 0  
R aci al C ate g or y  
A merica n I n dia n or Ala s ka n Nati ve 
 0  
 0  
 0  
Asia n  
2  
1  
3  
Blac k or Africa n A merica n  
6  
5  
1 1  
Nati ve Ha waiia n or ot her Pacific Isla n der  
 1  
 0  
 1  
W hite  
2 4  
2 1  
4 5  
R aci al C ate g or y: T ot al of all s u bjects  
3 3  
2 7  
6 0  
 


 
 
 
5 7  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
Et h nic 
C ate g ories:  
His p a nic or L ati n o –  a pers o n of C u ba n, Me xica n, P uert o Rica n, S o ut h or 
Ce ntral A merica n, or ot her S pa nis h c ult ure or ori gi n, re gar dless of race. 
T he ter m “ S pa nis h ori gi n” ca n als o be use d i n a d diti o n t o “ His pa nic or 
Lati n o.”  
 
N ot His p a nic or L ati n o  
 
R aci al 
C ate g ories:  
A meric a n I n di a n or Al as k a n N ati ve –  a pers o n ha vi n g ori gi ns i n a n y of 
t he ori ginal pe o ples of N ort h, Ce ntral, or S o ut h A merica, a n d w h o 
mai ntai ns tri bal affili ati o ns or c o m m u nit y attac h me nt. 
Asi a n –  a pers o n ha vi n g ori gi ns i n a n y of t he ori gi nal pe o ples of t he Far 
East, S o ut heast Asia, or t he I n dia n s u bc o nti ne nt i ncl u di n g, f or e xa m ple, 
Ca m b o dia, C hi na, I n dia, Ja pa n, K orea, Mala ysia, Pa kista n, t he P hili p pi ne 
Isla n ds, T haila n d, a n d Viet na m. ( N ote: I n di vi d uals fr o m t he P hili p pi ne 
Isla n ds ha ve bee n rec or de d as Pacific Isla n ders i n pre vi o us data c ollecti o n 
strate gies.)  
Bl ac k or Afric a n A meric a n –  a pers o n ha vi n g ori gi ns i n a n y of t he blac k 
racial gr o u ps of Africa. Ter ms s uc h as “ Haitia n” or “ Ne gr o” ca n be use d i n 
a d diti o n t o “ Blac k or Africa n A merica n.”  
N ati ve H a w aii a n or ot her P acific Isl a n der –  a pers o n ha vi n g ori gi ns i n 
a n y of t he ori gi nal pe o ples of Ha waii, G ua m, Sa m oa, or ot her Pacific 
Isla n ds. 
W hite –  a pers o n ha vi n g ori gi ns i n a n y of t he ori gi nal pe o ples of E ur o pe, 
t he Mi d dle East, or N ort h Africa. 
 
 
 


 
 
 
5 8  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
1 7. 0  
P at h ol o g y C o nsi der ati o ns/ Tiss ue Bi os peci me ns  
 
1 7. 1  
Tiss ue Bi os peci me n S u b missi o n  
 
1 7. 1 1  
S u m mar y Ta ble of Tiss ue Bi os peci me ns f or T his Pr ot oc ol  
 
T y pe of tiss ue 
bi os peci me n t o s u b mit  
M a n d at or y 
or o pti o n al  
W he n t o 
s u b mit 
Re as o n f or 
s u b missi o n 
( b ac k gr o u n d/ 
met h o d ol o g y 
secti o n) 
W her e t o 
fi nd s pecific 
det ails f or 
bi os peci me n 
s u b missi o n 
F or mali n -fi xe d paraffi n-
e m be d de d ( F F P E) tiss ue 
bl oc ks wit h c orres p o n di n g 
H & E ( O R  ( 2 0) 5  micr o n - 
a n d ( 1 0)  1 0 -micr o n 
u nstai ne d sli des wit h 
c orres p o n di n g H & E)  
Ma n dat or y  
≤6 0  da ys  after 
re gistrati o n 
C orrelati ve 
st u dies 
( Secti o n 1 7.3 ) 
Secti o n 1 7. 2  
If a n i nstit uti o n is n ot a ble t o pr o vi de t he tiss ue, it d oes n ot ca use t he patie nt t o be i neli gi ble; 
h o we ver, t he c ollecti o n of t hese tiss ues is str o n gl y rec o m me n de d . 
 
1 7. 2  
Paraff i n E m be d de d Tiss ue Bl oc ks/ Sli des ( ma n dat or y f or researc h tiss ue) 
 
1 7. 2 1  
S u b mit o ne f or mali n fi xe d paraffi n -e m be d de d ( F F P E) t u m or tiss ue bl oc k fr o m t he 
p ri mar y or rec urre nt/ metastatic t h yr oi d ca ncer. A c orres p o n di n g H & E sli de fr o m t he 
s u b mitte d bl oc k m ust be pr o vi de d t o per mit q ualit y assess me nt ( Q A) of tiss ue bl oc k.  
 
1 7. 2 2  
T he F F P E tiss ue bl oc k is preferre d; h o we ver, if a n i nstit uti o n is u na ble t o pr o vi de a 
tiss ue bl oc k, c ut 2 0 fi ve-micr o n u nstai ne d sli des a n d m o u nt o n c har ge d glass sli des 
a n d 1 0 te n -micr o n  u nstai ne d sli des m o u nte d o n u nc har ge d sli des. L a bel t he sli des 
wit h t he A C C R U p atie nt I D n u m ber, accessi o n n u m ber, a n d or der of secti o ns 
(i.e., 1-1 1) .  D o n ot use stic k y l a bels o n t he sli des. H & E st ai n t he first c ut sli de 
(i.e., sli de l a bele d 1). F or sa m p les c o ntai ni n g less t ha n 7s q uare milli meters of t u m or 
tiss ue, m ulti ple secti o ns s h o ul d be m o u nte d o nt o eac h sli de t o e ns ure t hat t he 
a p pr o priate a m o u nt of t u m or tiss ue is a vaila ble. I deall y, eac h sli de m ust ha ve a 
mi ni m u m of 7 5 % t u m or tiss ue o n t he sli de t o be dee me d a de q uate f or st u d y. D o n ot 
b a ke or pl ace c o ver sli ps o n t he sli des.   
 
1 7. 2 3  
T he f oll o wi n g materials bel o w are ma n dat or y ( u nless i n dicate d ot her wise) a n d 
re q uire d f or s hi p me nt: 
 
•  
Paraffi n e m be d de d tiss ue bl oc ks wit h c orres p o n di n g H & E ( or 3 0 sli de s per 
i nstr ucti o ns i n secti o n 1 7. 2 2) 
•  
Researc h Tiss ue S peci me n S u b missi o n F or m  
•  
S ur gical Pat h ol o g y Re p ort  ( D o n ot re dact t he accessi o n n u m ber(s)) 
•  
O perati ve Re p ort -O pti o nal  


 
 
 
5 9  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
1 7. 2 4  
S hi p all bl oc k/sli de tiss ue s peci me ns a n d acc o m pa n yi n g materials t o t he f oll o wi n g:  
 
A C C R U O perati o ns Office  
Att n: P C Office ( St u d y R U 2 4 1 3 0 6 I) 
 
 
 
 
1 7. 3  
St u d y Met h o d ol o g y a n d St ora ge  I nf or mati o n 
 
1 7. 3 1  
S u b mitte d tiss ue sa m ples will be a nal yze d as f oll o ws:  
 
1 7. 3 1 1  
F F P E t u m or  tiss ue bl oc ks/ u nstai ne d sli des will be c ollecte d i n searc h of 
bi o mar kers t hat ma y c orrelate t o cli nical res p o nses t o eit her  1 3 1I i n 
c o m bi nati o n wit h place b o or sel u meti ni b. T o ma xi mize t he i nf or mati o n 
gar nere d fr o m li mite d arc hi val tiss ues , hi g hl y se nsiti ve arra y-base d 
tec h n ol o gies will be use d t o  q ua ntif y t he ge ne e x pressi o n a n d se q ue nce  of  
ca ncer ge nes. 
 
We will is olate R N A fr o m t he tiss ues f or i nterr o gati o n wit h a c ust o m-
desi g ne d Na n ostri n g platf or m f or t w o p ur p oses: a) Detecti o n of f usi o n 
o nc o ge nic tr a nscri pts (t hat ca n n ot be detecte d b y a n e x o n -ca pt ure met h o d), 
a n d b) T o meas ure m R N A le vels of t hree maj or classes of tra nscri pts: 1) 
Mar kers of t he M A P K pat h wa y tra nscri pti o nal o ut p ut (e. g. Et v 1, Et v 4, 
Et v 5, S pr y 2, S pr y 4, D us p 6); 2) Ge nes re q uire d f or t h yr oi d h or m o ne 
bi os y nt hesis (e. g. N k x 2. 1, Pa x 8, F o xe 1, T g, T p o, Ts h R, Nis, Pe n dri n, 
Di o 2); a n d 3) P ossi ble deter mi na nts of i ntri nsic resista nce t o t hera p y, 
i ncl u di n g a da pti ve res p o nses t o M A P K pat h wa y i n hi biti o n t hat ha ve 
alrea d y  bee n  f o u n d t o be rele va nt for B R A F M U T t u m ors (i.e. ne ure g uli n 
me diate d acti vati o n of H E R 3 ki nase) : e. g. Nrg 1 (a n d ot her R T K li ga n ds), 
Her 2, Her 3, T G F β R 2). T he  assa y will i nterr o gate ~ 2 0 0 tra nscri pts, of 
w hic h o nl y a fe w e xa m ples of eac h class are liste d a b o ve.  
 
E x pressi o n of a pa nel of c yt o kerati ns , a m o n g ot her ge nes, will be use d t o 
sta n dar dize f or e pit helial cell c o nte nt i n t he bi o ps y material.   
 
A p orti o n of t he t u m or will be pr ocesse d f or D N A e xtracti o n usi n g sta n dar d 
la b orat or y pr ot oc ols. A p pr o xi matel y 2 0 0 n g D N A is olate d fr o m arc hi val 
sa m ples will be a nal yze d b y e x o n ca pt ure-base d ne xt ge nerati o n 
se q ue ncin g of a c ust o m pa nel of a p pr o xi matel y 3 0 0 ca ncer ge ne e x o mes or 
m ore, w hic h i nc or p orates all k n o w n t h yr oi d ca ncer o nc o ge nes a n d t u m or 
s u p press ors. Ge n o mic D N A fr o m t he 1 0 ml bl o o d dra w will be use d as a 
ger mli ne c o m parat or t o ai d i n i de ntif yi n g t u m or s peci fic alterati o ns. 
Acc or di n g t o patie nt c o nse nt i nf or mati o n, re mai ni n g D N A will be st ore d 
fr oze n at -7 0º C  b y B A P. As pr ot oc ols are de vel o pe d, t he y will be prese nte d 
f or A C C R U, I R B, a n d I T O G re vie w a n d a p pr o val. 
 
Gi ve n t he fast -pace d de vel o p me nt of ge n o mic a n d tra nscri pt o mic 
platf or ms, it is p ossi ble t hat b y t he ti me tiss ues fr o m t his st u d y are a vaila ble 
f or a nal ysis, m ore a d va nce d D N A a n d R N A a nal ytic tec h ni q ues f or F F P E 
tiss ues (e. g., w h ole e x o me, w h ole ge n o me, R N Ase q, etc.) ma y be a vaila ble 
a n d preferre d o ver t he a p pr oac h detaile d a b o ve.  If s o, t he st u dies disc usse d 


 
 
 
6 0  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
a b o ve ma y be perf or me d o n o ne of t hese ne wer platf or ms t o i n vesti gate t he 
o verall ai m of i de ntif yi n g mar kers t hat c orrelate t o cli nical efficac y.  
 
All a nal yses of t he arc hi val t u m or tiss ue will  be perf or me d b y Dr. Ja mes 
Fa gi n, Me m orial Sl oa n -Ketteri n g Ca ncer Ce nter ( Ne w Y or k, Ne w Y or k) . 
 
1 7. 3 2  
At t he c o m pleti o n of t he st u d y, a n y u n use d/re mai ni n g material will be st ore d i n t he 
A C C R U Ce ntral O perati o ns Office (att n: Pat h ol o g y C o or di nat or) f or f ut u re researc h 
acc or di n g t o  t he patie nt c o nse nt per missi o n. P ote ntial f ut ure researc h ma y i ncl u de 
i m m u n o hist oc he mistr y (I H C) a nal yses, D N A e xtracti o n, R N A e xtracti o n, a n d/ or 
tiss ue micr oarra y ( T M A) c o nstr ucti o n t o a nal yze pre dicti ve bi o mar kers, c ha n ges i n 
e x p ressi o n patter n wit h t hera p y, a n d c orrelati o n wit h res p o nse a n d/ or a d verse e ve nts. 
F or T M As, t he d o n or bl oc k re mai ns i ntact e xce pt f or 6 s mall ( 0. 6 m m) h oles w here 
t he c ores were ta ke n. T his pr ocess has mi ni mal i m pact o n t he utilit y of t he bl oc k f or 
f ut ure cli nical dia g n ostic nee ds. W he n a pr ot oc ol is de vel o pe d, it will be prese nte d f or  
A C C R U,  I R B a n d I T O G re vie w a n d a p pr o val. (T hese s peci me ns ma y o nl y be use d 
s u bse q ue ntl y f or I T O G-a p pr o ve d researc h pr ot oc ols .) 
 
1 7. 3 4  
T he i nstit uti o nal pat h ol o gist will be n o tifie d b y t he A C C R U O perati o ns Office 
( Pat h ol o g y C o or di nat or) if t he bl oc k ma y be de plete d. 
 
1 7. 3 5  
Bl oc ks re q ueste d t o acc o m m o date i n di vi d ual patie nt ma na ge me nt will be ret ur ne d 
pr o m ptl y u p o n re q uest.  
 
1 7. 4  
Ret ur n of Ge netic Testi n g Researc h Res ults  
 
Beca use t he res ults ge nerate d b y t he ge netic testi n g i ncl u de d i n t his secti o n are n ot c urre ntl y 
a ntici pate d t o ha ve cli nical rele va nce t o t he patie nt or t heir fa mil y me m bers, t he ge netic res ults 
will n ot be discl ose d t o t he patie nts or t heir p h ysicia ns.  
 
If, at a n y ti me, ge netic res ults are o btai ne d t hat ma y ha ve cli nical rele va nce, I R B re vie w a n d 
a p pr o val will be s o u g h re gar di n g t he m ost a p pr o priate ma n ner of discl os ure a n d w het her or n ot 
vali dati o n i n a C LI A certifie d setti n g will be re q uire d. S hari n g of rese arc h data wit h i n di vi d ual 
patie nts s h o ul d o nl y occ ur w he n data ha ve bee n vali date d b y m ulti ple st u dies a n d testi n g has 
bee n d o ne i n C LI A -a p pr o ve d la b orat ories.  
 


 
 
 
6 1  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
1 8. 0  
Rec or ds a n d D at a C ollecti o n Pr oce d ures  
 
All data m ust be e ntere d b y Re m ote Date E ntr y ( R D E) a n d c o m plete d b y q ualifie d a n d a ut h orize d 
pers o n nel. Access t he R A V E R D E s yste m t hr o u g h t he i Me di data p ortal at htt ps://l o gi n.i me di data.c o m . 
All data o n t he C R F m ust reflect t he c orres p o n di n g s o urce d oc u me nt. Please refer t o t he A C C R U 
we bsite f or i nstr ucti o ns 
N O T E: All re p orts m ust be de -i de ntifie d a n d la bele d 
wit h t he st u d y n u m ber, A C C R U patie nt I D n u m ber a n d i nitials.  
 
1 8. 1  
S u b missi o n Ti meta ble  
 
I niti al M ateri al(s)  
C R F  
Acti ve -M o nit ori n g P h ase  
( C o m plia nce wit h Test Sc he d ule Secti o n 4. 0) 
O n -St u d y  
2 wee ks  after re gistrati o n  
Baseli ne A d verse E ve nt  
R E CI S T Meas ure me nt –  Baseli ne  
Researc h Bl o o d S u b missi o n –  Baseli ne (see 
Secti o n 1 4. 0)  
Rese arc h Tiss ue S u b missi o n - Baseli ne  (see 
Secti o n 1 7. 0) 2  
E n d ocri ne La b orat or y - Baseli ne   
O P a n d Pat h Re p orts (see Secti o n 1 7. 0) 1 
E n d of Acti ve Treat me nt/ Ca ncel N otificati o n F or m  
S u b mit 2 w ee ks  after re gistrati o n if 
wit h dra wal/ref usal occ urs pri or t o b e gi n ni n g 
pr ot oc ol t hera p y  
1.  Attac h  a c o p y of O P a n d pat h re p orts i n R A V E usi n g t he S u p p orti n g D oc u me ntati o n F or m f or 
d oc u me ntati o n of disease.  T his is i n a d diti o n t o t he pat h ol o g y material re q uire me nts f or tiss ue 
s u b missi o n ( Secti o n 1 7. 0). 
2.  As per Sec ti o n 1 7. 0, researc h tiss ue bi os peci me n s h o ul d be s u b mitte d ≤ 6 0 da ys after re gistrati o n. 
 
