Clinical trial NCT02807597
Conditions: Breast Cancer Cancer of the Breast
Sponsor: Samuel Achilefu
Start date: 2020-02-18; Completion date: 2022-01-27
Enrollment: 9 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The investigators' preclinical data have demonstrated the feasibility of fluorescence-guided tumor resection by Cancer Vision Goggles (CVG) with LS301 in animal models. In this study, the investigators will conduct intraoperative imaging procedures that have minimal interference with ongoing surgery. The underlying hypothesis is that the accurate detection of all cancer cells highlighted by LS301 during surgery will reduce the number of breast cancer patients with margin positivity to less than 5%, compared to the current surgical paradigm of greater than 20%. The pilot study will obtain critical data required to address the larger question of surgical margin assessment in a full Phase I clinical trial.

Phase 1: to determine the safety and optimal imaging dose of LS301 injected in breast cancer patients.

Phase 2: to determine the ability of this novel fluorescence imaging agent to predict the presence of positive margins around partial mastectomy specimens and positive SLNs during surgical therapy for breast cancer.

Detailed description:
A rolling six design which is intended for relatively safe trials and shortening the study duration is proposed for the phase 1 portion 74. In the rolling six design, three to six patients can be enrolled to a dose each time. The dose de-escalation occurs when two or more DLT occur at a dose level while dose escalation occurs when 3/3, 4/4, 5/5, 5/6 or 6/6 patients are evaluated without DLT 75. Three dose levels will be tested in the phase I study, 0.05, 0.075 and 0.10 mg/kg. LS301 will be administered intravenously at a starting dose of 0.05 mg/kg to a cohort of six patients and escalate/de-escalate following the decision rule of the rolling six design. Once six patients have been included at the current dose level, inclusions are suspended until at least five of the six patients have completed the procedure without DLT observed in the evaluation period. MTD is hit where two or more patients out of six at a dose level experience DLT. The investigators do not expect any serious adverse events related to LS301 at the initial Dose Level 1. Once the MTD is determined, an expansion cohort with 9 patients will be tested at the MTD and an optimal imaging dose will be recommended for the subsequent phase II trial.

At the completion of the expansion cohort, a single arm phase 2 trial will be performed at the optimal imaging dose. A breast surgeon will perform breast conserving surgery per standard of care. At the completion of the surgery, a second investigator (to reduce bias in data collection) will wear the cancer vision goggle (CVG) to visualize the excised tissue to determine if there are any positive margins based on the presence of LS301 fluorescence. If any positive margins are observed, the subject will be considered to have a positive margin; otherwise, the margin is considered negative. The excised tissue will later be examined by a breast cancer pathologist. Standard pathologic techniques will be used to determine if there are positive margins. Particular attention will be paid to the sites marked following CVG assessment to confirm whether the margin is positive or negative at any of these sites, or positive at other locations not identified by CVG. No interventions will be allowed based on the CVG results.

This study was initiated at Washington University in St. Louis and is being transferred to UTSW. Phase 1a was initiated at Washington University in St. Louis where 9 subjects were enrolled. The PI is continuing with Phase 1B at UTSW where 9 more subjects will be enrolled. Once completed, the results of Phase 1 (a and b) will be sent to the FDA for review. Phase II will begin once the FDA has reviewed the interim data and authorized Phase II to open. After phase 1 data has been submitted to and discussed with the FDA, an additional cohort of 88 patients will be enrolled to the phase 2 portion of the trial to assess the diagnostic capabilities of LS301 for identification of positive margins at surgery. FDA-approved fluorescence imaging systems may be used to benchmark CVG data.

Arms: arm 1: * Patient will undergo surgery 4-24 hours after administration of LS301 (0.05 mg/kg)
* Excised tissue will be examined for the presence of LS301 fluorescence using the Cancer Vision Goggles (CVG) to determine if LS301 accumulated in the breast cancer. The investigators will quantify fluorescence intensity in the cancer to establish the feasibility of observing LS301 fluorescence with the imaging system. FDA-approved fluorescence imaging systems may be used to benchmark CVG data. arm 2: * Patient will undergo surgery 4-24 hours after administration of LS301 (0.075 mg/kg)
* Excised tissue will be examined for the presence of LS301 fluorescence using the Cancer Vision Goggles (CVG) to determine if LS301 accumulated in the breast cancer. The investigators will quantify fluorescence intensity in the cancer to establish the feasibility of observing LS301 fluorescence with the imaging system. FDA-approved fluorescence imaging systems may be used to benchmark CVG data. arm 3: * Patient will undergo surgery 4-24 hours after administration of LS301 (0.1 mg/kg)
* Excised tissue will be examined for the presence of LS301 fluorescence using the Cancer Vision Goggles (CVG) to determine if LS301 accumulated in the breast cancer. The investigators will quantify fluorescence intensity in the cancer to establish the feasibility of observing LS301 fluorescence with the imaging system. FDA-approved fluorescence imaging systems may be used to benchmark CVG data. arm 4: * Patient will undergo surgery 4-24 hours after administration of LS301 (dose to be determined in Phase I dose escalation portion)
* 9 patients will be enrolled (6 invasive ductal carcinoma and 3 DCIS)
* Excised tissue will be examined for the presence of LS301 fluorescence using the Cancer Vision Goggles (CVG) to determine if LS301 accumulated in the breast cancer. The investigators will quantify fluorescence intensity in the cancer to establish the feasibility of observing LS301 fluorescence with the imaging system. FDA-approved fluorescence imaging systems may be used to benchmark CVG data. arm 5: * Patient will undergo surgery 4-24 hours after administration of LS301 (dose to be determined in Phase I portion)
* Excised tissue will be examined for the presence of LS301 fluorescence using the Cancer Vision Goggles (CVG) to determine if LS301 accumulated in the breast cancer. The investigators will quantify fluorescence intensity in the cancer to establish the feasibility of observing LS301 fluorescence with the imaging system. FDA-approved fluorescence imaging systems may be used to benchmark CVG data.
Interventions: intervention 1: LS301 intervention 2: Cancer Vision Goggles and standard fluorescence imaging systems intervention 3: Surgery
Intervention descriptions: intervention 1: -LS301 is a small molecule consisting of a NIR fluorescent dye and an octapeptide that is cyclized through a disulfide bond. intervention 2: -Member of the operating team will wear the CVG during surgery intervention 3: -Standard of care

Protocol documents:
Prot_SAP_002.pdf: 
S T U D Y P R O T O C O L A N D S T A TI S TI C A L A N A L Y SI S P L A N  
 
 
 
Offi ci al titl e:  E v al u ati o n of L S 3 0 1 U pt a k e i n T u m or s of 
P ati e nt s U n d er g oi n g P arti al M a st e ct o m y a n d S e nti n el L y m p h 
N o d e Bi o p s y f or Br e a st C a n c er  
 
N C T n u m b er:  N C T 0 2 8 0 7 5 9 7  
I R B A p pr o v e d d at e : 0 6 -0 6 - 20 2 3  


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 1 of 5 4  
 
 
 
 
 
E v al u ati o n of L S 3 0 1 U pt a ke i n T u m ors of P atie nts U n der g oi n g P arti al M astect o m y a n d 
Se nti nel L y m p h N o de Bi o ps y f or Bre ast C a ncer  
 
 
P h ase 1 A: 
Was hi n gt o n U ni versit y Sc h o ol of Me dici ne 
De part me nt of S ur g er y  
6 6 0 S o ut h E ucli d A ve n ue, Ca m p us B o x 8 1 0 9 
St. L o uis, M O  6 3 1 1 0 
 
P h ase 1 B/ P h ase 2:  
U T S o ut h wester n Me dical Ce nter  
5 3 2 3 Harr y Hi n es Bl v d.  
Dallas, T X 7 5 3 9 0 
 
Pr ot oc ol #: 2 0 1 9 0 7 1 3 5  
Versi o n D ate: 0 5/ 1 5/ 2 0 2 3  
S T U - 2 0 2 2- 0 3 8 5 
 
  
P h ase 1 A: 
Pri nci p al I n vesti g at or:  
 
J ulie Mar ge nt haler , M. D. 
P h o ne:  ( 3 1 4) 3 6 2- 7 5 3 4 
E m ail:  j mar ge nt haler @ w ustl.e d u  
 
P h ase 1 B & P h ase 2 : 
Pri nci p al I n vesti g at or:  
 
De b ora h Farr, M. D. 
  
  
  
  
 
U T S o ut h wester n Me dical Ce nter  
  
  
  
  
 
De part me nt of S ur g er y  
  
  
  
  
  
5 3 2 3 Harr y Hi n es Bl v d., Dallas, T X 7 5 3 9 0 
  
  
  
  
 
P h o ne:  ( 2 1 4) 6 4 8- 5 8 7 0 
  
  
  
  
 
E m ail:  De b ora h.farr @ uts o ut h wester n.e d u  
 
P h ase 1 A: 
C o - Pri nci p al I n vesti g at or:   
Sa m uel Ac hilef u, P h D 
U T S o ut h wester n Me dical Ce nter  
  
  
  
  
 
De part me nt of Bi o me dical E n gi neeri n g 
5 3 2 3 Harr y Hi n es Bl v d., Dallas, T X 7 5 3 9 0 
P h o ne:  ( 3 1 4) 3 6 2- 8 5 9 9 
E m ail:  ac hilef u @ w ustl.e d u  
 
 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 2 of 5 4  
 
 
P h ase 1 B & P h ase 2: 
C o - Pri nci p al I n vesti g at ors or Le a d S u b-I n vesti g at or(s):   
 
  
  
  
  
 
Sa m uel Ac hilef u, P h D 
U T S o ut h wester n Me dical Ce nter  
  
  
  
  
  
De part me nt of Bi o me dical E n gi neeri n g 
5 3 2 3 Harr y Hi n es Bl v d., Dallas, T X 7 5 3 9 0 
                                                           P h o ne:  2 1 4- 6 4 5- 9 9 0 0 
                                                           E m ail:  Sa m uel. Ac hilef u @ U T S o ut h wester n.e d u  
  
 
P h ase 1 A: 
S u b -I n vesti g at or(s):    
  
  
 
S u ma n M o n dal, P h. D.  
  
  
Ra di ol o g y 
C hristi ne O’ Brie n, P h. D.  
  
  
Ra di ol o g y 
R ui Ta n g, P h. D.  
  
  
  
Ra di ol o g y 
Xia o X u, P h. D.  
  
  
  
Ra di ol o g y 
Ji n g qi n ( R os y) L u o, P h. D.  
  
  
Bi ostatistics 
Ti m ot h y E berlei n, M. D.  
  
  
S ur gical O nc ol o g y 
Willia m E. Gilla n ders, M. D.     
  
S ur gical O nc ol o g y 
Re becca L. Aft, M. D., P h. D.    
  
S ur gical O nc ol o g y 
Kat heri ne Gl o v er - C olli ns, M. D., P h. D.  
S ur gical O nc ol o g y 
De b ora h Veis ( N o v ac k), M. D., P h. D.  
Pat h ol o g y 
 
P h ase 1 B & P h ase 2 : 
S u b -I n vesti g at or(s):   
N/ A     
 
                                                               
 
Bi ost atistici a n:   
 
Mi nJae Lee, P h D  
  
  
  
 
U T S o ut h wester n Me dical Ce nter  
  
  
  
  
5 3 2 3 Harr y Hi n es Bl v d., Dallas, T X 7 5 3 9 0 
  
  
  
 
P h o ne:  ( 2 1 4) 6 4 8- 3 8 0 3 
  
  
  
 
F a x:  ( 2 1 4) 6 4 8- 3 9 3 4 
  
  
  
  
Mi nJae. Lee @ U T S o ut h wester n.e d u 
 
I N D N u m ber:  
1 3 1 3 5 3 
 
N C T N u m ber:   
N C T 0 2 8 0 7 5 9 7 
 
 
 
C O N FI D E N TI A L  
T he i nf or m ati o n c o nt ai ne d i n t his d oc u m e nt is re g ar de d as c o nfi de nti al a n d, e xce pt t o t he e xte nt necess ar y t o 
o bt ai n i nf or m e d c o nse nt, m a y n ot be discl ose d t o a n ot her p art y u nless l a w or re g ul ati o ns re q uire s uc h 
discl os ure.  Pers o ns t o w h o m t he i nf or m ati o n is discl ose d m ust be i nf or m e d t h at t he i nf or m ati o n is 
c o nfi de nti al a n d m a y n ot be f urt her discl ose d b y t he m  
 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 3 of 5 4  
 
 
 
 
Si g n at ure P a ge 
 
 
T he si g nat ure bel o w c o nstit utes t he a p pr o val of t his pr ot oc ol a n d t he attac h me nts a n d pr o vi des t he 
necessar y ass ura n ces t hat t his st u d y will be c o n d ucte d acc or di n g t o all sti p ulati o ns of t he pr ot oc ol, 
i ncl u di n g all state me nts re gar di n g c o nfi de ntialit y, a n d acc or di n g t o l ocal le gal a n d re g ulat or y 
re q uire me nts a n d a p plica ble U. S. fe deral re g ulati o ns a n d I C H g ui deli nes. 
 
A m e n d m e nt/ Versi o n # _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
S T U - 2 0 2 2- 0 3 8 5 
E v al u ati o n of L S 3 0 1 U pt a ke i n T u m ors of P atie nts U n der g oi n g P arti al M astect o m y a n d 
Se nti nel L y m p h N o de Bi o ps y f or Bre ast C a ncer  
 
 
Pri nci p al I n vesti g at or ( PI) N a m e : _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
PI Si g n at ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
D ate: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 4 of 5 4  
 
 
S C H E M A  
 
 
 
L S 3 0 1 D ose Le vel  
L S 3 0 1 D ose  
Le vel 1 (starti n g d ose)  
0. 0 5 m g/ k g  
Le vel 2  
0. 0 7 5 m g/ k g  
Le vel 3  
0. 1 m g/ k g  
 
P hase 1 will be c o m plete after esta blis hi n g t he safet y a n d deter mi ni n g t he o pti mal i ma gi n g d ose 
of L S 3 0 1.  E nr oll me nt t o p hase 2 will o nl y be gi n after t he F D A h as re vi e w e d a n d a p pr o v e d t he 
p hase 1 data.
N e wl y dia g n ose d Sta ge I -II breast ca n cer patie nts u n der g oi n g breast-c o nser vi n g 
t hera p y a n d S L N  bi o ps y.  Ne gati ve n o dal b asi n o n cli nical e xa m. 
I njecti o n of L S 3 0 1 
( da y pri or t o s ur g er y if p ossi ble ( preferre d) or at l east 4 h o urs 
pri or t o s ur ger y o n d a y of s ur ger y) 
Patie nt m o nit ori n g f or 
o ne h o ur p ost-
i njecti o n 
3 0 -da y S O C la bs  
(f oll o w- u p) 
S ur ger y wit h Ca ncer Visi o n 
G o g gle S yste m  


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 5 of 5 4  
 
 
T a ble of C o nte nts  
 
S C H E M A ....................................................................................................................................................... 4 
1. 0  
B A C K G R O U N D A N D R A TI O N A L E  .............................................................................................. 7 
1. 1  
S ur gi c al R e s e cti o n of Br e a st C a n c er a n d S e nti n el L y m p h N o d e Bi o p s y  .. 7 
1. 2  
I m a g e- G ui d e d N e ar-I nfr ar e d Fl u or e s c e n c e S y st e m s f or I ntr a o p er ati v e 
C a n c er I m a gi n g  ...................................................................................................................... 7 
1. 3  
W e ar a bl e C a n c er Vi si o n G o g gl e s f or S ur gi c al R e s e cti o n of C a n c er  ........... 8 
1. 4  
H u m a n Pil ot St u di e s U si n g W e ar a bl e C V G  ..................................................... 1 0 
1. 5  
NI R Fl u or e s c e nt M ol e c ul ar Pr o b e s f or t h e A c c ur at e I d e ntifi c ati o n of 
Di v er s e a n d H et er o g e n e o u s T u m or s u si n g NI R- FI G S I s L a c ki n g  ........................ 1 0 
1. 6  
NI R Fl u or e s c e nt M ol e c ul ar Pr o b e, L S 3 0 1, S el e cti v el y A c c u m ul at e s i n 
Br e a st C a n c er a n d Ot h er M ali g n a n ci e s  ....................................................................... 1 1 
1. 7  
M e c h a ni s m of L S 3 0 1 C a n c er- Bi n di n g A cti o n  ................................................. 1 1 
1. 8  
L S 3 0 1 Hi g hli g ht s T u m or s i n Di v er s e A ni m al M o d el s of C a n c er  ............... 1 3 
1. 9  
I N D- E n a bli n g Pr e cli ni c al St u di e s ........................................................................ 1 6 
1. 1 0  Cli ni c al St u d y Pl a n  .................................................................................................. 1 7 
1. 1 1  R ati o n al e  ..................................................................................................................... 1 8 
1. 1 2  P ote ntial  C o ntri b uti o n ............................................................................................... 1 8 
2. 0  
O B J E C TI V E S  ................................................................................................................................ 1 9  
2. 1  
Pri m ar y O bj e cti v e s  ................................................................................................... 1 9 
3. 0  
P A TI E N T S E L E C TI O N  ................................................................................................................ 1 9  
3. 1  
I n cl u si o n Crit eri a ...................................................................................................... 1 9 
3. 2  
E x cl u si o n Crit eri a  .................................................................................................... 1 9 
3. 3  
I n cl u si o n of W o m e n a n d Mi n oriti e s ................................................................... 1 9 
4. 0  
R E GI S T R A TI O N P R O C E D U R E S  ............................................................................................... 1 9  
4. 1  
C o nfir m ati o n of P ati e nt Eli gi bilit y  ....................................................................... 2 0 
4. 2  
P ati e nt R e gi str ati o n i n t h e Sit e m a n C a n c er C e nt er O n C or e D at a b a s e  
f or P h a s e 1 A & U T S o ut h w e st er n M e di c al C e nt er V el o s D at a b a s e f or P h a s e 
1 B / P h a s e 2  ............................................................................................................................ 2 0 
4. 3  
A s si g n m e nt of U P N  .................................................................................................. 2 0 
    4. 4     Baseli ne Data C ollecti o n  
5. 0  
S T U D Y P R O C E D U R E S ................................................................................................................ 2 0  
5. 1  
L S 3 0 1 Pr e p ar ati o n  ................................................................................................... 2 0 
5. 2  
Pr o c e d ur e s  .................................................................................................................. 2 1 
5. 3  
E v al u a bilit y  ................................................................................................................. 2 5 
5. 4  
S af et y E v al u ati o n  ..................................................................................................... 2 5 
5. 5  
Ri s k s a n d A d v er s e E v e nt M o nit ori n g  ................................................................. 2 7 
5. 6  
C oll e cti o n of S p e ci m e n s f or R e s e ar c h A n al y s e s ( P h a s e 2 O N L Y)  .............. 2 9 
5. 7  
D at a S u b mi s si o n S c h e d ul e  ................................................................................... 2 9 
5. 8  
W o m e n of C hil d b e ari n g P ot e nti al  ........................................................................ 3 0 
5. 9  
D ur ati o n of St u d y P arti ci p ati o n  .......................................................................... 3 0 
6. 0  
R E G U L A T O R Y A N D R E P O R TI N G R E Q UI R E M E N T S  ........................................................... 3 0  
6. 1  
S p o n s or-I n v e sti g at or R e p orti n g R e q uir e m e nt s – W a s hi n gt o n U ni v er sit y
  
3 1 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 6 of 5 4  
 
 
6. 2  
S p o n s or-I n v e sti g at or R e p orti n g R e q uir e m e nt s – U T S o ut h w e st er n 
M e di c al C e nt er  ...................................................................................................................... 3 3 
6. 3  
E x c e pti o n s t o E x p e dit e d R e p orti n g  .................................................................... 3 5 
7. 0  
D A T A A N D S A F E T Y M O NI T O RI N G  ......................................................................................... 3 5 
7. 1 P h a s e 1 A: W a s hi n g t o n U ni v e r si t y  ............................................................................................... 3 5  
7. 2  
P h a s e 1 B & P h a s e 2: U T  S o u t h w e s t e r n M e di c al C e n t e r ...................................................... 3 6  
8. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  ........................................................................................... 3 7 
8. 1  
St u d y D e si g n  .............................................................................................................. 3 7 
8. 2  
E n d p oi nt s  .................................................................................................................... 3 7 
8. 3  
D at a A n al y si s  ............................................................................................................. 3 8 
8. 4  
S a m pl e Si z e  ................................................................................................................ 3 9 
8. 5  
E arl y st o p pi n g r ul e  .................................................................................................. 4 0 
8. 6  
A n al y si s s et  ................................................................................................................ 4 0 
9. 0  
R E F E R E N C E S  .............................................................................................................................. 4 1  
1 0. 0  A P P E N DI X A:  D efi ni ti o n s f o r A d v e r s e E v e n t R e p o r ti n g  ................................................. 4 6 
1 1. 0  A P P E N DI X B:  R e p o r ti n g Ti m eli n e s  ....................................................................................... 4 8  
1 2. 0  A P P E N DI X C:  W a s hi n g t o n U ni v e r si t y U n a n ti ci p a t e d P r o bl e m R e p o r ti n g C o v e r 
S h e e t  5 2  
1 3. 0  A P P E N DI X D:  D S M C S e ri o u s A d v e r s e E v e n t R e p o r t F o r m  ............................................. 5 3  
 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 7 of 5 4  
 
 
1. 0  
B A C K G R O U N D A N D R A TI O N A L E 
 
1. 1  
S ur gic al Resecti o n of B re ast C a ncer a n d Se nti nel L y m p h N o de Bi o ps y  
 
S ur gical res ecti o n is t he sta n dar d of care f or ma n y s oli d t u m ors s uc h as breast ca ncer, a n d 
se nti nel l y m p h n o de ( S L N) bi o ps y is use d f or ca ncer sta gi n g1. Bef ore breast s ur g er y, 
sta n dar d i ma gi n g met h o ds i ncl u di n g ma m m o gra p h y a n d ultras o u n d are use d t o i de ntif y 
t u m or l ocati o n. H o w e ver, t hese pre o perati ve i ma gi n g met h o ds are n ot a bl e t o pr o vi de real-
ti me i ma ge g ui da nce i n t he o perati n g r o o m t o e ns ure c o m plete re m o val of t u m ors or assess 
s ur gical mar gi ns. U nf ort u natel y, i nc o m plete t u m or re m o val i ncreases t he c ha nces of ca ncer 
rec urre nce b y  t w o -f ol d2 a n d  necessitates  re p eat  s ur ger y,  w hereas  i nacc urate  S L N  
i de ntificati o n ma y mis dia g n ose t he ca n cer sta ge. D es pite rece nt a d va n ces i n pre-o p erati ve 
i ma gi n g met h o ds, s ur ge o ns rel y o n vis ual i ns pecti o n, pal pati o n, a n d tactile e val uati o n t o 
disti n g uis h ca ncer fr o m u ni n v ol ve d tiss ue i ntra o perati vel y, lea di n g t o s u bjecti ve decisi o n-
ma ki n g a n d varia ble o ut c o mes. F or e x a m ple, u p t o 7 0 % 3- 5 of patie nts u n der g oi n g breast -
c o nser vi n g r ec o nstr u cti ve s ur ger y ( B CS) ha v e p ositi ve mar gi ns, de pe n di n g o n w here t h e 
s ur ger y wa s perf or me d, e x perie n ce of t he s ur ge o n, a n d t he t u m or c haract eristics6- 8.  F or 
t hese reas o ns, we see k t o de vel o p a n i ma ge-g ui de d met h o d f or differe ntiat i n g t u m ors fr o m 
s urr o u n di n g tiss ues a n d offer real-ti me s ur gi cal na vi gati o n 1 0 ,1 1. 
 
Si milarl y, assess me nt of t he S L N f or t he prese nce of ca ncer cells is sta n dar d of care f or 
sta gi n g  breast  ca ncer 1 ,1 2 ,1 3. I nacc urat e  S L N  re m o val  ofte n  re q uires  a d diti o nal  s ur gical  
i nter ve nti o ns1 4.  C o n ve nti o nall y,  patie nts  are  i njecte d  perit u m orall y  wit h  9 9 mTc  s ulf ur -
c oll oi d or a ne w C D 2 0 6 rece pt or -tar g ete d ra di o p h ar mace utical, 9 9 mTc Til ma n oce pt a n d a 
visi ble l y m p h otr o pic bl ue d ye. A ha n d h el d ga m ma -c o u nter is use d t o l o calize t he re gi o n of 
hi g hest ra di oacti vit y, a n d t he bl ue d y e ca n b e use d t o vis ualize t he S L N.  H o w e ver, 
ra di oacti ve S L N trac ki n g e x p oses p atie nts a n d h ealt h pr ofessi o nals t o i o nizi n g ra diati o n 
wit h o ut a direct S L N vis ualizati o n ca pa bilit y. Alt h o u g h bl ue d y es ca n b e vis ualize d wit h 
t he na ke d e ye, S L N tr ac ki n g b y t his met h o d is li mite d t o i ns pecti o n of o nl y s uperficial 
l y m p h  n o des  a n d  re q uir es  a  hi g h  d ose  of  t he  d ye,  w hic h  ma y  lea d  t o  har mf ul  si de 
effects 1 5 ,1 6. Wit h o ut k n o wi n g w hic h l y m p h n o des are p ositi ve, m ulti ple n o d es are re m o ve d 
ra n d o ml y f or s u bs e q ue nt hist ol o gic assess me nt. T h e a b o ve c halle n g es ha v e s p urre d i nterest 
i n de vel o pi n g met h o ds f or acc urate i ntra o perati v e detecti o n of t u m ors a n d S L Ns i n real-
ti me.  
 
