Clinical trial NCT04535141
Conditions: Chemotherapy-induced Nausea and Vomiting
Keywords: Chemotherapy-induced Nausea and Vomiting Chemotherapy Nausea and Vomiting Olanzapine
Sponsor: UNC Lineberger Comprehensive Cancer Center
Start date: 2020-08-18; Completion date: 2022-04-11
Enrollment: 91 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to see if olanzapine helps to prevent nausea and/or vomiting (throwing up) when it is added to other medicines in subjects having stem cell transplants. Subjects will either be given olanzapine or an inactive pill (called a placebo) before getting any chemotherapy that is known to cause nausea and vomiting. During the study, the study coordinators will ask the subjects to complete surveys to understand if the patient is having nausea and vomiting, and if so, how bad it is making the patient feel.

This trial will split subjects into two groups: one group will be given an inactive pill (placebo), and the other group will be given the active pill (olanzapine). Study coordinators will collect surveys every morning before chemotherapy and 5 days after the last dose of chemotherapy. These surveys may be given by members of the study team or possibly on a mobile device.

Subjects may benefit from being in this research study because olanzapine may reduce the frequency or severity of chemotherapy-induced nausea and vomiting (CINV). The most common risks of using olanzapine include possibly becoming more tired, mild dizziness, mild low blood pressure, and mild muscle "quivering." Other possible adverse effects include low blood pressure, muscle weakness, increased appetite, weight gain, constipation, and liver function test changes however these risks are less common in subjects with cancer. In addition, there may be a change detected in heart rhythm however subjects will be screened for this ahead of time.

Detailed description:
Chemotherapy induced nausea and vomiting (CINV) occurs in up to 80% of patients on active therapy and remains a significant barrier to quality of life. CINV can alter electrolytes and enteral nutrition which can have a detrimental effect on patient adherence and health outcomes. Hematopoietic Stem Cell Transplant (HCT) patients are at increased risk for CINV because many of the conditioning regimens require multiple days of high-dose chemotherapy that are, in many cases, associated with highly-emetogenic potential.

Thus, most conditioning regimens require a 3-drug regimen for optimal CINV prophylaxis.

Current Standard of Care Current guidelines support the use of olanzapine in addition to a 3 drug CINV regimen for highly emetogenic chemotherapy, however some controversy remains as to olanzapine's place in therapy with moderately emetogenic chemotherapy. In HCT, current practice at University of North Carolina utilizes an neurokinin-1 receptor antagonist (NK1 RA), serotonin receptor antagonists (5-HT3 RA) and corticosteroid for CINV prophylaxis in conditioning regimens including moderate and highly emetogenic chemotherapy in accordance with American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) recommendations.

Olanzapine, an atypical antipsychotic, antagonizes dopamine, serotonin, catecholamines, acetylcholine, and histamine receptors which helps prevent acute, breakthrough and delayed nausea. Olanzapine has shown benefit when used as prophylaxis in solid tumor patients receiving single-day highly emetogenic chemotherapy. The addition of olanzapine to 5HT-3 antagonist, NK-1 antagonist, and dexamethasone resulted in significantly more complete responses (CR) and more patients without CINV when compared to placebo in the acute, delayed and overall time periods. Data with olanzapine as CINV prophylaxis is not clear in HCT patients, but one retrospective study by Trifilio et. al. illustrates possible benefit in HCT. They compared an aprepitant-based regimen (aprepitant, ondansetron, and steroid) to an olanzapine-based regimen (olanzapine, ondansetron, and steroid) and found that patients in the olanzapine group had significantly less acute and delayed nausea. In addition, the olanzapine-based regimen required significantly less PRN rescue medication compared to the aprepitant based regimen. These results ultimately provided the foundation for the FOND-O study, a prospective trial that added olanzapine as part of CINV prophylaxis in both hematologic malignancies and HCT patients. The FOND-O study compared fosaprepitant, ondansetron, and dexamethasone (FOND) to fosaprepitant, ondansetron, dexamethasone and olanzapine (FOND-O). The inclusion of olanzapine resulted in significantly less delayed and overall nausea but did not affect the acute phase. While the FOND-O study was the first to look at utilizing olanzapine as part of 4 drug CINV prophylaxis in HCT, there were only 68 HCT patients included in the study. Only 24 allogeneic transplants and 44 autologous transplants were enrolled, and only 34 of these patients actually received olanzapine.

In addition, the FOND-O study utilized an olanzapine dose of 10 mg on each day of chemotherapy continued through chemotherapy day 3. Rationale for Clinical Study The purpose of our proposed study is to build upon the FOND-O results by doing a prospective, randomized, placebo-controlled study, focused entirely on HCT recipients, and powered to detect olanzapine's potential role in CINV prophylaxis in recipients of HCT. Based upon the available literature in both solid and hematologic malignancies the benefit outweighs the risk of adding olanzapine to standard CINV prophylaxis. The primary endpoint is complete response- defined as no emesis and no more than minimal nausea starting with the first dose of highly or moderately emetogenic conditioning chemotherapy and continuing 5 days beyond the last dose of highly or moderately emetogenic conditioning chemotherapy. Secondary endpoints are defined explicitly

Arms: arm 1: Olanzapine 5mg tablet with chemotherapy, and 3 days after arm 2: None
Interventions: intervention 1: Olanzapine 5 MG intervention 2: Placebo
Intervention descriptions: intervention 1: It will be a de-identified pill created by investigational drug services at University of North Carolina intervention 2: It will be a de-identified pill created by investigational drug services at University of North Carolina

Protocol documents:
Prot_SAP_000.pdf: 




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LI S T  O F  A B B R E VI A TI O N S  
A E  
A d v ers e  e v e nt  
BI D  
Bis i n  di e  (t wi c e  d ail y) 
CI N V  
C h e m ot h er a p y I n d u c e d  N a us e a  a n d  V o miti n g  
C P O  
Cli ni c al  Pr ot o c ol  Offi c e  
C R F  
C as e  R e p ort  F or m  
C R  
C o m pl et e r es p o ns e  
D O C  
D e p art m e nt  of  C orr e cti o ns   
D S M C  
D at a s af et y  m o nit ori n g  c o m mitt e e  
e C R F  
El e ctr o ni c  C as e  R e p ort  F or ms  
F D A  
F o o d  a n d  Dr u g  A d mi nistr ati o n  
H C T  
H e m at o p oi eti c  St e m  C ell  Tr a ns pl a nt  
I D S 
In v esti g ati o n al  dr u g s er vi c e  
L C C C  
Li n e b er g er  C o m pr e h e nsi v e  C a n c er  C e nt er  
N CI -C T C A E  
N ati o n al  C a n c er I nstit ut e  –  C o m m o n  T er mi n ol o g y  Crit eri a f or 
A d v ers e  E v e nts  
PI  
Pri n ci p al i n v esti g at or  
P R O -C T C A E  
P ati e nt  R e p ort e d  O ut c o m es -C o m m o n  T er mi n ol o g y  Crit eri a f or 
A d v ers e  E v e nts  
P R C  
Pr ot o c ol r e vi e w  c o m mitt e e  
S A E  
S eri o us  a d v ers e  e v e nt  
U N C  
U ni v ersit y  of  N ort h  C ar oli n a  
 
 
 