 


 
 
 
6 2  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
Test Sc he d ule M ateri al(s)  
C R F  
Acti ve -M o nit ori n g P h ase  
( C o m plia nce wit h Test Sc he d ule Secti o n 4. 0) 
At eac h e val uati o n 
d uri n g treat me nt  
At e n d of 
treat me nt 
O bser va ti o n 
E val uati o n/ Treat me nt  
X 3  
X  
 
E val uati o n/ O bser vati o n  
 
 
X  
Na dir/ A d verse E ve nt  
X  
X  
X 2 
R E CI S T  Meas ure me nt 
 
 
 
X 1 
E n d ocri ne La b orat or y   
 
 
X  
R T Material  
 
X  
 
E n d of Acti ve Treat me nt/ Ca ncel N otificati o n   
X  
 
N otificati o n  –  Gra de 4 or 5 N o n -A E R 
Re p ort a ble E ve nts/ H os pitalizati o n  
At eac h occ urre nce  
(see Secti o n 1 0. 0) 
 
 
A D R/ A E R  
At eac h occ urre nce  
(see Secti o n 1 0. 0) 
 
 
1.  Attac h a c o p y i n R A V E f or d oc u me ntati o n of res p o nse or pr o gressi o n o n t he S u p p orti n g 
D oc u me ntati o n F or m . 
2.  C o m plete o nl y at 1 m o nt h p ost I -1 3 1 e val uati o n d uri n g O bser vati o n (see Secti o n 4. 0).  
3.  C o m plete at eac h e val uati o n d uri n g Acti ve Treat me nt (see Secti o n 4. 0).  
 
 
 
F oll o w -u p M ateri al(s)   
C R F  
E ve nt M o nit ori n g P h ase 1 
q. 3  m o nt hs 
u ntil P D  f or t he 
first 1 2 m o nt hs 
p ost -I1 3 1 
t hera p y a n d 
e ver y 6 m o nt hs 
after t hat 2  
At P D  
After P D  
q.  6  m os.  
Deat h  
Ne w Pri mar y  
E ve nt M o nit ori n g 2  
X  
X  
X  
X  
At eac h 
occ urre nce  
1.  If a patie nt is still ali ve 2  years after r a n d o mizati o n , n o f urt her f oll o w-u p is re q uire d.  
2.  A ttac h a c o p y i n R A V E f or d oc u me ntati o n o f pr o gressi o n o n t he S u p p orti n g D oc u me ntati o n F or m. 
 
 


 
 
 
6 3  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
1 9. 0  
B u d get  
 
1 9. 1  
C osts c har ge d t o patie nt:  
 
Eac h site s h o ul d re vie w t he test sc he d ule ( Secti o n 4. 0) ta ki n g i nt o acc o u nt l ocal a n d re gi o nal 
c o vera ge p olicies t o deter m i ne w hic h ite ms are sta n dar d of ca re a n d w hic h are researc h at t heir 
site. Refer t o t he pa y me nt s y n o psis f or f u n di n g pr o vi de d per accr ual f or c o veri n g st u d y c osts, as 
well as a n y a d diti o nal  i n v oicea bles t hat ma y be all o we d.  
 
1 9. 2  
Tests t o be researc h f u n de d:   Bl o o d a n d tiss ue c orrelati ve c ollecti o n a n d a nal ysis.  
 
1 9. 3  
Ot her b u d get c o ncer ns:  Place b o/sel u meti ni b pr o vi de d b y Astra Ze neca.  
 
 
2 0. 0  
Refere nces  
 
C ha kra vart y, D., Sa nt os, E., R y der, M., K na uf, J. A., Lia o, X. H., West, B. L., B olla g, G., K oles nic k, R., 
T hi n, T. H., R os e n, N., et al. ( 2 0 1 1). S mall-m olec ule M A P K i n hi bit ors rest ore ra di oi o di ne i nc or p orati o n 
i n m o use t h yr oi d ca ncers wit h c o n diti o nal B R A F acti vati o n. J Cli n I n vest 1 2 1 , 4 7 0 0-4 7 1 1.  
 
C o he n, Y., Xi n g, M., Ma m b o, E., G u o, Z., W u, G., Tri n k, B., Beller, U., Westra , W. H., La de ns o n, P. W., 
a n d Si dra ns k y, D. ( 2 0 0 3). B R A F m ut ati o n i n pa pillar y t h yr oi d carci n o ma. J Natl Ca ncer I nst  9 5 , 6 2 5-
6 2 7.  
 
De Vita, G., Ba uer, L., da C osta, V. M., De Felice, M., Baratta, M. G., De Me n na, M., a n d Di La ur o, R. 
( 2 0 0 5). D ose-de pe n de nt i n h i biti o n of t h yr oi d differe ntiati o n b y R A S o nc o ge nes. M ol E n d ocri n ol 1 9 , 7 6-
8 9.  
 
D or n, R., K o p p, J., V o gt, H., Hei de nreic h, P., Carr oll, R. G., a n d G ulec, S. A. ( 2 0 0 3). D osi metr y -g ui de d 
ra di oacti ve i o di ne treat me nt i n patie nts wit h metastatic differe ntiate d th yr oi d ca ncer: lar gest safe d ose 
usi n g a ris k -a da pte d a p pr oac h. J N ucl Me d  4 4 , 4 5 1-4 5 6.  
 
D ura nte, C., Ha d d y, N., Ba u di n, E., Le b o ulle u x, S., Hartl, D., Tra va gli, J. P., Caill o u, B., Ricar d, M., 
L u m br os o, J. D., De Vat haire, F. , et al. ( 2 0 0 6). L o n g-ter m o utc ome of 4 4 4 patie nts wit h dista nt 
metastases fr o m pa pillar y a n d f ollic ular t h yr oi d carci n o ma: be nefits a n d li mits of ra di oi o di ne t hera p y. J 
Cli n E n d ocri n ol Meta b  9 1 , 2 8 9 2-2 8 9 9.  
 
D ura nte, C., P u xe d d u, E., Ferretti, E., M orisi, R., M oretti, S., Br u n o, R., Bar b i, F., A ve nia, N., Sci pi o ni, 
A., Verrie nti, A. , et al. ( 2 0 0 7). B R A F m utati o ns i n pa pillar y t h yr oi d carci n o mas i n hi bit ge nes i n v ol ve d 
i n i o di ne meta b olis m. J Cli n E n d ocri n ol Meta b 9 2 , 2 8 4 0-2 8 4 3.  
 
Eise n ha uer, E. A., T herasse, P., B o gaerts, J., Sc h wartz, L. H.,  Sar ge nt, D., F or d, R., Da nce y, J., Ar b uc k, 
S., G w yt her, S., M o o ne y, M. , et al. ( 2 0 0 9). Ne w res p o nse e val uati o n criteria i n s oli d t u m o urs: re vise d 
R E CI S T g ui deli ne ( versi o n 1. 1). E ur o pea n j o ur nal of ca ncer  4 5 , 2 2 8-2 4 7.  
 
Elisei, R., U g oli ni, C., Vi ola, D., L u pi, C., Bia gi ni, A., Gia n ni ni, R., R o mei, C., Micc oli, P., Pi nc hera, 
A., a n d Bas ol o, F. ( 2 0 0 8). B R A F( V 6 0 0 E) m utati o n a n d o utc o me of patie nts wit h pa pillar y t h yr oi d 
carci n o ma: a 1 5 -year me dia n f oll o w -u p st u d y. J Cli n E n d ocri n ol Meta b  9 3 , 3 9 4 3-3 9 4 9.  
 
Ha u ge n, B., Ale xa n der, E., Bi ble, K., D o hert y, G., Ma n del, S., Ni kif or o v, Y., et al. ( 2 0 1 5). 2 0 1 5 
A merica n T h yr oi d Ass ociati o n Ma na ge me nt G ui deli nes f or A d ult Patie nts wit h T h yr oi d N o d ules a n d 
Differe ntiate d T h yr oi d Ca ncer. T h yr oi d . E p u b a he a d of pri nt. 


 
 
 
6 4  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
 
Ha yes, D. N., L ucas, A. S., Ta n vet ya n o n, T., Krz yza n o ws ka, M. K., C h u n g, C. H., M ur p h y, B. A., Gil bert, 
J., Me hra, R., M o ore, D. T., S hei k h, A., et al. ( 2 0 1 2). P hase II efficac y a n d p har mac o ge n o mic st u d y of 
Sel u meti ni b ( A Z D 6 2 4 4; A R R Y -1 4 2 8 8 6) i n i o di ne -1 3 1 refract or y pa pillar y t h yr oi d carci n o ma wit h or 
wit h o ut f ollic ular ele me nts. Cli nical ca ncer researc h : a n official j o ur nal of t he A merica n Ass ociati o n 
f or Ca ncer Researc h 1 8 , 2 0 5 6-2 0 6 5.  
 
H o, A. L., Gre wal, R. K., Le b oe uf, R., S her ma n, E.J., Pfister, D. G., Dea n dreis, D., Pe ntl o w, K. S., 
Za nz o nic o, P. B., Ha q ue, S., Ga va ne, S. , et al. ( 2 0 1 3). Sel u meti ni b-e n ha nce d ra di oi o di ne u pta ke i n 
a d va nce d t h yr oi d ca ncer. T he Ne w E n gla n d j o ur nal of me dici ne  3 6 8 , 6 2 3-6 3 2.  
 
Ki m ura, E. T., Ni kif or o va, M. N., Z h u, Z., K na uf, J. A., Ni kif or o v, Y. E., a n d Fa gi n, J. A. ( 2 0 0 3). Hi g h 
pre vale nce of B R A F m utati o ns i n t h yr oi d ca ncer: ge netic e vi de nce f or c o nstit uti ve acti vati o n of t he 
R E T/ P T C -R A S -B R A F si g nali n g pat h wa y i n pa pillar y t h yr oi d carci n o ma. Ca ncer Res  6 3 , 1 4 5 4-1 4 5 7.  
Kir k w o o d, J. M., Bast h olt, L., R o bert, C., S os ma n, J. A., Lar ki n, J., Herse y, P., Mi d dlet o n, M. R., 
Ca ntari ni, M. V., Zaz uli na, V., Ke msle y, K. , et al. ( 2 0 1 1). P hase II, O pe n-La bel, Ra n d o mize d Trial of 
t he M E K 1/ 2 I n hi bit or Sel u meti ni b as M o n ot hera p y vers us Te m oz ol o mi de i n Patie nts wit h A dva nce d 
Mela n o ma. Cli nical ca ncer researc h : a n official j o ur nal of t he A merica n Ass ociati o n f or Ca ncer 
Researc h.  
 
Kl u b o -G wiez dzi ns ka, J., B ur ma n, K. D., Va n N ostra n d, D., Mete, M., J o n klaas, J., a n d Wart ofs k y, L. 
( 2 0 1 1a). Ra di oi o di ne Treat me nt of Metastatic T h yr oi d Ca ncer: Relati ve Efficac y a n d Si de Effect Pr ofile 
after Pre parati o n b y T h yr oi d H or m o ne Wit h dra wal Vs. Rec o m bi na nt H u ma n Ts h. T h yr oi d : official 
j o ur nal of t he A merica n T h yr oi d Ass ociati o n. 
 
Kl u b o -G wiez dzi ns ka, J., Va n N ostra n d, D., At ki ns, F., B ur ma n, K., J o n klaas, J., Mete, M., a n d 
Wart ofs k y, L. ( 2 0 1 1 b). Efficac y of d osi metric vers us e m piric prescri be d acti vit y of 1 3 1I f or t hera p y of 
differe ntiate d t h yr oi d ca ncer. J Cli n E n d ocri n ol Meta b  9 6 , 3 2 1 7-3 2 2 5.  
 
K na uf, J. A., a n d Fa gi n, J. A. ( 2 0 0 9). R ole of  M A P K pat h wa y o nc o pr otei ns i n t h yr oi d ca ncer 
pat h o ge nesis a n d as dr u g tar gets. C urr O pi n Cell Bi ol  2 1 , 2 9 6-3 0 3.  
 
K na uf, J. A., K ur o da, H., Bas u, S., a n d Fa gi n, J. A. ( 2 0 0 3). R E T/ P T C -i n d uce d de differe ntiati o n of 
t h yr oi d cells is me diate d t hr o u g h Y 1 0 6 2 si g nalin g t hr o u g h S H C -R A S -M A P ki nase. O nc o ge ne  2 2 , 4 4 0 6-
4 4 1 2.  
 
K ul kar ni, K., N ostra n d, D., At ki ns, F., Ai ke n, M., B ur ma n, K., & Wart ofs k y, L. ( 2 0 0 6). T he Relati ve 
Fre q ue nc y i n W hic h E m piric D osa ges of Ra di oi o di ne W o ul d P ote ntiall y O vertreat or U n dertreat 
Patie nts  W h o Ha ve Metastatic Well -Differe ntiate d T h yr oi d Ca ncer. T h yr oi d  1 6 , 1 0 1 9-1 0 2 3.  
 
Lee, J. H., Lee, E. S., a n d Ki m, Y. S. ( 2 0 0 7). Cli nic o pat h ol o gic si g nifica nce of B R A F V 6 0 0 E m utati o n i n 
pa pillar y carci n o mas of t he t h yr oi d: a meta -a nal ysis. Ca ncer  1 1 0 , 3 8-4 6.  
 
Li u, D., H u, S., H o u, P., Jia n g, D., C o n d o uris, S., a n d Xi n g, M. ( 2 0 0 7). S u p pressi o n of 
B R A F/ M E K/ M A P ki nase pat h wa y rest ores e x pressi o n of i o di de -meta b olizi n g ge nes i n t h yr oi d cells 
e x pressi n g t he V 6 0 0 E B R A F m uta nt. Cli nical ca ncer researc h : a n official j o ur nal of t he A merica n 
Ass ociati o n f or Ca ncer Researc h  1 3 , 1 3 4 1-1 3 4 9.  
 
Ma x o n, H. R., 3r d, E n glar o, E. E., T h o mas, S. R., Hertz ber g, V. S., Hi n nefel d, J. D., C he n, L. S., S mit h, H., 
C u m mi n gs, D., a n d A de n, M. D. ( 1 9 9 2). Ra di oi o di ne -1 3 1 t hera p y f or well -differe nti ate d t h yr oi d ca ncer -
-a q ua ntitati ve ra diati o n d osi metric a p pr oac h: o utc o me a n d vali dati o n i n 8 5 patie nts. J N ucl Me d  3 3 , 
1 1 3 2 -1 1 3 6.  


 
 
 
6 5  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
 
Ma x o n, H. R., T h o mas, S. R., Hertz ber g, V. S., Kereia kes, J. G., C he n, I. W., S perli n g, M.I., a n d Sae n ger, 
E. L. ( 1 9 8 3). Relati o n  bet wee n effecti ve ra diati o n d ose a n d o utc o me of ra di oi o di ne t hera p y f or t h yr oi d 
ca ncer. T he Ne w E n gla n d j o ur nal of me dici ne  3 0 9 , 9 3 7-9 4 1.  
 
Mazzaferri, E. L., a n d Kl o os, R. T. ( 2 0 0 1). Cli nical re vie w 1 2 8: C urre nt a p pr oac hes t o pri mar y t hera p y 
f or pa pillar y an d f ollic ular t h yr oi d ca ncer. J Cli n E n d ocri n ol Meta b  8 6 , 1 4 4 7-1 4 6 3.  
 
Ni kif or o v, Y. E., a n d Ni kif or o va, M. N. ( 2 0 1 1). M olec ular ge netics a n d dia g n osis of t h yr oi d ca ncer. Nat 
Re v E n d ocri n ol  7 , 5 6 9-5 8 0.  
 
Pe ntl o w, K. S., Gra ha m, M. C., La m brec ht, R. M., Da g hi g hia n , F., Bac harac h, S. L., Be n drie m, B., Fi n n, 
R. D., J or da n, K., Kalai gia n, H., Kar p, J. S. , et al. ( 1 9 9 6). Q ua ntitati ve i ma gi n g of i o di ne-1 2 4 wit h P E T. J 
N ucl Me d  3 7 , 1 5 5 7-1 5 6 2.  
 