1. 2  
I m a ge-G ui de d Ne ar -I nfr are d Fl u oresce nce S yste ms f or I ntr a o per ati ve 
C a ncer I m a gi n g  
 
T he pri mar y g oal of i ma ge g ui da nce i n t he o p erati n g r o o m is t o pr o vi de t h e s ur ge o n wit h 
acc ur ate, r eal-ti me i nf or mati o n a b o ut t he precise l ocati o n a n d b o u n dar y of t u m ors. T his 
will  als o  all o w  t he  s ur ge o n  t o  e x pl ore  alter nati ve  treat me nt  pla n ni n g  base d  o n  t he  
a g gressi ve ness of t he t u m or. A d va nce d i nstr u me nts t hat mi mic gl o bal p ositi o ni n g s yste ms 
ha ve als o bee n de vel o p e d, w here a pre o p erati ve C T or M R i ma ge ca n be pr ojecte d o nt o 
t he a p pr o priate a nat o mical str uct ures. T hese s yste ms s uffer fr o m t he li mitati o ns of t he pre -
o perati ve  i ma gi n g  met h o d,  u nsatisfact or y  re gistrati o n  d ue  t o  tiss ue  def or mati o n  a n d  
m oti o n, a n d lac k of t he a bilit y t o i ntra o perati vel y i nterr o gate s ur gical mar gi ns f or t he 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 8 of 5 4  
 
 
prese nce of t u m ors.  
 
R ece nt a d v a nces i n bi o p h ot o nics a n d se mic o n d u ct or tec h n ol o gies h a ve accelerate d t h e 
e mer ge n ce of o ptical i ma gi n g as a para di g m -s hifti n g met h o d f or real-ti me ca ncer detecti o n. 
O ptical i ma gi n g ca n det ect bi ol o gical e ve nts ra n gi n g fr o m m olec ular a n d s u b -cell ular 
le vels t o t he le vel of e ntire or ga n s yst e m s. I n t he near i nfrare d ( NI R ) re gi o n bet wee n 7 0 0 
a n d 9 0 0 n m, a bs or pti o n b y i ntri nsic p h ot oacti ve bi o m olec ules is l o w, w hic h mi ni mizes 
tiss ue a ut ofl u oresce n ce a n d facilitates t hic k tiss ue assess me nt2 1. U nli ke n uclear met h o ds, 
o ptical i ma gi n g utilizes n o ni o nizi n g ra diati o n. T his e x plai ns t he rece nt s ur g e i n i nterest i n 
a p pl yi n g t he met h o d i n i ntra o perati ve pr o ce d ures, w here t u m or b o u n daries, l y m p h n o de 
assess me nt, treat me nt res p o nse, a n d i m p orta nt p h ysi ol o gical para meters ca n be m o nit ore d 
i n real-ti me. T o date, vari o us o ptical tec h n ol o gies s uc h as fl u oresce nce i ma gi n g ha ve bee n 
a p plie d t o assess t u m or m ar gi ns 2 2 -3 1. Nearl y all t he s yste ms utilize t he NI R li g ht, w hic h ca n 
detect fl u or esce nt o bjects u p t o 1 c m d ee p i n s oli d tiss ue a n d 5 c m i n l u n g tiss ue. T hese 
o ptical i ma gi n g de vices offer hi g h -res ol uti o n (t y picall y 1 2 5 – 6 2 5 µ m) a n d lar ge fiel d s-of -
vie w ( 7 - 1 5 c m).  
 
T o da te, s evera l NIR-f l u oresce nce i ma ge - g uide d s u r ger y ( NI R- FI G S) s yste ms ha ve be en 
d e vel o pe d a n d s uccessf ully use d f or  i ntra o perative t u m or ima gi n g a n d S L N   ma p pi n g 
( S L N M), incl u di n g F L A R E 3 2, Fl uo bea m 3 3, S P Y 3 4, Pal o mar, a n d H a ma mat s u P D E3 5. T he 
S p y ™ s yste m fr o m N o va da q uses a n NI R laser t o e xcite t he s ur gical fiel d. T he S p y ™ 
s yste m has alrea d y b ee n gra nte d t hree se parate 5 1 0( k) a p pr o v als.  
 
1. 3  
We ar a ble C a ncer Visi o n G o g gles f or S ur gic al R esecti o n of C a ncer  
 
M ost  of  t he  c urre nt  o ptical  i ma gi n g  s yste ms  use d  i n  t he  NI R-FI G S  ha ve  m aj or  
s h ortc o mi n gs t hat i m pe de t he ra pi d a d o pti o n a n d sea mless i nte grati o n i nt o t he w or kfl o w 
of o nc ol o gic s ur ger y. T hese li mitati o ns i ncl u de t he use   of b ul k y har d w are, p ote ntiall y 
disr u pti ve i nf or mati o n dis pl a y o n a re mote m o nit or, m ismat c h betwee n t he  s ystem ’s a n d 
s ur ge o n’s fiel d of view ( F O V ), a d diti o nal eff ort fr o m a n ot her s ur gical staff t o c o ntr ol t he 
de v ice,  hi g h c ost , a n d c o m ple x i nstr u me ntati o n. T o o verc o me t hese li mitati o ns, our tea m 
rece ntl y  de vel o pe d a n d teste d  i n ca ncer patie nts  a ne w hea d -m o u nte d i ma gi n g s yste m, 
Ca ncer Visi o n G o g gles  ( C V G), f or use i n t he o perati n g r o o m3 6 -4 3. T he sc he matics a n d 
pr ot ot y pes of t he C V G s yste m are s h o w n i n Fi g ure s 1 a n d 2.    
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 9 of 5 4  
 
 
 
Fi g ure 1: Sc he matics of t he Ca ncer Visi o n G o g gles s yste m. F P G A - fiel d- pr o gra m ma ble 
gate arr a y; H D MI - hi g h-defi niti o n m ulti me dia i nterface; NI R – near -i nfrare d li g ht; R G B 
– re d, bl ue, gr ee n c ol or s pace; P C – pr ocessi n g c o m p uter u nit 4 3.   
 
 
Fi g ure 2: Pr ot ot y pes of t he Ca ncer Visi o n G o g gles s yste ms. (a) Vi de o -s ee-t hr o u g h versi o n 
w or n b y Dr. J ulie Mar g e nt haler i n t he o perati n g r o o m. ( B) O ptical -see-t hr o u g h versi o n 
w or n b y a r esearc her. B ot h s yste ms ha ve b ee n use d i n t he o p erati n g r o o m f or breast -
c o nser vi n g s ur ger y b y Dr. Mar ge nt haler 4 3. 
 
T he C V G h ol ds great pr o mise t o o verc o m e t he c hallen ges of t he  c urre nt NI R -FI G S  s yste ms 
a n d  e x pa n d  fl u ores ce nce -g ui de d  s ur ger y  i nt o  a d va nce d  cli nical  ce nters  as  well  as  
u n derser v e d areas, es peciall y t h ose i n l o w -res o urce setti n gs. T h is si m ple g o g gle-base d 
de vice is aff or da bl e, c o m pact, weara ble, a n d all o ws ha n ds -free s ur gi cal o perati o n. Wit h 
t his de vice, f u n cti o nal i nf or mati o n pr o vi de d b y t he NI R fl u oresce n ce of c o ntrast a ge nts i n 
ca ncer  cells  or  t he t u m or  e n vir o n me nt  ca n  be  directl y  dis pla ye d  wit h  a dj usta ble  
a m plificati o n o n t he g o g gles’ e ye piece. T h e C V G s yste m pr ojects b ot h NI R  fl u oresce n ce 
fr o m t u m ors a n d t he nat ural c ol or i ma ges of tiss ue o nt o a hea d m o u nte d dis pla y wit h o ut 
late nc y4 3.  
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 1 0  of 5 4  
 
 
1. 4  
H u m a n Pil ot St u dies U si n g We ar a ble C V G  
 
Cli nical feasi bilit y was d e m o nstrate d i n 1 5 breast ca ncer a n d 5 m ela n o ma patie nts d uri n g 
S L N   bi o ps y after l u m pect o m y  or mastect o m y f or breast or wi de e xcisi o n s ur geries  f or 
mela n o ma .  I n d oc ya ni n e  gree n  (I C G),  a n  F D A-a p pr o ve d  NI R  fl u oresce nt  d ye,  was  
e m pl o ye d as t he i ma gi n g a ge nt. S ur ge o ns use d t he i ma gi n g s yste m c o mf orta bl y wit h 
mi ni mal disr u pti o n t o t he s ur gical w or kfl o w. T he C V G all o we d clear vis ualizati o n of 3 0 
S L Ns fr o m 1 0 breast ca n cer a n d 5 mel a n o ma patie nts. Usi n g hist ol o gic a nal ysis as t he g ol d 
sta n dar d, t he C V G ha d a detecti o n se nsiti vit y of 1 0 0 % i n c o m paris o n t o 9 2. 8 6 % ± 1 7. 5 % 
f or t he bl ue d ye a n d 9 6. 4 3 % ± 1 2. 9 % f or ra di oacti ve trac ki n g. I n o ne mela n o ma patie nt 
( Fi g. 6), bl u e d ye di d n ot i de ntif y t w o dee p-seate d S L Ns. Si milarl y, i n o ne breast ca n cer 
patie nt, i nitial vis ual i ns pecti o n di d n ot re veal t he S L N a n d i n a n ot her patie nt, ra di oacti ve 
trac ki n g was u na bl e t o i de ntif y t w o S L Ns. I n t hese cases, t he S L Ns were clearl y i de ntifie d 
b y C V G. Alt h o u g h t he i ma gi n g de pt h wit h reas o na ble res ol uti o n is a b o ut 5 m m, hi g h 
fl u oresce n ce si g nal fr o m dee p-seat e d S L Ns is rea dil y pr ojecte d t o t he s urface, all o wi n g 
vis ualizati o n of S L Ns at > 5 m m dee p after defl ecti o n of t he o verl yi n g tiss ue la yer. T his 
pil ot st u d y de m o nstrates t he p ote ntial cli nical utilit y of t he s yste m f or ra pi d i de ntificati o n 
of S L Ns d uri n g s ur ger y. 
 
B y F D A g ui deli nes, t he C V G de vice is c o nsi dere d a “ n o n-si g nifica nt ris k” ( N S R) de vice 
a n d d oes n ot c o me i nt o direct c o ntact wit h patie nt tiss ue d uri n g s ur ger y. We will use t hese 
s yste ms t o assess t he NI R fl u oresce nce of t u m or-tar geti n g o ptical c o ntrast a ge nts i n t he 
pla n ne d st u d y. 
 
1. 5  
NI R Fl u oresce nt M olec ul ar Pr o bes f or t he A cc ur ate I de ntific ati o n of 
Di verse a n d Heter o ge n eo us T u m ors usi n g NI R -FI G S Is L ac ki n g 
 
M ost NI R - FI G S s yste ms are desi g ne d t o o perate i n t he NI R wa v ele n gt hs. S uccessf ul 
i m ple me ntati o n of real-ti me NI R -FI G S  f or m ore acc urate t u m or resecti o n re q uires t he 
de vel o p me nt of NI R fl u oresce nt i ma gi n g a ge nts t h at ca n s electi vel y bi n d or acc u m ulate i n 
heter o ge n e o us ca ncer  cells ,  i n de pe n de nt  of  t u m or  t y pe. Clearl y,  t he  de vel o p me nt  of  
acc ur ate a n d br oa d ca n cer -s pecifi c i ma gi n g a ge nts will accelerate cli nical tra nslati o n a n d 
use of o ptical i ma gi n g m et h o ds i n cli nics . O ptical m olec ular  i ma gi n g has e v ol ve d fr o m a 
pre d o mi na ntl y precli nical i ma gi n g tec h n ol o g y t o i ncreasi n g a p plicati o n s i n cli nics. T he 
pr o mise of hi g h detecti o n se nsiti vit y a n d real-ti me i ma gi n g fee d b ac k has res ulte d i n t he 
de vel o p me nt of a m yria d of o ptical m olec ular i ma gi n g pr o bes f or ca ncer a p plicati o n, 
ra n gi n g  fr o m  r ece pt or-me diate d  t o  e nz y m e  acti vata ble  m olec ular  pr o b es. 4 4 ,4 5 N ota ble 
e xa m ples i ncl u de t he use of fl u oresce nt i ma gi n g a ge nts i n l y m p h n o de ma p pi n g, i ma ge -
g ui de d  s ur ger y,  o p ht hal m ol o gic  a p plicati o ns,  a n d  e val uati o n of  l y m p h atic  fl o w. 
Researc h ers are acti vel y p urs ui n g t w o maj or re p orti n g strate gies i n de vel o pi n g m olec ular 
i ma gi n g pr o bes f or h u m a n use. First, a ffi nit y-bas e d  m olec ular pr o b es are c o ntrast a g e nts 
t hat selecti vel y acc u m ul ate i n t u m or tiss ue relati ve t o t he s urr o u n di n g n or mal tiss ue b y 
bi n di n g t o o ver -e x press e d pr otei ns or t hr o u g h ot her u pta k e mec ha nis ms. Affi nit y pr o bes 
t y picall y i n v ol ve t he c o nj u gati o n of a fl u oresce nt d ye t o t u m or-tar geti n g bi o m olec ules, 
s uc h as m o n ocl o nal a nti b o dies or hi g h affi nit y p e pti de li ga n ds. H o we ver, t his met h o d is 
c o m plicate d  b y  i ntri nsic  e x pressi o n  of  tar gete d  pr otei ns  i n  healt h y  tiss ues,  t u m or  


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 1 1  of 5 4  
 
 
heter o ge n eit y,  a n d  patie nt -de pe n d e nt  varia bilit y. 4 6 -5 3  A  sec o n d a p pr oac h  is  t o  use  
acti vata ble fl u or esce nt m olec ular pr o bes.  T hes e m olec ular pr o bes are d esi g ne d t o ha ve 
l o w fl u oresce nce yiel d u ntil t he y e nc o u nter a m olec ular tar get (e. g. e n z y me acti vata ble 
pr o bes) 5 4 or l ocalize i n f a v ora ble p h ysi ol o gical m e di u m (e. g. p H acti vata ble pr o bes). 5 5 ,5 6 
Alt h o u g h t hese pr o bes h a ve l o w b ac k gr o u n d fl u oresce n ce, t h e p ol y meric materials use d 
f or t heir de v el o p me nt res ults i n ver y sl o w fl u oresce nce e n ha n ce me nt, re q uiri n g se veral 
h o urs f or o pti mal si g nal e n ha nce me nt i n t u m ors, a n d ma y be c o m plicate d b y n o n -s pecifi c 
acti vati o n. F urt her, s yste mic a d mi nistrati o n of s u c h macr o m olec ules ca n elicit reacti o ns i n 
patie nts, a ris k t hat ma y li mit t heir use.  
 
W hat is nee d e d t o har n ess t he f ull p ote ntial of o ptical i ma gi n g (si m plicit y, u n parallele d 
detecti o n se nsiti vit y, a n d real-ti me fee d bac k) is t he de vel o p me nt of a NI R m olec ular pr o b e 
t hat ca n selecti vel y acc u m ulate i n ca ncer cells wit h hi g h s pecificit y, a n d a m olec ule wit h 
wi de a p plicati o ns si milar t o 2- de o x y- 2- [fl u ori n e-1 8]fl u or o - D-gl uc ose ( 1 8F- F D G), w hic h 
re v ol uti o nize d ca n cer dia g n osis t hr o u g h t he use of P E T.  
 
1. 6  
NI R Fl u oresce nt M olec ul ar Pr o be, L S 3 0 1, Selecti vel y Acc u m ul ates i n  Bre ast 
C a ncer a n d Ot her M ali g n a ncies  
 
We ha ve c h a m pi o ne d t he de vel o p me nt of di vers e NI R fl u oresce nt d ye -la bele d pe pti des 
(affi nit y pr o b es) f or use i n t he m olec ular o ptical i ma gi n g of t u m ors, as e vi de nce d b y t h e 
first de m o nstrati o n of t his a p pr oac h i n r o de nts5 7 ,5 8. As n ote d a b o ve, ca n cer heter o ge n eit y, 
e ve n wit hi n t he sa m e ca ncer p atie nt, c o nfi nes t he use of t hese i ma gi n g a ge nts t o o nl y 
s pecific ca n cer s u b-t y p es t hat o vere x press t he tar g et bi ol o gical bi o mar kers. We ha ve n o w 
disc o vere d a n e w m olec ular pr o be, L S 3 0 1, w hic h selecti vel y acc u m ulates i n pri mar y breast 
a n d ot her ca ncers (es p eci all y at t he t u m or peri p her y), s yste mic metastases a n d metastatic 
l y m p h n o des.  
 
1. 7  
Mec h a nis m of L S 3 0 1 C a ncer- Bi n di n g Acti o n  
 
L S 3 0 1 ( Fi g ure 3 ) is a s mall m olec ule ( < 1. 6 k D a) c o nsisti n g of a NI R fl u oresce nt d ye 
(c y pate)5 9 ,6 0 a n d a n octa pe pti de t hat is c y clize d t hr o u g h a dis ulfi de b o n d. T he NI R d ye, 
i n d oc ya ni ne gr ee n (I C G), is a n F D A-a p pr o ve d d y e f or use i n h u m a n s u bjects. T he s pectral 
pr o perties of I C G are s uita ble f or NI R -FI G S (e x citati o n/e missi o n 7 8 5/ 8 1 0 n m i n ser u m 
a n d a s ol uti o n of 2 0 % D M S O i n a n a q u e o us me di u m; m olar a bs or pti vit y, ε, 2 4 0, 0 0 0 M -
1.c m- 1;  a n d  fl u oresce nce  q ua nt u m  yiel d,  ψ,  1 0 %).  T his  d ye  has  bee n  e m pl o ye d  t o 
de m o nstrate  t he  feasi bilit y  of  usi n g  o ptical  i ma gi n g  met h o ds  t o  st u d y  h u ma n  
pat h o p h ysi ol o gical c o n diti o ns. U nf ort u natel y, I C G is n ot t u m or -selecti ve a n d its i na bilit y 
t o react wit h bi o m olec ul es has pre v e nte d its use f or la beli n g t u m or-tar g eti n g bi ol o gical 
carri ers 6 1 ,6 2. T o a d dress t his nee d, w e d e vel o pe d a n I C G deri vati ve, c y p ate, w hic h has 
si milar bi ol o gical cleara n ce pr ofile a n d s pectral pr o perties (a bs or pti o n, e missi o n, q ua nt u m 
yiel d) t o I C G. C y pate bi n ds re versi bl y t o t he h y dr o p h o bic p oc ket of al b u mi n, 6 3 ,6 4 a s o urce 
of nitr o ge n a n d e n er g y f or t u m ors. 6 5 -6 7 U nli ke c o vale ntl y d ye -la bel e d al b u mi n m olec ular 
pr o bes, c y pate is r elease d i n t u m ors u n der mil d aci dic c o n diti o ns as it traffics t hr o u g h t he 
e n d os o mal pat h wa y. T h e releas e d c y pate is o nl y tra nsie ntl y retai ne d i n t u m ors bef ore 
effl u x, li miti n g t he t u m or -t o- bac k gr o u n d c o ntrast.  


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 1 2  of 5 4  
 
 
 
 
Fi g ure 3: Str uct ure ( Left) a n d s pectral pr o perties of L S 3 0 1 ( Ri g ht). 
 
T o i m pr o ve t u m or rete nti o n, we e x pl ore d usi n g p e pti des t o tra p t he i nter n alize d c y pat e. 
T he hi g hl y re d uci n g e n vir o n me nt of t u m or cells is k n o w n t o re d uce dis ulfi de b o n ds t o 
t hi ols, w hic h ca n tra ns-t hi olate wit h c ystei ne-c o nt ai ni n g i ntracell ular pr otei ns a n d tra p t he 
m olec ular pr o be  i n ca ncer cells . T heref ore, we c o nj u gate d a variet y of dis ulfi de-c o ntai ni n g 
pe pti des t o c y pate a n d s cree n e d t he c o m p o u n ds i n i m m ortalize d h u ma n ca ncer cell li nes 
a n d mice wit h di vers e ca ncer xe n o grafts . O ur res ults s h o we d t hat L S 3 0 1 was selecti vel y 
retai ne d  i n  t u m or tiss ues c o m pare d  t o  t he  ot her  pe pti de  c o nj u gates.  Str uct ure-t u m or 
rete nti o n a nal ysis re v eal e d t hat t he u n nat ural D -cystei ne li n ke d t o c y pat e c o nfers hi g h 
bi ol o gical sta bilit y o n t he m olec ular pr o be b eca us e of its resista nce t o ra pi d de gra dati o n b y 
p r oteases. 
 
NI R  fl u ores ce nce  micr osc o p y  of  L S 3 0 1  i n  di verse  t u m or  cells  s h o we d  p u nct ate  
i ntracell ular fl u ores ce nce t y pical of rece pt or-me diate d e n d oc yt osis ( Fi g ure 4 ). Wester n 
bl ot, pr ote o mic a nal ysis, a n d bl oc ki n g st u dies i n cells wit h di verse i n hi bit ors of al b u mi n 
e n d oc yt osis p oi nt t o a n i nitial al b u mi n -me diate d e n d oc yt osis. T his mec ha nis m of u pta ke 
was f urt her s u p p orte d i n vitr o a n d i n viv o b y c o -i nc u bati o n of Ale xa 6 8 0 l a bele d b o vi n e 
ser u m al b u mi n ( B S A) wit h L S 3 0 1, w hic h s h o we d c o-l ocalizati o n of t he t w o fl u or o p h ores 
i n ca ncer cells at earl y ti me p oi nts. Di ver ge nce of t he d ye si g nals was o bser ve d at later 
ti me-p oi nts, i n dicati n g t he effl u x of t he Ale xa 6 8 0 fr o m t he ca ncer cells, w hile L S 3 0 1 
fl u oresce n ce w as retai ne d. Calci u m als o accelerates i nter nalizati o n of L S 3 0 1 i n ca ncer 
cells a n d a d diti o nal cell st u dies i n dicate t h at o ne of t he i ntracell ular pr otei ns t hat bi n d t his 
m olec ular pr o b e is p h os p h or ylate d  A n n e xi n A 2  ( p A n x A 2), a n i n dicat or of t he c hr o nic 
i nfla m mat or y e n vir o n me nt of t u m ors. Base d o n t he o n g oi n g st u dies, part of t he mec ha nis m 
of L S 3 0 1 u pta ke a n d r ete nti o n i n ca ncer cells i n v ol ves al b u mi n -facilitate d tra ns p ort t o 
t u m ors, f oll o we d b y bi n di n g t o p A n x A 2 o n t u m or cells a n d t u m or-ass ociat e d str o mal cells. 
T he  c o m ple x  traffics  i nt o  t he  cells  w here  L S 3 0 1  ca n  be  f urt her  sta bilize d  via  tra ns-
t hi olati o n  of  t he  D-c ystei ne wit h  i ntracell ular  pr otei ns  u n der  t he  hi g hl y  re d uci n g  
e n vir o n me nt of ca ncer cells. T he pe pti de is e ve nt uall y de gra de d a n d cleare d fr o m t he b o d y 
a n d t he d ye is cleare d vi a he pat o biliar y e xcreti o n pat h wa y si milar t o I C G.  


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 1 3  of 5 4  
 
 
 
Fi g ure 4: I nter nalizati o n of L S 3 0 1 i n breast ca n cer ( 4 T 1cells. Re d: L S 3 0; Bl ue: n uclear 
stai n ( D A PI). 
 
1. 8  
L S 3 0 1 Hi g hli g hts T u m ors i n Di verse A ni m al M o dels of C a ncer  
 
L S 3 0 1 is pr o d uce d at t he O ptical Ra di ol o g y L a b orat or y  at Was hi n gt o n U ni versit y Sc h o ol 
of Me dici ne i n c o nf or ma nce wit h G o o d L a b orat or y Practices as descri be d i n C F R 2 1 Parts 
2 1 0 a n d 2 1 1.  We ha v e e v al uate d L S 3 0 1 i n di verse t u m or m o dels i n mice, i ncl u di n g breast, 
l u n g,  c ol o n,  li ver,  pr ostate,  pa ncreatic,  a n d  brai n  t u m ors.  I n  all  cas es,  L S 3 0 1  was  
selecti vel y retai n e d i n o nl y t he t u m or tiss ue f or all differe nt t u m or t y pes ( Fi g ure 5 ).  
 
 
Fi g ure 5: Re pr ese ntati v e pla nar i ma ges of t u m or m o dels t hat selecti vel y retai n L S 3 0 1. 
Ort h ot o pic 4 T 1l uc m uri ne ( Left), D B T brai n ( Mi d dle), a n d H T 2 9 c ol o n ( Ri g ht) ca ncer 
m o dels. False c ol or f or L S 3 0 1 fl u oresce nce is re d  i n t he first t w o pa n els a n d rai n b o w i n 
t he last pa nel wit h bl ue as l o west i nte nsit y a n d re d as hi g hest i nte nsit y o btai ne d 2 4 h o urs 
after i njecti o n of L S 3 0 1.    
 
We  ha v e  als o  de m o nstrate d  t hat  L S 3 0 1  ca n  disti n g uis h  i nfla m mati o n  fr o m  c ol o n  
a de n ocarci n o ma i n c olitis m o del of c ol o n ca ncer , as w ell as p a ncreatitis fr o m pa ncreatic 
ca ncer.  T he  i ma gi n g  a g e nt  als o  i de ntifies  s p o nta ne o us  micr osc o pic  breast  t u m ors  or  
disse mi nate d cer v ical t u m ors wit h hi g h acc urac y, as well as p ositi ve l y m p h n o des (Fi g ure 
6 ).  


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 1 4  of 5 4  
 
 
 
Fi g ure 6:  L S 3 0 1 i de ntifies  l y m p h n o des i nfiltrate d b y met astatic breast  ca ncer cells. 
Pre o perati ve ( Left) a n d after re m o vi n g t he s ki n. Gree n: L S 3 0 1 fl u ores ce nce i n p ositi ve 
l y m p h n o des. 
 
T o si m ulate h u ma n breast ca ncer a p plicati o n, we teste d L S 3 0 1 i n tri ple -ne gati ve breast 
ca ncer usi n g t he cli nicall y-rele v a nt patie nt- deri v e d xe n o graft ( P D X) m o dels (Fi g ure 7 ).   
 