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T A B L E  O F  C O N T E N T S 
LI S T  O F  A B B R E VI A TI O N S   .......................................................................................... i 
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. 1  
St u d y  S y n o psis  ...................................................................................................... 1 
1. 2  
B a c k gr o u n d  ........................................................................................................... 1 
1. 3  
C urr e nt  St a n d ar d  of  C ar e ....................................................................................... 1 
1. 4  
St u d y  Tr e at m e nt  .................................................................................................... 2 
1. 5  
R ati o n al e f or  Cli ni c al  St u d y  .................................................................................. 2 
2. 0  
S T U D Y  O B J E C T I V E S .......................................................................................... 3 
2. 1  
Pri m ar y  O bj e cti v es  ................................................................................................3  
2. 2  
S e c o n d ar y  O bj e cti v es  ............................................................................................ 3 
3. 0  
C rit e ri a f o r  E v al u ati o n /  St u d y  E n d p oi nts  .......................................................... 3 
3. 1    Pri m ar y  E n d p oi nt: ..................................................................................................... 3 
3. 2  
S e c o n d ar y  E n d p oi nts ............................................................................................. 4 
4. 0  
S U B J E C T  E LI GI BI LI T Y  ..................................................................................... 7 
4. 1  
I n cl usi o n  Crit eri a ................................................................................................... 7 
4. 2  
E x cl usi o n  Crit eri a  .................................................................................................. 7 
5. 0  
S T U D Y  D E SI G N  .................................................................................................... 8 
5. 1  
G e n er al  D esi g n  ...................................................................................................... 8 
5. 2  
S c h e m a  .................................................................................................................. 9 
5. 3  
Tr e at m e nt  D os a g e  a n d  A d mi nistr ati o n  ................................................................. 9 
5. 4  
T o xi citi es  a n d  D osi n g  D el a ys/ D os e  M o difi c ati o ns  ............................................. 1 0 
5. 5  
C o n c o mit a nt  M e di c ati o ns/ Tr e at m e nts/ S u p p orti v e  C ar e  All o w e d  ...................... 1 1 


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5. 6  
Pr o hi bit e d  M e di c ati o ns ....................................................................................... 1 1  
5. 7  
D ur ati o n  of  T h er a p y ............................................................................................ 1 1  
5. 8  
D ur ati o n  of  F oll o w  U p ........................................................................................ 1 1  
5. 9  
St u d y  Wit h dr a w al ................................................................................................ 1 2  
6. 0  
D R U G I N F O R M A TI O N  ..................................................................................... 1 3 
6. 1  
Ol a n z a pi n e  ........................................................................................................... 1 3 
6. 2    
Pl a c e b o … … … … … … … … … … … … … … … … … … … … … … … … … … … … 1 3 
7. 0  
C LI NI C A L  A S S E S S M E N T S  .............................................................................. 1 5 
7. 1  
Ass ess m e nt  D es cri pti o ns … … … … … … … … … … … … … … … … … … … … …. 1 4  
7. 2  
P ati e nt  R e p ort e d  O ut c o m es ( Q u alit y  of lif e  ass ess m e nt)  .................................... 1 5 
8. 0  
E V A L U A TI O N S  A N D  A S S E S S M E N T S  ........................................................... 1 6 
8. 1  
Ti m e  a n d  E v e nts  T a bl e  ........................................................................................ 1 6 
8. 2  
Ass ess m e nt  of  S af et y  .......................................................................................... 1 9 
8. 3  
Ass ess m e nt  of  Effi c a c y  ....................................................................................... 1 9 
9. 0  
A D V E R S E  E V E N T S ........................................................................................... 2 0  
9. 1  
D efi niti o ns  ........................................................................................................... 2 0 
9. 2  
D o c u m e nt ati o n  of  n o n-s eri o us  A Es  or  S A Rs ...................................................... 2 1  
9. 3  
S A Es  or  S eri o us  S A R s  ........................................................................................ 2 2 
9. 4  
A d v ers e  E v e nt  R e p orti n g .................................................................................... 2 2  
9. 5  
D at a  a n d  S af et y  M o nit ori n g  Pl a n ........................................................................ 2 2  
1 0. 0  
S T A TI S T I C A L  C O N SI D E R A TI O N S  ............................................................... 2 4 
1 0. 1  St u d y  D esi g n ....................................................................................................... 2 4  
1 0. 2  S a m pl e  Si z e,  A c cr u al  a n d  D ur ati o n  of  A c cr u al  .................................................. 2 4 


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S T U D Y  M A N A G E M E N T  ................................................................................... 2 6 
1 1. 1  I nstit uti o n al  R e vi e w  B o ar d (I R B)  A p pr o v al  a n d  C o ns e nt .................................. 2 6 
1 1. 2  R e q uir e d  D o c u m e nt ati o n..................................................................................... 2 6  
1 1. 3  R e gistr ati o n  Pr o c e d ur es....................................................................................... 2 7  
1 1. 4  D at a  M a n a g e m e nt  a n d  M o nit ori n g/ A u diti n g  ...................................................... 2 7 
1 1. 5  A d h er e n c e t o t h e  Pr ot o c ol ................................................................................... 2 7  
1 1. 6  A m e n d m e nts t o t h e  Pr ot o c ol  ............................................................................... 2 8 
1 1. 7  R e c or d  R et e nti o n ................................................................................................. 2 8  
1 1. 8  O bli g ati o ns  of I n v esti g at ors ................................................................................ 2 9  
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R E F E R E N C E S  ..................................................................................................... 3 0 
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A P P E N DI C E S  ...................................................................................................... 3 1 