P oc oc k SJ, Si m o n R.  Se q ue ntial Treat me nt Assi g n me nt wit h Bala nci n g f or Pr o g n osti c Fact ors i n t he 
C o ntr olle d Cli nical Trial. Bi o metrics 1 9 7 5; 3 1( 1): 1 0 3 -1 1 5.  
 
Ricarte -Fil h o, J. C., R y der, M., C hitale, D. A., Ri vera, M., He g u y, A., La da n yi, M., Ja na kira ma n, M., 
S olit, D., K na uf, J. A., T uttle, R. M. , et al. ( 2 0 0 9). M utati o nal pr ofile of a d va nce d pri mar y a n d metastatic 
ra di oacti ve i o di ne-refract or y t h yr oi d ca ncers re veals disti nct pat h o ge netic r oles f or B R A F, PI K 3 C A, 
a n d A K T 1. Ca ncer Res  6 9 , 4 8 8 5-4 8 9 3.  
 
Riesc o -Eiza g uirre, G., G utierrez -Marti nez, P., Garcia -Ca bezas, M. A., Nistal, M., a n d Sa ntist e ba n, P. 
( 2 0 0 6). T he o nc o ge ne B R A F V 6 0 0 E is ass ociate d wit h a hi g h ris k of rec urre nce a n d less differe ntiate d 
pa pillar y t h yr oi d carci n o ma d ue t o t he i m pair me nt of Na +/I - tar geti n g t o t he me m bra ne. E n d ocr Relat 
Ca ncer  1 3 , 2 5 7-2 6 9.  
 
Sa bra, M. M., D o mi n g uez, J . M., Gre wal, R. K., Lars o n, S. M., G h ossei n, R. A., T uttle, R. M., a n d Fa gi n, 
J. A. ( 2 0 1 3). Cli nical o utc o mes a n d m olec ular pr ofile of differe ntiate d t h yr oi d ca ncers wit h ra di oi o di ne -
a vi d dista nt metastases. J Cli n E n d ocri n ol Meta b  9 8 , E 8 2 9-8 3 6.  
 
S g o ur os, G., K ol bert, K. S., S hei k h, A., Pe ntl o w, K. S., M u n, E. F., Bart h, A., R o b bi ns, R.J., a n d Lars o n, 
S. M. ( 2 0 0 4). Patie nt -s pecific d osi metr y f or 1 3 1I t h yr oi d ca ncer t hera p y usi n g 1 2 4I P E T a n d 3 -
di me nsi o nal -i nter nal d osi metr y ( 3 D-I D) s oft ware. J N ucl Me d 4 5 , 1 3 6 6-1 3 7 2 . 
 
S oares, P., Tr o visc o, V., R oc ha, A. S., Li ma, J., Castr o, P., Pret o, A., Ma xi m o, V., B otel h o, T., Ser uca, 
R., a n d S o bri n h o -Si m oes, M. ( 2 0 0 3). B R A F m utati o ns a n d R E T/ P T C rearra n ge me nts are alter nati ve 
e ve nts i n t he eti o pat h o ge nesis of P T C. O nc o ge ne  2 2 , 4 57 8 -4 5 8 0.  
 
Tala, H., R o b bi ns, R., Fa gi n, J. A., Lars o n, S. M., a n d T uttle, R. M. ( 2 0 1 1). Fi ve -year s ur vi val is si milar 
i n t h yr oi d ca ncer patie nts wit h dista nt metastases pre pare d f or ra di oacti ve i o di ne t hera p y wit h eit her 
t h yr oi d h or m o ne wit h dra wal or rec o m bi na nt h u ma n T S H. J Cli n E n d ocri n ol Meta b  9 6 , 2 1 0 5-2 1 1 1.  
 
T h o mas, S. R., Ma x o n, H. R., a n d Kereia kes, J. G. ( 1 9 7 6). I n vi v o q ua ntitati o n of lesi o n ra di oacti vit y 
usi n g e xter nal c o u nti n g met h o ds. Me dical p h ysics  0 3 , 2 5 3-2 5 5.  
 
T uttle, R., Le b oe uf, R., R o b bi ns, R., Q uale y, R., Pe ntl o w, K., Lars o n, S., & C ha n, C. ( 2 0 0 6). E m piric 
ra di oacti ve i o di ne d osi n g re gi me ns fre q ue ntl y e xcee d ma xi m u m t olerate d acti vit y le vels i n el derl y 
patie nts wit h t h yr oi d ca ncer. J o ur nal of N uclear Me dici ne, 4 7 , 1 5 8 7-9 1.  
 
 


 
 
 
6 6  
R U 2 4 1 3 0 6I  
 
 
A d de n d u m 9  
Z h u, Z., Cia m pi, R. , Ni kif or o va, M. N., Ga n d hi, M., a n d Ni kif or o v, Y. E. ( 2 0 0 6). Pre vale nce of 
R E T/ P T C rearra n ge me nts i n t h yr oi d pa pillar y carci n o mas: effects of t he detecti o n met h o ds a n d ge netic 
heter o ge neit y. J Cli n E n d ocri n ol Meta b  9 1 , 3 6 0 3-3 6 1 0.  
 


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 1  of 1 7  
 
 
A C C R U I nf or m e d C o nse nt T e m pl ate f or C a ncer Tre at m e nt T ri als  
( E n glis h L a n g u a ge) 
 
* N O T E S F O R L O C A L I N V E S TI G A T O R S  
 
•  
T he g oal of t he i nf or me d c o nse nt pr ocess is t o pr o vi de pe o ple wit h s ufficie nt i nf or mati o n f or 
ma ki n g i nf or me d c h oices. T he i nf or me d c o nse nt f or m pr o vi des a s u m mar y of t he cli nical st u d y 
a n d t he i n di vi d ual's ri g hts as a researc h partici pa nt. It ser ves as a starti n g p oi nt f or t he necessar y 
e xc ha n ge of i nf or mati o n bet wee n t he i n vesti gat or a n d p ote ntial researc h partici pa nt. T his 
te m plate f or t he i nf or me d c o nse nt f or m is o nly o ne part of t he lar ger pr ocess of i nf or me d c o nse nt. 
F or m ore i nf or mati o n a b o ut i nf or me d c o nse nt, re vie w t he " Rec o m me n dati o ns f or t he 
De vel o p me nt of I nf or me d C o nse nt D oc u me nts f or Ca ncer Cli nical Trials" pre pare d b y t he 
C o m pre he nsi ve W or ki n g Gr o u p o n I nf o r me d C o nse nt i n Ca ncer Cli nical Trials f or t he Nati o nal 
Ca ncer I nstit ute.  T he We b site a d dress f or t his d oc u me nt is 
 
 
•  
A bla n k li ne, _ _ _ _ _ _ _ _ _ _, i n dicates t hat t he l ocal i n vesti gat or s h o ul d pr o vi de t he a p pr o priate 
i nf or mati o n bef ore t he d oc u me nt is re vie we d wit h t he pr os pecti ve researc h partici pa nt.  
 
•  
S u g gesti o n f or L oc al I n vesti gat ors: A n N CI pa m p hlet e x plai ni n g cli nical trials is a vaila ble f or 
y o ur patie nts.  T he pa m p hlet is e ntitle d: "If Y o u Ha ve Ca ncer … W hat Y o u S h o ul d K n o w a b o ut 
Cli nical Trials".  T his pa m p hlet ma y be or dere d o n t he N CI We b site at  
htt ps://cissec ure. nci. ni h. g ov/ nci p u bs/  or call 1 -8 0 0 -4 -C A N C E R ( 1 -8 0 0 -4 2 2 -6 2 3 7) t o re q uest a 
free c o p y.  
 
•  
O pti o nal feat ure f or L ocal I n vesti gat ors: Refere nce a n d attac h dr u g s heets, p har mace utical 
i nf or mati o n f or t he p u blic, or ot her material o n ris ks. C hec k wit h y o ur l ocal I R B re gar di n g re vie w 
of a d diti o nal materials.  
 
* T hese n otes f or i n vesti gat ors are i nstr ucti o nal a n d s h o ul d n ot be i ncl u de d i n t he i nf or me d c o nse nt 
f or m gi ve n t o t he pr os pecti ve researc h partici pa nt.  
 


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 2  of 1 7  
 
 
R a n d o mize d D o u ble -Bli n d P h ase II St u d y of R a di o acti ve I o di ne ( R AI)  i n C o m bi n ati o n wit h 
Pl ace b o or Sel u meti ni b  f or t he Tre at me nt of R AI-A vi d Rec urre nt/ Met ast atic T h yr oi d C a ncers  
 
T his is a n i m p ort a nt f or m. Ple ase re a d it c ar ef ully. It tells y o u w h at y o u need t o k n o w a b o ut t his 
rese arc h st u dy.  If y o u a gree t o t a ke p art i n t his st udy, y o u nee d t o si g n t his f or m.  Y o ur si g n at ure 
me a ns t h at y o u h ave bee n t ol d a b o ut t he  st u dy a n d w h at t he ris ks are. Y o ur si g n at ure o n t his f or m als o 
me a ns t h at y o u w a nt t o t a ke p ar t i n t his st u dy. 
 
T his is a cli nical tr ial, a t y pe of researc h st u d y. Y o ur st u d y d oct or will e x pla i n t he cli nical trial t o y o u. 
Cli nical trials i ncl u de o nl y pe o ple w h o c h o ose t o ta ke part. Please ta ke y o ur ti me t o ma ke y o ur decisi o n 
a b o ut ta ki n g part. Y o u ma y disc uss y o ur decisi o n  wit h y o ur frie n ds a n d fa mil y. Y o u ca n als o disc uss it 
wit h y o ur healt h care tea m. If y o u ha ve a n y q uesti o ns, y o u ca n as k y o ur st u d y d oct or f or m ore 
e x pla nati o n.  
 
Y o u are bei n g as ke d t o ta ke part i n t his researc h st u d y beca use y o u  ha ve t h yr oi d ca ncer t hat has s prea d 
a n d c o ul d p ote ntiall y be treate d wit h ra di oacti ve i o di ne.   
 
 
W h y is t his rese arc h st u d y bei n g d o ne ?  
 
T he p ur p ose of t his researc h st u d y is t o fi n d o ut if ra di oacti ve i o di ne is m ore effecti ve w he n use d i n 
c o m bi nati o n wit h t he st u d y dr u g, sel u meti ni b, f or t he treat me nt of t h yr oi d ca ncer t hat has s prea d.  
 
Ma n y t h yr oi d ca ncers a bs or b i o di ne. Beca use of t his, d oct ors ofte n gi ve ra di oacti ve i o di ne al o ne t o treat 
t h yr oi d ca ncer as part of sta n dar d practice. It is t h o u g ht t hat the m ore t h yr oi d t u m ors are a ble t o a bs or b 
ra di oacti ve i o di ne, t he m ore li kel y it is t hat t he ra di oacti ve i o di ne will ca use t h ose t u m ors t o s hri n k.   
 
T he g oal of t his st u d y is t o fi n d o ut if sel u meti ni b ca n hel p ra di oacti ve i o di ne w or k better i n patie nts 
w h ose t u m ors st ill a bs or b ra di oacti ve i o di ne. T o fi g ure t his o ut, treat me nt wit h ra di oacti ve i o di ne pl us a 
place b o i n o ne gr o u p of patie nts will be c o m pare d t o treat me nt wit h ra di oacti ve i o di ne pl us sel u meti ni b  i n 
a n ot her gr o u p of patie nts. A place b o is a n i nacti ve s u bsta nce t hat l o o ks t he sa me as, a n d is gi ve n t he sa me 
wa y as, t he acti ve st u d y dr u g bei n g teste d (sel u meti ni b, i n t his case).    
 
I n t his st u d y, y o u will get eit her t he ra di oacti ve i o di ne a n d a place b o, or t he ra di oacti ve i o di ne a n d 
sel u meti ni b. Y o u will n ot get b ot h. T he effects, g o o d a n d/ or ba d, of ra di oacti ve i o di ne pl us place b o or 
ra di oacti ve i o di ne pl us sel u meti ni b o n y o u a n d y o ur t h yr oi d ca ncer will be st u die d. 
 
 
H o w m a n y pe o ple will t a ke p art i n t he rese arc h st u d y ?  
 
A b o ut 6 0  pe o ple  will ta k e part i n t his st u d y. T hese pe o ple will be ra n d o ml y di vi de d i nt o t w o gr o u ps of 3 0 
pe o ple per gr o u p. O ne gr o u p will recei ve ra di oacti ve i o di ne pl us sel u meti ni b; t he ot her gr o u p will recei ve 
ra di oacti ve i o di ne pl us a place b o. 
 


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 3  of 1 7  
 
 
W h at will h a p pe n if I t a ke p ar t i n t his rese arc h st u d y ? 
 
 
Bef ore y o u be gi n t he st u d y …   
 
Y o u will nee d t o ha ve t he f oll o wi n g e xa ms, tests or pr oce d ures t o fi n d o ut if y o u ca n be i n t he st u d y. 
T hese e xa ms, t ests or pr oce d ures are part of re g ular ca ncer care a n d ma y be d o ne e ve n  if y o u do n ot j oi n 
t he st u d y. If y o u ha ve ha d s o me of t he m rece ntl y, t hey ma y n ot nee d t o be re peate d. T his will be u p t o 
y o ur st u d y d oct or.  
 
•  
Me dical hist or y a n d p h ysical e xa m, i ncl u di n g  p ulse, bl o o d press ure, hei g ht, wei g ht a n d a n 
assess me nt of h o w well y o u perf or m acti vities of dail y li vi n g.  
•  
R o uti ne bl o o d tests. A b o ut 2 teas p o o ns of bl o o d will be dra w n.  
•  
E ye e xa m.  
•  
A pre g na nc y test d o ne b y ta ki n g a bl o o d sa m ple fr o m a vei n i n y o ur ar m wit hi n 2 8 da ys of bei n g 
re gistere d o n t he st u d y (if y o u are a w o ma n of c hil d beari n g p ote ntial). 
•  
A meas ure me nt a n d e val uati o n of y o ur t u m or b y M RI a n d/ or C T sca n.  
•  
A n ec h ocar di o gra m a n d electr ocar di o gra m t o l o o k at y o ur heart a n d heart val ves t o see h o w well 
t he y are w or ki n g. 
•  
A c hec k t o see if a n y of t he si de effects t hat ma y be ca use d  b y t he st u d y dr u gs are alrea d y prese nt.  
 
 
D uri n g t he st u d y   
 
If t he e x a ms, tests a n d pr oce d ures s h o w t h at y o u c a n be i n t he st u d y, a n d y o u c h o ose t o t a ke p art, 
t he n y o u will nee d t he f oll o wi n g tests a n d proce d ures. T he y are p art of re g ul ar c a ncer c are. T h e y 
are bei n g d o ne m ore ofte n bec a use y o u are i n t his st u d y.  
 
•  
P h ysical e xa m, w hic h ma y i ncl u de p ulse, bl o o d press ure, wei g ht a n d a test of h o w well y o u 
perf or m acti vities of dail y li vi n g.  
•  
R o uti ne bl o o d tests. A b o ut 2 teas p o o ns of bl o o d will be dra w n.  
•  
Pre g na nc y test (if a p plica ble).  
 
 
Y o u will nee d t hese tests a n d pr oce d ures t h at are eit her bei n g teste d i n t his st u d y or bei n g d o ne t o 
see h o w t he st u d y is affecti n g y o ur b o d y. 
 
•  
P h ysical e xa m, w hic h ma y i ncl u de  p ulse, bl o o d press ure, wei g ht a n d a test of h o w we ll y o u 
perf or m acti vities of dail y li vi n g.  
•  
R o uti ne bl o o d tests. A b o ut 2 teas p o o ns of bl o o d will be dra w n.  
•  
A meas ure me nt a n d e val uati o n of y o ur t u m or b y M RI a n d/ or C T sca n.  
•  
Pre g na nc y test (if a p plica ble).  
 