 
Fi g ure 7:  L S 3 0 1 u pta ke i n P D X breast ca n cer m o del. Re d: L S 3 0 1 fl u oresce nce. 
 
1. 8. 1  Preli mi n ar y ( N o n -G L P) A ni m al T o xicit y Testi n g  i n Mice  
 
P ote ntial t o xicit y of L S 3 0 1 has bee n test e d i n 6 0 y o u n g a d ult male a n d fe male C D -
1 I G S mice  wit h a n a v era ge b o d y wei g ht of 2 0 g .  T w e nt y males a n d 2 0 fe males 
were eac h a d mi nistere d a si n gle d ose of 7. 5 m g/ k g L S 3 0 1 ( 1 5 0 µ g i n 1 0 0 µ L sali ne 
c o ntai ni n g 1 % m uri ne ser u m al b u mi n ) i ntra ve n o usl y via t he lateral tail vei n. Te n 
c o ntr ols of eac h ge n der w ere a d mi nistere d a si n gle d ose of 1 0 0 µ L sali ne. Te n male 
a n d 1 0 fe m ale dr u g -treat e d a ni mals a n d 5 male a n d 5 fe male c o ntr ol a ni mals were 
e ut ha nize d  2  da ys  p ost -L S 3 0 1  a d mi nistrati o n .   T he  re mai ni n g  a ni mals  were  
e ut ha nize d  1 4 d a ys p ost- L S 3 0 1 a d mi nistrati o n. 
 
T here was n o i nci de nce of u ne x pecte d deat h. All a ni mals s ur vi ve d a n d re mai ne d 
healt h y u ntil t he pla n ne d e n d p oi nts. N o cli nical a b n or malities were n ot e d i n a n y of 
t he a ni mals. T her e w ere n o differe nces bet wee n t he treat e d a n d c o ntr ol gr o u ps f or 
all meas ure d he m at ol o g y para meters f or b ot h t he D a y 2 a n d Da y 1 4 ti me p oi nts.  
T he s o di u m a n d c hl ori d e le vels of treat e d male a ni mals e val uate d o n Da y 2 were 
sli g htl y l o wer t ha n t h ose of t he c o m para ble c o ntr ol a ni mals, b ut were n or mal b y 
Da y 1 4. T her e were n o a b n or mal gr oss necr o ps y fi n di n gs attri b uta ble t o L S 3 0 1. 
 
We f o u n d t hat  micr o gra n ul o mata  f or me d ar o u n d g ol de n-br o w n f oci of pi g me nt i n 
t he l u n gs.  T his fi n di n g was o bser ve d i n 1 6 of t h e 2 0 treate d a ni mals e val uate d o n 
Da y 2, wit h b ot h g e n ders si milarl y affecte d, a n d was n ot f o u n d i n a n y c o ntr ol 
a ni mals.  S o me of t hese f oci were f o u n d  wit hi n vessel l u me ns, b ut n o f urt her t ha n 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 1 5  of 5 4  
 
 
t he al ve olar wall.  T hese lesi o ns were a bse nt i n t he Da y 1 4 a ni mals, s u g gesti n g 
res ol uti o n of t his lesi o ns wit hi n t he 2 -wee k ti me fra me.  
 
1. 8. 2  Preli mi n ar y ( N o n -G L P) T o xicit y Testi n g i n C a ni nes 
 
T hree 4 - m o nt h-ol d fe mal e d o gs were treate d wit h 0. 9 m g/ k g L S 3 0 1 i ntra ve n o usl y 
o ver 5 mi n utes.  A ni mals were m o nit ore d cl osel y f or t he first h o ur f or c h a n ges i n 
be ha vi or, r es pirati o n, heart rate, a n d bl o o d press ure, t he n a gai n at 4, 2 4 a n d 4 8 h o urs 
p ost i njecti o n (see attac he d t o xicit y re p ort). Bl o o d was dra w n f or he mat ol o g y a n d 
cli nical c he mistries bef ore ( baseli ne) a n d at 1, 4, 2 4, 4 8 a n d 7 da ys after i njecti o n. 
O ne of t he d o gs v o mite d s o o n after i nf usi o n wit h o ut a n y ot her a d vers e effects. All 
a ni mals  be ha v e d  n or m all y  w he n  release d  a n d  c o nti n ue d  n or m al  b e ha vi or  
t hr o u g h o ut t he d urati o n of t he trial.  
 
T he w h ole bl o o d was ce ntrif u ge d at 3 0 0 0  x g  f or 1 0 mi nutes a n d  t he plas ma was 
se parat e d fr o m re d bl o o d cells wit h pi pettes. T he plas ma sa m ples at differe nt ti me 
p oi nt were meas ure d o n Bec k ma n C o ulter D U 6 4 0 s pectr o p h ot o meter directl y 
usi n g u n -treate d plas ma sa m ples as baseli nes  (Fi g ure 8 ). T he c o nce ntrati o ns of t he 
pr o be wer e cal c ulate d usi n g t he  Beer – La m bert la w a n d t he e xti ncti o n c oefficie nt 
of t he pr o be L S 3 0 1. O ne -p hase e x p o n e ntial fitti n g was perf or me d t o det er mi ne t he 
half -life. 
 
Fi g ure 8:  L S 3 0 1 c o n ce ntrati o ns i n serial plas ma sa m ples deter mi ne d b y a bs or pti o n 
s pectr osc o p y wit h pre-i nj ecti o n plas ma val ues as baseli ne. O ne-p h ase e x p o ne ntial 
least-s q uar es fitti n g deter mi ne d a n a vera g e eli mi nati o n half-life of 4. 8 +/- 0. 5 h o ur 
(T a ble 1 ). 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 1 6  of 5 4  
 
 
T a ble 1:  Calc ulate d bl o o d cleara nce para meters f or L S 3 0 1 i n d o gs. 
P ar a m eter  
D o g 5 2 0 8  
D o g 5 2 1 4  
D o g 5 2 1 5  
K  
0. 0 0 2 1 9 0  
0. 0 0 2 7 4 5  
0. 0 0 2 3 7 8  
Half Life  
3 1 6. 5  
2 5 2. 5  
2 9 1. 5  
R²  
0. 9 7 3 5  
0. 9 7 5 4  
0. 9 7 9 6  
 
O ne of t he pri mar y fi n di n gs was n ote d i n t he p eri p heral bl o o d of d o g 5 2 1 4 i n t he 
i nitial  p ost-treat me nt  peri o d.   T his  a ni mal  s h o we d  a  dr o p  i n  ne utr o p hils  fr o m  
baseli ne le vels o v er t he c o urse of 5 -6 0 mi n utes p ost -dr u g a d mi nistrati o n, wit h 
rec o ver y of t hese ne utr o p hil n u m bers 4 h o urs p ost-treat me nt.  T his c ha n ge was 
n ota ble, a n d ma y ha v e s u g geste d eit her mar gi nati o n of ne utr o p hils, or a s hift of 
ne utr o p hils t o t he or ga ns.  Base d o n o ur c o ns ultati o n wit h a veteri n ar y cli nical 
pat h ol o gist, t hese fi n di n gs ma y res ult fr o m eit her e n d ot o xe mia or i di os y ncratic 
dr u g reacti o n; platelets ma y f oll o w a s a me patter n as t he n e utr o p hils.  T he ot her 
a ni mals di d n ot s h o w a si milar patter n i n t hese n u m bers.  Gi ve n e n d ot o xe mia w o ul d 
be e x p ecte d t o ha ve affecte d all a ni mals, t his  fi n di n g was pres u me d t o reflect a n 
i di os y ncratic dr u g r eacti o n i n d o g 5 2 1 4.   
 
A n ot her fi n di n g i n t he p eri p heral bl o o d t hat was n ote d i n all t hree a ni mals was a 
sli g ht ele vati o n i n cr eati ni ne le vels at t he 4 h o ur a n d 2 4 h o ur ti me p oi nts (t his 
a nal yte w as n ot meas ure d at earlier ti me p oi nts).  F oll o wi n g f urt her i n v esti gati o n, 
it was deter mi ne d t h at t his li kel y reflecte d a n i nteracti o n of t he test c o m p o u n d wit h 
picric aci d use d as p art of t he test met h o d ol o g y  f or meas uri n g creati ni ne, f or mi n g 
a c hr o m o ge n t hat mi mic ke d t he a bs or b a nce e x pecte d f or creati ni ne. 
 
Asi de fr o m t he p ul m o n ar y c o n gesti o n a n d e d e ma alrea d y dis c usse d a b o ve, t he 
pri mar y fi n di n gs i n t he l u n gs i ncl u de d mi ni mal t o mil d s mall f oci of p ne u m o nitis.  
T hese wer e of li mite d distri b uti o n.  T he ca use a n d si g nifica nce of t hese, al o n g wit h 
t he s mall f oci of i nfla m mati o n n ote d i n t he li vers of all d o gs is n ot k n o w n; h o we ver, 
t hese are c o nsi dere d c o m m o n fi n di n gs i n y o u n g d o gs, a n d are t h o u g ht t o b e rel ate d 
t o pri or parasitic i nfecti o n.  I n partic ular, i nfecti o n wit h Ascari ds earl y i n life ca n 
pr o d uce s uc h lesi o ns.  C o m paris o n wit h c o ntr ol a ni mals o n a f ut ure st u d y ma y hel p 
clarif y  t his   o bser vati o n.   Als o  n ote d  i n  all  t hree  d o gs  were  s mall  f oci  of  
mi neralizati o n i n t he re n al pa pillae.  T h ese are ver y c o m m o n fi n di n gs i n d o gs a n d 
were n ot li kel y a tr eat me nt effect.  
 
1. 9  
I N D-E n a bli n g Precli nic al St u dies  
 
L S 3 0 1 was ma n ufact ur e d as re q uire d b y t he C urre nt G o o d Ma n ufact uri n g Practice (c G M P) 
Re g ulati o ns a n d use d i n safet y st u dies rec o m me n de d b y t he A ge nc y t o s u p p ort cli nical 
i n vesti gati o n of L S 3 0 1. A n a de q uatel y-d esi g ne d a n d c o ntr olle d safet y p har mac ol o g y st u d y 
i n  d o gs,  a n  a de q uatel y  desi g ne d  si n gle-d ose  t o xicit y  st u d y  i n  rats,  a n d  a  bacterial  
m uta ge nicit y te st ( A mes assa y) w ere c o n d ucte d i n c o m plia nce wit h G L P re g ulati o ns, a n d 
t he st u d y re p orts c o ntai n all re q uire d i nf or mati o n f or G L P c o m plia nce. T he test s yste ms 
use d i n t he st u dies were a p pr o priate a n d t he st u d y desi g ns i ncl u de d a p pr o priate c o ntr ols, 
a n d use d a p pr o priate/ vali date d a nal ytical met h o ds. Details of t hese st u dies are i ncl u de d i n 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 1 7  of 5 4  
 
 
t he re vise d s u b missi o n ( S N 0 0 0 1).  
 
1. 1 0  
Cli nic al St u d y Pl a n  
 
T he pri mar y g o al of t his h u ma n pil ot st u d y is t o tra nslate t he n o v el i ma gi n g a ge nt L S 3 0 1, 
w hic h selecti vel y i de ntifies breast ca ncer cells wit h hi g h acc urac y , t o h u ma n patie nts. 
Di verse a ni mal m o dels of breast ca ncer ha v e bee n i n vesti gate d  t o s ur gi cal re m o val of 
s p o nta ne o us, disse mi nate d, a n d diff use t u m ors, w hic h were detecte d t o si n gle ca ncer cell 
le vel b y L S 3 0 1. We ha ve als o s h o w n t hat t hat t he NI R fl u oresce nce ca n be ca pt ure d 
efficie ntl y usi n g C V G.  
 
T he ma xi m u m r ec o m me n de d starti n g d os e ( M R S D) f or t his cli nical trial w as base d o n t he 
N O A E L fr o m a ni mal st u dies. As s h o w n i n t he G L P t o xic ol o g y d oc u me nt, t he N O A E L 
fr o m t he rat t o xicit y st u d y is 1 0 m g/ k g f or fe males a n d 0. 5 m g/ k g f or male rats, w hic h is 
e qui vale nt t o h u ma n e q ui vale nt d ose ( H E D ) of 1. 6 m g/ k g a n d 0. 0 8 1 m g/ k g, res pecti vel y. 
A p pl yi n g a safet y mar gi n (t y picall y 1 0 -f ol d) t o t he N O A E L gi ves M R S D of 0. 1 6 m g/ k g 
base d o n fe male N O A E L a n d 0. 0 0 8 1 m g/ k g base d o n t he N O A E L i n male rats. T he hi g hest 
n o n-s e ver el y t o xic d ose ( H N S T D)  i n t he rat t o xicit y st u d y was deter mi ne d t o be 1 0 m g/ k g 
( H E D 1. 6 m g/ k g) i n b ot h male a n d fe male rats.  A n ot her a p pr oac h t hat is c o nsi dere d 
a p pr o priate t o deter mi ne a safe starti n g d ose is usi n g 1/ 6 t h of t he H N S T D i n a m ore 
se nsiti ve s pecies. Bas e d o n t he N O A E L a n d H N S T D fr o m t he rat t o xi cit y st u d y, t he 
ma xi m u m rec o m me n de d safe d ose t o test i n t he FI H st u d y was esti mate d t o be bet wee n 
0. 1 6 a n d 0. 2 6 m g/ k g. W hile pre vi o us i n vesti gati o ns wit h L S 3 0 1 i n mice s h o we d t he l o w est 
detecta ble d ose wit h t h e C V G t o be 0. 0 7 5 m g/ k g (e q ui vale nt t o H E D of t hat is 0. 0 0 6 
m g/ k g), a n a ntici pate d o pti mal starti n g d ose of 0. 1 m g/ k g will be use d as t h e starti n g d os e 
i n t he cli nical st u d y. T his d ose is well wit hi n t he esti mate d ra n ge f or t he M R S D esti mate d 
fr o m t he rat t o xicit y st u d y.  
 
We pr o p ose a p hase 1 r olli n g si x d ose- escalati n g desi g n gi ve n  t hat t his is t he first-i n- h u ma n 
use of L S 3 0 1, f oll o we d b y a p h ase 2 trial f or preli mi nar y e v al uati o n of its dia g n ostic 
ca pa bilities  (i ncl u di n g  se nsiti vit y  a n d  s pecificit y).   D uri n g  p hase  1 ,  L S 3 0 1  will  be  
a d mi nistere d i ntra ve n o usl y t o a c o h ort of si x patie nts at a d ose of 0. 0 5 m g/ k g; if fe wer t ha n 
2 D L Ts ar e o bser v e d, L S 3 0 1 will be gi ve n at t he ne xt hi g h d ose le vel of 0. 0 7 5 m g/ k g; if 
fe wer t ha n 2 D L Ts are o bser ve d, L S 3 0 1 will be gi ve n at t he e x p ecte d o pti mal d ose of 0. 1 
m g/ k g .  O nce safet y is c o nfir me d a n d t he o pti mal i ma gi n g d ose is esta blis he d , a n a d diti o nal 
9 patie nts will be e nr olle d i n t he p hase 1 e x pa nsi o n c o h ort t o e val uate f or s afet y. 
 
After p h ase 1 d ata has bee n s u b mitte d t o a n d disc usse d wit h t he F D A, a n a d diti o nal c o h ort 
of 8 8 patie nts will be e nr olle d t o t he p hase 2 p orti o n of t he trial t o assess t he dia g n ostic 
ca pa bilities of L S 3 0 1 f or i de ntificati o n of p ositi ve mar gi ns at s ur ger y.  Base d o n precli nical 
st u dies3 6 ,3 7 ,4 0 ,4 3 ,6 8, t he a ntici pate d o pti mal d ose f or L S 3 0 1 is 0. 1 m g/ k g b o d y wei g ht ( B W). 
T his d ose is a fracti o n of I C G c o n ce ntrati o n c urre ntl y a p pr o ve d f or h u ma n use . L S 3 0 1 will 
be f or m ulate d i n 1 % h u m a n ser u m al b u mi n ( H S A) i n sali ne a n d a d mi nistere d i ntra ve n o usl y 
as a sl o w i nf usi o n o ver 5 -1 0 mi n utes. Base d o n L S 3 0 1 i n 1 % H S A a n d ass u mi n g a 6 0 k g 
a d ult wit h 1. 6 m 2 s urface area a n d usi n g t he c o n v ersi o n fact or k m = 6 0/ 1. 6 = 3 7 k g/ m 2, the 
e q ui vale nt d ose is 1 0 0 µ g/ k g × 3 7 k g/ m 2 = 3. 7 m g/ m2.  


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 1 8  of 5 4  
 
 
 
I n all patie nts, L S 3 0 1 will be a d mi nistere d 4- 2 4 h o urs bef ore l u m pect o m y. L S 3 0 1 u pta ke 
i n pri mar y breast ca ncer or S L N vers us u ni n v ol ve d tiss ue will be vis ualize d wit h t he C V G 
s yste m d uri n g s ur ger y b y a me m b er  ( o p erati n g or n o n- o perati n g) of t h e s ur gical tea m . T he 
NI R li g ht s o urce f or t he C V G is base d o n li g ht -e mitti n g di o des ( L E Ds)  or laser li g ht 
o perati n g at 1 5 -2 0 m W/c m 2 o ut p ut at tiss ue, w hic h ca n deli ver s ufficie nt li g ht t o bi ol o gical 
tiss ues a n d i n d uce fl u oresce nce e missi o n t o meet t he nee ds of t he pla n ne d cli nical st u dies. 
It s h o ul d be n ote d t hat t h e li g ht s o urce is bel o w t h e U S F D A rec o m me n de d li mit f or NI R 
e x p os ure a n d A N SI sta n dar d. T he fl u oresce nce si g nals will be recei ve d b y t he detect or 
p orti o n of o ur de vi ce. G ai n -setti n gs c o ul d be easil y a dj uste d d uri n g o perati o n t o o pti mize 
t he c o ntrast bet wee n hi g h fl u oresce n ce areas (t u m ors) a n d l o w fl u ores ce n ce areas ( n or mal 
tiss ues). Real-ti me fl u oresce nce i ma g e will be dis pla ye d i n t he g o g gle e ye piece as w ell as 
o n a sec o n dar y m o nit or t o facilitate vie wi n g b y ot her me m bers of t he s ur gi cal tea m i n t he 
O R . I ma g es fr o m t he C V G or S P Y will n ot be use d t o alter t he s ur gical pla n i n a n y wa y. 
 
Fl u oresce nce i n t he e xcis e d tiss ue at t he mar gi ns will be deter mi ne d b y q u a ntitati ve near -
i nfrare d fl u ores ce nce micr osc o p y. F or eac h p atie nt, at least 4 s peci me ns fr o m e xcise d 
tiss ue  will  be  a nal yze d,  i ncl u di n g  s us pecte d  t u m or  a n d  s us pecte d  h ealt h y  tiss ue. De -
i de ntifie d data will be st ore d o n a c o m p uter. St ore d i nf or mati o n will o nl y ha ve c o de d 
n u m bers a n d n ot t he na m es of t he patie nts t o e ns ure patie nce pri vac y. 
   
1. 1 1  
R ati o n ale 
 
O ur  precli nical  data  ha ve  de m o nstrate d  t he  feasi bilit y  of  fl u oresce nce -g ui de d  t u m or  
resecti o n b y o ur C V G  wit h   L S 3 0 1 i n a ni mal m o dels. I n t his st u d y, we will  c o n d uct  
i ntra o perati ve i ma gi n g pr oce d ures t hat ha v e mi ni mal i nterfere nce wit h o n g oi n g s ur ger y. 
T he u n del yi n g h y p ot h esis is t hat t he acc urat e det ecti o n of all ca ncer cells hi g hli g hte d b y 
L S 3 0 1  d uri n g  s ur ger y  will  re d uce  t he  n u m ber  of  breast  ca ncer  p atie nts  wit h  mar gi n  
p ositi vit y t o less t ha n 5 %, c o m pare d t o t he c urre nt s ur gical para di g m of greater t ha n 2 0 % . 
T he pil ot st u d y will o btai n critical data re q uire d t o a d dress t he lar g er q uesti o n of s ur gical 
mar gi n assess me nt i n a f ull p hase I cli nical trial.  
 
1. 1 2  
P ote nti al C o ntri b uti o n  
 
T he a bilit y t o i de ntif y t u m ors i n viv o w o ul d be a hi g hl y usef ul cli nical t o ol f or o nc ol o gic 
s ur ge o ns.  W he n  utilize d  i n  t u m or  resecti o n,  i ncl u di n g  S L N  bi o ps y,  t he  pr o p ose d  
pr oce d ur es ca n rea dil y detect t u m or mar gi ns, s mall n o d ules, resi d ual t u m ors, a n d p ositi ve 
S L Ns, t here b y re d uci n g t he i nci de nce of i nc o m plete resecti o n, t he size of h ealt h y tiss ues 
resect e d, a n d t h e nee d f or re visi o n s ur g eries. M ore o ver, t h e pr o p ose d tec h n ol o g y ca n als o 
offer hi g h s p atial res ol uti o n i n real -ti me wit h o ut t he use of ra di oacti ve tracers.  I n a d diti o n 
t o i m pr o vi n g healt hcar e, t he a p pr o ac h  ca n p ote ntiall y s h orte n O R ti me t o f urt her re d u ce 
c ost of s ur ger y. T heref or e, t he L S 3 0 1 -me dia te d fl u oresce n ce i ma gi n g of t u m ors has hi g h 
p ote ntial i m pact o n breast ca ncer ma na g e me nt.  
 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 1 9  of 5 4  
 
 
2. 0  
O B J E C TI V E S  
 
2. 1  
Pri m ar y O bjecti ves  
 
P hase 1 :  to deter mi ne t h e saf et y a n d o pti mal i ma gi n g d ose of L S 3 0 1 i nj ecte d i n breast 
ca ncer patie nts.  
 
P hase 2 : t o deter mi ne t he a bilit y of t his n o vel fl u oresce n ce i ma gi n g a ge nt t o pre dict t he 
prese nce of p ositi ve mar gi ns ar o u n d partial mastect o m y s peci me ns a n d p ositi ve S L Ns 
d uri n g s ur gical t her a p y f or breast ca ncer. 
 
3. 0  
P A TI E N T S E L E C TI O N  
 
3. 1  
I ncl usi o n Criteri a 
 
1.  N e wl y  dia g n ose d  Sta ge  I -II  breast  ca ncer  pati e nts  u n der g oi n g  breast-c o nser vi n g 
t hera p y a n d S L N  bi o ps y. 
2.  N e gati ve n o dal b asi n cli nical e xa m.  
3.  At least  1 8 years of a ge.   
4.  A ble t o u n dersta n d a n d willi n g t o si g n a writte n i nf or me d c o ns e nt d oc u me nt. 
 
3. 2  
E xcl usi o n Criteri a  
 
1.  C o ntrai n dicati o ns f or s ur ger y.  
2.  Recei vi n g a n y i n vesti gati o nal a ge nts. 
3.  H ist or y of aller gic reacti o ns attri b ute d t o I C G or ot her a g e nts use d i n t he st u d y, i ncl u de 
k n o w n i o di de or seaf o o d aller g y . We d o n ot e x pect ma n y of t hese a d vers e reacti o ns 
wit h L S 3 0 1 beca use it is n ot ra di oacti ve a n d d o es n ot p ossess i o di nate d c o u nteri o ns. 
4.  Prese nce of u n derl yi n g l u n g disease.   
5.  Pre g na nt.   Fe m ale p atie nts of c hil d beari n g p ote ntial m ust ha ve a n e gati ve ser u m or 
uri ne pre g n a nc y test n o m ore t ha n 7 da ys bef ore start of partici pati o n. 
6.  Breastfee di n g. Patie nts w h o are breastfee di n g are e xcl u de d fr o m t his st u d y beca use 
t here is a n u n k n o w n b ut p ote ntial ris k f or a d v erse e ve nts i n n ursi n g i nfa nts sec o n d ar y 
t o treat me nt of t he m ot her wit h L S 3 0 1.  
 
3. 3  
I ncl usi o n of W o m e n a n d Mi n orities  
 
Breast ca n cer is r are i n m e n; t heref ore, it is li kel y t hat o nl y w o me n will e nr oll i n t his trial , 
alt h o u g h me n are eli gi ble.  Pe o ple of all races a n d et h nicities ma y e nr oll.  
 
4. 0  
R E GI S T R A TI O N P R O C E D U R E S  
 
P atie nts m ust n ot st art a n y pr ot oc ol i nter v e nti o n pri or t o re gistr ati o n t hr o u g h t he Site m a n 
C a ncer Ce nt er  f or p h ase 1 A a n d U T S o ut h wester n Me dic al Ce nter V el os d at a b ase f or p h ase 
1 B a n d p h ase 2 . 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 2 0  of 5 4  
 
 
T he f oll o wi n g ste ps m ust be ta ke n bef ore re gisteri n g patie nts t o t his st u d y: 
 
1.  C o nfir mati o n of patie nt eli gi bilit y  
2.  Re gistrati o n of patie nt i n t he Site ma n Ca ncer Ce nter O n C ore data b ase  f or p hase 1 A a n d 
U T S o ut h wester n Me dical Ce nter Vel os dat a base f or p hase 1 B a n d  ph ase 2.  
3.  Assi g n me nt of u ni q ue patie nt n u m ber ( U P N) 
 
4. 1  
C o nfir m ati o n of P atie nt Eli gi bilit y  
 
C o nfir m patie nt eli gi bilit y b y c ollecti n g t he i nf or mati o n liste d bel o w:  
 
1.  Re gisteri n g M D’s na me 
2.  Patie nt’s race, s e x, a n d D O B  
3.  T hree letters ( or t w o letters a n d a das h) f or t he p atie nt’s i nitials  
4.  C o p y of si g ne d c o nse nt f or m 
5.  C o m plete d eli gi bilit y c hec klist, si g ne d a n d date d b y a me m ber of t h e st u d y tea m 
6.  C o p y of a p pr o priate s o urce d oc u me nt ati o n c o nfir mi n g patie nt eli gi bilit y 
 
4. 2  
P atie nt Re gist r ati o n i n t he Site m a n C a ncer Ce nter O n C ore D at a b ase f or 
p h ase 1 A U T S o ut h wester n Me dic al Ce nter V el os D at a b ase f or p h ase 1 B 
a n d p h ase 2. 
 