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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   
St u d y  S y n o psis  
T his is  a  si n gl e i nstit uti o n  pr os p e cti v e,  r a n d o mi z e d,  d o u bl e  bli n d, pl a c e b o -
c o ntr oll e d  tri al  e v al u ati n g  ol a n z a pi n e’s r ol e  as  a pr o p h yl a xis f or  c h e m ot h er a p y 
i n d u c e d  n a us e a  a n d  v o miti n g ( CI N V) i n  h e m at o p oi eti c st e m  c ell tr a ns pl a nt (H C T ) 
r e ci pi e nts. T h e s t u d y s u bj e cts will  b e r a n d o mi z e d i nt o t w o  ar ms ,  pl a c e b o  a n d 
st u d y  dr u g ar ms . Wit hi n  e a c h  ar m , t h er e  will  b e  2  c o h orts  c o nsisti n g  of 
a ut ol o g o us r e ci pi e nts  a n d  all o g e n ei c r e ci pi e nts.   All  s u bj e cts will r e c ei v e  st a n d ar d 
CI N V  pr o p h yl a xis  i n  a c c or d a n c e  wit h  N C C N  g ui d eli n e- b as e d t h er a p y  a n d  p er 
i nstit uti o n al st a n d ar d. S u bj e cts  r a n d o mi z e d t o t h e st u d y  dr u g  ar m  will r e c ei v e 
st a n d ar d  pr o p h yl a xis  pl us  ol a n z a pi n e  st arti n g  wit h t h e first  d os e  of   hi g hl y  or 
m o d er at el y  e m et o g e ni c   c o n diti oni n g  c h e m ot h er a p y  (s e e A p p e n di x  D )  a n d 
c o nti n ui n g f or  3  d a ys  aft er  t h e l ast  d os e  of  hi g hl y  or  m o d er at el y  e m et o g e ni c 
c o n diti o ni n g  c h e m ot h er a p y.   S u bj e cts  r a n d o mi z e d t o t h e  pl a c e b o  ar m  will f oll o w 
t h e s a m e s c h e d ul e  as t h os e r e c ei vi n g st u d y  dr u g  h o w e v er  will r e c ei v e  a  m at c h e d 
pl a c e b o i nst e a d  of  ol a n z a pi n e.   S u bj e cts  will  b e  m o nit or e d (s e e s e cti o n  8. 1)  pri or 
t o t h e st art  of st u d y  dr u g  or  pl a c e b o,  o n  e a c h  d a y t h e y r e c ei v e st u d y  dr u g  or 
pl a c e b o,  a n d f or t w o  a d diti o n al  d a ys  b e y o n d t h e l ast  d os e  of st u d y  dr u g  or  pl a c e b o 
(f or  a t ot al  of  5  d a ys  of  m o nit ori n g  aft er t h e l ast  d os e  of  hi g hl y  or  m o d er at el y 
e m et o g e ni c  c h e m ot h er a p y).   C o n diti o ni n g r e gi m e ns  ar e  p ati e nt s p e cifi c  a n d  c a n 
r a n g e fr o m  1- 7  d a ys, t h er ef or e s u bj e cts will t a k e  ol a n z a pi n e  or  pl a c e b o  f or  a 
m a xi m u m  of  1 0  d a ys.  T h e  effi c a c y  of  ol a n z a pi n e  will  b e  e v al u at e d  b y  c o m p ari n g 
t h e r at es  of  c o m pl et e r es p o ns e  as  d efi n e d i n s e cti o n  3. 1. 
1. 2   
B a c k g r o u n d  
C h e m ot h er a p y i n d u c e d  n a us e a  a n d  v o miti n g ( CI N V)  o c c urs i n  u p t o  8 0 %  of 
p ati e nts  o n  a cti v e t h er a p y  a n d r e m ai ns  a si g nifi c a nt  b arri er t o  q u alit y  of lif e [1 ].  
CI N V  c a n  alt er  el e ctr ol yt es  a n d  e nt er al  n utriti o n  w hi c h  c a n  h a v e  a  d etri m e nt al 
eff e ct  o n  p ati e nt  a d h er e n c e  a n d  h e alt h  o ut c o m es [2 ].  H C T  p ati e nts  ar e  at i n cr e as e d 
ris k f or  CI N V  b e c a us e  m a n y  of t h e  c o n diti o ni n g r e gi m e ns r e q uir e m ulti pl e  d a ys 
of  hi g h- d os e  c h e m ot h er a p y t h at  ar e, i n  m a n y  c as es,  ass o ci at e d  wit h  hi g hl y -
e m et o g e ni c  p ot e nti al .  T h us,  m ost  c o n diti o ni n g r e gi m e ns re q uir e  a  3 - dr u g r e gi m e n 
f or  o pti m al  CI N V  pr o p h yl a xis.  
1. 3   
C u r r e nt  St a n d a r d  of  C a r e 
C urr e nt  g ui d eli n es s u p p ort t h e  us e  of  ol a n z a pi n e i n  a d diti o n t o  a  3  dr u g  CI N V 
r e gi m e n f or  hi g hl y  e m et o g e ni c  c h e m ot h er a p y,  h o w e v er s o m e  c o ntr o v ers y r e m ai ns 
as t o  ol a n z a pi n e’s  pl a c e i n t h er a p y  wit h  m o d er at el y  e m et o g e ni c  c h e m ot h er a p y. I n 
H C T,  c urr e nt  pr a cti c e  at  U N C  utili z es  a n  n e ur o ki ni n - 1  r e c e pt or  a nt a g o nist ( N K 1 
R A),  s er ot o ni n  r e c e pt or   a nt a g o nists  ( 5 -H T 3   R A)   a n d   c orti c ost er oi d  f or   CI N V  
pr o p h yl a xis i n  c o n diti o ni n g r e gi m e ns i n cl u di n g  m o d er at e  a n d  hi g hl y  e m et o g e ni c 
c h e m ot h er a p y  i n  a c c or d a n c e  wit h  A S C O  a n d  N C C N r e c o m m e n d ati o ns [3 , 4 ].  


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1. 4   
St u d y   T r e at m e nt 
 
Ol a n z a pi n e,  a n  at y pi c al  a nti ps y c h oti c,  a nt a g o ni z es  d o p a mi n e,  s er ot o ni n, 
c at e c h ol a mi n es,  a c et yl c h oli n e,  a n d  hist a mi n e r e c e pt ors  w hi c h  h el ps  pr e v e nt  a c ut e, 
br e a kt hr o u g h  a n d  d el a y e d  n a us e a [ 5 ].  Ol a n z a pi n e  h as s h o w n  b e n efit  w h e n  us e d  as 
pr o p h yl a xis i n s oli d t u m or  p ati e nts r e c ei vi n g si n gl e- d a y  hi g hl y  e m et o g e ni c 
c h e m ot h er a p y  [2 ].  T h e  a d diti o n  of  ol a n z a pi n e t o  5 H T- 3  a nt a g o nist,  N K- 1 
a nt a g o nist,  a n d  d e x a m et h as o n e r es ult e d i n si g nifi c a ntl y  m or e  c o m pl et e r es p o ns es 
( C R)  a n d  m or e p ati e nts  wit h o ut  CI N V  w h e n  c o m p ar e d t o  pl a c e b o i n t h e  a c ut e, 
d el a y e d  a n d  o v er all ti m e  p eri o ds.   D at a  wit h  ol a n z a pi n e  as  CI N V  pr o p h yl a xis is 
n ot  cl e ar i n  H C T  p ati e nts,  b ut  o n e r etr os p e cti v e st u d y  b y  Trifili o  et.  al . ill ustr at es 
p ossi bl e  b e n efit i n  H C T [ 6 ].  T h e y  c o m p ar e d  a n  a pr e pit a nt-b as e d r e gi m e n 
( a pr e pit a nt,  o n d a ns etr o n,  a n d st er oi d) t o  a n  ol a n z a pi n e-b as e d r e gi m e n 
( ol a n z a pi n e,  o n d a ns etr o n,  a n d st er oi d)  a n d f o u n d t h at  p ati e nts i n t h e  ol a n z a pi n e 
gr o u p  h a d si g nifi c a ntl y l ess  a c ut e  a n d  d el a y e d  n a us e a. I n  a d diti o n,  t h e  ol a n z a pi n e-
b as e d r e gi m e n r e q uir e d si g nifi c a ntl y l ess  P R N r es c u e  m e di c ati o n  c o m p ar e d t o t h e 
a pr e pit a nt  b as e d r e gi m e n.  T h es e r es ults  ulti m at el y  pr o vi d e d t h e f o u n d ati o n f or t h e 
F O N D -O st u d y,  a  pr os p e cti v e tri al t h at  a d d e d  o l a n z a pi n e  as  p art  of  CI N V 
pr o p h yl a xis i n  b ot h  h e m at ol o gi c  m ali g n a n ci es  a n d  H C T  p ati e nts.   
 