 


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 4  of 1 7  
 
 
Rese arc h Tests  
 
•  
A bl o o d sa m ple f or researc h tes ts is re q uire d f or t his st u d y. Bef ore treat me nt starts, t he researc h 
bl o o d sa m ple will be ta ke n at t he sa me ti me as t he r o uti ne bl o o d sa m ples b y dra wi n g s o me bl o o d 
fr o m a vei n. A b o ut 2 a d diti o nal teas p o o ns of bl o o d will be dra w n. 
•  
Ma n dat or y t u m or tiss ue s u b m issi o n: T his st u d y als o i ncl u des researc h tests t hat will be perf or me d 
o n t u m or tiss ue sa m ples t hat y o u will pr o vi de. T hese sa m ples s h o ul d be tiss ues t hat were o btai ne d 
fr o m previ o us  s ur geries or bi o psies; n o a d diti o n al t u m or tiss ue will be t ake n fr o m y o u d uri n g t his 
st u dy.  
 
S o me of t he researc h tests d o ne o n t he researc h bl o o d a n d tiss ue sa m ples are ge netic tests. Beca use t hese 
ge netic tests are n ot use d f or re g ular me dical care, neit her y o u n or y o ur d oct or will be t ol d t he res ults of 
t he test(s).  T he test res ults will n ot be p ut i n y o ur me dical rec or d eit her. 
 
T here is m ore i nf or mati o n a b o ut t hese researc h tests at t he e n d of t his f or m.  
 
 
Y o u will be "r a n d o mize d " i nt o o ne of t he st u d y gr o u ps descri be d bel o w.  
 
Ra n d o mizati o n mea ns t hat y o u are p ut i nt o a gr o u p b y c ha nce, as i n t he fli p of a c oi n. A c o m p uter 
pr o gra m will place y o u i n o ne of t he st u d y gr o u ps.  Neit her y o u n or y o ur d oct or ca n c h o ose t he gr o u p y o u 
will be i n. Y o u will ha ve a n e q ual  c ha nce of  bei n g place d i n eit her gr o u p. I n t he e ve nt of a n e mer ge nc y, 
y o ur d oct or ma y c o ntact t he s p o ns or t o lear n w hic h gr o u p y o u ha ve bee n place d i n. T his is calle d 
“ u n bli n di n g”. 
 
Y o u will ta ke t he st u d y dr u g (sel u meti ni b  or place b o ) i n pill f or m, b y m o ut h, t w o ti mes e ver y da y 
be gi n ni n g o n da y o ne of t he first wee k , a n d c o nti n ue ta ki n g t his u ntil 2 da ys after y o u recei ve t he 
ra di oacti ve i o di ne (1 3 1I) t hera p y.  
 
After a b o ut  t w o wee k s of  treat me nt wit h sel u meti ni b or place b o , y o u will be as ke d t o start a l o w-
i o di ne diet f or t he 5 da ys bef ore t he pr ocess f or 1 3 1I t herap y is starte d.  Y o u will  c o nti n ue o n t he l o w -
i o di ne diet u ntil o ne da y after y o u recei ve t he 1 3 1I t hera p y. A sa m ple diet a n d i nstr ucti o ns will be 
pr o vi de d b y y o ur st u d y d oct or.   
 
After a b o ut  t hree wee ks of  treat me nt wit h sel u meti ni b or place b o , y o u will recei ve t w o i njecti o ns of 
T h yr o ge n ™ t o hel p t he t h yr oi d ca ncer cells  t o ta ke u p ra di oacti ve i o di ne. Y o u  will n ot nee d t o  st o p 
y o ur t h yr oi d h or m o ne re place me nt,  s o y o u s h o ul d n ot s uffer fr o m s y m pt o ms of h y p ot h yr oi dis m. 
After t he T h yr o ge n ™ i njecti o ns, y o u will be treate d wit h 1 3 1I. If y o u are y o u n ger t ha n 7 0 years ol d, 
y o u will recei ve a b o ut 1 5 0 m Ci of 1 3 1I.  If y o u are 7 0 years or ol der, y o ur d oct or will deci de w hat 
d ose , fr o m a b o ut 1 0 0 m Ci t o a b o ut 1 5 0 m Ci , w o ul d be a p pr o priate f or y o u.  L o wer d oses ma y be 
gi ve n if y o ur d oct or deter mi nes t his is safer f or y o u.  
 
Y o u will be as ke d t o kee p a dail y rec or d of w he n y o u ta ke t he st u d y me dicati o n ( Patie nt Me dicati o n 
Diar y), a n d e ver y da y write d o w n t he da y a n d ti me y o u ta ke t he me dicati o n. If y o u n otice a n y si de effects , 
y o u ca n i ncl u de t his i nf or mati o n i n t he C o m me nts secti o n of t he diar y.  
 
T hi n gs t o a v oi d w hile partici pati n g i n t his st u d y:  
 
•  
D o n ot s pe n d ti me i n t he s u n; if y o u d o s pe n d ti me i n t he s u n, o nl y sta y o ut f or a s h ort peri o d of 
ti me a n d be s ure t o use s u nscree n pr otecti o n. 


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 5  of 1 7  
 
 
•  
D o n ot d o nate bl o o d.  
•  
D o n ot use a vita mi n E s u p ple me nt.  
•  
D o n ot bec o me pre g na nt; b ot h males a n d fe males s h o ul d use c o ntr ace pti o n  w he n e n ga gi n g i n 
se x ual acti vit y w hile partici pati n g i n t his st u d y a n d f or u p t o 3 m o nt h after  ta ki n g t he last d ose of 
st u d y me dicati o n. 
•  
D o n ot breastfee d.  
 
St u d y C ale n d ar  
Y o u will t ake sel u meti ni b or pl ace b o ( 7 5 m g by m o ut h) t wice every d ay be gi n ni n g o n d ay 1 of week 1 
t hr o u g h 2 d ays f oll o wi n g 1 3 1I t her a py, ( a t ot al of a p pr oxi m ately 3 0 d ays) d uri n g t his st u dy. T he c h art 
bel o w s h o ws w h at will h a p pe n t o y o u d uri n g t he tre at me nt peri o d a n d f ut ure f oll o w -u p v isits as 
previ o usly ex pl ai ne d. T he left -h a n d c ol u m n s h o ws t he d ay i n t he st u dy peri o d a n d t he ri g ht -h a n d c ol u m n 
tells y o u w h at t o d o o n t h at d ay. 
 
Sel u meti ni b or Pl ace b o  
All P atie nts i n B ot h Gr o u ps 1 a n d 2  
D a y  
W h at y o u d o  
U p t o 2 8 da ys 
bef ore starti n g 
st u d y 
•  
Me dical hist or y a n d p h ysical e xa m, i ncl u di n g p ulse, bl o o d press ure, hei g ht, wei g ht 
a n d a n assess me nt of h o w well y o u perf or m acti vities of dail y li vi n g.  
•  
R o uti n e bl o o d tests.  
•  
Ma n dat or y researc h bl o o d sa m ple.  
•  
Pre g na nc y test (if a p plica ble).  
•  
E ye e xa m.  
•  
M RI a n d/ or C T sca n f or t u m or meas ure me nt.  
•  
Ec h ocar di o gra m a n d electr ocar di o gra m.  
•  
Ma n dat or y arc hi val tiss ue c ollecti o n. ( N O T E: Recei pt of arc hi val t u m or tiss ue is 
n ot  re q uire d f or st u d y re gistrati o n a n d i nitiati o n of t hera p y.) 
 
Wee k 1  
•  
Me dical hist or y a n d p h ysical e xa m, i ncl u di n g  bl o o d press ure, wei g ht a n d a n 
assess me nt of h o w well y o u perf or m acti vities of dail y li vi n g.  
•  
R o uti ne bl o o d tests. N O T E: t his d oes n ot nee d t o be re peate d if t he pre -re gistrati o n 
bl o o d w or k was d o ne wit hi n 7 da ys or less bef ore starti n g t he st u d y dr u g 
(sel u meti ni b or place b o).  
•  
Be gi n ta ki n g sel u meti ni b or place b o t wice eac h da y o n a n e m pt y st o mac h ( 1 h o ur 
bef ore or 2 h o urs after a meal), a p pr o x i matel y 1 2 h o urs a part wit h a glass of water. 
Kee p ta ki n g sel u meti ni b or place b o t wice eac h da y u ntil t he e n d of st u d y, u nless 
t ol d t o st o p b y y o ur healt h care tea m. 
•  
Eac h da y, i n t he Patie nt Me dicati o n Diar y, write d o w n w he n y o u ta ke t he st u d y 
me dicati o n a n d a n y si de effects y o u n otice.  


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 6  of 1 7  
 
 
Wee k 2  
•  
C o nti n ue ta ki n g sel u meti ni b or place b o t wice eac h da y o n a n e m pt y st o mac h ( 1 
h o ur bef ore or 2 h o urs after a meal), a p pr o xi matel y 1 2 h o urs a part wit h a glass of 
water. Kee p ta ki n g sel u meti ni b or place b o t wice eac h da y  u ntil t he e n d of st u d y, 
u nless t ol d t o st o p b y y o ur healt h care tea m.  
•  
Eac h da y, i n t he Patie nt Me dicati o n Diar y, write d o w n w he n y o u ta ke t he st u d y 
me dicati o n a n d a n y si de effects y o u n otice.  
Wee k 3  
•  
Be gi n l o w i o di ne diet ( 5 da ys bef ore treat me nt wit h T h y r o ge n™).  
•  
Me dical hist or y a n d p h ysical e xa m, i ncl u di n g bl o o d press ure, wei g ht a n d a n 
assess me nt of h o w well y o u perf or m acti vities of dail y li vi n g.  
•  
R o uti ne bl o o d tests.  
•  
C o nti n ue ta ki n g sel u meti ni b or place b o t wice eac h da y o n a n e m pt y st o mac h ( 1 
h o ur bef ore  or 2 h o urs after a meal), a p pr o xi matel y 1 2 h o urs a part wit h a glass of 
water. Kee p ta ki n g sel u meti ni b or place b o t wice eac h da y u ntil t he e n d of st u d y, 
u nless t ol d t o st o p b y y o ur healt h care tea m.  
•  
Eac h da y, i n t he Patie nt Me dicati o n Diar y, write d o w n w he n y o u ta ke t he st u d y 
me dicati o n a n d a n y si de effects y o u n otice.  
Wee k 4  
•  
Pre g na nc y test (if a p plica ble).  
•  
Recei ve t w o i njecti o ns of T h yr o ge n T M o ver t w o da ys.  
•  
Recei ve ra di oacti ve i o di ne t hera p y (1 3 1I t hera p y).  
•  
C o nti n ue ta ki n g sel u meti ni b or place b o t wice eac h da y o n a n e m pt y st o mac h ( 1 
h o ur bef ore or 2 h o urs after a meal), a p pr o xi matel y 1 2 h o urs a part wit h a glass of 
water. Kee p ta ki n g sel u meti ni b or place b o t wice eac h da y u ntil 2 da ys after y o u 
recei ve t he ra di oacti ve i o di ne t hera p y (1 3 1I t hera p y), u nless tol d t o st o p b y y o ur 
healt h care tea m.  
•  
Eac h da y, i n t he Patie nt Me dicati o n Diar y, write d o w n w he n y o u ta ke t he st u d y 
me dicati o n a n d a n y si de effects y o u n otice.  
•  
C o nti n ue t he l o w -i o di ne diet f or 1 da y after y o u recei ve t he ra di oacti ve i o di ne 
t hera p y (1 3 1I t hera p y).  
 
W he n I a m fi nis he d wit h tre at me nt  
 
W he n y o u fi nis h treat me nt, y o u will nee d t he f oll o wi n g tests a n d pr oce d ures t hat ar e part of re g ular 
ca ncer care. T he y are bei n g d o ne m ore ofte n beca use y o u are i n t his st u d y.   
 
 


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 7  of 1 7  
 
 
St u d y C ale n d ar F oll o wi n g C o m p leti o n of T her a p y 
 
W he n  
W h at y o u d o  
O ne m o nt h after 
recei vi n g 1 3 1I 
•  
Me dical hist or y a n d p h ysical e xa m, i ncl u di n g  p ulse, bl o o d press ure, hei g ht, 
wei g ht a n d a n assess me nt of h o w well y o u perf or m acti vities of dail y li vi n g.  
•  
R o uti ne bl o o d tests.  
•  
Assess me nt o f si de effects. 
E ver y 3 m o nt hs 
after recei vi n g 
1 3 1I 
•  
M RI a n d/ or C T sca n f or t u m or meas ure me nt.  
•  
T h yr oi d tests, i ncl u di n g t h yr o gl o b uli n.  
 
1 2 m o nt hs 
f oll o wi n g 1 3 1I, 
e ver y 6 m o nt hs 
u p t o 2 years 
after starti n g t he 
st u d y 
•  
M RI a n d/ or C T sca n f or t u m or meas ure me n t. 
•  
T h yr oi d tests, i ncl u di n g t h yr o gl o b uli n.  
 
 
 
H o w l o n g will I be i n t he rese arc h st u d y ?   
 
We will c o nti n ue t o f oll o w y o u f or u p t o 2 years fr o m t he date y o u were ra n d o mize d o n t he st u d y.  
 
 
C a n I st o p bei n g i n t he rese arc h st u d y ?  
 
Yes. Y o u c a n deci de t o s t o p at a n y ti me. Tell t he st u d y d oct or if y o u are t hi n ki n g a b o ut st o p pi n g or deci de 
t o st o p.  He or s he will tell y o u h o w t o st o p safel y.  
 
It is i m p orta nt t o tell t he st u d y d oct or if y o u are t hi n ki n g a b o ut st o p pi n g s o a n y ris ks fr o m t he sel u meti ni b 
can be  e val uate d b y y o ur d oct or. A n ot her reas o n t o tell y o ur d oct or t hat y o u are t hi n ki n g a b o ut st o p pi n g is 
t o disc uss w hat f oll o w-u p care a n d testi n g c o ul d be m ost hel pf ul f or y o u.  
 
T he st u d y d oct or ma y st o p y o u fr o m ta ki n g part i n t his st u d y at a n y ti me if he/ s he belie ves it is i n y o ur 
best i nterest; if y o u d o n ot f oll o w t he st u d y r ules; or if t he st u d y is st o p pe d.  
 
 
W h at si de effects or ris ks c a n I e x pect fr o m bei n g i n t he rese arc h st u d y ?  
 
Y o u ma y ha ve si de effects w hile o n t he st u d y. E ver y o ne ta ki n g part i n t he st u d y will be watc he d c aref ull y 
f or a n y si de effects. H o we ver, d oct ors d o n’t k n o w all t he  si de effects t hat ma y ha p pe n. Si de effect s ma y 
be mil d or ver y seri o us. Y o ur healt h care tea m ma y gi ve y o u me dici ne s t o hel p lesse n si de effects. Ma n y 
si de effects g o a wa y s o o n after y o u st o p ta ki n g t he sel u meti ni b. I n s o me cases, si de effects ca n be seri o us, 
l o n g lasti n g, or ma y ne ver g o a wa y. T here als o is a ris k of deat h.  
 
Y o u s h o ul d t al k t o y o ur st u dy d oct or a b o ut a ny si de effects t h at y o u h ave w h ile t a ki n g p art i n t he st u dy. 
 