All patie nts m ust be re gistere d t hr o u g h t he Site ma n Ca ncer Ce nter O n C ore data b ase  f or 
p hase 1 A U T S o ut h wester n Me dical Ce nter Vel os data base f or p has e 1 B a n d  phase 2 . 
 
4. 3  
Assi g n m e nt of U P N  
 
Eac h p atie nt will be i de ntifie d wit h a u ni q ue p atie nt n u m ber ( U P N) f or t his st u d y.  All dat a 
will be rec or d e d wit h t his i de ntificati o n n u m ber o n t he a p pr o priat e C R Fs. 
 
4. 4  
B aseli ne D at a C ollecti o n 
1.  Patie nt de m o gra p hic i nf or mati o n: a ge, se x, race, et h nicit y 
2.  Patie nt hei g ht, wei g ht, a n d b o d y mass i n de x ( B MI) 
3.  Patie nt me dical hist or y a n d c o nc o mita nt me dicati o ns  
 
5. 0  
S T U D Y P R O C E D U R E S  
 
5. 1  
L S 3 0 1 Pre p ar ati o n  
 
L S 3 0 1 will be pre p are d u n der c G M P pr ot oc ol a n d s u p plie d i n a n a m b er -c ol ore d vial as a 
l y o p hilize d pr o d uct i n 1 % H S A/ P B S a q ue o us s ol uti o n. Eac h vial will c o ntai n 2 m g L S 3 0 1. 
Bef ore a d mi nistrati o n, 1 0 m L of P B S will be a d de d t o t he l y o p hilize d p o w der a n d mi xe d 
b y s ha ki n g f or 1 mi n ute. T he a q ue o us f or m ulati o n is sta ble at r o o m te m perat ure f or 4 h o urs 
or i n t he refri ger at or ( 2- 8° C) f or 2 4 h o urs. T he a ge nt will be a d mi nistere d 4 -2 4 h o urs b ef ore 
s ur ger y.   
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 2 1  of 5 4  
 
 
5. 2  
Pr oce d ures  
 
5. 2. 1  P h ase 1  
 
A r olli n g si x desi g n (refer t o Secti o n 8. 1) will be use d t o e nr oll patie nts w h o are 
bei n g treate d f or p at h ol o gicall y pr o ve n breast ca ncer pri or t o defi niti ve s ur gical 
i nter ve nti o ns i n t he p hase 1 A d ose escalati n g p orti o n of t he st u d y, d uri n g w hic h 
L S 3 0 1 will be a d mi nistere d i ntra ve n o usl y at o ne of t hree d oses (see ta ble bel o w) .  
Patie nts  will  be  o bser ve d f or  d ose-li miti n g  t o xicities  ( D L T) (refer  t o  Secti o n  
5. 2. 1. 3). 
 
L S 3 0 1 D ose Le vel  
L S 3 0 1 D ose  
Le vel 1 (starti n g d ose)  
0. 0 5 m g/ k g  
Le vel 2  
0. 0 7 5 m g/ k g  
Le vel 3  
0. 1 m g/ k g  
 
T he patie nt will u n der g o s ur ger y 4- 2 4 h o urs after a d mi nistrati o n of L S 3 0 1 usi n g 
c urre nt b est pr actices.  Breast tiss ue  a n d a xillar y L Ns  will be i ma ge d n o n-i n vasi vel y 
pri or t o start of s ur ger y a n d e xcise d breast tiss ue a n d S L Ns will be e xa mi ne d e x 
vi v o f or t h e pr ese nce of L S 3 0 1 fl u ores ce n ce usi n g o ur Ca n cer Visi o n G o g gles 
( C V G) t o deter mi ne if L S 3 0 1 acc u m ulate d i n t he breast ca n cer. We will q ua ntif y 
fl u oresce n ce i nte nsit y i n t he ca ncer t o esta blis h t he feasi bilit y of o bser vi n g L S 3 0 1 
fl u oresce n ce wit h t he i m a gi n g s yste m. 
 
T he d ose us e d i n c o h ort 1 is  t he l o west d ose ( 0. 0 5 m g/ k g) a n d was use d e xcl usi vel y 
f or safet y assess me nt. T h e i n vesti gat ors di d n ot e x pect t o d etect L S 3 0 1- ass ociate d 
t u m or tiss ue  fl u oresce nce bef ore  i ncisi o n  at  t h is l o west  d ose  le vel. T heref ore, 
c o h ort  1  patie nts  will  n ot  be  i ma ge d  n o n-i n v asi vel y t o  assess  t u m or tiss ue 
fl u oresce n ce bef ore i ncisi o n. N o n -i n vasi ve t u m or fl u oresce n ce e xa mi nati o n will be 
i nitiate d fr o m c o h ort 2 o n war ds, w here hi g her d oses will be use d. 
 
I n v esti gat ors d o n ot e x pect t he 1st d ose ( 0. 0 5 m g/ k g) or 2 n d d ose ( 0. 0 7 5 m g/ k g) t o 
lea d t o a n y detecta ble fl u oresce n ce n o n-i n vasi v el y i n t he a xilla bef ore se nti nel 
l y m p h n o de e xcisi o n d u e t o t he l o w c o nce ntrati o n of e x p ecte d L S 3 0 1 re t e nti o n i n 
l y m p h  n o des.  T heref ore,  l y m p h  n o de  fl u ores ce nce  will  n ot  be  assesse d  n o n-
i n vasi vel y bef or e i ncisi o n f or c o h orts 1 a n d 2. I n vesti gat ors will pla n t o i ma ge 
l y m p h n o de re gi o ns n o n-i n vasi vel y starti n g wit h c o h ort 3 d ue t o t he hi g her i njecte d 
d ose ( 0. 1 m g/ k g). 
 
After t he o pti mal d ose h as bee n deter mi ne d, a n a d diti o nal 9 patie nts will be e nr olle d 
i n t he p hase 1 e x pa nsi o n c o h ort t o e val uate f or safet y. T his e x pa nsi o n c o h ort is  
c o nsi dere d p h ase 1 B a n d will be c o n d ucte d at U T S o ut h wester n Me dical C e nter.  
 
 
 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 2 2  of 5 4  
 
 
5. 2. 1. 1  D ose Esc al ati o n Sc he m a  
 
L S 3 0 1 D ose Le vel  
L S 3 0 1 D ose  
Le vel 1 (starti n g d ose)  
0. 0 5 m g/ k g  
Le vel 2  
0 .0 7 5 m g/ k g  
Le vel 3  
0. 1 m g/ k g  
 
D ose  escalati o n  ma y  o cc ur  as  s o o n  as  t he  last  patie nt  i n  a  c o h ort  has  
c o m plete d her o n e- h o ur p ost -i njecti o n t o xicit y m o nit ori n g. 
 
5. 2. 1. 2  Defi niti o n of O pti m al D ose  
 
T he o pti mal d ose will be t he d ose at w hic h fe wer t ha n 2 D L Ts are o bser v e d  
a n d  o pti mal  i ma ge  q ualit y  is  o bser ve d.   It  n ee d  n ot  be  t he  ma xi m u m  
t olerate d d ose if o pti mal i ma ge q ualit y is o bser v e d at a l o w er d os e t ha n t h e 
M T D.  
 
5. 2. 1. 3  Defi niti o n of D ose -Li miti n g T o xicities  
 
D L T is defi ne d as a n y gra de 2 or a b o v e t o xicit y t hat occ urs d uri n g t he 
h o ur after i njecti o n t hat is c o nsi dere d p ossi bl y, pr o ba bl y, or defi nitel y 
relate d t o L S 3 0 1. 
 
5. 2. 1. 4  D ose Esc al ati o n Criteri a  
 
T he m olec ular pr o b e L S 3 0 1 is a n i ma gi n g a ge nt bi n di n g t o breast ca ncer 
cells a n d ot her mali g na nt cells a n d will be vis ualize d t hr o u g h b y C V G 
w hic h is a n o n -si g nifica nt ris k de vice. Si milar t o t he F D A-a p pr o v e d a ge nt 
I C G, w e d o n ot e x pect a n y seri o us a d vers e e v e nts ca use d b y t he a ge nt.  
 
A r olli n g si x desi g n will be use d f or t he p h ase 1 p orti o n.  I n t he r olli n g si x 
desi g n, 2 t o 6 patie nts ca n be e nr olle d t o a d ose eac h ti me.  T he d ose de -
escalati o n o cc urs w he n t w o or m ore D L Ts occ ur at a d os e le v el, w hile d os e 
escalati o n occ urs wit h 3/ 3/, 4/ 4, 5/ 5, 5/ 6, or 6/ 6 patie nts are e v al uate d 
wit h o ut D L T.  ( Refer t o Secti o n 8. 1 f or f urt her details.)   
 
5. 2. 2  P h ase 2  
 
After  data fr o m  t he p hase 1 p orti o n of t he st u d y have bee n s u b mitte d t o a n d 
re vie we d b y t he F D A, a n d if a nal ysis of t he data fr o m p hase 1 c o nfir ms t he safet y 
of a d mi nisteri n g L S 3 0 1 i n h u ma ns  a n d esta blis hes t he o pti mal i ma gi n g d ose , 8 8 
patie nts will be e nr olle d i n t he p hase 2 p orti o n of t he st u d y  aft er a n y n ecessar y 
pr ot oc ol re visi o ns ha ve b ee n ma de b ase d o n p has e 1 data a n d F D A a p pr o val.   
 
 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 2 3  of 5 4  
 
 
It  is  e x p ecte d  t hat  t he  st u d y  pr oce d ures  f or  p h ase  2  will  be  t he  s a me  as  t he  
pr oce d ur es i n p has e 1.  T he o pti mal i ma gi n g d ose of L S 3 0 1 deter mi ne d i n p hase 1 
will be a d mi nistere d i n p hase 2. 
 
T he breast tiss ue  a n d a xillar y L Ns will be i ma ge d n o n -i n vasi vel y usi n g t he C V G 
a n d w or n b y a n o n -o p erati n g me m ber of t he s ur gical tea m. After re m o v al of t he 
breast ca ncer a n d S L Ns usi n g c urre nt best practice, a me m ber of t he s ur gical tea m  
w h o is n ot c o n d ucti n g t he s ur g er y will wear t h e C V G t o deter mi ne if L S 3 0 1 
fl u oresce n ce is pr ese nt at t he mar gi n a n d i n S L Ns, usi n g a gl o bal t hres h ol d of 2 0 % 
si g nal a b o ve bac k gr o u n d or a d y na mic statistical t hres h ol d t o i n dicate a p ositi ve 
mar gi n.  T he acc ur ac y of deter mi ni n g mar gi n p ositi vit y will be esta blis he d b y 
c o m pari n g t he C V G ass ess me nt t o hist o pat h ol o g y. 
 
5. 2. 3  A d mi nistr ati o n of L S 3 0 1 
 
T he  patie nt  will  u n der g o  i ntra ve n o us i njecti o n  of  L S 3 0 1  4-2 4  h o urs  pri or  t o  
s ur ger y.  A st u d y n urse or ot her q ualifie d me m ber of t he st u d y tea m will i nject t he 
L S 3 0 1 via I V o ver 5- 1 0 mi n utes i n t he office or pre -o p r o o m  (as a p plica ble) a n d 
will m o nit or t he patie nt as descri be d i n Secti o n 5. 4 bel o w. A d mi nistrati o n of L S 3 0 1 
will n ot i nterfer e wit h t he sta n dar d of care, i ncl u di n g all sta n dar d of care f or l y m p h 
n o de assess me nt usi n g 9 9 mTc Til ma n oce pt  i njecti o n o n t he da y of or d a y bef ore 
s ur ger y. 
 
5. 2. 4  I ntr a o per ati ve R e vie w 
 
T he o perati n g s ur g e o n will c o n d uct breast ca ncer s ur ger y as us ual wit h o ut usi n g a 
de vice t o vis ualize L S 3 0 1 fl u oresce nce. T o pre v e nt bias i n data ac q uisiti o n, a n o n-
o perati n g me m ber of t he st u d y tea m  will wear t he C V G  bef ore t he start of s ur ger y 
t o e xa mi ne t he br east tiss ue a n d a xillar y L Ns  n o n-i n vasi vel y a n d at t he c o m pleti o n 
of t he s ur ger y t o e x a mi ne t he e xcise d tiss ue , S L Ns  a n d s ur gical ca vit y . Fi n di n gs 
wit h t he st u d y will be rec or de d b ut will n ot c ha n ge t he sta n dar d of care.  T he 
o perati n g s ur g e o n will re mai n bli n de d t o t he fl u oresce n ce i ma g es t hr o u g h o ut t he 
o perati o n. T he e x a mi ni n g s ur gical tea m me m ber will wear t he C V G a n d i ma ge all 
si x a nat o mical as pects (s u peri or, i nferi or, a nteri or, p osteri or, me dial a n d lateral) of 
t he s ur gical s peci me n as well as t he s ur gical ca vit y f or L S 3 0 1 fl u oresce n ce. T he 
S P Y s yste m will be use d f or c o nfir mat or y fl u oresce nce i ma gi n g a n d c o m pare d wit h 
C V G detecti o n of L S 3 0 1 fl u oresce n ce, d uri n g p hase 2 of t he st u d y. 
 
Detecti o n of L S 3 0 1 fl u oresce n ce at t he c ut e d ge of t he e xcise d s peci me n will 
deter mi ne mar gi n p ositi vit y  a n d prese n ce of fl u oresce n ce i n t h e S L Ns i n dicate 
prese nce of metastatic ca ncer cells . Gi ve n t hat C V G ca n detect L S 3 0 1 fl u oresce nce 
i n t u m ors se veral milli meters dee p, i n vesti gat ors will use pat h ol o g y data t o i nitially 
trai n t he s yste m b y c orrelat i n g fl u ores ce nce i nte nsit y t o bac k gr o u n d rati o wit h 
pat h ol o gist’s mar gi n ass ess me nt . T he i nf or mati o n will t he n be use d i n p h ase 2 t o 
pre dict mar gi n p ositi vit y i n t he O R. T he d etecti o n of fl u oresce n ce o n e xcise d tiss ue 
wit h o ut c o rrelati ve fl u oresce nce i n t he t u m or ca vit y after l u m pect o m y will pre dict 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 2 4  of 5 4  
 
 
a ne gati ve mar gi n f or i n v asi ve d uctal carci n o ma. F or D CI S, laser p o wer m o d ulati o n 
wit hi n t he a p pr o ve d li mit or d ual e xcitati o n or e missi o n met h o d will be use d t o 
esti mate t he d e pt h of fl u oresce n ce s o urce. I n ge n eral, a  si g nal t o bac k gr o u n d rati o 
of 1. 2 ( 2 0 % hi g her i nte nsit y t ha n bac k gr o u n d) will be use d as a gl o bal t hres h ol d t o 
deter mi ne mar gi n a n d S L N p ositi vit y  stat us. I n a d diti o n, a d y na mic statistical 
t hres h ol di n g a p pr oac h will be use d t o deli neate t he b o u n dar y of tiss ue fl u oresce nce . 
A n i nte nsit y-base d  heat c ol or ma p will be use d f or false c ol or re prese ntati o n of t he 
fl u oresce n ce t o g ui de t he e xa mi ni n g s ur ge o n. Areas wit h hi g h L S 3 0 1 acc u m ulati o n, 
will be r e pres e nte d as r e d -h ot c o m pare d t o gree n a n d bl ue f or s urr o u n di n g tiss ue. 
A c o nti n u u m of re d fl u oresce n ce will i n dicate t hat t he e ntire e xcise d tiss ue is 
ca ncer.  Fl u oresce nce gra d ie nt usi n g t he heat c ol or ma p s h o wi n g re d t o bl ue fr o m 
t he e d ge of t u m or tiss ue will i n dicate a p ositi ve mar gi n. W he n t he fl u oresce nce 
e ma nati n g fr o m t u m ors a wa y fr o m t he mar gi n ( > 2 m m), haz y bl ue fl u oresce n ce 
will be o bser ve d at t he s ur gical mar gi n  a n d will be classifie d as cl ear mar gi n .   
 
If t his si m ple a p pr oac h fails t o acc uratel y i de ntif y p ositi ve or clea n m ar gi ns, we 
will  use  a  d ual  wa vele n gt h  e xcitati o n  f or  t he  de pt h -pr ofili n g  of  fl u oresce nce  
e missi o n. It  is  well  k n o w n  t hat  li g ht  tra vels  t hr o u g h  tiss ue  differe ntl y  acr oss  
wa vele n gt hs d ue t o wa vele n gt h -de pe n de nt o ptical pr o perties. W he n a fl u or o p h ore 
is e xcite d  usi n g  t w o  wa vele n gt hs,  t he  i nte nsit y  fall off  wit h  de pt h  of  eac h  
wa vele n gt h  will  be r elate d  t o  t he  de pt h  of  t he  fl u or o p h ore.  B eca us e  b ot h  
wa vele n gt hs  ar e  e xciti n g  t he  sa me  fl u or o p h ore  c o nce n trati o n,  t he  rati o  of  t he  
fl u oresce n ce  g e nerate d  yiel ds  t he  de pt h  of  t he  fl u or o p h ore  irres p ecti ve  of  
c o nce ntr ati o n  acc u m ulat e d i n t he t u m or tiss ue . The de pt h of fl u oresce n ce i n t he 
resect e d sa m ple will be esti mate d usi n g t w o s pectrall y se parat e d NI R w a vel e n gt hs 
t o e xcite L S 3 0 1 fl u oresce nce. T h e rati o of t he e mitte d i nte nsities i ma ge d f or b ot h 
e xcitati o n wa vel e n gt hs will be cl oser t o o n e w h e n t he t u m or tiss ue is at t he c ut 
s urface.  At  hi g her  d e pt hs  t he  rati o  will  de viat e  a w a y  fr o m  1  as  t he  s h orter  
wa vele n gt h  e xcitati o n is atte n uate d m ore t ha n l o n ger e x citati o n. A de pt h ma p of 
tiss ue fl u oresce nce will be create d a n d c o m pare d t o hist o pat h ol o g y f or deter mi ni n g 
t he acc ur ac y of pr e dicti n g p ositi ve or clear mar gi n stat us  a n d S L N metastatic stat us . 
T he d ual- w a vele n gt h m et h o d will i nitiall y be i m ple me nte d as a sta n d al o ne p orta ble 
cl ose d b o x c o nfi g urati o n w hic h will t he n be mi niat urize d a n d i m ple me nte d i n t he 
C V G.  
  
T he s ur gicall y re m o ve d t u m or mass a n d S L Ns will be pat h ol o gicall y e xa mi ne d 
u n der sta n d ar d pr ot oc ols. At least 4 s peci me ns fr o m t he e x cise d tiss ue of a patie nt, 
t w o s us pecte d t u m or a n d t w o s us pecte d healt h y tiss ue per patie nt will be a n al yze d. 
 
T he t u m or s peci me ns ge nerate d after brea dl oafi n g b y t he s ur gi cal pat h ol o gist will 
be i n di vi d uall y i ma ge d usi n g t he C V G a n d t he d ual -wa vele n gt h cl ose d b o x i ma gi n g 
s yste m bef ore fi xati o n a n d paraffi n e m be d di n g t o rec or d t he fl u oresce nce i nte nsit y 
l ocalizati o n a n d de pt h pr ofiles. Pat h ol o gist will pr o vi de tiss ue sa m ples t hat will be 
secti o ne d a n d m o u nte d o n sli des. T he secti o ne d tiss ue sli des will be i m a ge d f or 
L S 3 0 1 fl u oresce nce usi n g hi g h -res ol uti o n c o nf ocal micr osc o pes. T h ese will be 
c o m pare d t o sta n d ar d H e m at o x yli n & E osi n stai ni n g of t u m or tiss ue t o verif y 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 2 5  of 5 4  
 
 
L S 3 0 1  s pecificit y  f or  ca ncer  cells.  A d diti o nal  i m m u n o hist oc he mistr y  will  be 
perf or me d  o n  t hes e  tiss ue  secti o ns  t o  v erif y  or  i de ntif y   L S 3 0 1-ass ociate d 
bi o mar kers.   
  
5. 3  
E v al u a bilit y 
 
All  patie nts  w h o  recei ve  a n  L S 3 0 1  i njecti o n  are  e val ua bl e  f or  t o xicit y.   Patie nts  are  
e val uate d fr o m ti me of i njecti o n t o o ne- h o ur p ost-i njecti o n. 
 
Patie nts e nr olle d i n p h ase 1  are  e val u a ble f or D L T  assess me nt  d uri n g  t he h o ur  aft er 
i njecti o n.  Patie nts i n p hase 2 will n ot be assesse d f or D L T. 
 
5. 4  
S afet y E v al u ati o n  
 
T he safet y of t he L S 3 0 1 will be assesse d b y cl osel y m o nit ori n g t he patie nts ’ vital si g ns a n d 
la b orat or y tests as des cri be d bel o w. 
 
5. 4. 1  Vit al Si g ns  
 
All vital si g ns will be r ec or de d o n t h e case re p ort f or m. Vital si g ns ma y b e o btai ne d 
wit h t he s u bject i n t he s u pi ne or u pri g ht p ositi o n. Care will be ta ke n t o o btai n 
s u bse q ue nt rec or di n gs wit h t he s u bject i n t he sa me p ositi o n (s u pi ne or u pri g ht). 
Alt h o u g h aller gic or ot her i m me diate a d vers e reacti o ns are n ot a ntici pate d, s u bjects 
will be m o nit ore d f or at l east 6 0 mi n utes  p ost i njecti o n i n a n area w here e m er ge nc y 
e q ui p me nt is a vaila ble. Vital si g ns will be o btai ne d pre -i njecti o n ( wit hi n 3 0 mi n utes 
pri or t o i njecti o n of L S 3 0 1), wit hi n 3 0 mi n utes  p ost i njecti o n, at 6 0 mi n utes  p ost 
i njecti o n, a n d pri or t o s ur ger y. Vital si g ns will i ncl u de t he f oll o wi n g: heart rate, 
s yst olic  bl o o d  press ure,  diast olic  bl o o d  press ure,  res pirat or y  rate,  a n d  b o d y  
te m perat ur e. T he f oll o wi n g c ha n ges fr o m baseli ne will be c o nsi dere d n ote w ort h y:   
 
•  Heart r ate  > 2 0 b eats per mi n ute 
•  S yst olic bl o o d press ure > 2 0 m m H g 
•  Diast olic bl o o d press ure > 1 0 m m H g 
 
N ote w ort h y c ha n g es will be d oc u me nte d o n t he C R F, a n d t he y will be mar ke d as 
cli nicall y si g nifica nt or n ot. If cli nicall y si g nifica nt, t he pri nci pal i n vesti gat or will 
assess t he ca us alit y of t he c ha n g e t o t he i njecti o n of L S 3 0 1. Cli nicall y si g nifica nt 
c ha n ges i n vital si g ns will be f oll o we d u p h o url y u ntil t he y ret ur n t o bas eli ne or 
n or mal le vels, or u ntil f ol l o w-u p is n o l o n ger warra nte d. If a cli nicall y si g nifica nt 
c ha n ge of a vital si g n is n ote d, it will be re p orte d o n t he a d vers e e ve nt l o g.  
 
5. 4. 2  Cli nic al L a b or at or y Testi n g 
 
La b orat or y  tests  will  c o nsist  of  t he  f oll o wi n g:  sta n dar d  C B C,  c o m pre h e nsi ve  
meta b olic pa nel a n d uri nal ysis o btai ne d at t he f oll o wi n g ti me p oi nts:  


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 2 6  of 5 4  
 
 
•  Baseli ne: wit hi n 3 0 mi n utes pri or t o i njecti o n of L S 3 0 1 
•  6 0 mi n utes after i njecti o n of L S 3 0 1 
•  A p pr o xi matel y o ne h o ur p ri or t o s ur ger y 
 
A p pr o xi matel y 1 4 ml of bl o o d a n d a uri ne sa m ple will be c ollecte d at eac h ti me 
p oi nt.  F or patie nts e nr olle d i n p hase 1 B a n d p has e 2 of t he st u d y, a  p orti o n of t he 
bl o o d sa m ples fr o m eac h ti me p oi nt will be use d t o i de ntif y t he pre d o mi na nt bl o o d 
pr otei n(s) t hat bi n ds L S 3 0 1 a n d me diates t he bi oa vaila bilit y of t he a ge nt (refer t o 
Secti o n 5. 6).  P hase 1 B refers t o p has e 1 st u d y after c o m pleti n g dr u g safet y a n d 
selecti n g o pti mal d ose f or testi n g at 2 a n d 4 h o urs fr o m i njecti o n t o s ur ger y. T he 
c urre nt pr oject is t hat if 3 patie nts at eac h of t he 3 d ose le vel d o n ot e x p erie nce 
a d verse e ve nts, w e will nee d o nl y 9 patie nts f or t he dr u g safet y st u d y ( p h ase 1 A) 
an d a d diti o nal 9 patie nts  at t he selecte d d os e f or testi n g at 2, 4, a n d > 1 2 h o urs ( 3 
patie nts f or eac h ti me p oi nt) fr o m i njecti o n t o s ur ger y. 
 
T he res ults of sta n dar d of care la b orat or y t esti n g o btai ne d u p t o 3 0 d a ys p ost 
i njecti o n will be re vie we d. A nal ysis of t his will ta ke i nt o acc o u nt t hat t he s u bject 
has u n der g o n e s ur gical re m o val of t u m or a n d n e oa dj u va nt treat me nt i n cl u di n g 
h or m o nal t hera p y or c he m ot hera p y.  
  