T h e   F O N D -O  st u d y   c o m p ar e d  f os a pr e pit a nt,   o n d a ns etr o n,   a n d   d e x a m et h as o n e  
( F O N D) t o f os a pr e pit a nt,  o n d a ns etr o n,  d e x a m et h as o n e  a n d  ol a n z a pi n e ( F O N D- O). 
T h e i n cl usi o n  of  ol a n z a pi n e r es ult e d i n si g nifi c a ntl y l ess  d el a y e d  a n d  o v er all  n a us e a 
b ut  di d  n ot  aff e ct t h e  a c ut e  p h as e.  W hil e t h e  F O N D -O  st u d y  w as t h e first t o l o o k  at 
utili zi n g  ol a n z a pi n e  as  p art  of  4  dr u g  CI N V  pr o p h yl a xis i n  H C T, t h er e  w er e  o nl y 
6 8   H C T   p ati e nts  i n cl u d e d  i n  t h e  st u d y.   O nl y   2 4   all o g e n ei c  tr a ns pl a nts   a n d   4 4  
a ut ol o g o us  tr a ns pl a nts   w er e   e nr oll e d,   a n d   o nl y   3 4   of  t h es e   p ati e nts   a ct u all y  
r e c ei v e d  ol a n z a pi n e. I n  a d diti o n, t h e  F O N D-O st u d y  utili z e d  a n  ol a n z a pi n e  d os e  of 
1 0  m g  o n  e a c h  d a y  of  c h e m ot h er a p y  c o nti n u e d t hr o u g h  c h e m ot h er a p y  d a y  3 [ 7].  
1. 5   
R ati o n al e  f o r  Cli ni c al  St u d y 
T h e  p ur p os e  of  o ur  pr o p os e d st u d y is t o  b uil d  u p o n t h e  F O N D -O r es ults  b y  d oi n g 
a   pr os p e cti v e,  r a n d o mi z e d,   pl a c e b o -c o ntr oll e d   st u d y,  f o c us e d   e ntir el y   o n   H C T  
r e ci pi e nts, a n d  p o w er e d t o  d et e ct  ol a n z a pi n e’s  p ot e nti al r ol e i n  CI N V  pr o p h yl a xis 
i n  r e ci pi e nts   of   H C T.   B as e d   u p o n  t h e   a v ail a bl e  lit er at ur e  i n   b ot h  s oli d   a n d  
h e m at ol o gi c  m ali g n a n ci es t h e  b e n efi t o ut w ei g hs  t h e ris k  of  a d di n g  ol a n z a pi n e t o 
st a n d ar d  CI N V  pr o p h yl a xis.  T h e  pri m ar y  e n d p oi nt is  c o m pl et e r es p o ns e - d efi n e d 
as  n o  e m esis  a n d  n o  m or e t h a n  mi ni m al  n a us e a ( s e e  s e cti o n  3. 1) st arti n g  wit h t h e 
first   d os e   of   hi g hl y   or  m o d er at el y   e m et o g e ni c   c o n diti o ni n g   c h e m ot h er a p y   a n d  
c o nti n ui n g   5   d a ys   b e y o n d  t h e  l ast   d os e   of   hi g hl y   or   m o d er at el y   e m et o g e ni c  
c o n diti o ni n g  c h e m ot h er a p y.  S e c o n d ar y  e n d p oi nts  ar e  d efi n e d  e x pli citl y i n  s e cti o n 
3. 2.  P ati e nt r e p ort e d fr e q u e n c y  a n d s e v erit y  of  n a us e a  ar e s e c o n d ar y  e n d p oi nts t h at 
will  b e  c oll e ct e d  wit h  a  v ali d at e d  P R O - C T C A E  q u esti o n n air e [8 ].  
 
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
3 
D os e  R ati o n al e:   C urr e nt  g ui d eli n es r e c o m m e n d  a n  ol a n z a pi n e  d os e  of  5  or  1 0  m g 
f or  CI N V  pr o p h yl a xis,  b ut  m or e  e vi d e n c e s u g g ests t h at t h e  5  m g  d os e is as  eff e cti v e 
as t h e  1 0  m g  d os e i n  b ot h  d el a y e d  a n d  o v er all  n a us e a [ 9 ].  
2. 0   S T U D Y  O B J E C TI V E S  
 
All  a n al ys es  will  b e  d o n e s e p ar at el y f or t h e  p ati e nts r e c ei vi n g  all o g e ni c  a n d 
a ut ol o g o us tr a ns pl a nts.   
2. 1   
P ri m a r y  O bj e cti v es  
2. 1. 1   T o  c o m p a r e  t h e o v e r all   r at e  of c o m pl et e  r es p o ns e  ( C R) [s e cti o n  3. 1] b et w e e n  
p ati e nts  o n st u d y tr e at m e nt  [ e x p eri m e nt al  ar m],  d efi n e d  as r e c ei vi n g  ol a n z a pi n e 
pl us st a n d ar d t hr e e  dr u g  CI N V  pr o p h yl a xis r e gi m e n,  a n d  p ati e nts r e c ei vi n g   us u al 
c ar e  [st a n d ar d  of  c ar e  ar m],  d efi n e d  as r e c ei vi n g  pl a c e b o  pl us st a n d ar d t hr e e dr u g 
CI N V  pr o p h yl a xis  d u ri n g t h e st u d y  a ss e ss m e nt  p e ri o d (s e e  s e cti o n  3. 1 f o r 
st u d y  ass ess m e nt  p e ri o d) . 
2. 2   
S e c o n d a r y  O bj e cti v es   
2. 2. 1   T o  c o m p a r e  t h e t ot al n u m b e r  of  r es c u e  m e di c ati o ns  n e e d e d f o r  b r e a kt h r o u g h 
CI N V  b et w e e n t h e  e x p eri m e nt al  a n d st a n d ar d  of  c ar e  ar ms  f or t h e s a m e 
ass ess m e nt  p eri o d  
2. 2. 2   T o  c o m p ar e t h e  n u m b er  of  p ati e nts  a c hi e vi n g  mi ni m al  n a us e a  b et w e e n t h e 
e x p eri m e nt al  a n d st a n d ar d  of  c ar e  ar ms f or t h e s a m e  ass ess m e nt  p eri o d  f or t h e 
s a m e  ass ess m e nt  p eri o d 
2. 2. 3   T o  c o m p ar e t h e  p ati e nt r e p ort e d fr e q u e n c y  of  n a us e a  b et w e e n  p ati e nts  o n t h e 
e x p eri m e nt al  a n d st a n d ar d  of  c ar e  ar ms f or t h e s a m e  ass ess m e nt  p eri o d  f or t h e 
s a m e  ass ess m e nt  p eri o d 
2. 2. 4   T o  c o m p a r e t h e  p ati e nt  r e p o rt e d s e v e rit y  of  n a us e a  b et w e e n  p ati e nts  t h e 
e x p e ri m e nt al  a n d st a n d a r d  of  c a r e  a r ms f o r t h e s a m e  ass ess m e nt  p e ri o d f o r 
t h e s a m e  ass ess m e nt  p e ri o d 
2. 2. 5   T o  c o m p ar e  n u m b er  of  e pis o d es  of  e m esis  b et w e e n  p ati e nts  t h e  e x p eri m e nt al  a n d 
st a n d ar d  of  c ar e  ar ms f or t h e s a m e  ass ess m e nt  p eri o d  f or t h e s a m e  ass ess m e nt 
p eri o d  
 