 
 
 
 


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 8  of 1 7  
 
 
Ris ks a n d si de effects rel ate d t o sel u meti ni b i ncl u de t h ose w hic h are:  
 
Li kel y ris ks of Sel u meti ni b  (e ve nts occ urri n g gre ater t h a n 2 0 % of t he ti me) 
•  
L o ose st o ols ( Diarr hea)  
•  
Ur ge t o v o mit ( Na usea)  
•  
T hr o wi n g u p ( V o miti n g)  
•  
S welli n g of t he e x tre mities (ar ms a n d/ or le gs) 
•  
Feeli n g tire d ( Fati g ue)  
•  
Ac ne /s ki n ras h 
 
Less li kel y ris ks of Sel u meti ni b  (eve nts occ urri n g less t h a n or e q u al t o 2 0 % of t he ti me) 
•  
Decrease i n re d bl o o d cells, w hic h are t he o x y ge n carr yi n g cells, w hic h c o ul d ma ke y o u feel tire d  
( A ne mia) 
•  
Decrease i n w hite bl o o d cell ( ne utr o p hil) c o u nt a n d p ote ntial f or i ncrease d i nfecti o n ris k (se psis)  
•  
Decrease i n platelet cell c o u nt (re q uire d f or bl o o d cl otti n g)  
•  
Decrease i n l y m p h oc yte c o u nt (i n v ol ve d i n i m m u ne s yste m)  
•  
Bl urre d visi o n  
•  
S welli n g or feeli n g of f ull ness a n d ti g ht ness i n t he a b d o me n ( bell y) 
•  
Bell y pai n  
•  
Diffic ult y passi n g st o ol ( C o nsti pati o n)  
•  
Irritati o n or s ores i n t he m o ut h S welli n g of t he face  
•  
Fe ver   
•  
I ncrease d bl o o d le vel of a li ver e nz y me ( A L T/ S G P T) 
•  
I ncrease d bl o o d le vel of a li ver e nzy me ( A S T/ S G O T)  
•  
I ncrease d bl o o d le vels of p h os p hate 
•  
L oss of a p petite  (a n ore xia) 
•  
J oi nt pai n  
•  
Bac k pai n  
•  
Se nsati o n of li g ht hea de d ness, u nstea di ness, gi d di ness, s pi n ni n g or r oc ki n g ( Dizzi ness)  
•  
Hea dac he or hea d pai n  
•  
Feeli n gs of sa d ness, w ort hless ness, t h o u g hts o f s uici de or deat h ( De pressi o n) 
•  
Diffic ult y slee pi n g or falli n g aslee p   
•  
C o u g h  
•  
S h ort ness of breat h   
•  
Hair l oss   
•  
Dr y s ki n   
•  
Nail c ha n ges  
•  
Itc hi n g S ki n ras h wit h t he prese nce of mac ules (flat disc ol ore d area) a n d pa p ules (raise d b u m p)  
•  
Hi g h bl o o d press ure ( h y pertensi o n)  
•  
L o w bl o o d p otassi u m  
•  
I ncrease d le vels of creati ni ne p h os p h o ki nase/creati ni ne ki nase 
•  
S ki n i nfecti o ns (i n c o m bi nati o n wit h d oceta xel)  
•  
Oral st o matitis (i n c o m bi nati o n wit h d oceta xel), ( m o ut h blisters/s ores)  
•  
Dr y m o ut h  
 
R are b ut seri o us ris ks of Sel u meti n i b (eve nts occ urri n g less t h a n 2-3 % of t he ti me)  
•  
Decrease i n heart's a bilit y t o p u m p bl o o d d uri n g t he "acti ve" p hase of t he heart beat ( S yst ole)  a n d 
heart fail ure  


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 9  of 1 7  
 
 
•  
Pr o ble ms/ da ma ge wit h t he reti na p orti o n of t he e ye, w hic h ca n lea d t o bl urre d visi o n.  
•  
I ntesti nal perf orati o n (a h ole i n t he b o wel)  
•  
Ki d ne y i nj ur y  
•  
Li ver i nj ur y/fail ure  
•  
I nterstitial l u n g disease (i n c o m bi nati o n wit h d oceta xel) 
•  
P ne u m o nitis (i n c o m bi nati o n wit h d oceta xel)  
•  
P ne u m o nia (i n c o m bi nati o n wit h d oceta xel)  
•  
Fe brile ne utr o pe nia (i n c o m bi nati o n wit h  d oceta xel), ( Fe ver wit h da n ger o usl y l o w w hite bl o o d 
cell c o u nt) 
•  
L o w al b u mi n  
•  
Re pr o d ucti ve ris ks: A d verse effects o n offs pri n g gr o wt h a n d de vel o p me nt ( i ncl u di n g 
malf or mati o ns, cleft palate, e ye c ha n ges)  
 
W h en sel u meti ni b is us ed i n co m bi n ati o n wit h radi o acti ve i o di ne, t he n u m b er of  p atients wit h si de 
effects or t he stren g t h of s o me si de effects ass ociated wit h eit her treat ment m ay  b e i ncreased. W e d o n ot 
k n o w w h at t hese risk s may  b e. 
 
Earl y i nf or mati o n fr o m cli nical st u dies i n pe o ple of Asia n ori gi n, w hic h ha ve l o o ke d at   t he le vels of 
sel u meti ni b i n t he bl o o d, s u g gest t hat pe o ple of Asia n ori gi n ma y e x perie nce hi g her bl o o d le vels of 
sel u meti ni b t ha n ot her pe o ple (w h o are n ot of Asia n ori gi n). Hi g her le vels of sel u meti ni b i n t he bl o o d 
ma y ca use a greater a m o u nt of si de effects.  Y o ur St u d y D oct or will disc uss w het her t his i nf or mati o n has 
a n y effect o n y o ur partici pati o n i n t his st u d y.  
 
Re pr o d ucti ve ris ks:  Y o u s h o ul d n ot bec o me pre g na nt or fat her a ba b y w hile o n t his st u d y beca use t he 
dr u gs i n t his st u d y ca n af fect a n u n b or n ba b y. W o me n s h o ul d n ot breastfe e d a ba b y w hile o n t his st u d y. 
W o me n of c hil d -beari n g p ote ntial a n d me n m ust a gree t o use a de q uate  c o ntrace pti o n  pri or t o st u d y e ntr y, 
f or t he d urati o n of st u d y partici pati o n, a n d 6 m o nt hs after c o m pleti o n of ra di oacti ve i o di ne pl us eit her 
place b o or sel u meti ni b. A de q uate c o ntrace pti o n c o ul d be eit her 1) h or m o nal/ n o n -h or m o nal pill P L U S a 
barrier met h o d (e. g. male c o n d o m) or 2) t otal a bsti ne nce.   
 
Sel u meti ni b/ place b o ca ps ules c o ntai n vita mi n E. W hile ta ki n g st u d y  me dicati o n, y o u will be as ke d n ot t o 
ta ke a n y s u p ple me ntal vita mi n E beca use hi g h le vels of vita mi n E ca n i nterr u pt t he b o d y’s cl otti n g 
pr ocesses. If y o u are c urre ntl y ta ki n g a ntic oa g ula nt ( bl o o d cl otti n g s uc h as warfari n) me dicati o ns, 
a d diti o nal bl o o d te sts ma y be or dere d t o m o nit or y o ur cl otti n g a bilit y w hile y o u are ta ki n g st u d y 
me dicati o n if y o ur p h ysicia n feels it is necessar y. Y o ur p h ysicia n ma y als o a dj ust y o ur a ntic oa g ula nt 
me dicati o n d osa ge if necessar y.  
 
As wit h a n y me dicati o n, aller gic reacti o ns  are a p ossi bilit y 
 
T he ris ks of dra wi n g bl o o d i ncl u de pai n, br uisi n g or rarel y i nfecti o n at t he nee dle site.  
 
F or m ore i nf or m ati o n a b o ut risks a n d si de effects, ask y o ur st u dy d oct or.  
 
 
Are t here be nefits t o t a ki n g p art i n t he rese arc h st u d y ?  
 
Ta ki n g part  i n t his st u d y ma y or may n ot ma ke y o ur healt h better. W hile d oct ors h o pe usi n g sel u meti ni b 
i n a d diti o n t o ra di oacti ve i o di ne t hera p y will be m ore usef ul a gai nst ca ncer c o m pare d t o t he us ual 
treat me nt, t here is n o pr o of of t his yet. We d o k n o w t hat t he i nf or mati o n fr o m t his st u d y will hel p d oct ors 
lear n m ore a b o ut a d di n g sel u meti ni b t o ra di oacti ve i o di ne t hera p y as a treat me nt f or ca ncer. T his 


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 1 0  of 1 7  
 
 
i nf or mati o n c o ul d hel p f ut ure ca ncer patie nts. 
 
 


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 1 1  of 1 7  
 
 
W h at ot her c h oices d o I h a ve if I d o n ot t a ke p art i n t his rese ar c h st u d y ? 
Y o u d o n ot ha ve t o be i n t his st u d y t o recei ve treat me nt f or y o ur ca ncer.  
 
Y o ur ot her c h oices ma y i ncl u de:  
 
•  
Getti n g treat me nt or care f or y o ur ca ncer wit h o ut bei n g i n a st u d y  
•  
Ta ki n g part i n a n ot her st u d y  
•  
Getti n g n o treat me nt  
•  
Getti n g c o mf ort care , als o calle d palliati ve care. T his t y pe of care hel ps re d uce pai n, tire d ness, 
a p petite pr o ble ms a n d ot her pr o bl e ms ca use d b y t he ca ncer. It d oes n ot treat t he ca ncer directl y, b ut 
i nstea d tries t o i m pr o ve h o w y o u feel. C o mf ort care tries t o kee p y o u as act i ve a n d c o mf orta ble as 
p ossi ble.  
 
Tal k t o y o ur d oct or a b o ut y o ur c h oices bef ore y o u deci de if y o u will ta ke part i n t his st u d y.  
 
 
Will m y me dic al i nf or m ati o n be ke pt pri v ate ?  
 
We will d o o ur best t o ma ke s ure t hat t he pers o nal i nf or mati o n i n y o ur me dica l rec or d will be ke pt 
pri vate. H o we ver, we c a n n ot g uara ntee t otal pri vac y. Y o ur pers o nal i nf or mati o n ma y be  gi ve n o ut if 
re q uire d b y la w. If i nf or mati o n fr o m t his st u d y is p u blis he d or prese nte d at scie ntific meeti n gs, y o ur na me 
a n d ot her pers o nal i nf or mati o n  will n ot be use d.  
 
Als o, y o ur rec or ds ma y be re vie we d b y t he f oll o wi n g gr o u ps (as a p plica ble t o t he researc h):  
 
•  
Office f or H u ma n Researc h Pr otecti o ns or ot her fe deral, state, or i nter nati o nal re g ulat or y 
a ge ncies; 
•  
U. S. F o o d a n d Dr u g A d mi nistrati o n;  
•  
L ocal I nstit uti o nal Re vie w B oar ds; 
•  
P har mace utical c o m pa n y s u p p orti n g t he st u d y ( Astra Ze neca);  
•  
Y o ur i ns ura nce c o m pa n y (if c har ges are bille d t o i ns ura nce);  
•  
I nter nati o nal T h yr oi d O nc ol o g y Gr o u p (I T O G); 
•  
Aca de mic a n d C o m m u nit y Ca ncer Researc h U nite d ( A C C R U) C o or di na ti n g Ce nter. 
 
A descri pti o n of t his cli nical trial will be a vaila ble o n htt p:// w w w. Cli nical Trials. g o v , as re q uire d b y U. S. 
La w. T his We b site will n ot i ncl u de i nf or mati o n t hat ca n i de ntif y y o u. At m ost, t he We b site will i ncl u de 
a s u m mar y of st u d y res ults.  Y o u ca n searc h t his We b site at a n y ti me.  
 
Tests d o ne at h os pit als or cli nics ot her t h a n t he st u d y cli nic  
 
If y o u ha ve bl o o d tests or ot her me dical tests s uc h as sca ns or x-ra ys at a cli nic or h os pital ot her tha n t he 
st u d y cli nic [i nsert n a me of i nstit uti o n], y o ur st u d y d oct or ma y nee d t o re vie w res ults of t hese tests as 
t he y relate t o t his st u d y.  
 
Ple ase re a d t he f oll o wi n g st ate me nts a n d m ar k y o ur c h oice:  
 
I per mit  
 
 
 [i nvesti g at or’s n a me(s)] t o o btai n me dic al i nf or mati o n fr o m m y pri mar y 
care gi ver  
 
 
 
[pri m ary c are giver’s  n a me (s)] as it relates t o t his st u d y. T his 
ma y i ncl u de i nf or mati o n re gar di n g a n y bl o o d tests, x -ra ys or sca ns. 
 


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 1 2  of 1 7  
 
 
Will I be p ai d f or t a ki n g p art i n t his st u d y ?  
 
Y o u will n ot be pai d f or ta ki n g part i n t his st u d y.  
 
W h at are t he c osts of t a ki n g p art i n t his rese arc h st u d y ?  
 
Y o u a n d/ or y o ur healt h pla n/ i ns ura nce c o m pa n y will nee d t o pa y f or s o me or all of t he c osts of treati n g 
y o ur c a ncer i n t his st u d y. S o me healt h pla ns will n ot pa y t hese c osts  f or pe o ple ta ki n g part i n st u dies. 
C hec k wit h y o ur healt h pla n or i ns ura nce c o m pa n y t o fi n d o ut w hat t he y will pa y f or. Ta ki n g part i n t his 
st u d y ma y or ma y n ot c ost y o ur i ns ura nce c o m pa n y m ore t ha n t he c ost of ge tti n g re g ular ca ncer 
treat me nt. 
 
Tests s uc h as p h ysical e xa mi nati o ns, sca ns, T h yr o ge n ™, ra di oacti ve i o di ne, a n d r o uti ne bl o o d tests t hat 
w o ul d n or mall y be perf or me d as part of y o ur re g ular me dical care will be t he res p o nsi bilit y of y o u a n d 
y o ur healt h pla n.  
 
Y o u will n ot nee d t o pa y f or a n y tests  d o ne o nl y f or researc h. T his w o ul d i n v ol ve t he researc h st u dies 
d o ne o n t he bl o o d a n d tiss ue sa m ples.  
 
T he st u d y a ge nt, sel u meti ni b  or place b o , will be pr o vi de d free of c har ge w hile y o u are ta ki n g part i n t his 
st u d y. 
 
F or m ore i nf or m ati o n o n cli nic al tri a ls a n d i ns ur a nce c over a ge, y o u c a n visit t he N ati o n al C a ncer 
I nstit ute’s We b site at htt p://c a ncer. g ov/cli nic altri als/ u n derst a n di n g/i ns ur a nce -c over a ge  . Y o u c a n 
pri nt a c o py  of t he  “ Cli nic al Tri als a n d I ns ur a nce C over a ge ” i nf or m ati o n fr o m  t his We b site. 
 
A n ot her w ay t o get t he i nf or m ati o n is t o c all 1 -8 0 0 -4 -C A N C E R ( 1 -8 0 0 -4 2 2 -6 2 3 7) a n d as k t he m t o se n d 
y o u a free c o py. 
 
 
W h at h a p pe ns if I a m i nj ure d bec a use I t o o k p art i n t his  rese arc h st u d y ? 
 
It is i m p orta nt t hat y o u tell y o ur st u d y d oct or, _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ [i nvesti g at or’s n a me(s)], if y o u feel 
t hat y o u ha ve bee n i nj ure d beca use of ta ki n g part i n t his st u d y. Y o u ca n tell t he d oct or i n pers o n or call 
hi m/ her at _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ [tele p h o ne n u m ber]. 
 
Y o u will get me dical treat me nt if y o u are i nj ure d as a res ult  of ta ki n g part i n t his st u d y. Y o u a n d/ or y o ur 
healt h pla n will be c har ge d f or t his treat me nt.   T he st u d y will n ot pa y f or me dical treat me nt.   
 
 
W h at are m y ri g hts if I t a ke p art i n t his rese arc h st u d y ? 
 
Ta ki n g part  i n t his st u d y is y o ur c h oice. Y o u ma y c h o ose eit her t o ta ke part or n ot t o ta ke part i n t he 
st u d y. If y o u deci de t o ta ke part i n t his st u d y, y o u ma y lea ve t he st u d y at a n y ti me. N o matter w hat 
decisi o n y o u m a ke, t here will be n o pe nalt y t o y o u a n d y o u will n ot l ose  a n y of y o ur re g ular be nefits. 
Lea vi n g t he st u d y will n ot affect y o ur me dic al care. Y o u ca n still get y o ur me dic al care fr o m o ur 
i nstit uti o n. 
 
We will tell y o u a b o ut ne w i nf or mati o n or c ha n ges i n t h e st u d y t hat ma y affect y o ur healt h or y o ur 
willi n g ness t o c o nti n ue i n t he st u d y.  


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 1 3  of 1 7  
 
 
 
I n t he case of i nj ur y res ulti n g fr o m t his st u d y, y o u d o n ot l ose a n y of y o ur le gal ri g hts t o see k pa y me nt b y 
si g ni n g t his f or m. 
 
 
W h o c a n a ns wer m y q uesti o ns a b o ut t he rese a rc h st u d y ? 
 
Y o u ca n tal k t o y o ur st u d y d oct or a b o ut a n y q uesti o ns or c o nce r ns y o u ha ve a b o ut t his st u d y. C o ntact 
y o ur st u d y d oct or _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ [ n a me(s)] at _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ [tele p h o ne n u m ber]. 
 
 
F or q uesti o ns a b o ut y o ur ri g hts w hile t a ki n g p art i n  t his st u d y, c all t he _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
[ n a me of ce nter] I nstit uti o n al Re vie w B o ar d ( a gr o u p of pe o ple w h o re vie w t he rese arc h t o pr otect 
y o ur ri g hts) at _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  (tele p h o ne n u m ber). [ N ote t o L oc al I nvesti g at or: C o nt act 
i nf or m ati o n f or p atie nt re prese nt atives or ot her i n divi d u als i n a l oc al i nstit uti o n w h o are n ot o n t he 
I R B or rese arc h te a m b ut t a ke c alls re g ar di n g cli nic al tri al q uesti o ns c a n be liste d here.]    
 