T he f oll o wi n g c ha n ges fr o m baseli ne cli nical la b orat or y val ues are c o nsi d ere d t o 
be n ote w ort h y a n d re q uire assess me nt as t o cli nical si g nifica nce w he n t h e y fall 
o utsi de of n or mal li mits. Cli nicall y si g nifica nt c ha n ges i n la b orat or y val ues s h o ul d 
be f oll o we d u p dail y u ntil t he y ret ur n t o baseli ne or n or mal le vels, or u ntil f oll o w -
u p is n o l o n ger warra nte d. La b orat or y val ues t hat are a b n or mal at baseli ne b ut m o ve 
i nt o n or mal ra n ge will n ot be c o nsi dere d cli nicall y si g nifica nt.  If a cli nicall y 
si g nifica nt c ha n ge of a la b orat or y val ue is n ote d, it will be re p orte d o n t he A E  l o g.   
 
A n al yte  
C h a n ge fr o m b aseli ne  
He m o gl o bi n  
> 2 g/ d L  
W B Cs  
> 1 K/ m m 3  
Ne utr o p hils  
> 1 0 %  
L y m p h oc ytes  
> 1 0 %  
Platelets  
> 5 0 K/ m m 3  
Creati ni ne  
> 0. 7 5 m g/ d L  
B U N  
> 2 0 m g/ d L  
Calci u m  
> 1 m g/ d L  
S o di u m  
> 5 m m ol// L  
P otassi u m  
> 0. 5 m m ol/ L  
C O 2  
> 4 m m ol/ L  
A L T ( S G P T)  
> 1 5 0 I U/ L  
A S T ( S G O T)  
> 1 0 0 I U/ L  
Al kali ne P h os p hatase  
> 1 5 0 I U/ L  
T otal Bilir u bi n  
> 0. 5 m g/ d L  
Al b u mi n  
> 1 g/ d L  


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 2 7  of 5 4  
 
 
 
C ha n ges i n pre a n d p ost i njecti o n uri nal ysis will be n ote d b ut d u e t o varia bilit y will 
n ot be use d t o deter mi ne cli nical si g nifica nce f or c ha n ges d ue t o t he i njecti o n of 
L S 3 0 1.     
 
 
5. 4. 3  Electr oc a r di o gr a ms ( E C Gs)  
 
A sta n dar d 1 2 -lea d E C G will be o btai ne d o n all s u bjects at bas eli ne ( wit hi n 3 0 
mi n utes pri or t o i njecti o n of L S 3 0 1), 5 -1 0 mi n utes  p ost i njecti o n, a n d pri or t o 
disc har ge at 6 0 mi n utes.   
 
T he f oll o wi n g ta ble lists criteria f or n or mal li mits a n d cli nicall y n ota ble li mits f or 
E C Gs i n a d ults.  
 
 
N or m al Li mits ( msec)  
N ot a ble Li mits ( msec)  
E C G V ari a bles  L o w  
Hi g h  
L o w  
Hi g h  
P R i nter val  
1 2 0  
2 0 0  
< 1 2 0  
> 2 0 0  
Q R S i nter val  
5 0  
1 0 0  
< 5 0  
> 1 0 0  
R R i nter val  
6 0 0  
1 0 0 0  
< 6 0 0  
> 1 0 0 0  
Q T i nter val  
N o l o wer li mit  
≥ 4 6 0  
N o l o wer li mit  
≥ 4 6 0  
 
5. 4. 4  I de ntific ati o n of Bl o o d h alf-life of L S 3 0 1 
 
L S 3 0 1 half- life will be d eter mi ne d usi n g 5 0 0 µ L of bl o o d c ollecte d at t he sa me 
ti me as t he C B C a n d C M P at baseli ne, 6 0 mi n utes p ost-i njecti o n, a n d o ne h o ur 
bef ore s ur ger y . T h ese bl o o d sa m ples f or researc h use will be dra w n i nt o pi n k t o p 
li g ht- pr otecte d t u bes, br o u g ht t o t he Ac hilef u la b f or a nal ysis, t o i de ntif y t he 
c o nce ntr ati o n of L S 3 0 1 a n d deter mi ne of t he h alf- life of t he a g e nt.   
 
5. 5  
Ris ks a n d A d verse E ve nt M o nit ori n g  
 
A p ote ntial ris k s pecific t o t his e x peri me nt pr o ce d ure is t he i njecti o n of L S 3 0 1. T he 
i ma gi n g a ge nt is n ot k n o w n t o ca use a n y s eri o us a d vers e eve nts i n precli nical m o dels. 
H o we ver, it is p ossi ble t hat s o me p atie nts ma y e x perie nce mil d reacti o ns si milar t o t h ose 
t he y mi g ht e x perie n ce relate d t o Octre o Sca n (a n uclear ( S P E C T) i ma gi n g a ge nt) s u c h as 
dizzi ness, fe ver, c ha n g es i n li ver e nz y mes, a n d na usea. T he d ose escalati o n pr oce d ure will 
all o w us t o m o nit or t hese reacti o ns fr o m l o w t o hi g h d oses of L S 3 0 1. T her e are ot her 
e x peri me ntal t u m or tar gete d i ma gi n g a ge nts c urre ntl y bei n g e val uate d i n h u ma n patie nts  
(see t he ta ble bel o w). M ost of t he m eit her user a nti b o dies ta g ge d wit h I C G  or d ye- la bele d 
bi o m olec ule.  
 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 2 8  of 5 4  
 
 
List of i m a gi n g a ge nts u n der cli nic al i n vesti g ati o n f or i m a ge- g ui de d s ur ger y  
Sl 
n o  
A ge nt  
Cli nic al Tri al  
Tri al t y pe  
C a ncer 
t y pe 
A d verse 
re acti o ns  
1  
Cet u xi m u b 
I R D y e 8 0 0 
N C T 0 1 9 8 7 3 7 5  
P hase 1 d ose 
escalati o n st u d y  
Hea d a n d 
nec k  
Yes, i n 
h u ma ns 6 9 
a n d 
m o n ke ys 7 0 
2  
Pa nit u m u ma b 
I R D y e 8 0 0 
N C T 0 2 4 1 5 8 8 1  
P hase 1 safet y/ 
efficac y st u d y  
Hea d a n d 
nec k  
N o re p orts 
f o u n d 
3  
Be vaciz u ma b -
8 0 0 C W 
N C T 0 1 5 0 8 5 7 2  
N C T 0 2 5 8 3 5 6 8 
P hase 1  
P hase 2  
Breast  
N o re p orts 
f o u n d. 
N o ne 
re p orte d 
f or P E T 
versi o n 7 1 
4  
I C G a n d g o g gle  
N C T 0 2 3 1 6 7 9 5  
Pil ot  
Breast a n d 
Mela n o ma  
N o ne 
re p orte d4 3 
5  
I C G a n d 
Fl u o bea m  
N C T 0 1 7 3 8 2 1 7  
P hase 1 a n d 
P hase 2  
Li ver  
N o re p orts 
f o u n d 
6  
B L Z 1 0 0 a n d 
Fl u o bea m 
N C T 0 2 0 9 7 8 7 5  
P hase 1 d ose 
escalati o n  
S ki n 
ca ncer  
N o ne i n 
h u ma ns 7 2 
a n d d o gs 7 3 
7  
B L Z 1 0 0 a n d 
u ns pecifie d 
s yste m 
N C T 0 2 2 3 4 2 9 7  
P hase 1 safet y 
Gli o ma  
N o ne i n 
h u ma ns 7 2 
a n d d o gs 7 3 
 
T he ris ks fr o m t h e C V G  s yste m are e xtre mel y l o w. T he s yste m d oes n ot c o me i nt o c o ntact 
wit h t he test s u bject. It utilizes safe i n visi ble NI R li g ht bet wee n 7 0 0 a n d 9 0 0 n m at a ver y 
l o w fl ue nce rate ( ≤ 2 5 m W/c m2). T his i ma gi n g s yste m meets t he U S F D A defi niti o n of a 
“ n o n-si g nifica nt ris k” de vice, a n d i n dee d c o ul d be c o nsi dere d “e q ui vale nt ” t o t he S p y ™ 
s yste m, w hic h has alrea d y o btai ne d U S F D A a p pr o val as a n o n-si g nifica nt ris k de vice.  
 
T he U S F D A li mit f or NI R e x p os ure is 1 0, 0 0 0 m W/c m 2 a n d t he c urre nt s yste m utilizes 
2. 5- 2 5 m W/c m 2 f or a t otal d urati o n of less t h a n 3 0 mi n utes i n t he i nitial i ma gi n g a n d 1 0 
mi n utes per s u bse q ue nt i ma gi n g se g me nts. T his is e q ui vale nt t o t he c urre nt NI R d ose 
e mitte d fr o m t he sta n dar d 5 -la nter n s ur gical li g hts c o m m o nl y use d i n t he o perati n g r o o m. 
 
Patie nt safet y m o nit ori n g f or a d v erse e ve nts as a res ult of t his st u d y will be c o n d uct e d as 
descri be d  i n  S ecti o n 5. 4  a b o ve.  A n y  re p orta bl e a d verse  e v e nt  will  be  re p orte d  i n  
acc or d a nce t o Was hi n gt o n U ni versit y H R P O re g ulati o ns  (see Secti o n 6. 0) f or p hase 1 A . 
A n y re p orta ble a d verse e ve nt i n p hase 1 B/ p hase 2 will be re p orte d i n acc or d a nce t o U T S W 
H R P P/I R B g ui deli nes (see Secti o n 6. 0). 
 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 2 9  of 5 4  
 
 
5. 6  
C ollecti o n of S peci m e ns f or Res e arc h A n al yses  ( P h ase 1 B a n d P h ase 2 
O N L Y)  
 
5. 6. 1  I de ntific ati o n of Bl o o d Pr otei ns t h at Bi n d L S 3 0 1 
 
Fi ve m L  of bl o o d c ollect e d at t he sa me ti me as t h e  C B C a n d C M P at baseli ne, 6 0 
mi n utes p ost -i njecti o n, a n d o ne h o ur bef ore s ur g er y will be use d t o i de ntif y t he 
pre d o mi na nt bl o o d pr otei ns t hat bi n d L S 3 0 1 a n d me diate t he bi oa vaila bilit y of t he 
a ge nt.  T his r esearc h bl o o d will be dra w n i nt o a pi n k t o p li g ht-pr otecte d t u be a n d 
br o u g ht t o t he Ac hilef u l a b. 
 
5. 6. 2  Deter mi n ati o n of L S 3 0 1- Ass oci ate d Bi o m ar kers i n Bre ast C a ncer 
Tiss ue  
 
After  s ur gical  re m o val  of t he ca ncer,  t he sec o n d  ( n o n -o perati n g) s ur ge o n will  
e xa mi ne t he tiss ue wit h t he g o g gles a n d a n a d diti o nal i n k will be use d t o i de ntif y 
a n y L S 3 0 1 fl u oresce nce i n t he s ur gical mar gi n.  T his s ur ge o n will t he n use t he 
g o g gles  t o  pr oc ure  c ores  fr o m  t he  i n ke d  a n d  secti o ne d  s peci me ns  i n  s ur gical  
pat h ol o g y.  T hese c or es will t he n be fr o ze n a n d d eli vere d t o t he bi os peci m e n c ore 
f or accessi o ni n g, pr ocessi n g, a n d st ora ge.  T he s peci me ns will t he n be a nal yze d t o 
i de ntif y L S 3 0 1-ass ociate d bi o mar kers.  
 
5. 7  
D at a S u b missi o n Sc he d ule  
 
Case re p ort f or ms wit h a p pr o priate s o urce d oc u m e ntati o n will be c o m plete d acc or di n g t o t he 
sc he d ule liste d i n t his st u d y. 
 
C ase Re p ort F or m  
S u b missi o n Sc he d ule  
Ori gi nal C o nse nt F or m  
Pri or t o re gistrati o n  
O n St u d y F or m  Me dical Hist or y F or m  
At t he ti me of st u d y e ntr y  
L S 3 0 1 I njecti o n F or m  
After i njecti o n  
S ur ger y F or m  
After s ur g er y  
F oll o w -U p La bs F or m  
3 0 da ys after i njecti o n  
T o xicit y  F or m  
C o nti n u o us  
Deat h F or m  
Ti me of deat h  
Me d Watc h F or m  
As descri be d i n Secti o n 6. 0  
 
5. 7. 1  A d verse E ve nt C ollecti o n i n t he C ase Re p ort F or ms  
 
All a d verse e ve nts t hat o cc ur be gi n ni n g wit h start of treat me nt ( mi n us e x ce pti o ns 
defi ne d i n Secti o n 6. 0) m ust be ca pt ure d i n t he T o xicit y F or m.  Baseli ne A Es 
s h o ul d be ca pt ure d o n t h e Me dical Hist or y F or m. 
 
Partici pa nt deat h d ue t o disease pr o gressi o n s h o ul d be re p ort e d o n t he T o xicit y 
F or m as gr a de 5 disease pr o gressi o n.  If d eat h is d ue t o a n A E (e. g. car diac 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 3 0  of 5 4  
 
 
dis or ders: car diac arrest), re p ort as a gra d e 5 e ve nt u n der t hat A E.  Partici pa nt 
deat h m ust als o be rec or d e d o n t he Deat h F or m. 
 
5. 8  
W o m e n of C hil d be ari n g P ote nti al 
 
W o me n of c hil d beari n g p ote ntial ( defi ne d as w o me n wit h re g ular me nses, w o me n wit h 
a me n orr h ea, w o me n  wit h  irre g ular  c y cles,  w o m e n  usi n g  a  c o ntrace pti ve  met h o d  t hat  
precl u des wit h dr a wal blee di n g, a n d w o me n w h o h a ve ha d a t u b al li gati o n) are re q uire d t o 
ha ve a n e gati ve ser u m or uri ne pre g n a nc y test wit hi n 7 da ys  pri or t o a d mi nistrati o n of 
L S 3 0 1 bef ore  i ncl usi o n i n t his st u d y.   
 
5. 9  
D ur ati o n of St u d y P artici p ati o n 
 
If at a n y ti me t he c o nstrai nts of t his pr ot oc ol are c o nsi dere d t o be detri me ntal t o t he 
patie nt’s healt h a n d/ or t he patie nt n o l o n ger wis hes t o c o nt i nue i n t he pr ot oc ol, t he patie nt 
s h o ul d be re m o v e d fr o m t he st u d y a n d t h e reas o n f or disc o nti n uati o n d oc u me nte d i n t he 
case r e p ort f or ms . 
 
Patie nts will be o n st u d y f or t he d urati o n of t he scree ni n g pr ocess a n d t he s ur ger y or u ntil 
o ne of t he f oll o wi n g criteria a p plies: 
•  Deat h  
•  A d verse e ve nt(s) t h at, i n t he j u d g me nt of t he i n vesti gat or, ma y ca use s e vere or 
per ma ne nt har m 
•  S us pecte d pre g n a nc y  
•  Seri o us n o nc o m plia nce wit h t he st u d y pr ot oc ol 
•  L ost t o f oll o w- u p 
•  Patie nt wit h dra ws c o nse nt  
•  I n v esti gat or re m o v es t he patie nt fr o m st u d y 
•  T he Site ma n Ca ncer C e nter deci des t o cl ose t he st u d y  f or p hase 1 A  
•  T he U T S W De p art me nt of S ur ger y or Si m m o ns C o m pre he nsi ve Ca ncer Ce nter t o 
cl ose t he st u d y f or p has e 1 B  a n d phase 2  
 
F oll o w- u p will c o nti n ue f or 3 0 da ys p ost-s ur g er y (f or c ollecti o n of f oll o w- u p la b data). 
 
6. 0  
R E G U L A T O R Y A N D R E P O R TI N G R E Q UI R E M E N T S  
 
T he e ntities pr o vi di n g o versi g ht of safet y a n d c o m plia nce wit h t he pr ot oc ol re q uire re p orti n g as 
o utli ne d bel o w.   Please r efer t o A p p e n di x A f or defi niti o ns a n d A p pe n di x B f or a gri d of re p orti n g 
ti meli nes. 
 
A d verse e ve nts will be tr ac ke d f or o ne h o ur f oll o wi n g a d mi nistrati o n of L S 3 0 1.   
•  Baseli ne a d vers e e v e nts, w hic h s hall be rec or de d o n t he me dical hist or y C R F. 
•  F or p ur p os es of t his pr ot oc ol, a d vers e e v e nts c oll ecte d a n d d oc u me nte d o n C R Fs will n ot 
i ncl u de a n y e v e nts relate d t o s ur ger y. 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 3 1  of 5 4  
 
 
Refer t o t he d ata s u b missi o n sc he d ule i n Secti o n 5. 7  f or i nstr ucti o n o n t he c ollecti o n of A Es i n t he 
E D C.  
 
Re p orti n g re q uire m e nts f or Was hi n gt o n U ni versit y st u d y tea m ma y be f o u n d i n Secti o n 6. 1 a f or 
p hase 1 A .   
 
Re p orti n g re q uire me nts f or U T  S o ut h wester n M e dical Ce nter  st u d y tea m ma y be f o u n d i n Secti o n 
6. 1 b f or p hase 1 B a n d  ph ase 2.   
 
T he Was hi n gt o n U ni versit y H u ma n Researc h Pr otecti o n Office ( H R P O) re q uires t hat all e ve nts 
meeti n g t he defi niti o n of u na ntici pate d pr o ble m or seri o us n o nc o m plia nce be re p orte d as o utli ne d 
i n Secti o n 6. 2 f or p hase 1 A .  
 
T he U T S W H u ma n Researc h Pr otecti o n Pr o gra m Office ( H R P P O) re q uires t hat all e ve nts meeti n g 
t he defi niti o n of u na ntici pate d pr o ble m  or s eri o us n o nc o m plia nce be re p orte d as o utli ne d i n 
Secti o n 6. 2 f or p hase 1 B a n d  phase 2.  
 
T he F D A re q uires t hat all seri o us a n d u ne x pect e d a d verse e v e nts be re p ort e d as o utli ne d i n Secti o n 
6. 4.  I n a d diti o n, a n y fatal or life -t hreate ni n g a d verse e x p erie n ces w h ere t here is a reas o na bl e 
p ossi bilit y of relati o ns hi p t o st u d y i nter ve nti o n m ust be re p orte d. 
 
F or t he p ur p oses of t his st u d y, A Es relat e d t o s ur ger y will n ot be c ollect e d or c o nsi dere d re p ort a ble.  
 
6. 1  
S p o ns or -I n vesti g at or Re p orti n g Re q uire me nts – W as hi n gt o n U ni versit y 
 
P h ase 1 A: W as hi n gt o n U ni versit y  
 
6. 1. 1  Re p orti n g t o t he H u m a n Rese arc h Pr otecti o n Office ( H R P O) at 
W as hi n gt o n U ni versit y 
 
Re p orti n g will be c o n d ucte d i n acc or d a nce wit h Was hi n gt o n U ni versit y I R B 
P olicies.  
 
Pre -a p pr o v al of all pr ot o c ol e xce pti o ns m ust be o btai ne d pri or t o i m ple me nti n g 
t he c ha n ge. 
 
6. 1. 2  Re p orti n g t o t he Q u alit y Ass ur a nce a n d S afet y M o nit ori n g 
C o m mittee ( Q A S M C) at W as hi n gt o n U ni versit y  
 
T he  S p o ns or  I n vesti gat or  ( or  desi g nee)  is  re q uire d  t o  n otif y  Q A S M C  of  a n y  
u na ntici pate d pr o ble ms i n v ol vi n g ris ks t o partici pa nts or ot hers occ urri n g at W U or 
a n BJ H or S L C H i nstit uti o n t hat ha ve bee n re p orte d t o a n d ac k n o wle d ge d b y 
H R P O.  ( U na ntici pate d pr o ble ms re p orte d t o H R P O a n d wit h dra w n d uri n g t he 
re vie w pr o cess nee d n ot be re p ort e d t o Q A S M C.) 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 3 2  of 5 4  
 
 
Q A S M C m ust be n otifie d wit hi n 1 0 d a ys  of recei pt of I R B ac k n o wle d ge m e nt via 
e mail t o qas mc @ w ustl.e d u .  S u b missi o n t o Q A S M C m ust i ncl u de t he m yI R B f or m 
a n d a n y s u p p orti n g d oc u me ntati o n se nt wit h t he f or m. 
 
6. 1. 3  Re p orti n g t o t he F D A  
 
T he c o n d uct of t he st u d y will c o m pl y wit h all F D A safet y re p orti n g re q uire me nts.  
P L E A S E N O T E T H A T R E P O R TI N G R E Q UI R E M E N T S F O R T H E F D A 
DI F F E R F R O M R E P O R TI N G R E Q UI R E M E N T S F O R H R P O/ Q A S M C.  It 
is t he res p o nsi bilit y of t he i n vesti gat or t o re p ort a n y u na ntici pate d pr o ble m t o t he 
F D A as f oll o ws:  
•  Re p ort a n y u n e x pect e d fatal or life -t hreate ni n g s us pecte d a d vers e reacti o n 
(ref er t o A p pe n di x A f or defi niti o ns) n o later t ha n 7 c ale n d ar d a ys  after 
i nitial recei pt of t he i nf or mati o n.   
•  Re p ort a s us pecte d a d verse reacti o n t hat is b ot h seri o us a n d u ne x pecte d 
( S U S A R, refer t o A p pe n di x A), n o later t ha n 1 5 c ale n d ar d a ys  after it is 
deter mi ne d t hat t he i nf or mati o n q ualifies f or re p orti n g.  Re p ort a n a d v erse 
e ve nt (refer t o A p pe n di x A) as a s us pecte d a d v ers e reacti o n o nl y if t here is 
e vi de nce t o s u g gest a ca usal relati o ns hi p bet w ee n t he dr u g a n d t he a d v erse 
e ve nt, s uc h as: 
o  A si n gle occ urre nce of a n e ve nt t hat is u nc o m m o n a n d k n o w n t o be 
str o n gl y ass ociate d wit h dr u g e x p os ure 
o  O ne or m ore o cc urre n ces of a n e ve nt t hat is n ot c o m m o nl y ass ociate d 
wit h dr u g e x p os ure b ut is ot her wise u nc o m m o n i n t he p o p ulati o n 
e x p ose d t o t he dr u g 
o  A n a g gre g ate a n al ysis of s pecific e v e nts o bser ve d i n a cli nical trial t hat 
i n dicates t h ose e ve nts occ ur m ore fre q u e ntl y i n t he dr u g treat me nt 
gr o u p t ha n i n a c o nc urre nt or hist orical c o ntr ol gr o u p 
•  Re p ort a n y fi n di n gs fr o m e pi de mi ol o gical st u dies, p o ole d a nal ysis of 
m ulti ple st u dies, or cli nical st u dies t hat s u g gest a si g nifica nt ris k i n 
h u ma ns e x p ose d t o t he dr u g n o later t ha n 1 5 c ale n d ar d a ys  after it is 
deter mi ne d t hat t he i nf or mati o n q ualifies f or re p orti n g. 
•  Re p ort a n y fi n di n gs fr o m a ni mal or i n vitr o testi n g t hat s u g gest si g nifica nt 
ris k i n h u ma ns e x p ose d t o t he dr u g n o later t ha n 1 5 cale n dar da ys after it is 
deter mi ne d t hat t he i nf or mati o n q ualifies f or re p orti n g.  
•  Re p ort a n y cli nicall y i m p orta nt i ncrease i n t he rate of a seri o us s us pect e d 
a d verse reacti o n of t hat liste d i n t he pr ot oc ol or I B wit hi n 1 5 cale n d ar d a ys 
after it is deter mi ne d t hat t he i nf or mati o n q ualifies f or re p orti n g.  
 
S u b mit eac h r e p ort as a n I N D safet y re p ort i n a n arrati ve f or m at or o n F D A F or m 
3 5 0 0 A or i n a n electr o nic f or mat t hat F D A ca n pr o cess, re vie w, a n d arc hi ve.  St u d y 
tea ms m ust n otif y t he Site ma n Ca ncer Ce nter Pr ot oc ol De vel o p me nt tea m of eac h 
p ote ntiall y  re p orta ble  e ve nt  wit hi n  1  b usi ness  da y  after  i nitial  recei pt  of  t he  
i nf or mati o n, a n d m ust bri n g t he si g ne d 1 5 7 1 a n d F D A F or m 3 5 0 0 A t o t he Site ma n 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 3 3  of 5 4  
 
 
Ca ncer Ce nt er Pr ot oc ol De vel o p me nt tea m n o lat er t ha n 1 b usi ness d a y pri or t o t he 
d ue date f or re p orti n g t o t he F D A. 
 
Eac h n otificati o n t o F D A m ust bear pr o mi ne nt i de ntificati o n of its c o nte nts (“I N D 
Safet y Re p ort”) a n d m ust be tra ns mitte d t o t h e re vie w di visi o n i n t he Ce nter f or 
Dr u g E val u ati o n a n d Researc h ( C D E R) or i n t h e Ce nter f or Bi ol o gics E v al uati o n 
a n d Researc h ( C B E R) t hat has res p o nsi bilit y f or re vie w of t he I N D.  R ele va nt 
f oll o w-u p i nf or mati o n t o a n I N D safet y re p ort m ust be s u b mitte d as s o o n as t he 
i nf or mati o n is a vaila bl e a n d m ust be i de ntifie d as s uc h (“ F oll o w-u p I N D Safet y 
Re p ort”).  
 
6. 2  
S p o ns or -I n vesti g at or Re p orti n g Re q uire me nts – U T S o ut h wester n  
 
P h ase 1 B a n d P h ase 2:  
 
6. 2. 1  Re p orti n g t o t he H u m a n Rese arc h Pr otecti o n Pr o gr a m office 
( H R P P) at U T S o ut h wester n Me dic al C e nter 
 
Re p orti n g will be c o n d ucte d i n acc or d a nce wit h U T S o ut h wester n Me dical Ce nter 
I R B P olicies. 
 
Pre -a p pr o v al of all pr ot o c ol e xce pti o ns m ust be o btai ne d pri or t o i m ple me nti n g 
t he c ha n ge. 
 