3. 0   C rit e ri a f o r  E v al u ati o n /  St u d y  E n d p oi nts   
3. 1   P ri m a r y  E n d p oi nt:  
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
4 
3. 1. 1   C o m pl et e r es p o ns e -  M ust s atisf y  all t h r e e  of t h e f oll o wi n g  c rit e ri a f o r t h e 
e nti r e  d u r ati o n  of t h e  st u d y  ass ess m e nt  p e ri o d.   T h e st u d y  ass ess m e nt  p e ri o d  
is d efi n e d  as  st a rti n g wit h t h e  fi rst  d os e  of  hi g hl y  o r  m o d e r at el y  e m et o g e ni c 
c o n diti o ni n g  c h e m ot h e r a p y  a n d  c o nti n ui n g  f o r  5  d a ys  aft e r t he l ast  d os e  of  
hi g hl y  o r  m o d e r at el y  e m et o g e ni c   c o n diti o ni n g  c h e m ot h e r a p y.  T h e st u d y 
t r e at m e nt st a rts  wit h t h e fi rst  d os e  of  hi g hl y  o r  m o d e r at el y  e m et o g e ni c 
c h e m ot h e r a p y  a n d  c o nti n u es f o r  3  d a ys  aft e r t h e l ast  d os e  of  hi g hl y  o r 
m o d e r at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h e r a p y.  
•   N o  e m esis  
•   A s c or e  n o  hi g h er t h a n  “r ar el y ” t o t h e  P R O- C T C A E  q u esti o n  “I n t h e l ast 
2 4  h o urs,  h o w  oft e n  di d  y o u  h a v e  n a us e a ? ” 
•   A s c or e  n o  hi g h er t h a n  “ mil d ” t o t h e  P R O - C T C A E  q u esti o n  “I n t h e l ast  2 4 
h o urs,  w h at  w as t h e s e v erit y  of  y o ur  n a us e a  at its  w orst ? ” 
3. 2   
S e c o n d ar y  E n d p oi nts 
3. 2. 1   N u m b er  of r es c u e  m e di c ati o ns  a d mi nist er e d  d uri n g t h e f oll o wi n g ti m e  p eri o d: 
st arti n g  wit h t h e first  d os e  of  hi g hl y  or  m o d er at el y e m et o g e ni c  c h e m ot h er a p y  a n d 
c o nti n ui n g f or  5  d a ys  aft er l ast  d os e  of  hi g hl y  or  m o d er at el y  e m et o g e ni c 
c o n diti o ni n g  c h e m ot h er a p y  a d mi nistr ati o n .  A r es c u e  m e di c ati o n is  d efi n e d  as 
d o c u m e nt e d  a d mi nistr ati o n  of  a n  a nti- e m eti c  a g e nt  ot h er t h a n t h os e t h at  ar e 
s ch e d ul e d f or  CI N V  pr o p h yl a xis.  
•   W ill  b e r e p ort e d s e p ar at el y b as e d  o n t h e f oll o wi n g ti m e  p eri o ds   
o   A c ut e:  St arti n g  wit h t h e first  d os e  of  hi g hl y  or  m o d er at el y 
e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y  a n d  c o nti n ui n g f or  o n e 
d a y  aft er t h e l ast  d os e  of  hi g hl y  or  m o d er at el y  e m et o g e ni c 
c o n diti o ni n g  c h e m ot h er a p y.  
o   D el a y e d:  St arti n g   wit h t h e s e c o n d  d a y  aft er  c o m pl eti o n  of 
hi g hl y  or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y 
a n d  c o nti n ui n g t hr o u g h t h e fift h  d a y  aft er  c o m pl eti o n  of  hi g hl y 
or  m o d er at el y  e m et o g e ni c  c h e m ot h er a p y.   
3. 2. 2   P er c e nt  a c hi e vi n g  mi ni m al  n a us e a - M ust s atisf y  b ot h  of  t h e  crit eri a  b el o w st arti n g 
wit h t h e first  d os e  of  hi g hl y  or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y 
a n d  c o nti n ui n g f or  5  d a ys  aft er t h e l ast  d os e  of  hi g hl y  or  m o d er at el y  e m et o g e ni c 
c o n diti o ni n g  c h e m ot h er a p y.  
•   P r o -C T C A E  n a us e a f r e q u e n c y s c o r e  of  r a r el y  o r l ess  t o t h e  P R O-
C T C A E  q u esti o n  “I n t h e l ast  2 4  h o u rs,  h o w  oft e n  di d  y o u  h a v e 
n a us e a ? ”  
•   P r o -C T C A E  n a us e a s e v e rit y s c o r e  of  mil d  o r l ess  t o t h e  P R O-
C T C A E  q u esti o n  “I n t h e l ast  2 4  h o u rs,  w h at  w as t h e s e v e rit y  of 
y o u r  n a us e a  at its  w o rst ? ”  


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
5 
3. 2. 3   P ati e nt r e p ort e d fr e q u e n c y  of  n a us e a ( P R O- C T C A E  S c al e:  N e v er,  R ar el y, 
O c c asi o n all y,  Fr e q u e ntl y,  Al m ost  c o nst a ntl y)  t o t h e  P R O- C T C A E  q u esti o n  “I n 
t h e l ast  2 4 h o urs,  h o w  oft e n  di d  y o u  h a v e  n a us e a ? ” 
•   W ill  b e r e p ort e d s e p ar at el y b as e d  o n t h e f oll o wi n g ti m e  p eri o ds:   
o   A c ut e:  St arti n g  wit h t h e first  d os e  of  hi g hl y  or  m o d er at el y 
e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y  a n d  c o nti n ui n g f or  o n e 
d a y  aft er t h e l ast  d os e  of  hi g h l y  or  m o d er at el y  e m et o g e ni c 
c o n diti o ni n g  c h e m ot h er a p y.  
o   D el a y e d:  St arti n g   wit h t h e s e c o n d  d a y  aft er  c o m pl eti o n  of 
hi g hl y  or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y 
a n d  c o nti n ui n g t hr o u g h t h e fift h  d a y  aft er  c o m pl eti o n  of  hi g hl y 
or  m o d er at el y  e m et o g e ni c  c h e m ot h er a p y   
3. 2. 4   P ati e nt r e p ort e d s e v erit y  of  n a us e a ( P R O -C T C A E  S c al e:  N o n e,  Mil d,  M o d er at e, 
S e v er e,  V er y s e v er e)  t o t h e  P R O- C T C A E  q u esti o n  “I n t h e l ast  2 4  h o urs,  w h at  as 
t h e s e v erit y  of  y o ur  n a us e a  at its  w orst ? ” 
•   W ill  b e r e p ort e d s e p ar at el y  b as e d  o n t h e f oll o wi n g ti m e  p eri o ds:  
o   A c ut e:  St arti n g  wit h t h e first  d os e  of  hi g hl y  or  m o d er at el y 
e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y  a n d  c o nti n ui n g f or  o n e 
d a y  aft er t h e l ast  d os e  of  hi g hl y  or  m o d er at el y  e m et o g e ni c 
c o n diti o ni n g  c h e m ot h er a p y.  
o   D el a y e d:  St arti n g  wit h  t h e s e c o n d  d a y  aft er  c o m pl eti o n  of 
hi g hl y  or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y 
a n d  c o nti n ui n g t hr o u g h t h e fift h  d a y  aft er  c o m pl eti o n  of  hi g hl y 
or  m o d er at el y  e m et o g e ni c  c h e m ot h er a p y  
3. 2. 5   D o c u m e nt e d  e pis o d es  of  e m esis  d uri n g t h e st u d y  ass ess m e nt  p eri o d 
•   W ill  b e r e p ort e d s e p ar at el y b as e d  o n t h e f oll o wi n g ti m e  p eri o ds:   
o   A c ut e:  St arti n g  wit h t h e first  d os e  of  hi g hl y  or  m o d er at el y 
e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y  a n d  c o nti n ui n g f or  o n e 
d a y  a ft er t h e l ast  d os e  of  hi g hl y  or  m o d er at el y  e m et o g e ni c 
c o n diti o ni n g  c h e m ot h er a p y.  
o   D el a y e d:  St arti n g  wit h t h e s e c o n d  d a y  aft er  c o m pl eti o n  of 
hi g hl y  or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y 
a n d  c o nti n ui n g t hr o u g h t h e fift h  d a y  aft er  c o m pl eti o n  of  hi g hl y 
or  m o d er at el y  e m et o g e ni c  c h e m ot h er a p y.  
3. 2. 6   D o c u m e nt e d s o m n ol e n c e  a c c or di n g t o  C T C A E  v 5 
o   Will  b e  d o c u m e nt e d  d ail y st arti n g  wit h t h e first  d os e  of  ol a n z a pi n e  a n d 
c o nti n ui n g t hr o u g h  2  d a ys  aft er t h e l ast  d os e  of  ol a n z a pi n e 
3. 2. 7   Q T c  Pr ol o n g ati o n  a c c or di n g t o  C T C A E  v 5 
o   Will  b e  d o c u m e nt e d  a c c or di n g t o t h e  Ti m e  a n d  E v e nts t a bl e i n  S e cti o n  8 
a n d  wi ll  us e t h e  pr e-tr a ns pl a nt/s cr e e ni n g  E K G  as  a  b as eli n e 
o   Fr e d eri ci a  c al c ul ati o n  will  b e  us e d  (s e e  A p p e n di x  C)  