Ple ase n ote:  T his secti o n of t he i nf or me d c o nse nt f or m is a b o ut a d diti o n al rese arc h st u dies t h at are 
bei n g d o ne wit h pe o ple w h o are t a ki n g p art i n t he m ai n st u d y. Y o u m a y t a ke p art i n t hese 
a d diti o n al st u dies if y o u w a nt t o. Y o u c a n still be a p art of t he m ai n st u d y e ve n if y o u s a y ‘ n o’ t o 
t a ki n g p art i n a n y of t hese a d diti o n al st u dies. 
 
 
Y o u c a n s a y “ yes ” or “ n o ” t o e ac h of t he f oll o wi n g st u dies. Ple ase m ar k y o ur c h oice f or e ac h st u d y.   
 
 
A b o ut Usi n g Bi ol o gic al S a m ples f or Rese arc h  
 
T his st u d y als o has la b orat or y tests t hat will be perf or me d t o st u d y s mal l sa m ples of bl o o d a n d tiss ue. A 
bl o o d sa m ple will be d o ne b y d ra wi n g s o me bl o o d fr o m a vei n. T he bl o o d will be ta ke n j ust bef ore 
treat ment starts. T he bi o ps y tiss ue sa m ple will  be fr o m y o ur ori gi nal bi o ps y. N o a d diti o nal bi o psies will 
be d o ne t o get t his tiss ue.  
 
T he bl o o d a n d t iss ue will be se nt t o A C C R U/I T O G la b orat ories w here t he tests will be d o ne. T hese tests 
will be d o ne i n or der t o u n dersta n d h o w y o ur  ca ncer res p o n ds t o treat me nt. It is h o pe d t hat t his will hel p 
i n vesti gat ors better un dersta n d y o ur t y pe of ca ncer. T he res u lts of t hese tests will n ot be se nt t o y o u or 
y o ur st u d y d oct or a n d will n ot be use d i n pla n ni n g y o ur care.  T hese tests are f or researc h p ur p oses o nl y 
a n d y o u will n ot ha ve t o pa y f or t he m.   
 
 
Ple ase re a d t he f oll o wi n g st ate me nts a n d m ar k y o ur c h oice:  
 
1.  I a gree t o pr o vi de bl o o d sa m ples t o A C C R U/I T O G la b orat ories f or researc h testi n g pla n ne d as part of 
t his st u d y: 
 
 
  Yes  
  N o   
Please i nitial here: _ _ _ _ _ _ _ _  
Date: _ _ _ _ _ _ _ _  
 
 
2. I a gree t o pr o vi de m y ori gi nal bi o ps y tiss u e sa m ple(s) t o A C C R U/I T O G la b orat ories ass ociate d wit h 
A C C R U, f or researc h testi n g pla n ne d as part of t his st u d y:  


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 1 4  of 1 7  
 
 
 
 
  Yes  
  N o   
Please i nitial here: _ _ _ _ _ _ _ _  
Date: _ _ _ _ _ _ _ _  
 
We w o ul d li ke t o kee p s o me of t he bl o o d a n d tis s ue t hat is left o ver f or f ut ure researc h. If y o u a gree, t hese 
sa m ples will be ke pt a n d ma y be use d i n researc h t o lear n m ore a bo ut ca ncer a n d ot her diseases. Please 
rea d t he b o o klet  calle d " Pr o vi di n g Y o ur Tiss ue F or Researc h: W hat Y o u Nee d T o K n o w " t o lear n m ore 
a b o ut tiss ue researc h . A c o p y of t his b o o klet ca n be f o u n d at: htt p:// w w w.ca ncer. g o v/ p u blicati o ns/ patie nt -
e d ucati o n/ pr o vi di n g -tiss ue. 
 
Y o ur bl o o d a n d tiss ue ma y be hel pf ul f or researc h w het her  y o u d o or d o n ot ha ve ca ncer. T he researc h 
t hat ma y be d o ne wit h y o ur bl o o d a n d tiss ue is n ot desi g ned s pecificall y t o hel p y o u. It mi g ht hel p pe o ple 
w h o ha ve ca ncer a n d ot her diseases i n t he f ut ure.  
 
Re p orts a b o ut resear c h d o ne wit h y o ur bl o o d a n d tiss ue will n ot b e gi ve n t o y o u or y o ur d oct or. T hese 
re p orts will n ot be p ut i n y o ur healt h rec or d. T he researc h will n ot ha ve a n effect o n y o ur care.  
 
 
T hi n gs t o T hi n k A b o ut  
T he c h oice t o let us kee p left o ver bl o o d a n d tiss ue f or  f ut ure researc h is u p t o y o u. N o matter w hat y o u 
deci de t o d o, it will n ot affect y o ur care.  
 
If y o u deci de n o w t hat y o ur bl o o d a n d tiss ue ca n be ke pt f or researc h, y o u ca n c ha n ge y o ur mi n d at a n y 
ti me. J ust c o ntact us a n d let us k n o w t hat y o u d o not wa nt us t o use y o ur tiss ue. T he n a n y bl o o d a n d tiss ue 
t hat re mai ns will no l o n ger be use d f or researc h.  
 
I n t he f ut ure, pe o ple w h o d o researc h ma y nee d to k n o w m ore a b o ut y o ur healt h. W hile A C C R U ma y 
gi ve t he m re p orts a b o ut y o ur healt h, it will n ot gi ve  t he m y o ur na me, a d dress, p h o ne n u m ber, or a n y ot her 
i nf or mati o n t hat will let t he researc hers k n o w w h o y o u are.  
 
S o meti mes bl o o d a n d tiss ue is use d f or ge netic researc h (a b o ut diseases t h at are passe d o n i n fa milies). 
E ve n if y o ur bl o o d a n d tiss ue  are us e d f or t his ki n d of researc h, t he res ults will n ot be p ut i n y o ur healt h 
rec or ds.  
 
Y o ur bl o o d a n d tiss ue will be use d o nl y f or researc h a n d will n ot be s ol d. T he researc h d o ne wit h y o ur 
bl o o d a n d tiss ue ma y hel p t o de vel o p ne w pr o d ucts i n t he f ut ure.  
 
 
B e nefits  
T he be nefits of researc h usi n g bl o o d a n d tiss ue  i ncl u de lear ni n g m ore a b o ut w hat ca uses ca ncer a n d ot her 
diseases, h o w t o pre ve nt t he m, a n d h o w t o treat t he m.   
 
 
Ris ks  
T he greatest ris k t o y o u is t he release of i nf or ma ti o n fr o m y o ur healt h rec or ds. We will d o o ur best t o 
ma ke s ure t hat y o ur pers o nal i nf or mati o n will be ke pt pri vate. T he c ha nce t hat t his i nf or mati o n will be 
gi ve n t o s o me o ne else is ver y s mall.  
 
 


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 1 5  of 1 7  
 
 
M a ki n g Y o ur C h oice  
Please rea d eac h se nte nce bel o w a n d t hi n k a b o ut y o ur c h oice. Afte r rea di n g eac h se nte nce, circle " Yes" or 
" N o". If y o u ha ve a n y q uesti o ns, please tal k t o y o ur d oct or or n urse, or call o ur researc h re vie w b oar d at 
[i nsert t he I R B's p h o ne n u m ber].  
 
N o matter w hat y o u deci de t o d o, it will n ot affect y o ur care.  
 
1. M y bl o o d ma y be ke pt f or use i n researc h t o lear n a b o ut, pre ve nt, or treat ca ncer.  
 
 
  Yes  
  N o   
Please i nitial here: _ _ _ _ _ _ _ _  
Date: _ _ _ _ _ _ _ _  
 
2. M y bl o o d ma y be ke pt f or use i n researc h t o lear n a b o ut, pre ve nt or treat ot her  healt h pr o ble ms (f or 
e xa m ple: dia betes, Alz hei mer's disease, or heart disease).  
 
 
  Yes  
  N o   
Please i nitial here: _ _ _ _ _ _ _ _  
Date: _ _ _ _ _ _ _ _  
 
3. M y tiss ue ma y be ke pt f or use i n researc h t o lear n a b o ut, pre ve nt, or treat  ca ncer.  
 
 
  Yes  
  N o   
Please i nitial here: _ _ _ _ _ _ _ _  
Date: _ _ _ _ _ _ _ _  
 
4. M y tiss ue ma y be ke pt f or use i n researc h t o lear n a b o ut, pre ve nt or treat ot her healt h pr o ble ms (f or 
e xa m ple: dia betes, Alz hei mer's disease, or he art disease).  
 
 
  Yes  
  N o   
Please i nitial here: _ _ _ _ _ _ _ _  
Date: _ _ _ _ _ _ _ _  
 
If y o u wa nt y o ur sa m ple(s) destr o ye d at a n y ti me, write t o t he Secretar y of t he _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
I nstit uti o nal Re vie w B oar d _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _.   
 
A C C R U/I T O G has t he ri g ht t o e n d st ora ge of t he sa m ple(s) wit h o ut telli n g y o u.  
 
T he sa m ple(s) will be t he pr o pert y of A C C R U/I T O G.  O utsi de researc hers ma y o ne da y as k f or a part of 
y o ur sa m ple(s) f or st u dies n o w or f ut ure st u dies.  
 
 
H o w d o o utsi de rese arc hers get t he s a m ple ?  
Researc hers fr o m u ni versities, h os pitals, a n d ot her healt h or ga nizati o ns d o researc h usi n g bl o o d a n d 
tiss ue. T he y ma y call A C C R U a n d as k f or sa m ples f or t heir st u dies. A C C R U l o o ks at t he wa y t hat t hese 
st udies will be d o ne, a n d deci des if a n y of t he sa m ples ca n be use d. A C C R U se n ds t he  sa m ples a n d s o me 
i nf or mati on a b o ut y o u t o t he researc her. A C C R U will n ot se n d y o ur na me, a d dress, p h o ne n u m ber, s ocial 
sec urit y n u m ber, or a n y ot her i de ntif yi n g i nf or mati o n to t he researc her. If y o u all o w y o ur sa m ple(s) t o be 
gi ve n t o o utsi de researc hers, it will be gi v e n t o t he m wit h a c o de n u m ber. If researc hers o utsi de A C C R U 
use t he sa m ple(s) f or f ut ure researc h, t he y will deci de if y o u will be c o ntacte d a n d, if s o, t he y w o ul d ha ve 
t o c o ntact t he researc hers at A C C R U. T he n A C C R U will c o ntact t he cli nic w here y o u re gistere d f or t his 
st u d y, w h o will c o ntact y o u. 
 
 


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 1 6  of 1 7  
 
 
Ple ase re a d t he f oll o wi n g st ate me nts a n d m ar k y o ur c h oice:  
 
I per mit A C C R U/I T O G t o gi ve m y sa m ple(s) t o o utsi de researc hers:  
 
  Yes  
 
  N o   
Please i nitial here:  
 
 
Date:  
 
 
 
 
 
 
W here c a n I get m ore i nf or m ati o n ?  
 
Y o u ma y call t he Nati o nal Ca ncer I nstit ute's Ca ncer I nf or mati o n Ser vice at:  
 
1 -8 0 0 -4 -C A N C E R ( 1 -8 0 0 -4 2 2 -6 2 3 7)  
 
Y o u ma y als o visit t he N CI We b site at  htt p://ca ncer. g o v/    
 
•  
F or N CI’s cli nical trials i nf or mati o n, g o t o: htt p://ca ncer. g o v/cli nicaltrials/  
 
•  
F or N CI’s ge neral i nf or mati o n a b o ut ca nc er, g o t o htt p://ca ncer. g o v/ca nceri nf o/  
 
Y o u will get a c o p y of t his f or m.  If y o u wa nt m ore i nf or mati o n a b o ut t his st u d y, as k y o ur st u d y d oct or.  
 
 


 
 
A p pe n di x I  
A d de n d u m 9  
 
 
Pa ge 1 7  of 1 7  
 
 
Si g n at ure  
 
I h a ve bee n gi ve n a c o p y of all _ _ _ _ _ [i nsert t otal of n u m ber of p a ges]  p a ges of t his f or m. I h a ve re a d 
it or it h as bee n re a d t o me. I u n derst a n d t he i nf or m ati o n a n d h a ve h a d m y q uesti o ns a ns were d.  I 
a gree t o t a ke p art i n t his st u d y.  
 
 
Pri nte d P artici p a nt N a me: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
P artici p a nt Si g n at ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
D ate: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
Pri nte d n a me of pers o n o bt ai ni n g i nf or me d c o nse nt:  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
Si g n at ure of pers o n o bt ai ni n g i nf or m e d c o nse nt: 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
D ate _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
T his m o del i nf or me d c o nse nt f or m h as bee n re vie we d b y t he A C C R U a n d is t he offici al c o nse nt 
d oc u me nt f or t his st u d y. L oc al I R B c h a n ges t o t his d oc u me nt are all o we d.  Secti o ns “ W h at are t he 
ris ks of t he rese arc h st u d y ” or “ W h at ot her c h oices d o I h a ve if I d o n’t t a ke p art i n t his rese arc h 
st u d y ? ” s h o ul d al w a ys be use d i n t heir e ntiret y if p ossi ble. E dit ori al c h a n ges t o t hese secti o ns m a y 
be m a de as l o n g as  t he y d o n ot c h a n ge i nf or m ati o n or i nte nt. If t he i nstit uti o n al I R B i nsists o n 
m a ki n g deleti o ns or m ore s u bst a nti ve m o dific ati o ns t o t hese secti o ns, t he y m a y be j ustifie d i n 
writi n g b y t he i n vesti g at or a n d a p pr o ve d b y t he I R B. U n der t hese circ u mst a nces, t h e re vise d 
l a n g u a ge a n d j ustific ati o n m ust be f or w ar de d t o t he Ac a de mic a n d C o m m u nit y C a ncer Rese arc h 
U nite d ( A C C R U) O per ati o ns Office f or a p pr o v al bef ore a p atie nt m a y be re gistere d t o t his st u d y.  
 
C o nse nt f or ms will h a ve t o be m o difie d f or e ac h i nstit uti o n as it rel ates t o w here i nf or m ati o n m a y 
be o bt ai ne d o n t he c o n d uct of t he st u d y or rese arc h s u bject. T his i nf or m ati o n s h o ul d be s pecific f or 
e ac h i nstit uti o n. 
 
 


A p pe n di x II 
A d de n d u m 9  
Pa ge 1  of 2  
 
P A TI E N T’ S M E DI C A TI O N  DI A R Y  
 
T o da y’s date _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Patie nt Na me _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 Patie nt St u d y I D _ _ R U 2 4 1 3 0 6 I_ _ _ _ _ _  
(i niti als acce pt a ble) 
I N S T R U C TI O N S T O T H E P A TI E N T: 
1.  C o m plete o ne f or m f or eac h 2 8 -da y c ycle . 
2.  Y o u will ta ke y o ur d ose [ _ _ _ _ _ _ m g ( _ _ _ _ _ _ 2 5 m g pills)] T WI C E  eac h da y  (f or a t ot al d ose of _ _ _ _ _ _  
m g  per d a y ) be gi n ni n g o n Wee k 1, Da y 1 a n d c o nti n ue d t hr o u g h 2 da ys after t hera pe utic 1 3 1I t hera p y has 
bee n a d mi nistere d  .  It is rec o m me n de d t o ta ke sel u meti ni b ( or place b o) o n a n e m pt y st o mac h ( 1 h o ur bef ore 
or 2 h o urs after a meal), a p pr o xi matel y  1 2 h o urs a part wit h a glass of water.   ( N O T E: A v oi d e xcessi ve s u n 
e x p os ure a n d use a de q uate s u nscree n pr otecti o n if s u n e x p os ure is a ntici pate d. D o n ot ta ke vita mi n E or 
m ulti vita mi n s u p ple me nts t hat pr o vi de a t otal dail y d ose i n e xcess of 1 0 0 % of t he rec o m me n de d dail y 
all o wa nce f or vita mi n E.)  
3.  Rec or d t he date  a n d t he ti me y o u t o o k t he m.   
4.  If y o u ha ve a n y c o m me nts or n otice a n y si de effects, please rec or d t he m i n t he C o m me nts c ol u m n. 
3.  B ri n g y o ur pill b ottle a n d t his f or m t o y o ur p h ysicia n w he n y o u g o f or y o ur ne xt a p p oi nt me nt.  
 