6. 2. 2  Re p orti n g t o t he D at a a n d S afet y M o nit ori n g C o m mittee ( D S M C) at 
U T S o ut h wester n Me di c al Ce nter  
 
F or  l o cal  p atie nts,  i n  a d diti o n  t o  t he  s p o ns or  m o nit ori n g,  t he  Si m m o ns  
C o m pre he nsi ve Ca n cer Data Safet y a n d M o nit ori n g C o m mittee ( D S M C) will be 
m o nit ori n g o nl y l ocal u n a ntici pate d S A E’s as re p orte d t o t he I R B. T he c h air will 
re vie w  o nl y  l ocal  u na ntici pate d S A E’s  i n  real  ti me.  T hese  are  t he n  re vie we d  
q uarterl y at D S M C meeti n gs T he c hair ma n of t h e D S M C is res p o nsi ble f or t his 
o n g oi n g m o nit ori n g. M o nit ori n g of seri o us a d verse e ve nts ha p pe ns b y t he D S M C 
c hair ma n i n real ti me a n d a n a n n ual re vi e w ta kes place t o l o o k at tre n ds i n a d verse 
e ve nts, accr ual a n d ot her a p plica ble st u d y e ve nts. T he Pri nci pal I n vesti gat or ( or a 
desi g nate d  c o -i n v esti gat or)  will  be  pri maril y  res p o nsi ble  f or  m o nit ori n g  st u d y  
accr u al rate, st u d y attriti o n/ wit h dra wals/ dr o p o uts, patter ns of a d v erse e ve nts a n d/ or 
u na ntici pate d e ve nt a n d patter ns of pr ot oc ol vi olati o ns a n d/ or de viati o ns at t his site.  
 
Trial m o nit ori n g will be c o n d ucte d n o l ess t ha n a n n uall y a n d refers t o a re g ular 
i nter val re vi e w of trial rel ate d acti vit y a n d d oc u me ntati o n w hic h i ncl u des b ut is n ot 
li mite d  t o  acc urac y  of  case  re p ort  f or ms,  pr ot o c ol  c o m plia nce,  ti meli ness  a n d  
acc ur ac y of  Vel os e ntri es a n d A E/ S A E ma na ge me nt a n d re p orti n g. D oc u me ntati o n 
of trial m o nit ori n g will be mai ntai ne d al o n g wit h ot her pr ot oc ol relate d d o c u me nts 
a n d will be re vie w e d d uri n g i nter nal a u dit.   
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 3 4  of 5 4  
 
 
T he  S p o ns or  I n vesti gat or  ( or  desi g nee)  is  re q uire d  t o  n otif y  D S M C  of  a n y  
u na ntici pate d pr o ble ms i n v ol vi n g ris ks t o partici pa nts or ot hers occ urri n g at U T S W 
t hat ha ve bee n r e p orte d t o a n d ac k n o wle d ge d b y H R P P.  ( U na ntici pate d pr o ble ms 
re p orte d t o H R P P a n d wit h dra w n d uri n g t he re vie w pr ocess nee d n ot be re p orte d t o 
D S M C.)  
 
D S M C m ust be n otifie d i n real -ti me as t he y are re p orte d t o t he I R B t o t he U T S W 
Si m m o ns Ca ncer Ce nter D S M C C o or di nat or.  
 
6. 2. 3  Re p orti n g t o t he F D A  
 
T he c o n d uct of t he st u d y will c o m pl y wit h all F D A safet y re p orti n g re q uire me nts.  
P L E A S E N O T E T H A T R E P O R TI N G R E Q UI R E M E N T S F O R T H E F D A 
DI F F E R F R O M R E P O R TI N G R E Q UI R E M E N T S F O R H R P P/ D S M C.  It is 
t he res p o nsi bilit y of t h e i n vesti gat or t o re p ort a n y u na ntici pate d pr o ble m t o t he 
F D A as f oll o ws:  
•  Re p ort a n y u n e x pect e d fatal or life -t hreate ni n g s us pecte d a d vers e reacti o n 
(ref er t o A p pe n di x A f or defi niti o ns) n o later t ha n 7 c ale n d ar d a ys  after 
i nitial recei pt of t he i nf or mati o n.   
•  Re p ort a s us pecte d a d verse reacti o n t hat is b ot h seri o us a n d u ne x pecte d 
( S U S A R, refer t o A p pe n di x A), n o later t ha n 1 5 c ale n d ar d a ys  after it is 
deter mi ne d t hat t he i nf or mati o n q ualifies f or re p orti n g.  Re p ort a n a d v erse 
e ve nt (refer t o A p pe n di x A) as a s us pecte d a d v ers e reacti o n o nl y if t here is 
e vi de nce t o s u g gest a ca usal relati o ns hi p bet w ee n t he dr u g a n d t he a d v erse 
e ve nt, s uc h as: 
o  A si n gle occ urre nce of a n e ve nt t hat is u nc o m m o n a n d k n o w n t o be 
str o n gl y ass ociate d wit h dr u g e x p os ure 
o  O ne or m ore o cc urre n ces of a n e ve nt t hat is n ot c o m m o nl y ass ociate d 
wit h dr u g e x p os ure b ut is ot her wise u nc o m m o n i n t he p o p ulati o n 
e x p ose d t o t he dr u g 
o  A n a g gre g ate a n al ysis of s pecific e v e nts o bser ve d i n a cli nical trial t hat 
i n dicates t h ose e ve nts occ ur m ore fre q u e ntl y i n t he dr u g treat me nt 
gr o u p t ha n i n a c o nc urre nt or hist orical c o ntr ol gr o u p 
•  Re p ort a n y fi n di n gs fr o m e pi de mi ol o gical st u dies, p o ole d a nal ysis of 
m ulti ple st u dies, or cli nical st u dies t hat s u g gest a si g nifica nt ris k i n 
h u ma ns e x p ose d t o t he dr u g n o later t ha n 1 5 c ale n d ar d a ys  after it is 
deter mi ne d t hat t he i nf or mati o n q ualifies f or re p orti n g. 
•  Re p ort a n y fi n di n gs fr o m a ni mal or i n vitr o testi n g t hat s u g gest si g nifica nt 
ris k i n h u ma ns e x p ose d t o t he dr u g n o later t ha n 1 5 cale n dar da ys after it is 
deter mi ne d t hat t he i nf or mati o n q ualifies f or re p orti n g.  
•  Re p ort a n y cli nicall y i m p orta nt i ncrease i n t he rate of a seri o us s us pect e d 
a d verse reacti o n of t hat liste d i n t he pr ot oc ol or I B wit hi n 1 5 cale n d ar d a ys 
after it is deter mi ne d t hat t he i nf or mati o n q ualifies f or re p orti n g.  
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 3 5  of 5 4  
 
 
S u b mit eac h r e p ort as a n I N D safet y re p ort i n a n arrati ve f or m at or o n F D A F or m 
3 5 0 0 A or i n a n electr o nic f or mat t hat F D A ca n pr o cess, re vie w, a n d arc hi ve.  St u d y 
tea ms m ust n otif y t he D e part me nt of S ur ger y Researc h tea m or Si m m o ns Ca ncer 
Ce nter tea m of ea c h p ot e ntiall y re p orta ble e v e nt wit hi n 1 b usi ness da y after i nitial 
recei pt of t he i nf or mati o n, a n d m ust bri n g t he si g ne d 1 5 7 1 a n d F D A F or m 3 5 0 0 A 
t o t he De part me nt of S ur ger y Researc h tea m or Si m m o ns Ca ncer Ce nter tea m n o 
later t ha n 1 b usi ness da y pri or t o t he d ue date f or re p orti n g t o t he F D A. 
 
Eac h n otificati o n t o F D A m ust bear pr o mi ne nt i de ntificati o n of its c o nte nts (“I N D 
Safet y Re p ort”) a n d m ust be tra ns mitte d t o t h e re vie w di visi o n i n t he Ce nter f or 
Dr u g E val u ati o n a n d Researc h ( C D E R) or i n t h e Ce nter f or Bi ol o gics E v al uati o n 
a n d Researc h ( C B E R) t hat has res p o nsi bilit y f or re vie w of t he I N D.  R ele va nt 
f oll o w-u p i nf or mati o n t o a n I N D safet y re p ort m ust be s u b mitte d as s o o n as t he 
i nf or mati o n is a vaila bl e a n d m ust be i de ntifie d as s uc h (“ F oll o w-u p I N D Safet y 
Re p ort”).  
 
6. 3  
E xce pti o ns t o E x pe dite d Re p orti n g  – W as hi n gt o n U ni versit y a n d U T 
S o ut h wester n  
 
E ve nts t hat d o n ot re q uir e e x pe dite d re p orti n g as descri be d i n Secti o n 6. 1 i ncl u de: 
•  pla n ne d h os pitalizati o ns 
•  h os pitalizati o ns < 2 4 h o urs 
•  res pite care 
•  e ve nts relat e d t o disease pr o gressi o n  
 
E ve nts t hat d o n ot re q uir e e x pe dite d re p orti n g m ust still be ca pt ure d i n t he E D C.  
 
 
7. 0  
D A T A A N D S A F E T Y M O NI T O RI N G  
 
7. 1  
P h ase 1 A: W as hi n gt o n U ni versit y 
I n c o m plia nce wit h t he Was hi n gt o n U ni versit y I nstit uti o nal Data a n d Safet y M o nit ori n g Pla n, t he 
Pri nci pal I n vesti gat or will pr o vi de a Data a n d Safet y M o nit ori n g ( D S M) re p ort t o t he Was hi n gt o n 
U ni versit y  Q ualit y  Ass ura nce  a n d  Safet y  M o nit ori n g  C o m mittee  ( Q A S M C)  se mi -a n n uall y 
be gi n ni n g si x m o nt hs aft er accr ual has o pe n e d (if at least o ne p atie nt has bee n e nr olle d) or o n e 
year after accr ual has o p e ne d (if n o patie nts ha v e b ee n e nr olle d at t he si x - m o nt h mar k).   
 
T he Pri nci pal I n vesti gat or will re vie w all patie nt data at least e ver y 6 m o nt hs, a n d pr o vi de a se mi -
a n n ual re p ort t o t he Q A S M C.  T his re p ort will i ncl u de:  
•  H R P O pr ot oc ol n u m ber, pr ot oc ol title, Pri nci pal I n vesti gat or na me, data c o or di nat or na me, 
re g ulat or y c o or di nat or na me, a n d statisticia n na me  
•  Date of i nitial H R P O a p pr o val, date of m ost rece nt c o nse nt H R P O a p pr o v al/re visi o n, date 
of H R P O e x pirati o n, date of m ost rece nt Q A a u dit, st u d y stat us, a n d p hase of st u d y 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 3 6  of 5 4  
 
 
•  Hist or y of st u d y i ncl u di n g s u m mar y of s u bsta nti ve a me n d me nts; s u m mar y of accr u al 
s us pe nsi o ns i ncl u di n g start/st o p dates a n d reas o n; a n d s u m mar y of pr ot o c ol e xce pti o ns, 
err or, or breac h of c o nfi d e ntialit y i ncl u di n g start/st o p dates a n d reas o n 
•  St u d y- wi de tar get accr u al a n d st u d y -wi de act u al accr ual  
•  Pr ot oc ol acti vati o n date  
•  A vera g e rat e of accr u al o bser ve d i n year 1, year 2, a n d s u bse q ue nt years 
•  E x pecte d accr ual e n d dat e a n d accr u al b y c o h ort 
•  O bjecti ves of pr ot oc ol wit h s u p p orti n g data a n d list t he n u m ber of p artici p a nts w h o ha ve 
met eac h o bjecti ve  
•  Earl y st o p pi n g r ules wit h s u p p orti n g data a n d list t he n u m ber of partici pa nts w h o ha ve met 
t he earl y st o p pi n g r ules  
•  S u m mar y of t o xicities s e parat e d b y c o h orts wit h t he n u m ber of d ose-li miti n g t o xicities 
i n dicate d 
•  A bstract s u b missi o ns/ p u blicati o ns 
•  S u m mar y of a n y rece nt literat ure t h at ma y affect t he safet y or et hics of t he st u d y  
 
T he  st u d y  pri nci pal  i n vesti gat or  a n d  Researc h  Patie nt  C o or di nat or  will  m o nit or  f or  seri o us  
t o xicities o n a n o n g oi n g basis. O nce t he pri nci pal i n vesti gat or or Researc h Patie nt C o or di nat or 
bec o mes a war e of a n a d v erse e ve nt, t he A E will b e re p orte d t o t he H R P O a n d Q A S M C acc or di n g 
t o i nstit uti o nal g ui deli nes. 
 
7. 2  
P h ase 1 B a n d P h ase 2: U T S W  
I n c o m plia nce wit h t he Si m m o ns Ca ncer Ce nter Data a n d Safet y M o nit ori n g C o m mittee, t he 
Pri nci pal I n vesti gat or will pr o vi de a Data a n d Safet y M o nit ori n g ( D S M) re p ort t o t he Si m m o ns 
Ca ncer Ce nter Data a n d Safet y M o nit ori n g C o m mittee ( D S M C) se mi -a n n uall y be gi n ni n g si x 
m o nt hs after accr u al has o pe ne d (if at least o ne patie nt has bee n e nr olle d) or o ne year after accr ual 
has o pe ne d (if n o patie nts ha ve bee n e nr olle d at t he si x- m o nt h mar k).    
 
T he Pri nci pal I n vesti gat or will re vie w all patie nt data at least e ver y 6 m o nt hs, a n d pr o vi de a se mi -
a n n ual re p ort t o t he D S M C.  T his re p ort will i ncl u de: 
•  H R P P pr ot oc ol n u m ber, pr ot oc ol title, Pri nci pal I n vesti gat or na me, data c o or di nat or na me, 
re g ulat or y c o or di nat or na me, a n d statisticia n na me 
•  Date of i nitial H R P P a p pr o val, date of m ost rece nt c o nse nt H R P P a p pr o val/re visi o n, date 
of H R P P e x pirati o n, date of m ost rece nt Q A a u dit, st u d y stat us, a n d p hase of st u d y 
•  Hist or y of st u d y i ncl u di n g s u m mar y of s u bsta nti ve a me n d me nts; s u m mar y of accr u al 
s us pe nsi o ns i ncl u di n g start/st o p dates a n d reas o n; a n d s u m mar y of pr ot o c ol e xce pti o ns, 
err or, or breac h of c o nfi d e ntialit y i ncl u di n g start/st o p dates a n d reas o n 
•  St u d y- wi de tar get accr u al a n d st u d y -wi de act u al accr ual  
•  Pr ot oc ol acti vati o n date  
•  A vera g e rat e of accr u al o bser ve d i n year 1, year 2, a n d s u bse q ue nt years 
•  E x pecte d accr ual e n d dat e a n d accr u al b y c o h ort 
•  O bjecti ves of pr ot oc ol wit h s u p p orti n g data a n d list t he n u m ber of p artici p a nts w h o ha ve 
met eac h o bjecti ve  
•  Earl y st o p pi n g r ules wit h s u p p orti n g data a n d list t he n u m ber of partici pa nts w h o ha ve met 
t he earl y st o p pi n g r ules  


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 3 7  of 5 4  
 
 
•  S u m mar y of t o xicities s e parat e d b y c o h orts wit h t he n u m ber of d ose -li miti n g t o xicities 
i n dicate d 
•  A bstract s u b missi o ns/ p u blicati o ns 
•  S u m mar y of a n y rece nt literat ure t h at ma y affect t he safet y or et hics of t he st u d y  
 
T he st u d y pri nci pal i n vesti gat or a n d Researc h St u d y C o or di nat or will m o nit or f or seri o us t o xicities 
o n a n o n g oi n g basis. O nce t he pri nci pal i n vesti gat or or Researc h St u d y C o or di nat or bec o mes 
a war e  of  a n  a d verse  e v e nt,  t he  A E  will  be  re p orte d  t o  t he  H R P P  a n d  D S M C  acc or di n g  t o  
i nstit uti o nal g ui deli nes.  
 
8. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  
 
8. 1  
St u d y D esi g n 
 
A r olli n g si x desi g n w hi c h is i nte n de d f or relati v el y safe trial s a n d s h orte ni n g t he st u d y 
d urati o n is pr o p ose d f or t he p hase 1 p orti o n 7 4. I n t he r olli n g si x desi g n, three  t o si x patie nts 
ca n be e nr olle d t o a d ose eac h ti me. T h e d ose d e -escalati o n occ urs w he n t w o or m ore D L T 
occ ur at a d ose le v el w hile d ose escalati o n occ urs w he n 3/ 3, 4/ 4, 5/ 5, 5/ 6 or 6/ 6 patie nts 
are e val uate d wit h o ut D L T  7 5. T hree d ose le v els will be teste d i n t he p h ase 1 st u d y, 0. 05, 
0. 0 7 5 a n d 0. 10 m g/ k g. L S 3 0 1 will be a d mi nistere d i ntra ve n o usl y at a starti n g d ose of 0. 0 5 
m g/ k g t o a c o h ort of si x patie nts a n d escalate/ de -es calate f oll o wi n g t he decisi o n r ule of t he 
r olli n g si x desi g n. O nce si x patie nts ha ve bee n i ncl u de d at t he c urre nt d ose l e vel, i ncl usi o ns 
are s us pe n de d u ntil at least fi ve of t he si x patie nts  ha ve c o m plete d t he pr oce d ure wit h o ut 
D L T o bser ve d i n t he e val uati o n peri o d. M T D is hit w here t w o or m ore patie nts o ut of si x 
at a d ose le vel e x perie nce D L T . We d o n ot e x pect a n y seri o us a d verse e ve nts relate d t o 
L S 3 0 1 at t h e i nitial D ose Le vel 1. O nce  t he M T D is deter mi ne d, a n e x pa nsi o n c o h ort wit h 
9 patie nts will be teste d at t he M T D a n d an o pti mal i ma gi n g d ose will be rec o m me n de d f or 
t he s u bse q ue nt p hase 2 trial.  
 
At t he c o m pleti o n of t he e x pa nsi o n c o h ort , a si n gl e ar m p h ase 2 trial will b e perf or me d at 
t he o pti mal i ma gi n g d os e. A breast s ur g e o n will perf or m breast c o nser vi n g s ur ger y per 
sta n dar d of care. At t he c o m pleti o n of t he s ur ger y, a sec o n d i n vesti gat or (t o re d uce bias i n 
data c ollecti o n) will wear t he ca ncer visi o n g o g gle ( C V G) t o vis ualize t he e xcise d tiss ue t o 
deter mi ne if t h ere ar e a n y p ositi ve mar gi ns base d o n t he prese nce of L S 3 0 1 fl u oresce nce. 
If a n y p ositi ve mar gi ns are o bser v e d, t he s u bject will be c o nsi dere d t o ha ve a p ositi ve 
mar gi n; ot her wise, t h e mar gi n is c o nsi dere d ne gati ve. T he e xcise d tiss ue will later be 
e xa mi ne d b y  a breast ca ncer pat h ol o gist. Sta n dar d pat h ol o gic tec h ni q ues will be use d t o 
deter mi ne if t here are p ositi ve mar gi ns. Partic ular atte nti o n will be pai d t o t he sites mar ke d 
f oll o wi n g C V G ass ess me nt t o c o nfir m w het her t he mar gi n is p ositi ve or n e g ati ve at a ny of 
t hese sites, or p ositi ve at ot her l ocati o ns n ot i de ntifie d b y C V G. N o i nter v e nti o ns will be 
all o we d base d o n t he C V G res ults. 
    
8. 2  
E n d p oi nts  
 
8. 2. 1  E n d p oi nts f or S afet y A n al ysis 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 3 8  of 5 4  
 
 
T he pri mar y e n d p oi nts of t he p hase 1 p orti o n of t he trial are t o xicities a n d/ or 
a d verse e v e nts (as o utli ne d i n t he Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y 
Crite ria f or A d vers e E ve nts versi o n 5. 0) rec or de d after L S 3 0 1 i njecti o n w hic h are 
defi niti vel y or p ossi bl y relate d t o t he i njecti o n.  Safet y e val uati o n i ncl u des vital 
si g ns, cli nical la b orat or y testi n g a n d E C G, meas ure d pre- ( wit hi n 1 0-1 5 mi n utes or 
3 0  mi n utes  of  i njecti o n)  a n d  p ost -i njecti o n  ( wit hi n  3 0  mi n utes  or/a n d  at  ~ 6 0  
mi n utes). N ote w ort h y p ost - vers us-pre c ha n g es i n all t he safet y meas ures will be 
rec or d ed w hile cli nicall y si g nifica nt c ha n ges will be re p orte d as a d verse e v e nts i n 
acc or d a nce t o H R P O  re q uire me nts. All t he safet y e n d p oi nts are d escri be d i n detail 
i n Secti o n 5. 4 a n d a d vers e e ve nts detaile d  i n Secti o n 6. 0.  
 
8. 2. 2  E n d p oi nt f or P re dicti o n of P ositi ve M ar gi n a n d P ositi ve S L N 
A n al ysis 
 
T he pri mar y o bjecti ve is t o assess mar gi n stat us calle d b y L S 3 0 1 a n d C V G i n 
c o m paris o n t o t he g ol d sta n dar d hist o pat h ol o gical res ults. T he hist o pat h ol o gical 
res ults of mar gi n p ositi vit y has t he f oll o wi n g p ossi ble res ults: mar gi n ne gati ve, 
mar gi n p ositi ve at L S 3 0 1 a n d C V G i de ntifie d l ocati o ns, mar gi n p ositi ve at L S 3 0 1 
a n d C V G u ni de ntifie d l ocati o ns. Usi n g L S 3 0 1 a n d C V G, t he e xercise d tiss ue will 
be c o nsi der e d t o be m ar gi n p ositi ve a n d ha ve i n k mar ke d at t h e i de ntifie d l ocati o ns 
if a n y p ositi ve mar gi ns are o bser ve d; ot her wise, t he mar gi n is c o nsi dere d ne gati ve. 
Dia g n ostic test c haracteristics (se nsiti vit y a n d s pecificit y) of L S 3 0 1 a n d C V G f or 
mar gi n p ositi vit y b y hist ol o g y will esta blis he d a n d mar gi n p ositi vit y rate, defi ne d 
as t he pr o p orti o n of t u m ors wit h hist o pat h ol o gicall y c o nfir me d p ositi ve mar gi ns 
b ut misse d b y C V G, will be esti mate d. T he sec o n d ar y e n d p oi nt of t he p hase 2 trial 
is t o xicit y.  
 
8. 3  
D at a A n al ysis 
 
Cli nical a n d de m o gra p hic c haracteristics of t he partici pa nts will be s u m marize d usi n g 
descri pti ve statistics, o verall a n d b y d ose le v els. 
 
8. 3. 1  S afet y A n al ysis   
 
A d verse e ve nts will be s u m marize d b y descri pti ve statistics (c o u nts, perce nta ges) 
o verall a n d b y d ose le v el  (if a p plica ble).  T h e p ost-i njecti o n vital si g ns will be 
se parat el y c o m pare d t o t he pre-i njecti o n meas ure me nts b y t w o-sa m ple t-test or 
Wilc o x o n ra n k s u m test as a p pr o pri ate, acr oss all patie nts a n d b y d ose le vel  (if 
a p plica ble).  
 
8. 3. 2  M ar gi n P ositi vit y a n d S L N P ositi vit y P re dicti o n A n al ysis 
 
Mar gi n p ositi vit y as deter mi ne d b y L S 3 0 1 a n d C V G will be t a b ulate d wit h t he g ol d 
sta n dar d hist o pat h ol o gical e xa mi nati o n res ults as t he ta ble s h o w n bel o w. 
  
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 3 9  of 5 4  
 
 
  
  
Hist o p at h ol o g y res ults  
  
  
Ne gati ve  
P ositi ve at 
C V G i de ntifie d 
l ocati o ns 
P ositi ve at ot her 
u ni de ntifie d 
l ocati o ns 
C V G 
res ults  
Ne gati ve  
n 1 1 
0  
n 1 3 
P ositi ve at C V G 
i de ntifie d l ocati o ns 
n 2 1 
n 2 2 
0  
 
Dia g n ostic test o perati n g c haracteristics i ncl u di n g se nsiti vit y, s pecificit y, o verall 
acc ur ac y,  p ositi ve  a n d  ne gati ve  pre dicti ve  val u e  will  be  calc ulate d.  T he  tr ue  
p ositi ves ( = n 2 2) are t he t u m ors w hic h s h o w p ositi ve mar gi ns at a n y l ocati o n a gree d 
b y b ot h t he hist o pat h ol o g y e xa mi nati o n a n d b y L S 3 0 1 a n d C V G. S pecificit y is 
defi ne d as t he pr o p orti o n of t u m ors wit h hist o pat h ol o gicall y c o nfir me d n e gati ve 
mar gi ns w hic h are calle d t o ha ve  ne g ati ve mar gi ns b y L S 3 0 1 a n d C V G, calc ulate d 
as n 1 1/(n 1 1+  n 2 1). Se nsiti vit y is defi ne d as t he pr o p orti o n of t u m ors w hi c h are 
pre dicte d t o ha ve p ositi ve mar gi ns b y L S 3 0 1 a n d C V G a m o n g t he t u m ors wit h 
hist o pat h ol o gica ll y c o nfir me d p ositi ve mar gi ns b ot h at C V G i de ntifie d l ocati o ns 
a n d at ot her l ocati o ns u ni de ntifie d b y C V G, cal c ulate d as n 2 2/(n 1 3+ n 2 2). O verall 
acc ur ac y is defi ne d as t h e pr o p orti o n of t u m ors wit h mar gi n p ositi vit y/ ne gati vit y 
c orrectl y  pre dicte d  b y  t he  C V G  a m o n g  all  t u m ors,  calc ulate d  as  ( n 1 1+  n 2 2)/( 
n 1 1+ n 1 3+ n 2 1+ n 2 2). P ositi ve pre di cti ve val u e is defi ne d as t he pr o p orti o n of t u m ors 
wit h  mar gi ns  calle d  p ositi ve  at  L S 3 0 1  a n d  C V G  i de ntifie d  l ocati o ns  b y  t he  
hist o pat h ol o g y e xa mi nati o n a m o n g all t h ose pre di cte d t o ha ve p ositi ve mar gi ns b y 
C V G, calc ulat e d as n 2 2/(n 2 1+ n 2 2). Ne gati ve pre dicti ve val ue w as defi n e d as t he 
pr o p orti o n of t u m ors wit h tr ul y ne gati ve mar gi ns a m o n g t h ose pre dict e d s o b y 
C V G, calc ulate d as  n1 1/(n 1 1+ n 1 3). T he mar gi n p ositi vit y rate base d o n L S 3 0 1 a n d 
C V G  will  be  esti mate d  as  n 1 3/(  n1 1+ n 1 3+  n 2 1+ n 2 2).  All  t he  esti mates  will  be  
acc o m pa ni e d  wit h  9 5 %  c o nfi de n ce  i nter val.  Mar gi n  p ositi vit y  rate  will  be  
c o m pare d a g ai nst t he c urre nt 1 5. 5 % mar gi n p ositi vit y rate usi n g t he t w o -si de d o ne-
sa m ple bi n o mial e xact test. Gi ve n e n o u g h D CI S a n d i n vasi ve breast ca n cer (I B C), 
si milar dia g n ostic c har acteristics will be calc ulat e d se paratel y i n t he s u bset t u m ors 
of D CI S a n d I B C.  
 