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
6 
 
 
 
 
 
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
7 
4. 0   S U B J E C T  E LI GI BI LI T Y  
I n  or d er t o  p arti ci p at e i n t his st u d y  a s u bj e ct  m ust  m e et A L L  of t h e  eli gi bilit y 
crit eri a  o utli n e d  b el o w.    
4. 1   
I n cl usi o n  C rite ri a  
4. 1. 1   W ritt e n  i nf or m e d   c o ns e nt  o bt ai n e d  t o   p arti ci p at e  i n  t h e  st u d y   a n d   HI P A A  
a ut h ori z ati o n f or r el e as e  of  p ers o n al  h e alt h i nf or m ati o n.   
4. 1. 2   R e ci pi e nts r e c ei vi n g   a ut ol o g o us or  all o g e n ei c  H C T  f or  a n y  dis e as e  
4. 1. 3   A n y  c o n diti o ni n g  c h e m ot h er a p y r e gi m e n  c o nsi d er e d  a st a n d ar d  B M T 
c o n diti o ni n g r e gi m e n ( A p p e n di x  D ) 
4. 1. 4   A g e  > 1 8  y e ars  ol d 
4. 1. 5   E C O G  P erf or m a n c e  St at us  of  0- 2   
4. 1. 6   S u bj e ct is  willi n g  a n d  a b l e to  c o m pl y  wit h st u d y  pr o c e d ur es  b as e d  o n t h e j u d g e m e nt 
of t h e i n v esti g at or  or  pr ot o c ol  d esi g n e e.   
 
4. 2   
E x cl usi o n  C rit e ri a  
4. 2. 1   P ati e nts  m ust  n ot  h a v e st art e d  c o n diti o ni n g  c h e m ot h er a p y  pri or t o  c o ns e nt.   N ot e: 
t est  d os e  B us ulf a n is  n ot  p art  of  c o n diti o ni n g  c h e m ot h er a p y 
4. 2. 2   K n o w n  all er g y t o  ol a n z a pi n e  
4. 2. 3   B as eli n e  Q T c  > 5 0 0  ms e c  as  c al c ul at e d  b y  Fr e d eri ci a  f or m ul a (s e e A p p e n di x  C  f or 
c al c ul ati o n)  
4. 2. 4   P ati e nts  r e c ei vi n g   p ost -tra ns pl a nt   c y cl o p h os p h a mi d e   as   pl a n n e d   G V H D  
pr o p h yl a xis 
4. 2. 5   Pr e g n a nt   or   br e astf e e di n g  ( N O T E:   p ati e nts   pr e g n a nt   or   br e ast -f e e di n g   ar e   n ot  
eli gi bl e t o  pr o c e e d t o tr a ns pl a nt ).  
4. 2. 6   H as   a   k n o w n   a d diti o n al   m ali g n a n c y  t h at is   a cti v e   a n d/ or   pr o gr essi v e  r e q uiri n g 
tr e at m ent;   e x c e pti o ns  i n cl u d e   b as al   c ell   or  s q u a m o us   c ell  s ki n   c a n c er,  i n  sit u  


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
8 
c er vi c al  or  bl a d d er  c a n c er,  or  ot h er  c a n c er f or  w hi c h t h e  s u bj e ct h as  b e e n  dis e as e -
fr e e f or  at l e ast fi v e  y e ars.  
4. 2. 7   Tr e at m e nt  wit h  a n y i n v esti g ati o n al  dr u g  wit hi n  7  d a ys  pri or t o r e gistr ati o n.    
4. 2. 8   S u bj e ct is r e c ei vi n g  pr o hi bit e d  m e di c ati o ns ( ci pr ofl o x a ci n  or fl u v o x a mi n e)  as list e d 
i n S e cti o n  5. 6  of t h e  pr ot o c ol t h at  c a n n ot  b e  dis c o nti n u e d/r e pl a c e d  b y  a n  alt er n ati v e 
t h er a p y. 
 
5. 0   S T U D Y  D E SI G N  
5. 1   
G e n e r al  D esi g n  
 
T his st u d y  is  a si n gl e i nstit uti o n,  r a n d o mi z e d,  d o u bl e  bli n d,  pl a c e b o-c o ntr oll e d tri al 
e v al u ati n g  ol a n z a pi n e’s r ol e  w h e n  a d d e d t o st a n d ar d t hr e e- dr u g  a nti- e m eti c t h er a p y  as  a 
pr o p h yl a xis  a g e nt f or  c h e m ot h er a p y i n d u c e d  n a us e a  a n d  v o miti n g ( CI N V) i n  H C T 
p ati e nts . S u bj e cts  ar e r a n d o mi z e d  1: 1 t o  eit h er  pl a c e b o  or  ol a n z a pi n e.   A r a n d o mi z ati o n 
list  will  b e  g e n er at e d  b y t h e st atisti ci a n  a n d s e nt  dir e ctl y t o I D S f or i m pl e m e nt ati o n.  
R a n d o mi z ati o n  will  b e  d o n e s e p ar at el y f or t h e  all o g e ni c  a n d  a ut ol o g o us tr a ns pl a nt 
p ati e nts,  a n d  us e  bl o c ks  of si z e  6.   Wit hi n t h e  all o g e n ei c r e ci pi e nts, r a n d o mi z ati o n  will  b e 
str atifi e d  b y t h os e r e c ei vi n g  m y el o a bl ati v e  c o n diti o ni n g ( M A C)  vs. r e d u c e d i nt e nsit y 
c o n diti o ni n g ( RI C).   T h e st u d y  p o p ul ati o n  will  c o nsist  of s u bj e cts tr e at e d  at  U N C M C  o n 
t h e  B o n e  M arr o w  Tr a ns pl a nt s er vi c e ( M e d  T).  R es e ar c h  p ers o n n el  will  c o nt a ct s u bj e cts 
r e g ar di n g st u d y  p arti ci p ati o n d uri n g t h e  pr e a d missi o n  c o u ns eli n g  visit. 
 
All s u bj e cts  will  c o m pl et e  c o n diti o ni n g  c h e m ot h er a p y  as  d et er mi n e d  b y t h e ir U N C  B M T 
p h ysi ci a n’s  dis cr eti o n.  C o n diti o ni n g r e gi m e ns  ar e  p ati e nt s p e cifi c  a n d  c a n r a n g e fr o m  1- 7 
d a ys [ A p p e n di x  D ]. A  b as eli n e  ass ess m e nt   of  n a us e a s y m pt o ms will  o c c ur  pri or t o r e c ei pt 
of  a n y  hi g hl y  or  m o d er at el y  e m et o g e ni c  c h e m ot h er a p y  a n d t h e n   will  o c c ur  e v er y  m or ni n g 
of  hi g hl y  or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y  a n d  c o nti n u e f or  5  d a ys 
aft er t h e  l ast d os e  of  hi g hl y  or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y .  St u d y 
pr o c e d ur es  will i n cl u d e  a d mi nistr ati o n  of t h e st u d y  dr u g ( pl a c e b o  or  ol a n z a pi n e)  a n d 
a d mi nistr ati o n  of  a t ar g et e d  N CI  P ati e nt  R e p ort e d  O ut c o m es -C o m m o n  T er mi n ol o g y 
Crit eri a f or  A d v ers e  E v e nts  (P R O - C T C A E). A cti v e  p arti ci p ati o n i n t h e st u d y is  e x p e ct e d 
t o l ast  5  d a ys  aft er t h e l ast  d os e  of hi g hl y  or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g 
c h e m ot h er a p y r e gi m e n (t h e t ot al  n u m b er  of  tr e at m e nt d a ys  will  b e  d e p e n d e nt  o n t h e  
d ur ati o n  of t h e  c o n diti o ni n g  c h e m ot h er a p y r e gi m e n ).   A n  e n d  of st u d y  visit  will t h e n t a k e 
p l a c e  at tr a ns pl a nt  d a y  + 1 0 ( +/-  2  d a ys) 
 