D ate  
 
D a y  
Ti me  
T a ke n  
 
C o m me nts  
 
D ate  
 
D a y  
Ti me  
T a ke n  
 
C o m me nts  
 
1  
 
 
 
1 1  
 
 
 
 
 
 
 
 
 
 
 
2  
 
 
 
1 2  
 
 
 
 
 
 
 
 
 
 
 
3  
 
 
 
1 3  
 
 
 
 
 
 
 
 
 
 
 
4  
 
 
 
1 4  
 
 
 
 
 
 
 
 
 
 
 
5  
 
 
 
1 5  
 
 
 
 
 
 
 
 
 
 
 
6  
 
 
 
1 6  
 
 
 
 
 
 
 
 
 
 
 
7  
 
 
 
1 7  
 
 
 
 
 
 
 
 
 
 
 
8  
 
 
 
1 8  
 
 
 
 
 
 
 
 
 
 
 
9  
 
 
 
1 9  
 
 
 
 
 
 
 
 
 
 
 
1 0  
 
 
 
2 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




A p pe n di x  III 
A d de n d u m 9  
Pa ge 1  of 5  
 
T he L o w I o di ne Diet  
 
W h at is I o di ne ?  
I o di ne is a mi neral. It pla ys a n i m p orta nt r ole i n se veral pr ocesses t hat ta ke place i n t he b o d y. O ne is t he 
pr o d ucti o n of a h or m o ne calle d t h yr o xi ne, w hic h occ urs i n t he t h yr oi d gla n d.  
 
W here is I o di ne F o u n d ?  
T he a m o u nt  of i o di ne f o u n d i n f o o d varies. M uc h of t he i o di ne we get c o mes fr o m i o dize d salt a n d 
brea ds. A d ults nee d 1 5 0 micr o gra ms of i o di ne a da y. T his b o o klet descri bes a l o w i o di ne diet. T his is a 
diet wit h less t ha n 5 0 micr o gra ms of i o di ne per da y.  
 
W h y is a L o w I o di ne Diet Necess ar y ?  
T he i o di ne i n y o ur diet ca n bl oc k t he u pta ke of ra di oacti ve i o di ne b y t he t h yr oi d gla n d. Y o ur d oct or c o ul d 
p ut y o u o n a l o w i o di ne diet o ne or t w o wee ks bef ore y o u get t he ra di oacti ve i o di ne. Sta y o n t his diet u ntil 
y o ur test or tr eat me nt is c o m plete. Y o ur d oct or will tell y o u w he n t o be gi n a n d w he n t o st o p t his diet. If 
y o u ha ve a n y q uesti o ns, s pea k wit h y o ur d oct or. Y o u ma y als o see a dietitia n if necessar y. If y o u ha ve 
a n y q uesti o ns a b o ut y o ur diet, call ( 2 1 2) 6 3 9 -7 3 1 2 t o s pea k t o a dietitia n.  
 
W h at S h o ul d Y o u A v oi d ?  
 
Rea d all f o o d la bels t o c hec k f or i o di ne c o nte nt. D o N O T eat or use:  
 
•  
I o dize d salt. 
•  
Sea salt i n a n y f or m.  
•  
O ni o n salt.  
•  
Celer y salt.  
•  
Garlic salt.  
•  
Seas o ne d salt.  
•  
Kel p (sea wee d).  
•  
A n y f o o d t hat has:  
o   I o dates 
o   I o di des 
o   Al g i n 
o   Al gi nates  
o   Carra gee n  
o   A gar  
•  
C o m mercial brea ds a n d ba ker y pr o d ucts beca use t he y ofte n c o ntai n i o date.  
•  
Mil k (e xce pt f or 1 o u nce a da y), e g gs, a n d seaf o o d.  
•  
Vita mi ns a n d f o o d s u p ple me nts if t he y ha ve i o di ne. If y o u ha ve a n y d o u bt, d o n ot ta ke t he m.  
•  
F o o d, pi lls, or ca ps ules wit h f o o d d yes or t hat are ora n ge, re d, or br o w n i n c ol or. E xa m ples i ncl u de 
re d or pi n k cereals or ca n dies. 
•  
A ntise ptics, s uc h as ti nct ure of i o di ne ( Beta di ne ®) a p plie d o n a c ut.  
•  
C o u g h me dici nes (es peciall y t h ose wit h re d c ol ori n g).  
•  
S u p ple m e nts s uc h as: 
o   E ns ure ®  
o   B o ost ®  
o   C o m mercial s ha kes  
o   N utra me nt ®  
•  
Resta ura nt a n d pr ocesse d f o o ds, beca use t he y are ofte n hi g h i n i o di ne c o nte nt.  
•  
S o y pr o d ucts s uc h as e da ma me, t of u, s o y b ur gers (e. g., B oca ®), etc.  


A p pe n di x  III 
A d de n d u m 9  
Pa ge 2  of 5  
 
•  
All ca n ne d f o o ds, beca use t he li ni n g of t he ca n  c o ntai ns i o di ne. 
 
D o n ot st o p ta ki n g a n y of y o ur me dici nes u nless y o ur d oct or tells y o u. If y o u are recei vi n g t u be fee di n g 
f or m ula, as k y o ur dietitia n or d oct or w hat t o d o. T his l o w i o di ne diet d oes n ot meet t he s u g geste d dail y 
all o wa nce f or all n utrie nts . Y o u will be o n it f or a s h ort ti me o nl y. 
 
Dri n k Ple nt y of Fl ui ds  
N ote: U nless y o ur d oct or tells y o u differe ntl y, y o u m ust dri n k at least 8 t o 1 0, 8 -o u nce c u ps of fl ui d a da y. 
T his i ncl u des t he dri n ks i n t he diet g ui deli nes a n d as m uc h water as y o u wa nt.  
 
L o w I o di ne Diet G ui deli nes:  
 
Bre a ds a n d Cere als  
T otal n u m ber of ser vi n gs per da y: 6 -8  
( 1 ser vi n g e q uals 1 slice of brea d or 1/ 2 c u p of c o o ke d pasta) 
 
I ncl u de 
Plai n c o o ke d barle y, oats, millet, b uc k w heat, b ul g ur w heat, q ui n oa; u nsalte d, u n pr ocesse d preser v ati ve-
free b o xe d cereals s uc h as p uffe d rice a n d s hre d de d w heat; rice, plai n macar o ni, s pa g hetti, n o o dles; crea m 
of rice or crea m of w heat h ot cereals; u nsalte d rice ca kes, u nsalte d plai n matza h, E n glis h m uffi ns, plai n 
u nsalte d p o pc or n, h o me ma de brea ds pre pare d wit h o ut c o m mercial d o u g h.  
 
A v oi d  
All c o m mercial brea ds a n d r olls, pr ocesse d b o xe d cereals, salte d crac kers, p otat o c hi ps, pretzels, ba gels, 
bial ys, Mel ba t oast, all ot her crac kers, e g g n o o dles, pac ka ge d rice a n d pasta mi xes.  
 
Me at a n d Me at S u bstit ute s 
T otal n u m ber of ser vi n gs per da y: T w o – t hree 
( 1 ser vi n g e q uals 3 o u nces of meat, fis h, p o ultr y, or 2 Ta bles p o o ns of u nsalte d pea n ut or al m o n d b utter) 
 
I ncl u de 
Fres h beef, veal, p or k, la m b, c hic ke n a n d t ur ke y; u nsalte d pea n ut or al m o n d b utter; fres h -water fis h s uc h 
as car p, ri ver  bass, la ke tr o ut, a n d ri ver perc h; fres h e g g w hite.  
 
A v oi d  
E g g y ol ks a n d w h ole e g gs, f o o ds ma de wit h e g gs; all fast f o o ds; all ca n ne d fis h s uc h as sal m o n a n d t u na; 
seaf o o d, s hellfis h (cla ms, cra bs, o ysters, l o bsters), or a n y f o o d m a de wit h fis h st oc k; all pr ocesse d meats; 
li ver a n d all or ga n meats; all ca n ne d, drie d, salte d, or c ure d meats s uc h as bac o n, sa usa ge, ha m, 
fra n kf urters, c hi p pe d beef, l u nc he o n meats (sala mi, b ol o g na, pastra mi); s pic y meats s uc h as c hili, beef 
jer k y, li verw urst; all ca n ne d or pr ocesse d p o ultr y s uc h as t ur ke y or c hic ke n r oll; t of u a n d s o y pr o d ucts, 
s uc h as s o y b ur gers (e. g., B oca); salte d pea n ut b utter. 
 
Mil k a n d Mil k Pr o d ucts  
T otal n u m ber of ser vi n gs per da y: Zer o  
 
I ncl u de 
N o ne all o we d  
E xce pti o n: O nl y 1 o u n ce of mil k a da y i n y o ur c offee  or tea.  
 


A p pe n di x  III 
A d de n d u m 9  
Pa ge 3  of 5  
 
A v oi d  
All mil k (e xce pt f or o ne o u nce dail y) a n d mil k pr o d ucts s uc h as c o n de nse d or e va p orate d mil k, c heese, 
y o g urt, p u d di n gs, ice crea m, c ustar d; a n y crea m s uc h as hea v y or li g ht crea m, w hi p pe d crea m, s o ur 
crea m; a n y f o o ds ma de wit h crea m or mil k or c heese s uc h as crea m s o u p, pizza, macar o ni a n d c heese.  
 
Fr uits  
T otal n u m ber of ser vi n gs per da y: Fi ve  
( 1 ser vi n g e q uals 1 s mall piece of fr uit or 3/ 4 c u p of j uice) 
 
I ncl u de 
All fres h fr uit, e xce pti o n: li mit ba na nas t o 1 ser vi n g per da y; fres h a p ple sa uce; all nat ural fr oze n fr uits; 
fres h fr uit j uices (i ncl u di n g b ottles or cart o ns of fr uit j uice wit h o ut artificial c ol ori n g or preser vati ves); 
w hite gra pe j uice.  
 
A v oi d  
Cra n berries, all drie d fr uits, all ca n ne d fr uits a n d ca n ne d fr uit j uices; jarre d a p plesa uce; cra n berr y a n d 
gra pe j uice, ca n ne d or b ottle d c herries; r h u bar b.  
 
Ve get a bles  
T otal n u m ber of ser vi n gs per da y: F o ur  
( 1 ser vi n g e q uals 1/ 2 c u p of c o o ke d or 1 c u p ra w ve geta ble) 
 
I ncl u de 
All fres h ve geta bles e xce pt s pi nac h , fres h p otat oes wit h o ut s ki n, all plai n fr oze n ve geta bles wit h o ut a d de d 
salt, fres h or drie d le g u mes s uc h as le ntils a n d peas. 
 
A v oi d  
All ca n ne d ve geta bles a n d all ca n ne d ve geta ble j uices, fres h or drie d bea ns s uc h as re d ki d ne y bea ns, li ma  
bea ns, na v y be a ns, pi nt o bea ns a n d c o w peas; ca n ne d le g u mes (s uc h as bea ns, peas, a n d le ntils); ca n ne d 
s o u ps; sa uer kra ut, celer y; c o m merciall y pre pare d p otat oes (e. g. i nsta nt mas he d p otat oes); fr oze n 
ve geta bles wit h a d de d salt; s pi nac h.  
 
F at  
T otal n u m ber of ser vi n gs per da y:  
S u g gest f o ur t o si x ser vi n gs a da y  
( 1 ser vi n g e q uals 1 teas p o o n of b utter or oil) 
 
I ncl u de 
U nsalte d mar gari ne or s weet b utter ( n ot m ore t ha n 1 teas p o o n of eac h per da y), oils, ve geta ble s h orte ni n g, 
plai n oil a n d w hite vi ne gar dressi n g.  
 
A v oi d  
Salte d n uts a n d see ds, ma y o n naise, c o m mercial sala d dressi n gs, a n d lar d.  
 
Be ver a ges  
T otal n u m ber of ser vi n gs per da y: N o restricti o ns  
O ne ser vi n g e q uals 1 2 o u nces of a car b o nate d be vera ge or 1 c u p  
( 8 o u nces) of a n y of t he ot her be vera ges liste d 
 


A p pe n di x  III 
A d de n d u m 9  
Pa ge 4  of 5  
 
I ncl u de 
Water; b o ttle d car b o nate d be vera ges wit h o ut a d de d c ol ori n g (s uc h as S prite ®, 7-U p ®, s o di u m -free 
seltzer); bre we d c offee, tea stee pe d fr o m tea lea ves; w hite tea ba gs; fres h le m o na de or fres h ora n gea de.  
 
A v oi d  
Mi neral water c o ntai ni n g s o di u m; all b ottle d, ca n ne d, or p o w dere d: ice d tea, le m o na de, i nsta nt c offee, 
i nsta nt tea, i nsta nt ice d-tea, fr uit p u nc h, a n d ot her p o w dere d or c o m mercial dri n ks, s uc h as Hi-C ® a n d 
K o ol -Ai d ®; tea stee pe d fr o m tea ba gs; s o y mil k a n d rice mil k ( w hic h c o ntai n sea salt); gi n ger ale, 
C o ke ®, Pe psi ® or a n y ot her car b o nate d be vera ges wit h a d de d c ol ori n g.  
 
Desserts a n d s weets  
T otal n u m ber of ser vi n gs per da y: T w o  
( See bel o w f or ser vi n g e q ui vale nts) 
 
I ncl u de 
Eac h of t he f oll o wi n g e q uals  1 ser vi n g:  
•  
1 c u p K n o x ® clear gelati n  
•  
2 ta bles p o o ns ( T) s u gar  
•  
2 T H o ne y  
•  
2 T Ma ple s yr u p  
•  
2 re g ular size Mars h mall o ws  
•  
1/ 2 c u p Nat ural s or bets wit h n o c ol ori n g or a d de d salt  
 
A v oi d  
All ba ker y pr o d ucts s uc h as pies, ca kes, pastries,  da nis hes, m uffi ns, d o n uts a n d c o o kies; gra ha m crac kers;  
Jell-O ®, c ol ore d gelati ns; c h oc olat e a n d c h oc olate  desserts; ca n d y.  
 
Miscell a ne o us  
T otal n u m ber of ser vi n gs per da y: U nli mite d  
 
I ncl u de 
Pe p per, s pices s uc h as ci n na m o n; her bs s uc h as ore ga n o; w hite vi ne gar, a n d n o n -i o dize d salt (c o ntai ns 
trace a m o u nts of i o di ne, use s pari n gl y). 
 
A v oi d  
All s alte d f o o ds s uc h as salte d n uts, C hi nese f o o d, s o y sa uce, cats u p, W orcesters hire sa uce, c hili sa uce, all  
c o m mercial sa uces, t o mat o sa uce, all gra vies, oli ves, pic kles, relis h, b o uill o n c u bes, s o u p bases, i o dize d 
salt, sea salt, o ni o n salt, garlic salt, celer y salt, seas o ne d salt, kel p (sea wee d); m olasses; a n y f o o d 
c o ntai ni n g f o o d c ol ori n g, i o dates, i o di des, i o date d o u g h c o n diti o ners or sta bilizers, al gi n, al gi nate, 
carra gee ns, a gar, or n ori (sea wee d); all s us hi; re d wi ne vi ne gar, balsa mic vi ne gar ( wit h cara mel c ol ori n g);  
all a d diti ves, preser vati ves, or artificial c ol ori n gs.  
 
S a m ple Me n u f or a L o w I o di ne Diet  
 
B R E A K F A S T  
1 Fr uit 1⁄ 2 c u p ora n ge j uice  
3 Brea ds 1⁄ 2 c u p oat meal ( n o mil k)  
1 plai n u nsalte d matza h  
1 Meat 1 e g g w hite o melet  
Misc. 2 teas p o o ns s u gar  


A p pe n di x  III 
A d de n d u m 9  
Pa ge 5  of 5  
 
1 Be vera ge 1 c u p bre we d c offee  
 
MI D M O R NI N G S N A C K  
1 Fr uit 2 Rice ca kes  
1 teas p o o n u nsalte d b utter  
1 c u p water  
 
L U N C H  
1 Meat 3 oz fres h t ur ke y breast  
2 Fats 2 ts p oil  
2 Brea ds 2 slices h o me ma de w hite brea d  
1 Ve geta ble 1 c u p R o mai ne lett uce  
1 Be vera ge 1 c u p fres h le m o na de  
 
MI D A F T E R N O O N S N A C K  
1 Fr uit 1 fres h a p ple  
1 Meat 2 ta bles p o o ns u nsalte d pea n ut b utter  
DI N N E R  
1 Meat 3 oz r oast  beef  
2 Brea ds 1 ba ke d p otat o ( n o s ki n)  
2 Ve geta bles 1 c u p fres h br occ oli  
2 Fats 2 ts p oil ( use d i n c o o ki n g)  
1 Fr uit 1 ora n ge  
1 Be vera ge 1 c u p w hite tea  
 
B E D TI M E S N A C K  
1 Fr uit 1 s mall pear  
1 Be vera ge 1 c u p tea ma de fr o m fres h tea lea ves  
 
 
 
© 1 9 9 7 Me m orial S l oa n-Ketteri n g Ca ncer Ce nter  
1 2 7 5 Y or k A ve n ue, Ne w Y or k, Ne w Y or k 1 0 0 6 5  
Re vise d 2 0 0 2, 2 0 0 4, 2 0 0 6, 2 0 0 8  


A p pe n di x  I V 
A d de n d u m 9  
Pa ge 1  of 9  
 
 
G ui d a nce F or M a n a ge me nt a n d I n vesti g ati o n of Sel u meti ni b Rel ate d A d verse E ve nts  
 
T he f oll o wi n g are rec o m me n de d, n ot ma n dat or y , assess me nts a n d/ or i nter ve nti o ns f or p ote ntial 
sel u meti ni b-relate d a d verse e ve nts. 
 