8. 4  
S a m ple Size  
 
T he sa m ple size f or t he p hase 1 part  will de pe n d o n t he o bser ve d D L T at eac h d ose le vels . 
T he p hase 1 e x pa nsi o n c o h ort will use 9 e val ua ble patie nts. T he ta ble bel o w pr o vi des t he 
pr o ba bilit y of o bser vi n g D L T i n > = 3 3 % i n 9 patie nts  base d o n t he bi n o mial distri b uti o n . If 
t he tr ue D L T rate is as l o w as 5%, s uc h a pr o ba bilit y is s mall, o nl y 0. 0 0 8 4 b ut if t he tr ue 
D T L is 5 0 %, s uc h a pr o b a bilit y is ver y hi g h at 0. 9 1. 
 
 
 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 4 0  of 5 4  
 
 
T rue D L T  
pr o ba bilit y of o bser ve d D L T > = 3 3 % i n 9 
patie nts  
1 %  
0. 0 0 0 0 8 4  
5 %  
0. 0 0 8 4  
1 0 %  
0. 0 5 3  
2 0 %  
0. 2 6 2  
3 0 %  
0. 5 3 7  
4 0 %  
0. 7 6 8  
5 0 %  
0. 9 1  
 
T he sa m ple size f or t he p hase 2 p orti o n of t he st u d y was deter mi ne d usi n g t he f oll o wi n g 
calc ulati o ns. A t otal of 8 8 ( 1 4 are e x pecte d t o ha ve p ositi ve mar gi ns after sta n dar d  breast 
s ur ger y) si m ulta ne o usl y ac hie ves 8 4. 7 % p o wer t o detect a n e x p ecte d s e nsiti vit y of 0. 9 5 
a gai nst  a n u nacce pta ble s e nsiti vit y of 0. 7 a n d 1 0 0 % p o wer t o detect a n e x p ecte d s pecificit y 
0. 9 5 a gai nst a n u nfa v or a ble s pecificit y of 0. 7 usi n g a o ne -si de d bi n o mial test. T he tar g et 
si g nifica nce le vel is 0. 0 5. T he act ual si g nifica nce le vel ac hie ve d b y t he test o n se nsiti vit y 
is 0. 0 4 7 5 a n d ac hie ve d b y t he test o n s pecificit y is 0. 0 4 1.  T he c urre nt recall rate (i.e., 
mar gi n p ositi vit y rate) after t he use of ca vit y s ha v e mar gi n is ~ 1 9 % 
3 6, w hic h a grees wit h 
t he best practices i n Was hi n gt o n U ni versit y, ~ 1 5. 5 %. 8 8 patie nts all o ws 9 2. 6 6 % p o wer t o 
test a re d ucti o n i n p ositi ve mar gi n rate fr o m 1 5. 5 % t o 5 % base d o n a o ne- si de d Bi n o mial 
e xact test at a 5 % le vel.   
 
 
8. 5  
E arl y st o p pi n g r ule 
 
We d o n’t e x pect a n y t o xicities f or L S 3 0 1 b ut gra de 1 t o xicit y is us uall y acce pta ble f or 
i ma gi n g a ge nt. As s u c h, t he trial will st o p earl y i n t he p hase 1 part f oll o wi n g t he r olli n g si x 
desi g n r ule if d ose le v el 1 has t w o o ut of si x patie nts e x perie nce D L Ts.  
 
8. 6  
A n al ysis set  
 
T he safet y a nal ysis set i ncl u des all patie nts w h o recei ve a n y a m o u nt of L S 3 0 1.  
 
T he effi cac y a nal ysis set i ncl u de all patie nts w h o recei ve a n y a m o u nt of L S 3 0 1, c o m plete 
t he s ur ger y a n d ha ve e val ua ble t u m or hist ol o g y res ults. 
 
 
 
 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 4 1  of 5 4  
 
 
 
9. 0  
R E F E R E N C E S  
 
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2.  
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3.  
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4.  
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S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 4 2  of 5 4  
 
 
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S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 4 3  of 5 4  
 
 
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S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 4 4  of 5 4  
 
 
5 3. 
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4 8 5 ( 2 0 0 0). 
5 8.  
B u gaj, J. E., Ac hilef u, S., D ors h o w, R. B. & Raja g o pala n, R. N o vel fl u ores ce nt c o ntrast 
a ge nts f or o ptical i ma gi n g of i n vi v o t u m ors base d o n a rece pt or-tar gete d d ye- pe pti de 
c o nj u gate platf or m. J o ur n al of bi o me dic al o ptics  6 , 1 2 2- 1 3 3 ( 2 0 0 1). 
5 9.  
Ac hilef u, S., Wil hel m, R. R., Ji me nez, H. N., Sc h mi dt, M. A. & Sri ni vasa n, A. A ne w 
met h o d f or t he s y nt hesis of tri- tert-b ut yl diet h yle n etria mi ne pe ntaacetic aci d a n d its 
deri vati ves. T he J o ur n al of or g a nic c he mistry  6 5 , 1 5 6 2- 1 5 6 5 ( 2 0 0 0). 
6 0.  
Ac hilef u, S. , et al. S y ner gistic effects of li g ht-e mitti n g pr o bes a n d pe pti des f or tar geti n g 
a n d m o nit ori n g i nte gri n e x pressi o n. Pr oc. N atl. Ac a d. Sci. U. S. A.  1 0 2 , 7 9 7 6- 7 9 8 1 
( 2 0 0 5). 
6 1.  
Ac hilef u, S. Li g hti n g u p t u m ors wit h rece pt or-s p ecific o ptical m olec ular pr o bes. 
Tec h n ol o gy i n C a ncer Rese arc h & Tre at me nt  3 , 3 9 3- 4 0 9 ( 2 0 0 4). 
6 2.  
Ac hilef u, S., D ors h o w, R. B., B u gaj, J. E. & Raja g o pala n, R. N o vel rece pt or- tar gete d 
fl u oresce nt c o ntrast a g e nts f or i n vi v o t u m or i ma gi n g. I nvesti g ative R a di ol o gy 3 5 , 4 7 9-
4 8 5 ( 2 0 0 0). 
6 3. 
Berezi n, M. Y. , et al. Rati o nal a p pr oac h t o select s mall pe pti de m olec ular pr o bes la bele d 
wit h fl u oresce nt c y a ni ne d yes f or i n vi v o o ptical i ma gi n g. Bi oc he mistry  5 0 , 2 6 9 1- 2 7 0 0 
( 2 0 1 1). 
6 4.  
G oiff o n, R.J., A kers, W.J., Berezi n, M. Y., L ee, H. & Ac hilef u, S. D y na mic n o ni n vasi ve 
m o nit ori n g of re nal f u ncti o n i n vi v o b y fl u oresce n ce lifeti me i ma gi n g. J o ur n al of 
bi o me dic al o ptics  1 4 , 0 2 0 5 0 1 ( 2 0 0 9). 
6 5. 
T h ota, R., Pa uff, J. M. & Berli n, J. D. Treat me nt of metastatic pa ncreatic a d e n ocarci n o ma: 
a re vie w. O nc ol o gy  2 8 , 7 0- 7 4 ( 2 0 1 4). 
6 6. 
Al - Hajeili, M., Az mi, A. S. & C h oi, M. Na b-paclita xel: p ote ntial f or t he treat me nt of 
a d va nce d pa ncreatic ca n cer. O nc o T ar gets a n d t her a py  7 , 1 8 7- 1 9 2 ( 2 0 1 4). 
6 7.  
Kratz, F. Al b u mi n as a dr u g carri er: desi g n of pr o dr u gs, dr u g c o nj u gates a n d 
na n o particles. J o ur n al of c o ntr olle d rele ase : offici al j o ur n al of t he C o ntr olle d Rele ase 
S ociety  1 3 2 , 1 7 1- 1 8 3 ( 2 0 0 8). 
6 8.  
C hara n ya, T. , et al. Tri m o dal c ol or-fl u oresce n ce- p olarizati o n e n d osc o p y ai de d b y a t u m or 
selecti ve m olec ular pr o b e acc uratel y d etects flat l esi o ns i n c olitis-ass ociate d ca ncer. 
J o ur n al of bi o me dic al o ptics  1 9 , 1 2 6 0 0 2 ( 2 0 1 4). 
6 9.  
R ose nt hal, E. L. , et al. Safet y a n d T u m or S pecificit y of Cet u xi ma b-I R D ye 8 0 0 f or S ur gical 
Na vi gati o n i n Hea d a n d Nec k Ca ncer. Cli nic al C a ncer Rese ar c h  2 1 , 3 6 5 8- 3 6 6 6 ( 2 0 1 5). 
7 0.  
Zi n n, K. R. , et al. I N D- Directe d Safet y a n d Bi o distri b uti o n St u d y of I ntra v e n o usl y 
I njecte d Cet u xi ma b-I R D ye 8 0 0 i n C y n o m ol g us Maca q u es. M olec ul ar i m a gi n g a n d 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 4 5  of 5 4  
 
 
bi ol o gy : MI B : t he offici al p u blic ati o n of t he Ac a de my of M olec ul ar I m a gi n g  1 7 , 4 9- 5 7 
( 2 0 1 5). 
7 1.  
Ga y ke ma, S. B. M. , et al. 8 9 Zr-Be vaciz u ma b P E T I ma gi n g i n Pri mar y Breast Ca ncer. 
J o ur n al of N ucle ar Me di ci ne  5 4 , 1 0 1 4- 1 0 1 8 ( 2 0 1 3). 
7 2.  
Fra n kli n, H. L., Miller, D. M., He d ges, T., Perr y, J. & Parris h- N o va k, J. Cli nical 
de vel o p me nt of B L Z- 1 0 0 f or real -ti me o ptical i ma gi n g of t u m ors d uri n g res ecti o n. V ol. 
9 6 9 6 9 6 9 6 0 V- 9 6 9 6 0 V- 9 6 9 6 7 ( 2 0 1 6). 
7 3.  
Fi del, J. , et al. Precli nical Vali dati o n of t he Utilit y of B L Z - 1 0 0 i n Pr o vi di n g Fl u oresce nce 
C o ntrast f or I ma gi n g S p o nta ne o us S oli d T u m ors. C a ncer Rese ar c h  7 5 , 4 2 8 3- 4 2 9 1 
( 2 0 1 5). 
7 4.   
S k ol ni k J M, Barrett J S, Ja yara m a n B, Patel D, A d a ms o n P C ( 2 0 0 8) S h orte ni n g t he 
ti meli ne of pe diatric p has e I trials: t he r olli n g si x desi g n. J Cli n O nc ol  2 6 , 1 9 0- 1 9 5. 
7 5.  
D o ussa u A, Ge o er ger B, Ji me nez I, Pa oletti X. I n n o vati o ns f or p hase I d ose-fi n di n g 
desi g ns i n pe diatric o nc ol o g y cli nical trials. C o nte m p orar y cli nical trials. 2 0 1 6. 4 7: 2 1 7-
2 2 7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Pa ge 4 6  of 5 4  
 
 
 
 
1 0. 0  
A P P E N DI X A:  D efi niti o ns f or A d verse E ve nt Re p orti n g  
 
A.  A d verse E ve nts ( A Es)  
 
As defi ne d i n 2 1 C F R 3 1 2. 3 2: 
 
Defi niti o n:  a n y u nt o war d me dical occ urre n ce ass ociate d wit h t he use of a dr u g i n h u ma ns, 
w het her or n ot c o nsi dere d dr u g- relat e d. 
 
Gr a di n g:  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 5. 0 will be utilize d f or all t o xicit y re p orti n g.  A 
c o p y of t he C T C A E versi o n 5. 0 ca n be d o w nl o a de d fr o m t he C T E P we bsite. 
 
Attri b uti o n (rel ate d ness), E x pecte d ness, a n d Seri o us ness:  t he defi niti o ns f or t he ter ms 
liste d t hat s h o ul d be use d are t h ose pr o vi de d b y t he De part me nt of Healt h a n d H u ma n Ser vices’ 
Office f or H u ma n Researc h Pr otecti o ns ( O H R P).  A c o p y of t his g ui da n ce ca n b e f o u n d o n 
O H R P’s we bsite:  
htt p:// w w w. h hs. g o v/ o hr p/ p olic y/a d ve v nt g ui d. ht ml  
 
B.  S us pecte d A d verse Re a cti o n ( S A R)  
 
As defi ne d i n 2 1 C F R 3 1 2. 3 2: 
 
Defi niti o n:  a n y a d verse e ve nt f or w hic h t here is a reas o na ble p ossi bilit y t hat t he dr u g ca use d 
t he a d verse e ve nt.  “ R eas o na ble p ossi bilit y” mea ns t here is e vi de nce t o s u g gest a ca usal 
relati o ns hi p bet wee n t he dr u g a n d t he a d vers e e ve nt.  “ S us pecte d a d v erse reacti o n” i m plies a 
lesser de gree of certai nt y a b o ut ca usalit y t ha n a d verse reacti o n, w hic h mea ns a n y a d verse e ve nt 
ca use d b y a dr u g. 
 
C.  Life -T hre ate ni n g A d verse E ve nt / Life T hre ate ni n g S us pecte d A d verse Re acti o n  
 
As defi ne d i n 2 1 C F R 3 1 2. 3 2: 
 
Defi niti o n:  a n y  a d v ers e  dr u g  e v e nt  or  s us p ecte d  a d vers e  reacti o n  is  c o nsi dere d  “life -
t hreate ni n g” if, i n t he vie w of t he i n vesti gat or, its occ urre nce places t he patie nt at i m me diate 
ris k of deat h. It d o es n ot i ncl u de a n a d v erse e ve nt or s us pect e d a d v erse reacti o n t hat, ha d it 
occ urr e d i n a m ore s e ver e f or m, mi g ht ha ve ca use d deat h. 
 
D.   Seri o us A d verse E ve nt ( S A E) or Seri o us S us pecte d A d vers e Re a cti o n  
 
As defi ne d i n 2 1 C F R 3 1 2. 3 2: 
 
Defi niti o n:  a n a d verse e ve nt or s us pecte d a d verse reacti o n is c o nsi dere d “seri o us” if, i n t he 
vie w of t he i n vesti gat or, it res ults i n a n y of t he f oll o wi n g o utc o mes: 


 
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Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 4 7  of 5 4  
 
 
o  Deat h  
o  A life -t hreate ni n g a d vers e e ve nt 
o  I n p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
o  A 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 
o  A c o n ge nital a n o mal y/ birt h defect 
o  A n y ot her i m p orta nt me dical e ve nt t hat d oes n ot fit t he criteria a b o ve b ut, b ase d u p o n 
a p pr o priate me dical j u d g me nt, ma y je o par dize t he s u bject a n d ma y re q uire me dical or 
s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o m es liste d a b o ve 
 
E.  Pr ot oc ol E xce pti o ns 
 
Defi niti o n:  A pla n ne d c h a n ge i n t he c o n d u ct of t he researc h f or o ne p artici pa nt. 
 
F.  De vi ati o n 
 
Defi niti o n:  A n y alterati o n or m o dificati o n t o t h e I R B -a p pr o ve d researc h wit h o ut pr os pecti ve 
I R B a p pr o val.  T h e ter m “researc h ” e n c o m passes all I R B-a p pr o ve d m ateri als a n d d oc u me nts 
i ncl u di n g  t he  detaile d  pr ot oc ol,  I R B  a p plicati o n,  c o nse nt  f or m,  recr uit me nt  materials,  
q uesti o n naires/ data c ollecti o n f or ms, a n d a n y ot her i nf or mati o n relati n g t o t he researc h st u d y. 
 
A mi n or or a d mi nistrati ve de viati o n is o ne t hat d oes n ot ha ve t he p ote ntial t o ne gati vel y i m pact 
t he ri g hts, safet y, or w elf are of p artici pa nts or ot h ers or t he sci e ntific vali dit y of t he st u d y. 
 
A maj or de viati o n is o ne t hat d oes ha ve t he p ote ntial t o ne gati vel y i m pact t he ri g hts, safet y, or 
welfar e of partici pa nts or ot hers or t he scie ntific v ali dit y of t he st u d y. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Pr ot oc ol Versi o n:  1 1/ 4/ 2 0 2 1 ( A 2) 
 
Pa ge 4 8  of 5 4  
1 1. 0  
A P P E N DI X B:  Re p orti n g Ti meli nes  
 
 
 
E x pe dite d Re p orti n g Ti meli nes  
E ve nt  
H R P O –  W as hi n gt o n 
U ni versit y  
H R P P O –  U T  
S o ut h wester n  
Q A S M C –  
W as hi n gt o n 
U ni versit y  
D S M C –  U T  
S o ut h wester n  
F D A  
Seri o us A N D u ne x pecte d 
s us pecte d a d verse reacti o n 
 
 
 
S u b mit S A E 
Re p ort t o S C C C 
D S M C  wit hi n 5 
b usi ness da ys of 
st u d y tea m 
a ware ness of t he 
e ve nt(s) 
Re p ort n o later t ha n 1 5 cale n dar 
da ys after it is deter mi ne d t hat t he 
i nf or mati o n q ualifies f or 
re p orti n g 
U ne x pecte d fatal or life -
t hreate ni n g s us pecte d a d verse 
reacti o n 
 
 
 
S u b mit wit hi n 5 
b usi ness da ys of 
st u d y tea m 
a ware ness of t he 
e ve nt(s) 
Re p ort n o later t ha n 7 cale n dar 
da ys after i nitial recei pt of t he 
i nf or mati o n 
U na ntici pate d pr o ble m 
i n v ol vi n g ris k t o partici pa nts or 
ot hers 
Re p ort wit hi n 1 0 
w or ki n g da ys.  If t he 
e ve nt res ults i n t he 
deat h of a partici pa nt 
e nr olle d at 
W U/ BJ H/ S L C H, 
re p ort wit hi n 1 
w or ki n g da y.  
S u b mit wit hi n 5 
b usi ness da ys of 
st u d y tea m a ware ness 
of t he e ve nt(s)  
Re p ort via e mail 
after I R B 
ac k n o wle d g me nt 
S u b mit U PI R S O 
Re p ort t o S C C C 
D S M C  wit hi n 5 
b usi ness da ys of 
st u d y tea m 
a ware ness of t he 
e ve nt(s) 
 
Maj or de viati o n  
Re p ort wit hi n 1 0 
w or ki n g da ys.  If t he 
e ve nt res ults i n t he 
deat h of a partici pa nt 
e nr olle d at 
W U/ BJ H/ S L C H, 
re p ort wit hi n 1 
w or ki n g da y.  
S u b mit wit hi n 5 
b usi ness da ys of 
st u d y tea m a ware ness 
of t he e ve nt(s)  
 
 
Re p ort n o later t ha n 1 5 cale n dar 
da ys after it is deter mi ne d t hat t he 
i nf or mati o n q ualifies f or 
re p orti n g 


 
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Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 4 9  of 5 4  
 
 
 
 
E x pe dite d Re p orti n g Ti meli nes  
E ve nt  
H R P O –  W as hi n gt o n 
U ni versit y  
H R P P O –  U T  
S o ut h wester n  
Q A S M C –  
W as hi n gt o n 
U ni versit y  
D S M C –  U T  
S o ut h wester n  
F D A  
A series of mi n or de viati o ns 
t hat are bei n g re p orte d as a 
c o nti n ui n g n o nc o m plia nce 
Re p ort wit hi n 1 0 
w or ki n g da ys.   
S u b mit wit hi n 5 
b usi ness da ys of 
st u d y tea m a ware ness 
of t he e ve nt(s)  
 
 
 
Pr ot oc ol e xce pti o n  
A p pr o val m ust be 
o btai ne d pri or t o 
i m ple me nti n g t he 
c ha n ge 
A p pr o val m ust be 
o btai ne d pri or t o 
i m ple me nti n g t he 
c ha n ge 
 
 
 
Cli nicall y i m p orta nt i ncrease i n 
t he rate of a seri o us s us pecte d 
a d verse reacti o n of t hat list i n 
t he pr ot oc ol or I B 
 
 
 
 
Re p ort n o later t ha n 1 5 cale n dar 
da ys after it is deter mi ne d t hat t he 
i nf or mati o n q ualifies f or 
re p orti n g 
C o m plai nts  
If t he c o m plai nt 
re veals a n 
u na ntici pate d pr o ble m 
i n v ol vi n g ris ks t o 
partici pa nts or ot hers 
O R n o nc o m plia nce, 
re p ort wit hi n 1 0 
w or ki n g da ys.  If t he 
e ve nt res ults i n t he 
deat h of a partici pa nt 
e nr olle d at 
W U/ BJ H/ S L C H, 
re p ort wit hi n 1 
w or ki n g da y.  
Ot her wis e, re p ort at 
t he ti me of c o nti n ui n g 
re vie w. 
S u b mit wit hi n 5 
b usi ness da ys of 
st u d y tea m a ware ness 
of t he e ve nt(s)  
 
 
 
Breac h of c o nfi de ntialit y  
Wit hi n 1 0 w or ki n g 
da ys.  
 
 
 
 


 
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Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 5 0  of 5 4  
 
 
 
 
E x pe dite d Re p orti n g Ti meli nes  
E ve nt  
H R P O –  W as hi n gt o n 
U ni versit y  
H R P P O –  U T  
S o ut h wester n  
Q A S M C –  
W as hi n gt o n 
U ni versit y  
D S M C –  U T  
S o ut h wester n  
F D A  
I ncarcerati o n 
If wit h dra wi n g t he 
partici pa nt p oses a 
safet y iss ue, re p ort 
wit hi n 1 0 w or ki n g 
da ys.   
 
If wit h dra wi n g t he 
partici pa nt d oes n ot 
re prese nt a safet y 
iss ue a n d t he patie nt 
will be wit h dra w n, 
re p ort at c o nti n ui n g 
re vie w. 
 
 
 
 
 
 
 
R o uti ne Re p orti n g Ti meli nes  
E ve nt  
H R P O –  W as hi n gt o n 
U ni versit y  
H R P P O –  U T 
S o ut h wester n  
Q A S M C –  
W as hi n gt o n 
U ni versit y  
D S M C –  U T  
S o ut h wester n  
F D A  
A d verse e ve nt or S A E t hat d oes 
n ot re q uire e x pe dite d re p orti n g  
If t he y d o n ot meet t he 
defi niti o n of a n 
u na ntici pate d pr o ble m 
i n v ol vi n g ris ks t o 
partici pa nts or ot hers, 
re p ort s u m mar y 
i nf or mati o n at t he 
ti me of c o nti n ui n g 
re vie w 
A d verse e ve nts will 
be re p orte d at 
C o nti n ui n g Re vie w.  
A d verse e ve nts will 
be re p orte d i n t he 
t o xicit y ta ble i n t he 
D S M re p ort w hic h is 
t y picall y d ue e ver y 6 
m o nt hs. 
A d verse eve nt s 
will be re vie we d 
at A n n ual D S M C 
Re vie w  
T he m ost c urre nt t o xicit y ta ble 
fr o m t he D S M re p ort is pr o vi de d 
t o t he F D A wit h t he I N D’s a n n ual 
re p ort. 
Mi n or de viati o n  
Re p ort s u m mar y 
i nf or mati o n at t he 
ti me of c o nti n ui n g 
re vie w. 
Mi n or de viati o ns will 
be re p orte d at 
C o nti n ui n g Re vie w. 
 
Mi n or d e viati o ns 
will be  re vie we d 
at A n n ual D S M C 
Re vie w  
 


 
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Pr ot oc ol Versi o n:  0 5/ 1 5/ 2 0 2 3 ( A3)  
 
Pa ge 5 1  of 5 4  
 
 
C o m plai nts  
If t he c o m plai nt 
re veals a n 
u na ntici pate d pr o ble m 
i n v ol vi n g ris ks t o 
partici pa nts or ot hers 
O R n o nc o m plia nce, 
re p ort wit hi n 1 0 
w or ki n g da ys.  If t he 
e ve nt res ults i n t he 
deat h of a partici pa nt 
e nr olle d at 
W U/ BJ H/ S L C H, 
re p ort wit hi n 1 
w or ki n g da y.  
Ot her wis e, re p ort at 
t he ti me of c o nti n ui n g 
re vie w. 
All c o m plai nts are 
s u m marize d i n t he 
ne xt pr o gress re p ort 
s u b mitte d as part of 
c o nti n uati o n re vie w 
or i n t he fi nal 
re p ort s u b mitte d t o 
i nacti vate t he st u d y 
 
 
 
I ncarcerati o n 
 
 
 
 
 
 
 
If wit h dra wi n g t he 
partici pa nt p oses a 
safet y iss ue, re p ort 
wit hi n 1 0 w or ki n g 
da ys.   
 
If wit h dra wi n g t he 
partici pa nt d oes n ot 
re prese nt a safet y 
iss ue a n d t he patie nt 
will be wit h dra w n, 
re p ort at c o nti n ui n g 
re vie w. 
 