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
9 
5. 2   
S c h e m a  
 
 
 
Fi g u r e  1.  S c h e m ati c  of  St u d y  D esi g n  n e e ds t o  h a v e  e a c h  d a y  of  c o n diti o ni n g 
c h e m o   
 
P arti ci p a nts  will  b e  a d mi nist er e d  st u d y  dr u g ( pl a c e b o  or  ol a n z a pi n e) st arti n g  wit h 
t h e first  d os e  of  hi g hl y  or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y  a n d 
c o nti n ui n g f or  3  d a ys  aft er t h e l ast  d os e  of  hi g hl y  or  m o d er at el y  e m et o g e ni c 
c o n diti o ni n g  c h e m ot h er a p y.   
5. 3   
T r e at m e nt  D os a g e  a n d  A d mi nist r ati o n 
 
R E GI M E N  D E S C R I P TI O N  
 
A g e nt  
P r e -
m e di c ati o ns;  
P r e c a uti o ns  
 
D os e  
 
R o ut e  
 
S c h e d ul e  
 
St at us  
Ol a n z a pi n e   ( or 
pl a c e b o)  
N o n e   
5  m g    B y 
M o ut h  
Pri or t o 
c h e m ot h er a p y 
f or first 
a d mi nistr ati o n, 
t h e n  ni g htl y f or 
t h e r e m ai n d er 
of  d a ys  of 
a d mi nistr ati o n  
S t u d y  Dr u g 
O n d a ns etr o n *  
N o n e   
1 6 -2 4 
m g  
B y 
M o ut h 
or I V  
D ail y,  pri or t o 
e a c h  d os e  of 
c o n diti o ni n g 
c h e m ot h er a p y  
St a n d ar d  of  c ar e  


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
1 0 
D e x a m et h as o n e   N o n e   
8 -2 0 
m g  
B y 
M o ut h 
or I V  
D ail y,  pri or t o 
e a c h  d os e  of 
c o n diti o ni n g 
c h e m ot h er a p y  
St a n d ar d  of  c ar e  
A pr e pit a nt *  
N o n e   
1 3 0 
m g  
I V  
Pri or t o  first 
d os e  of 
c h e m ot h er a p y.  
A s e c o n d  d os e 
m a y  b e  gi v e n 
i n i nst a n c es 
w h er e 
c o n diti o ni n g 
c h e m ot h er a p y 
d ur ati o n 
e x c e e ds  5  d a ys, 
p er i nstit uti o n al 
st a n d ar d 
St a n d ar d  of  c ar e  
 
* A si mil ar  a g e nt  of t h e s a m e  cl ass  m a y  b e s u bstit ut e d  at  a n  e q ui v al e nt  d os e (s e e 
N C C N  A nti e m esis  g ui d eli n es f or s p e cifi c  d os e r e c o m m e n d ati o ns)  b as e d  o n 
pr o d u ct/f or m ul ar y  a v ail a bilit y  
5. 4   
T o xi citi es  a n d  D osi n g  D el a ys/ D os e  M o difi c ati o ns 
A n y  s u bj e ct w h o r e c ei v es  at l e ast  1  d os e  of  st u d y tr e at m e nt  o n t his  pr ot o c ol  will  b e 
e v al u a bl e f or t o xi cit y.   E a c h  s u bj e ct  will  b e  ass ess e d  for t h e  d e v el o p m e nt  of  a n y 
t o xi cit y  a c c or di n g t o t h e  Ti m e  a n d  E v e nts t a bl e (S e cti o n  8. 0).   T o xi cit y  will  b e 
ass ess e d   a c c or di n g  t o  t h e   N CI   C o m m o n   T o xi cit y   Crit eri a  f or   A d v ers e   E v e nts  
( C T C A E), v e rsi o n  5. 0 .  D os e  a dj ust m e nts s h o ul d  b e  m a d e  a c c or di n g t o t h e s yst e m 
s h o wi n g  t h e   gr e at est   d e gr e e   of  t o xi cit y.   Ol a n z a pi n e  is   w ell  t ol er at e d   wit h  
s o m n ol e n c e  a n d  Q T C  pr ol o n g ati o n  b ei n g t h e  m ost  c o m m o n  a d v ers e  eff e cts [ 1 0]. 
St u d y  dr u g ( ol a n z a pi n e  or  pl a c e b o)  m a y  b e  d os e r e d u c e d  or  h el d  at  t h e  dis cr eti o n 
of t h e  att e n di n g  p h ysi ci a n.   P ati e nts i n  w h o m  2  or  m or e  d os es  of st u d y  dr u g  ar e 
h el d  will  b e  e x cl u d e d fr o m t h e  effi c a c y  a n al ysis  h o w e v er still f oll o w e d f or t h e 
s af et y  a n al ysis.   
 
E x a m pl e  of  n o n -h e m at ol o gi c al  T o xi cit y  D os e  R e d u cti o ns  
E v e nt  
A cti o n  
S o m n ol e n c e  
Gr a d e  1  
N o n e  
Gr a d e  2 -3  
R e d u c e  st u d y  dr u g t o  2. 5  m g  ni g htl y  
Gr a d e  4  
H ol d  n e xt  d os e.  If t o xi cit y r es ol v es t o  gr a d e  1 -2 
wit hi n  2 4  h o urs, r es u m e st u d y  dr u g  at  a  d os e  of  2. 5 
m g   ni g htl y.    If   n ot  r es ol v e d   t o  ≤  gr a d e  2, 
p er m a n e ntl y  dis c o nti n u e st u d y  dr u g   
P r ol o n g e d  Q T C  ( c al c ul at e d  b y  F r e d e ri ci a) 
Gr a d e  1 -2  
R e d u c e  st u d y  dr u g t o  2. 5  m g  ni g htl y 
Gr a d e  3  
P er m a n e ntl y  dis c o nti n u e  st u d y  dr u g  
 
 
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
1 1 
5. 4. 1   Miss e d  D os es  
If  a  d os e is  n ot  a bl e t o  b e  gi v e n  wit hi n t h e s p e cifi e d ti m efr a m e, or if  a  p ati e nt  v o mits 
s o o n  aft er t a ki n g  a  d os e,  t h e n t h at  d os e  will  b e s ki p p e d,  a n d t h e  p ati e nt  will r es u m e 
as s c h e d ul e d t h e f oll o wi n g  d a y.  
5. 5   
C o n c o mit a nt  M e di c ati o ns/ T r e at m e nts/ S u p p o rti v e  C a r e  All o w e d  
S u bj e cts  will r e c ei v e  all  n e e d e d s u p p orti v e  c ar e  d uri n g t h e st u d y t o  m a n a g e  ot h er 
si d e  eff e cts r el at e d t o  a d mi nistr ati o n  of  c h e m ot h er a p y.   E x a m pl es  of s u p p orti v e 
a g e nts i n cl u d e  a nti -di arr h e al  a g e nts,  a nti - c o nsti p ati o n  a g e nts,  a n d  ot h er s u p p orti v e 
m e di c ati o ns  at t h e  dis cr eti o n  of t h e tr e ati n g  p h ysi ci a n. 
5. 6   
P r o hi bit e d  M e di c ati o ns  
Pr o hi bit e d    C o n c urr e nt  M e di c ati o ns/ Tr e at m e nts   i n cl u d e  
fl u v o x a mi n e  a n d 
ci p r ofl o x a ci n .    Ot h er   k n o w n  i n hi bit ors/i n d u c ers  of   C Y P 2 D 6   a n d   C Y P 1 A 2   ar e 
list e d  b el o w;  h o w e v er, n o  a cti o n is r e q uir e d f or  p ati e nts t a ki n g t h es e  m e di c ati o ns.  
 