1.  Rec o m me n d ati o ns f or di arr he a m a n a ge me nt  
Diarr hea ma y occ ur d uri n g treat me nt wit h sel u meti ni b ( A Z D 6 2 4 4) a n d acti o n s h o ul d be ta ke n as 
s o o n as s y m pt o ms de vel o p.  T he rec o m me n dati o ns f or diarr hea ma na ge me nt i n are base d o n 
g ui deli nes fr o m t he A merica n S ociet y of Cli nical O nc ol o g y (J  Cli n O nc ol 2 0 0 4; 2 2: 2 9 1 8 -2 6). 
T hese g ui deli nes rec o m me n d t hat treat me nt -i n d uce d diarr hea s h o ul d be caref ull y m o nit ore d a n d 
treate d a g gressi vel y t o e ns ure t hat se vere c o m plicati o ns are a v oi de d a n d t hat treat me nt is n ot 
dela ye d.  
 
Patie nts s h o ul d be ma de a ware t hat t he y are li kel y t o e x perie nce diarr hea  a n d be e nc o ura ge d t o 
rec or d t he n u m ber of st o ols a n d re p ort p ossi ble ass ociate d s y m pt o ms 
 
Patie nts s h o ul d be gi ve n l o pera mi de (i n acc or da nce wit h l ocal re g ulati o n a n d l ocal practice) t o 
ta ke h o me wit h t he m a n d be a d vise d t o start i m me diatel y after t he first e pis o de of u nf or me d st o ol. 
 
Patie nts s h o ul d be gi ve n dietar y a d vice i n case of diarr hea  (e. g. B R A T [ ba na nas, rice, a p ple 
sa uce, t oast, plai n pasta] diet; rea dil y di gesti ble f o o d; a v oi da nce of lact ose -c o ntai ni n g pr o d ucts, 
frie d, fatt y or s pic y f o o d) a n d i ncrease fl ui d i nta ke ( 8– 1 0 glasses of clear fl ui ds dail y, i ncl u di n g 
water a n d fl ui ds c o ntai ni n g salt a n d s u gar,  s uc h as s p orts dri n ks a n d clear br ot h). 
 
Patie nts s h o ul d see k a d vice earl y, fr o m t heir p h ysicia n or st u d y n urse, if  
 
•  
Persiste nt Gra de 1 or 2 diarr hea (see 2. 2) or  
•  
Gra de 3 or 4 diarr hea  
•  
Diarr hea  bec o mes c o m plicate d b y ass ociate d v o miti n g or i na bilit y t o t a ke oral fl ui ds; mar ke d 
a b d o mi nal diste nsi o n or cra m pi n g; bl o o d y st o ols, fe ver or s y m pt o ms of h y p ote nsi o n.  
 
T a ble 1  
C T C A E ( versi o n 4) gr a di n g f or di arr he a  
C T C A E 
Gr a de  
P atie nts wit h o ut c ol ost o mies  
P atie nts wit h c ol ost o mies  
Gra de 1  
I ncrease i n n u m ber of st o ols per 
da y ( < 4)  
Mil d i ncrease i n l o ose water y c ol ost o m y o ut p ut 
c o m pare d wit h pre -treat me nt 
Gra de 2  
I ncrease i n n u m ber of st o ols per 
da y ( 4 -6) or n oct ur nal e pis o des  
M o derate i ncrease i n l o ose water y c ol ost o m y 
o ut p ut c o m pare d wit h pre -treat me nt, n ot 
i nterferi n g wit h n or mal acti vit y 
Gra de 3  
I ncrease of m ore t ha n 7 st o ols per 
da y or i nc o nti ne nce or nee di n g 
s u p p ort f or de h y drati o n.   
Se vere i ncrease i n l o ose water y c ol ost o m y o ut p ut 
c o m pare d wit h pre -treat me nt a n d i nterferi n g wit h 
n or m al acti vit y 
Gra de 4  
Life -t hreate ni n g c o nse q ue nces (e g,  he m o d y na mic c olla pse) 
 
I nitial ma na ge me nt of u nc o m plicate d Gra de 1 or 2 diarr hea  
Patie nts s h o ul d i m me di atel y start l o pera mi de after t he first e pis o de of diarr hea  ( 4 m g i nitiall y) 
a n d c o nti n ue l o per a mi de ( 2 m g e ver y 4 h o urs or after eac h u nf or me d st o ol)  u ntil t he y ha ve bee n 
free fr o m diarr hea  f or at least 1 2 hrs 
 


A p pe n di x  I V 
A d de n d u m 9  
Pa ge 2  of 9  
 
If after 1 2 h o urs of l o per a mi de tre at me nt  t he diarr hea  is n ot i m pr o vi n g or res ol ve d, t he patie nt 
s h o ul d be i nstr ucte d t o c o ntact t he ce nte r a n d t o i ncrease t o hi g h d ose l o pera mi de ( 2 m g e ver y 2 
h o urs, or 4 m g e ver y 4 h o urs at ni g ht) a n d c o nti n ue t o ta ke l o pera mi de u ntil t he y ha ve bee n free 
fr o m diarr hea  f or at least 1 2 hrs.  A d diti o nal treat me nt ma y be c o nsi dere d acc or di n g t o l ocal 
practice.  
 
Ma na ge me nt of persiste nt ( > 2 4 h) Gra de 1 or 2 diarr hea des pite l o pera mi de at hi g h d ose  
T he patie nt s h o ul d be see n b y t he p h ysicia n or st u d y n urse f or f ull e val uati o n a n d t he f oll o wi n g 
s h o ul d be c o nsi dere d: 
 
•  
Re h y drati o n a n d electr ol ytes re place me nt as a p pr o priate  
•  
I nfecti o us ca uses a n d eti ol o gies s uc h as Cl ostri di u m difficile or viral gastr oe nteritis; 
•  
A nti bi otics if a p pr o priate (f or e xa m ple a n oral fl ur o q ui n ol o ne f or 7 da ys) partic ularl y if t he 
patie nt is ne utr o pe nic ( < 1 x 1 0 9/ L) or has a fe ver; 
•  
Disc o nti n uat i o n of l o pera mi de a n d start of octre oti de ( Sa n d ostati n); 
 
It ma y als o be a p pr o priate t o c o nsi der: 
 
•  
A d diti o n of ot her sec o n d -li ne a nti-diarr heal a ge nts acc or di n g t o l ocal practice  
•  
Sel u meti ni b ( or matc hi n g place b o) i nterr u pti o n u ntil res ol uti o n of t he diarr h ea 
•  
H os pitalizati o n  
 
I n st u dies i n v ol vi n g c o m bi nati o n of sel u meti ni b ( or matc hi n g place b o) wit h ot her a nti-ca ncer 
treat me nt, i nterr u pti o n or dela y of t he c o m bi nati o n a ge nt ma y be c o nsi dere d acc or di n g t o 
ma n ufact urer’s g ui da nce or l ocal practice.  
 
Ma na ge me n t of a n y gra de u nc o ntr olle d or c o m plicate d diarr hea, or Gra de 3-4 diarr hea  
H os pitali zati o n a n d f ull e val uati o n,  
I ntra ve n o us fl ui ds, electr ol ytes a n d a nti bi otics if nee de d (e. g. fl uo r o q ui n ol o ne) 
I nterr u pt sel u meti ni b ( or matc hi n g place b o) u ntil diarr hea  a nd ass ociate d s y m pt o ms res ol ve  
Start octre oti de ( Sa n d ostati n).  
 
I n st u dies i n v ol vi n g c o m bi nati o n of sel u meti ni b ( or matc hi n g place b o) wit h ot her a nti-ca ncer 
treat me nt, i nterr u pti o n or dela y of t he c o m bi nati o n a ge nt ma y be c o nsi dere d acc or di n g t o 
ma n ufact ure r’s g ui da nce or l ocal practice.  




A p pe n di x  I V 
A d de n d u m 9  
Pa ge 4  of 9  
 
2.  G ui d a nce f or t he M a n a ge me nt of P atie nts wit h R as h  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T a ble 1: E x a m ple t o pic al ster oi ds a n d a nti bi otics ( use acc or di n g t o l oc al g ui deli nes)  
T o pical ster oi d s 
m o derate stre n gt h  
Tria mci n ol o ne acet o ni de 0. 0 2 5 %  
Des o ni de 0. 0 5 %  
Fl uticas o ne pr o pri o nate 0. 0 5 %  Acl o metas o ne 0. 0 5 %  
T o pical a nti bi otics  
Cli n da m yci n 1 - 2 %  
 
Er yt hr o m yci n 1 % - 2 %  
Metr o ni daz ole 1 %  
 
Sil ver s ul p ha diazi ne 1 %   
Oral a nti bi otics  
D o x yc ycli ne 1 0 0 m g b d   
 Mi n oc ycli ne 1 0 0 m g b d O x ytetrac ycli ne 
5 0 0 m g b d  
‡ sel u meti ni b or matc hi n g place b o  
Rec o m me n d ati o ns t o st art o n d a y 1 of tre at me nt wit h sel u meti ni b ‡ a n d f or t he d ur ati o n 
of tre at me nt  
 
•  
Use s ki n m oist urizer (t hic k, al c o h ol -free) at be dti me 
•  
A v oi d e xcessi ve e x p os ure t o s u nli g ht  
•  
Use s u n glasses/s u nscree n ( P A B A -free, S P F ≥1 5; U V A a n d U V B pr otecti o n) as 
nee de d  
•  
Use of t o pical reti n oi ds or be nz o yl per o xi de is n ot rec o m me n de d  
 
C T C gr a de 3 r as hes  
C T C gr a de 2 r as hes c o nsi dere d b y t he p atie nt t o be i nt oler a ble  
 
M o derate stre n gt h t o pical ster oi d  
 
a n d oral a nti bi otic  
(c o nsi der br oa d s pectr u m/ gra m ne gati ve c o ver if i nfecti o n s us pecte d) 
 
C o nsi der referral  t o a der mat ol o gist: ma na ge ras h per rec o m me n dati o n 
 
I nterr u pt sel u meti ni b ‡  u ntil r as h i m pr o ves t o gr a de 2 or less  
 
Sel u meti ni b ‡ m a y be rest arte d at ori gi n al d ose or re d uce d at t he discreti o n of  t he 
i n vesti g at or 
C T C Gr a de 1 r as hes  
 
Mil d or m o derate stre n gt h t o pical ster oi d  
 
a n d/ or t o pical a nti bi otic  
 
C T C Gr a de 2 r as hes  
 
M o derate stre n gt h t o pical ster oi d  
 
a n d oral a nti bi otic 
 
 


A p pe n di x  I V 
A d de n d u m 9  
Pa ge 5  of 9  
 
 
3 . G ui d a nce f or m a n a ge me nt of p atie nts wit h a n as y m pt o m atic  re d ucti o n i n L V E F  ( pr o vi de d 
b y Astr a Ze nec a)  
 






A p pe n di x  I V 
A d de n d u m 9  
Pa ge 8  of 9  
 
6 . Rec o m me n d ati o ns of Or al C are ( pr o vi de d b y Astr a Ze nec a)  
 
Or al C ar e Rec o m me n d ati o ns f or P atie nts tre ate d wit h Sel u meti ni b:  
Patie nts s h o ul d be e nc o ura ge d t o ta ke res p o nsi bilit y f or t heir o w n oral care w here ver p ossi ble. T his 
ma y re q uire fre q ue nt e nc o ura ge me nt a n d e d ucati o n. T he ge neral rec o m me n dati o ns of R u be nstei n et 
al ( 2 0 0 4) are t o mai ntai n a clea n a n d pai n-free m o ut h w hic h re d uces patie nt disc o mf ort a n d hel ps 
pre ve nt i nfecti o n a n d pr o m ote dietar y i nta ke. E vi de nce fr o m t he literat ure re gar di n g i m ple me ntati o n 
a n d efficac y of oral pr ot oc ols a n d patie nt e d ucati o n, s u g gest t hat patie nts w h o are ta u g ht oral care 
pr ot oc ols perf or m oral care m ore dili ge ntl y, ta ke m ore res p o nsi bilit y f or t heir care a n d ma y s h o w a n 
i m pr o ve me nt i n oral s y m pt o ms.  
 
Pre ve nti o n, earl y dia g n osis a n d ma na ge me nt of st o matitis ma y re d uce t he nee d f or d os e i nterr u pti o n 
a n d / or re d ucti o ns of t he st u d y me dicati o ns d ue t o se vere st o matitis a n d s o all o w t he patie nt t o 
c o nti n ue o n t he st u d y dr u gs. It is str o n gl y rec o m me n de d t hat patie nts recei ve a d vice re gar di n g dail y 
oral healt h care re gi mes, b ot h bef ore a n d d uri n g treat me nt.  
 
M o ut h w as hes:  
Patie nts wit h a healt h y m o ut h ma y use n o nalc o h olic m o ut h was h se veral ti mes ( 4 t o 6 ti mes dail y, or 
acc or di n g t o t he i nstr ucti o ns) dail y (e. g. after eac h meal) d uri n g t he st u d y.  
 
Sali ne m o ut h was hes ( S o di u m c hl ori de 0. 9 %) s h o ul d be preferre d i n cases of st o matitis, a n d s h o ul d be 
use d at a differe nt ti me t o t o ot h br us hi n g (e. g. after tea).  
 
Use of a m o ut h was h i m me diatel y after sel u meti ni b i nta ke is rec o m me n de d.  
 
T he t o n g ue ca n be ge ntl y br us he d (if n ot s ore) wit h a s oft t o ot h br us h.  
 
Patie nts wit h, or at ris k of, st o matitis s h o ul d n ot use c o m mercial / o ver -t he-c o u nter m o ut h was hes 
beca use of t he alc o h ol c o nte nt a n d astri n ge nc y. C hl or he xi di ne m o ut h was hes are n ot rec o m me n de d f or 
t he treat me nt of esta blis he d st o matitis.  
 
T he m o ut h  s h o ul d be re g ularl y i ns pecte d b y t he patie nt a n d healt hcare pr ofessi o nals. 
 
S m o ki n g s h o ul d be str o n gl y disc o ura ge d; patie nts s h o ul d be offere d hel p wit h s m o ki n g cessati o n if 
necessar y i n t he f or m of nic oti ne re place me nt t hera p y or referral t o s m o ki n g cess ati o n ser vices.  
 
A hi g h alc o h ol i nta ke s h o ul d be disc o ura ge d a n d patie nts a d vise d t o a v oi d pai nf ul sti m uli s uc h as 
s pic y f o o ds, h ot f o o d a n d dri n k. 
 
De nt al c are:  
 
De nt ate p atie nts:  
•  
Patie nts w h o are free fr o m de ntal pr o ble ms ma y be at less ris k of st o matit is 
•  
Teet h s h o ul d be br us he d t wice dail y wit h a fl u ori de t o ot h paste a n d s oft t o ot h br us h, i n t he 
m or ni n g bef ore brea kfast a n d last t hi n g i n t he e ve ni n g bef ore be d, a b o ut 3 0 mi n utes after 
eati n g. T o ot h br us h s h o ul d be re place d re g ularl y, at least e ver y 3 m o nt hs . Patie nts wit h 
st o matitis s h o ul d c ha n ge t heir t o ot h br us h e ver y 4 - 6 wee ks.  
•  
Use of s oft t o ot h br us h is rec o m me n de d  
•  
De ntal fl oss s h o ul d be use d o nce dail y (ca uti o n i n patie nts wit h c oa g ul o pat hies i ncl u di n g a 
l o w platelet c o u nt)