 
 
 


 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  1 1/ 4/ 2 0 2 1 ( A 2) 
 
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1 2. 0  
A P P E N DI X C:  W as hi n gt o n U ni versit y U n a ntici p ate d Pr o ble m Re p orti n g C o ver 
S heet  
 
S A E C O V E R S H E E T - Sec o n d ar y Site Assess me nt  
 
Was hi n gt o n U ni versit y H R P O #:  
S p o ns or -I n v esti gat or:  
S u bject I nitials:   
S u bject I D:  
Treati n g M D:  
Treati n g Site:  
E V E N T T E R M:  
A d missi o n Date:  
E V E N T G R A D E:  
Date of site’s first n otificati o n:  
 
Tre ati n g M D E ve nt Ass ess m e nt:  
 
 
Is t his e v e nt p ossi bl y, pr o b a bl y, or defi nitel y  relate d st u d y treat me nt? 
 
 yes    
 
 n o 
 
If yes, pleas e list w hic h dr u g (if m ore t ha n o n e) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
       
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_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _           _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                            _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
           _ _ _ _ _ _ _ 
P h ysici a n’s N a m e  
  
 
P h ysici a n’s Si g n at ure   
 
D ate  
 
 
 
 
 
 
 
 
 
 
 
 
 




 
S T U 2 0 2 2- 0 3 8 5, Farr, F or m A 3 -Pr ot oc ol, M o d _ 3, 0 6 - 0 6-2 3 ( 2)  
 
Pr ot oc ol Versi o n:  1 1/ 4/ 2 0 2 1 ( A 2) 
 
Pa ge 5 4  of 5 4  
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                        Pl e as e Pri nt  
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I n v esti gat or’s N a me: 
                        Pl e as e Pri nt  
I n v esti gat or Si g nat ure: 
 
D at e
: 
            /                    / 
I n v esti gat or’s N a me: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
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                        Pl e as e Pri nt  
F or M ulti- Ce nter St u dies O nl y 
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: 
            /                    / 
Sc a n a n d e m ail t he c o m plete d re p ort wit h s o urce d oc u me nt ati o n (if av ail a ble) t o:  
S C C D S M C @ U T S o ut h w e st er n. e d u  f or re p orti n g t o t he D S M C ( D at a S afety a n d 
M o nit ori n g C o m mittee)  
 
  

ICF_003.pdf: 
INFORMED CONSENT FORM 
 
 
 
Official title:  Evaluation of LS301 Uptake in Tumors of 
Patients Undergoing Partial Mastectomy and Sentinel Lymph 
Node Biopsy for Breast Cancer 
 
NCT number: NCT02807597 
IRB Approved date: 01-29-24 


Title of Study: Evaluation of LS301 Uptake in Tumors of Patients Undergoing Partial Mastectomy and 
Sentinel Lymph Node Biopsy for Breast Cancer  
 
STU2022-0385, Farr, FormE-Consent, Mod_5, 01-29-24 
 
 
Page 1 of 8 
                           
UTSW Research Consent and Authorization Documents (v3 July 2020) 
 
Consent to be part of a Research Study 
To be conducted at  
The University of Texas Southwestern Medical Center  
 
Key Information about this Study  
The purpose of this research study is to look at how an imaging agent called LS301 works in your body when  
injected prior to surgery. 
 
When you enroll in this study, you will receive doses of LS301 until the safest and best tolerated dose is reached. 
LS301 is given via I.V. infusion 4-24 hours prior to surgery in the clinic at the University of Texas Southwestern 
Medical Center. The dose of LS301 you receive will depend on when you enroll in the study and the side effects that 
the people who enrolled before you experienced. You will be monitored for approximately one hour after injection for 
any side effects that might be related to LS301.  After that time period is up, you may remain in the hospital for your 
surgery or you may go home and return the next day for your surgery.  You will have tests, exams and procedures 
that are part of your standard care and for study purposes.  
 
There are risks to this imaging agent that are described in this document. Some risks include dizziness, fever, 
changes in liver enzymes, and nausea. 
 
Information about this form 
You may be eligible to take part in a research study.  This form gives you important information about the study.   
 
Please take time to review this information carefully.  You should talk to the researchers about the study and ask 
them any questions you have.  You may also wish to talk to others (for example, your friends, family, or a doctor) 
about your participation in this study.  If you decide to take part in the study, you will be asked to sign this form.  
Before you sign this form, be sure you understand what the study is about, including the risks and possible benefits 
to you. 
 
Please tell the researchers or study staff if you are taking part in another research study. 
 
Your doctor is a research investigator in this study.  S/he is interested in both your medical care and the conduct of 
this research study.  At any time, you may discuss your care with another doctor who is not part of this research 
study.  You do not have to take part in any research study offered by your doctor. 
 
Voluntary Participation - You do not have to participate if you don't want to.  You may also leave the study at any 
time.  If you decide to stop taking part in this research study, it will not affect your relationship with the UT 
Southwestern staff or doctors.  Whether you participate or not will have no effect on your legal rights or the quality of 
your health care. 
 
If you are a medical student, fellow, faculty, or staff at the Medical Center, your status will not be affected in any way. 
 
General Information – “Who is conducting this research?” 
 
Principal Investigator 
The Principal Investigator (PI) is the researcher directing this study; the PI is responsible for protecting your rights, 
safety and welfare as a participant in the research.  The PI for this study is Deborah Farr, M.D. Department of 
Surgery at the University of Texas Southwestern Medical Center. 
 
Funding  
The University of Texas, Department of Surgery, is funding this study.  The department designed the study, drafted 
the study plan and is providing money so that the researchers can conduct the study. 
IRB Approved Date: 1/29/2024


Title of Study: Evaluation of LS301 Uptake in Tumors of Patients Undergoing Partial Mastectomy and 
Sentinel Lymph Node Biopsy for Breast Cancer  
 
STU2022-0385, Farr, FormE-Consent, Mod_5, 01-29-24 
 
 
Page 2 of 8 
                           
UTSW Research Consent and Authorization Documents (v3 July 2020) 
 
 
Purpose – “Why is this study being done?” 
The purpose of this research study is to look at how a substance called LS301 works in your body when injected 
prior to surgery.  LS301 is a substance developed at Washington University School of Medicine that acts as a dye or 
an imaging agent.  It accumulates in cancer-containing tissue and not in normal tissue, and it fluoresces under near-
infrared light.  This means that researchers can use special goggles that function under near-infrared light to 
distinguish between normal tissue and tumor tissue.  This study is evaluating the extent to which LS301 can be 
found in cancerous tissue and not normal tissue by injecting you with LS301 before surgery and then looking at 
samples of tissue taken during your routine surgery to see whether the information created by viewing the samples 
with the goggles matches the results of the routine evaluation of your samples by a pathologist.  We will also be 
looking at any side effects that occur that might be related to LS301. It is important to note that your surgical plan 
and further treatment will not be altered due to your participation in this study.  
 
LS301 is considered investigational, which means that it has not been approved by the U.S. Food and  
Drug Administration (FDA).  Additionally, the goggles are considered investigational by the FDA. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web 
site will not include information that can identify you. At most, the Web site will include a summary of the results. You 
can search this Web site at any time.  
 
Information about Study Participants – “Who is participating in this research?” 
 
You are being asked to be a participant in this study because you have breast cancer.   
 
How many people are expected to take part in this study?  
This study will enroll approximately 9 study participants.  
 
How long will I be in this study? 
If you agree to take part in this study, your involvement will last for about a day (from the time of  
LS301 injection to the end of surgery). 
 
Information about Study Procedures – “What will be done if you decide to be in the research?” 
 
Screening – After you sign this consent to participate, exams, tests, and/or procedures may be done as described 
below to find out if you can continue in the study; this is called screening. We may be able to use the results of 
exams, tests, and/or procedures you completed before enrolling in this study.  You will be told which results we will 
obtain and which procedures will not have to be repeated.  Many of the procedures are described below as 
“standard care” and would be done even if you do not take part in this research study. You will be told which ones 
are for “research only”. 
 
Screening Procedures  
• 
Physical examination – We will collect information regarding your height, weight and body mass index (BMI) 
• 
Demographic information – We will collect information such as your age, sex, race and ethnicity.  
• 
Medical History – We will collect information about your medical history including any medications you are taking 
including prescription or over-the-counter drugs, vitamins or herbs. 
• 
Pregnancy Test – If you are capable of becoming pregnant, a pregnancy test will also be done before you 
receive study treatment.  
 
The results of the screening exams, tests, and/or procedures will be reviewed to determine whether you will be 
allowed to continue in the study.  If you are not allowed to continue in the study, the researcher will discuss the 
reasons with you and will discuss other possible options. 
IRB Approved Date: 1/29/2024


Title of Study: Evaluation of LS301 Uptake in Tumors of Patients Undergoing Partial Mastectomy and 
Sentinel Lymph Node Biopsy for Breast Cancer  
 
STU2022-0385, Farr, FormE-Consent, Mod_5, 01-29-24 
 
 
Page 3 of 8 
                           
UTSW Research Consent and Authorization Documents (v3 July 2020) 
 
 
Study Procedures - as a participant, you will undergo the following procedures: 
Between 4 and 24 hours before your scheduled surgery, the LS301 will be administered.  It will be given  
as an intravenous injection (by a needle through a vein in your arm).  The dose of LS301 you receive  
will depend on when you enroll in the study and the side effects that the people who enrolled before you  
experienced.  You will be monitored for approximately one hour after injection for any side effects that  
might be related to LS301.  After that time period is up, you may remain in the hospital for your surgery  
or you may go home and return the next day for your surgery. 
 
The safety monitoring will consist of the following procedures at the following time points:  
• 
Assessment of your vital signs (heart rate, blood pressure, respiratory rate, and body temperature) at 30 
minutes before the LS301 injection, 30 minutes and 60 minutes after the injection, and before surgery  
• 
Blood draw (approximately 1 tablespoon at each time point) to check your blood counts and organ function at 
30 minutes before the LS301 injection, 60 minutes after the injection, and approximately one hour before 
surgery; the results from any routine blood tests that you have for up to 30 days after the injection will also be 
reviewed  
• 
Collection of a urine sample for a urinalysis to check your organ function at 30 minutes before the LS301 
injection, 60 minutes after the injection, and approximately one hour before surgery  
• 
Electrocardiogram (ECG) to check how your heart is functioning at 30 minutes before the LS301 injection and 
again 5-10 minutes and 60 minutes after the injection; this test involves putting sticky pads on your skin while 
the electoral activity of your heart is recorded 
 
During your surgery, the study team member will wear the special goggles that will allow them to look for the  
fluorescence of the LS301. These goggles will not interfere with the routine surgical procedure.  Before  
removing any tissues, the study team member will use near-infrared light to look for fluorescence with the goggles.   
The study doctor will then perform the surgery as planned.  After the tissue has been removed, the goggles will be  
used again to look for any fluorescence at the edges of the tissue that was removed and also at the site of  
the surgery. Findings with the goggles will be recorded but will not change how the surgery is performed.  A pathologist 
will then evaluate the tissue in the standard way, and the pathologic results will be compared to the view while using 
the goggles.  A small piece of the tissue that was removed will be saved for research testing. 
 
Could your participation end early?  
There are several reasons why the researchers may need to end your participation in the study (early withdrawal).  
Some reasons are: 
• 
The researcher believes that it is not in your best interest to stay in the study. 
• 
You become ineligible to participate 
• 
You become pregnant 
• 
Your condition changes and you need treatment that is not allowed while you are taking part in the study. 
• 
You do not follow instructions from the researchers. 
• 
You withdraw your consent to participate 
• 
The study is stopped. 
 
Risks – “What are the risks of participation in the research?” 
You may experience one or more of the risks indicated below from being in this study. In addition to  
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this  
study.   
 
Some risks described in this consent document, if severe, may cause death.   
 
  
 
IRB Approved Date: 1/29/2024


Title of Study: Evaluation of LS301 Uptake in Tumors of Patients Undergoing Partial Mastectomy and 
Sentinel Lymph Node Biopsy for Breast Cancer  
 
STU2022-0385, Farr, FormE-Consent, Mod_5, 01-29-24 
 
 
Page 4 of 8 
                           
UTSW Research Consent and Authorization Documents (v3 July 2020) 
 
Risks of LS301  
LS301 is not known to cause any adverse effects, but it has not yet been tested in people. However, it is  
possible that some patients may experience mild reactions similar to those they might experience if  
given a different kind of imaging agent called OctreoScan, such as dizziness, fever, changes in liver  
enzymes, and nausea.  
 
Risks of Goggle System  
The fluorescence goggle imaging system uses safe, non-laser, invisible near-infrared wavelengths well  
below the US FDA limit for near-infrared exposure. It is equivalent to the current near-infrared dose  
emitted from the standard 5-lantern surgical lights commonly used in the operating room.  
 
Risks of Blood Draw  
Possible side effects from a blood draw include fainting, dizziness, pain, swelling, bruising, or bleeding  
where the needle is inserted. There is also a slight possibility of infection where the needle is inserted.  
 
Risks of ECG  
An ECG is considered a non-invasive test. Skin irritation from the ECG electrodes or pain when  
removing the electrodes is a possible risk. Also, you may experience discomfort from lying quietly for a  
long time. 
 
Risk of Breach of Confidentiality  
One risk of participating in this study is that confidential information about you may be accidentally  
disclosed.  We will use our best efforts to keep the information about you secure.  Please see the section  
in this consent form titled “Confidentiality – How will your records be kept confidential??” for more information. 
 
Are there Risks related to withdrawing from the study?  
If you decide to withdraw from this study early, please discuss your decision with the principal investigator.  The 
researcher may ask you to complete study withdrawal procedures at a final study visit. There is no risk to you if you 
do not complete the final withdrawal procedures and you can choose not to participate in them. 
 
Reproductive Risks  
 
 
Concerns for sexually active women:  You should not become pregnant while taking part in this study because we 
do not know how the LS301 and procedures could affect a fetus, if a woman becomes pregnant during the study.  It 
is important that you talk to your study doctor about avoiding pregnancy during this study.  If you think you might 
have become pregnant while you are in this study, you must tell one of the study doctors right away so that 
management of the pregnancy and the possibility of stopping the study can be discussed. 
 
If you are a woman who is pregnant or could be pregnant, you cannot take part in this study because we do not 
know how the LS301 and procedures might affect a developing fetus.  We will do a pregnancy test before you start 
treatment to make sure you are not pregnant.    
 
Risks to babies who are being breastfed:   Women who are breastfeeding cannot take part in this study because 
we do not know what effect the imaging agent and procedures might have on their breast milk. 
 
Are there risks if you also participate in other research studies? 
Being in more than one research study at the same time, or even at different times, may increase the risk to you.  It 
may also affect the results of the studies.  You should not take part in any other study where you will be receiving 
investigational agents.   
 
 
IRB Approved Date: 1/29/2024


Title of Study: Evaluation of LS301 Uptake in Tumors of Patients Undergoing Partial Mastectomy and 
Sentinel Lymph Node Biopsy for Breast Cancer  
 
STU2022-0385, Farr, FormE-Consent, Mod_5, 01-29-24 
 
 
Page 5 of 8 
                           
UTSW Research Consent and Authorization Documents (v3 July 2020) 
 
What if a research-related injury occurs?  
The researchers have taken steps to minimize the known or expected risks.  However, you may still experience 
problems or side effects, even though the researchers are careful to avoid them.  In the event of a research-related 
injury or if you experience an adverse reaction, please immediately contact your study doctor.  See the section “Contact 
Information” for phone numbers and additional information.  You may also need to tell your regular doctors. 
 
If you are injured or made sick from taking part in this research study, medical care will be provided. This care may 
be billed to you or your insurance. Depending on the circumstances, this care may be provided at no cost to you. We 
have no plans to give you money if you are injured. The investigator can provide you with more information. 
 
If you sign this form, you do not give up your right to seek additional compensation if you are harmed as a result of 
being in this study. 
 
Benefits – “How could you or others benefit from your taking part in this study?” 
You will not benefit from being in this study.    
 
However, we hope that, in the future, other people might benefit from this study because it will help  
investigators learn more about using LS301 in conjunction with the goggle system in an effort to reduce  
the incidence of incomplete removal of cancerous tissue and the need for follow-up surgery. 
 
Alternative procedures or course of treatment – “What other options are there to participation in this 
study?” 
There are other options available to you.  Please talk to researchers about these options.  
 
Costs – Will taking part in this study cost anything? 
You or your health insurance company will be responsible for the cost of treatments and procedures that would be 
done whether or not you took part in this study.  It is important to understand that some insurance companies do not 
cover some costs (for example, approved drugs used in a way different from the package instructions). If your 
insurance company does not cover these treatments or procedures, you will be required to pay for them. Ask the 
researchers if you have any questions about what it will cost you to take part in this study (for example bills, fees, or 
other costs related to the research). 
 
Confidentiality – How will your records be kept confidential? 
 
Information we learn about you in this study will be handled in a confidential manner, within the limits of the law.  If 
we publish the results of the study in a scientific journal or book, we will not identify you.  The Institutional Review 
Board and other groups that have the responsibility of monitoring research may want to see study records which 
identify you as a subject in this study.    
 
How will my information and/or tissue samples be used? 
With appropriate permissions, your samples and collected information may also be shared with other researchers 
here, around the world, and with companies. 
 
By agreeing to participate in this study, your information or tissue samples could be used for future research studies 
or sent to other investigators for future research studies without additional consent from you. The information that 
identifies you will first be removed from your information or tissue samples. If you do not want your information or 
tissue samples to be used for future research studies without your consent, you should not participate in this study. 
 
Research policies require that private information about you be protected and this is especially true for your health 
information.  However, the law sometimes allows or requires others to see your information.  The information given 
below describes how your privacy and the confidentiality of your research records will be protected in this study.  
 
IRB Approved Date: 1/29/2024


Title of Study: Evaluation of LS301 Uptake in Tumors of Patients Undergoing Partial Mastectomy and 
Sentinel Lymph Node Biopsy for Breast Cancer  
 
STU2022-0385, Farr, FormE-Consent, Mod_5, 01-29-24 
 
 
Page 6 of 8 
                           
UTSW Research Consent and Authorization Documents (v3 July 2020) 
 
Medical information collected during this study and the results of any test or procedure that may affect your medical 
care may be included in your medical record. The information included in your medical record will be available to 
health care providers and authorized persons including your insurance company. 
 
Some of the research being done in the future may include genetic research.  Genetic research can look  
at DNA to look for mutations (changes) that may increase the risk of disease or affect the way a person  
responds to treatment.  This could include the database of Genotypes and Phenotypes (dbGaP), which is  
a repository that shares genomic data.  The data within dbGaP remains anonymous, but de-identification  
of data cannot eliminate a risk of disclosure, which could affect you and even your family members. 
  
What is Protected Health Information (PHI)?   
Protected Health Information is information about a person’s health that includes information that would make it 
possible to figure out whose it is.  According to the law, you have the right to decide who can see your protected 
health information.  If you choose to take part in this study, you will be giving your permission to the investigators and 
the research study staff (individuals carrying out the study) to see and use your health information for this research 
study.  In carrying out this research, the health information we will see and use about you will include:  
• 
Demographic information: age, sex, race, ethnicity 
• 
Height, weight, and body mass index (BMI) 
• 
Medical history and concomitant medications 
 
We will get this information by asking you. 
 
How will your PHI be shared?   
Because this is a research study, we will be unable to keep your PHI completely confidential.  We may share your 
health information with people and groups involved in overseeing this research study including: 
• 
the Sponsor, The University of Texas Department of Surgery funding the study. The sponsor includes any 
people, entities, groups or companies working for or with the sponsor or owned by the sponsor.  The sponsor will 
receive written reports about your participation in the research. The sponsor may look at your health information 
to assure the quality of the information used in the research. 
• 
the following collaborators at other institutions that are involved with the study:  Washington University 
• 
the committee that checks the study data on an ongoing basis, to determine if the study should be stopped for 
any reason. 
• 
the members of the local research team. 
• 
The Institutional Review Board, Human Research Protection Program Office and the Compliance Office of the 
University of Texas Southwestern Medical Center, and other groups that oversee how research studies are 
carried out.  
• 
The Research offices at the University of Texas Southwestern Medical Center  
• 
the Food and Drug Administration (FDA) and other U.S. and international governmental regulatory agencies 
involved in overseeing drug or device research. 
• 
Representatives of domestic and foreign governmental and regulatory agencies may be granted direct access to 
your health information for oversight, compliance activities, and determination of approval for new medicines, 
devices, or procedures.   
 
If you decide to participate in this study, you will be giving your permission for the groups named above, to collect, 
use and share your health information.  If you choose not to let these groups collect, use and share your health 
information as explained above, you will not be able to participate in the research study. 
 
Parts of your PHI may be photocopied and sent to a central location or it may be transmitted electronically, such as 
by e-mail or fax. The groups receiving your health information may not be obligated to keep it private.  They may 
pass information on to other groups or individuals not named here.   
 
IRB Approved Date: 1/29/2024


Title of Study: Evaluation of LS301 Uptake in Tumors of Patients Undergoing Partial Mastectomy and 
Sentinel Lymph Node Biopsy for Breast Cancer  
 
STU2022-0385, Farr, FormE-Consent, Mod_5, 01-29-24 
 
 
Page 7 of 8 
                           
UTSW Research Consent and Authorization Documents (v3 July 2020) 
 
How will your PHI be protected?   
In an effort to protect your privacy, the study staff will use code numbers instead of your name, to identify your health 
information.  Initials and numbers will be used on any photocopies of your study records, and other study materials 
containing health information that are sent outside of the University of Texas Southwestern Medical Center for review 
or testing.  If the results of this study are reported in medical journals or at meetings, you will not be identified. 
 
Do you have to allow the use of your health information? 
You do not have to allow (authorize) the researchers and other groups to see and share your health information.  If 
you choose not to let the researchers and other groups use your health information, there will be no penalties but 
you will not be allowed to participate in the study.   
After you enroll in this study, you may ask the researchers to stop using your health information at any time .  
However, you need to say this in writing and send your letter to  
 
Deborah Farr, M.D. 
5323 Harry Hines Boulevard 
Dallas, TX 75390 
 
If you tell the researchers to stop using your health information, your participation in the study will end and the study 
staff will stop collecting new health information from you and about you for this study.  However, the study staff will 
continue to use the health information collected up to the time they receive your letter asking them to stop. 
 
Can you ask to see the PHI that is collected about you for this study?   
The federal rules say that you can see the health information that we collect about you and use in this study.  
Contact the study staff if you have a need to review your PHI collected for this study. 
 
Because of the type of research, you can only access your PHI when the study is done.  At that time, you have the 
right to see and copy the medical information we collect about you during the study, for as long as that information is 
kept by the study staff and other groups involved.   
 
How long will your PHI be used?   
By signing this form, you agree to let us use and disclose your health information for purposes of the study until the 
end of the study.  This permission to use your personal health information expires when the research ends and all 
required study monitoring is over. 
 
Contact Information – Who can you contact if you have questions, concerns, comments or complaints? 
 
If you have questions now, feel free to ask us.  If you have additional questions, concerns, comments or complaints 
later or you wish to report a problem which may be related to this study please contact: 
 
Primary contact: 
Deborah Farr, M.D. can be reached at 214-648-5890 during normal work hours and at 214-645-4673 after normal 
work hours.  
 
The University of Texas Southwestern Medical Center Human Research Protection Program (HRPP) oversees 
research on human subjects.  HRPP and Institutional Review Board (IRB) representatives will answer any questions 
about your rights as a research subject, and take any concerns, comments or complaints you may wish to offer.  You 
can contact the HRPP by calling the office at 214-648-3060. 
 
 
IRB Approved Date: 1/29/2024


Title of Study: Evaluation of LS301 Uptake in Tumors of Patients Undergoing Partial Mastectomy and 
Sentinel Lymph Node Biopsy for Breast Cancer  
 
STU2022-0385, Farr, FormE-Consent, Mod_5, 01-29-24 
 
 
Page 8 of 8 
                           
UTSW Research Consent and Authorization Documents (v3 July 2020) 
 
Research Consent & Authorization Signature Section 
If you agree to participate in this research and agree to the use of your protected health information in this research, 
sign this section.  You will be given a copy of this form to keep.  You do not waive any of your legal rights by signing 
this form. 
 
SIGN THIS FORM ONLY IF THE FOLLOWING STATEMENTS ARE TRUE: 
• 
You have read (or been read) the information provided above. 
• 
Your questions have been answered to your satisfaction about the research and about the collection, use and 
sharing of your protected health information. 
• 
You have freely decided to participate in this research or you are voluntarily giving your consent for another 
person to participate in this study because you believe this person would want to take part if able to make the 
decision and you believe it is in this person’s best interest.   
• 
You understand that a copy of this signed consent document, information about this study, and the results of 
any test or procedure that may affect your medical care, may be included in your medical record. Information 
in your medical record will be available to health care providers and authorized persons including your 
insurance company. 
• 
You authorize the collection, use and sharing of your protected health information (another person’s 
protected health information) as described in this form. 
 
 
Adult Signature Section  
 
 
 
 
 
 
 
AM 
PM 
Printed Name of Participant 
 
 
 
Signature of Participant 
 
 
 
Date 
 
Time 
 
 
 
 
 
 
 
AM 
PM 
Printed Name of Person 
Obtaining Consent 
 
Signature of Person Obtaining Consent  
 
 
Date 
 
Time 
 
 
 
 
 
 
 
 
 
Blind or Illiterate Signature Section  At the time of consent, also complete this section if consent is obtained from an 
individual who is unable to read and/or write but can otherwise communicate and/or comprehend English (e.g., blind, 
physically unable to write, etc.)  
 
Declaration of witness: 
By signing below, I confirm I was present for the entire consent process. The method used for communication (e.g., 
verbal, written, etc.) with the subject was:                                      .   
 
The specific means (e.g., verbal, written, etc.) by which the subject communicated agreement to participate  
was:                                             .          
 
 
 
 
 
 
 
 
AM 
PM 
Printed Name of Witness 
 
 
Signature of Witness 
 
 
Date 
 
Time 
 
  
 
IRB Approved Date: 1/29/2024