I n hi bit o rs  
Fl u v o x a mi n e 
( p r o hi bit e d) 
ci p r ofl o x a ci n 
( p r o hi bit e d) 
ci m eti di n e  
a mi o d ar o n e 
ef a vir e n z  
fl u or o q ui n ol o n es 
f ur af ylli n e 
i nt erf er o n 
m et h o xs al e n  
mi b efr a dil  
ti cl o pi di n e 
Cris a b or ol e 
R u c a p ari b 
C it al o pr a m 
Ri b o ci cli b  
I n d u c e rs  
c ar b a m a z e pi n e  
i ns uli n 
m et h yl c h ol a nt hr e n e  
m o d afi nil 
n af cilli n  
b et a - n a p ht h ofl a v o n e 
o m e pr a z ol e  
rif a m pi n 
R u c a p ari b 
T erifl u n o mi d e  
5. 7   
D u r ati o n  of  T h e r a p y 
Tr e at m e nt  wit h  ol a n z a pi n e  or  pl a c e b o st arts  wit h t h e first  d os e  of  hi g hl y  or 
m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y  a n d  c o nti n u es f or  3  d a ys  aft er 
t h e l ast  d os e  of  hi g hl y  or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y f or  a 
m a xi m u m  of  1 0  d a ys,  u nl ess s u bj e cts  d e ci d e t o  wit h dr a w fr o m t h e st u d y.  
5. 8   
D u r ati o n  of  F oll o w  U p 
All s u bj e cts  will  b e f oll o w e d  i n t h e h os pit al st arti n g  wit h t h e first  d os e  of  hi g hl y  or 
m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y  a n d  c o nti n ui n g f or  5  d a ys  aft er 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
1 2 
t h e l ast d os e  of  hi g hl y  or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y , or 
u ntil  d e at h,  w hi c h e v er  o c c urs first  aft er r e m o v al  or  c o m pl eti o n  of  st u d y tr e at m e nt 
f or d et er mi n ati o n  of st u d y  e n d p oi nts .  S u bj e ct s r e m o v e d fr o m st u d y tr e at m e nt f or 
u n a c c e p t a bl e  A Es  will  b e f oll o w e d f or r es ol uti o n  or st a bili z ati o n  of t h e  a d v ers e 
e v e nt(s).  
5. 9   
St u d y  Wit h d r a w al 
If  a s u bj e ct d e ci d es t o  wit h dr a w  fr o m t h e st u d y ( a n d  n ot j ust fr o m  pr ot o c ol t h er a p y) 
a n  eff ort s h o ul d  b e  m a d e t o  c o m pl et e  a n d r e p ort st u d y  ass ess m e nts  as t h or o u g hl y 
as  p ossi bl e .  At t h e ti m e  of  wit h dr a w al, t h e i n v esti g at or s h o ul d  att e m pt  t o  est a blis h 
as  c o m pl et el y  as   p ossi bl e t h e r e as o n f or t h e st u d y wit h dr a w al.   
•  
T h e  s u bj e ct  s h o ul d  b e  as k e d if t h e y  ar e  willi n g t o  all o w f or t h e  a bstr a cti o n 
of  r el e v a nt  i nf or m ati o n  fr o m  t h eir   m e di c al  r e c or d  i n   or d er  t o   m e et   t h e 
o bj e cti v es  o utli n e d  i n t h e  pr ot o c ol.   
•  
A  c o m pl et e fi n al  e v al u ati o n  at t h e ti m e  of t h e  s u bj e ct ’s st u d y  wit h dr a w al 
s h o ul d  b e  o bt ai n e d  wit h  a n  e x pl a n ati o n  of  w h y t h e  s u bj e ct  is  wit h dr a wi n g 
fr o m t h e st u d y.   
•  
If t h e s u bj e ct is  n o n c o m pli a nt  a n d  d o es  n ot r et ur n f or  a n  e n d  of st u d y f oll o w 
u p  ass ess m e nt, t his s h o ul d  b e  d o c u m e nt e d i n t h e  e C R F.  
•  
If t h e r e as o n f or r e m o v al  of  a s u bj e ct fr o m t h e st u d y is  a n  a d v ers e  e v e nt, t h e 
pri n ci p al s p e cifi c  e v e nt  will  b e r e c or d e d  o n t h e  e C R F.   
 
E x c essi v e  s u bj e ct  wit h dr a w als  fr o m  pr ot o c ol t h er a p y  or fr o m t h e st u d y c a n r e n d er 
t h e st u d y  u n-i nt er pr et a bl e; t h er ef or e,  u n n e c ess ar y  wit h dr a w al  of s u bj ect s s h o ul d  b e 
a v oi d e d. 
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
1 3 
6. 0   D R U G I N F O R M A TI O N  
6. 1   
Ol a n z a pi n e  
F or  a d diti o n al i nf or m ati o n  o n  ol a n z a pi n e r ef er t o t h e  p a c k a g e i ns ert.  
htt ps:// w w w. a c c ess d at a.f d a. g o v/ dr u gs atf d a  d o cs/l a b el/ 2 0 1 4/ 0 2 0 5 9 2s 0 6 2 0 2 1 0 8 6s
0 4 0 0 2 1 2 5 3s 0 4 8l bl. p df  
6. 1. 1   H o w  S u p pli e d  
O n d a ns etr o n,  a pr e pit a nt  a n d  d e x a m et h as o n e is  a  c o m m o nl y  us e d r e gi m e n f or 
c h e m ot h er a p y i n d u c e d  n a us e a  a n d  v o miti n g.  Ol a n z a pi n e  will  b e st or e d i n  a n d 
dis p e ns e d fr o m  U N C I n v esti g ati o n al  Dr u g  S er vi c e (I D S).  I D S is  bli n di n g t h e 
st u d y tr e at m e nt  b y pl a ci n g  ol a n z a pi n e  or  pl a c e b o  i nsi d e  of a  m as k e d  or al  c a ps ul e . 
Ol a n z a pi n e  is  a v ail a bl e  as a t a bl et  i n  2. 5,  5,  7. 5,  1 0,  1 5,  a n d  2 0  m g str e n gt hs. 
S c h e d uli n g  a n d  d osi n g  of st a n d ar d  of  c ar e  CI N V  pr o p h yl a xis  dr u gs ( o n d a ns etr o n, 
a pr e pit a nt,  a n d  d e x a m et h as o n e)  ar e  a d mi nist er e d  a c c or di n g t o t h e  c o n diti o ni n g 
r e gi m e n (A p p e n di x  D ) 
6. 1. 2   St o r a g e  a n d  H a n dli n g  
Ol a n z a pi n e s h o ul d  b e st or e d  at  c o ntr oll e d r o o m t e m p er at u r e,  2 0° t o  2 5° C ( 6 8° t o 
7 7° F) [ 1 0] .  Ol a n z a pi n e  will  b e st or e d  a n d  h a n dl e d  b y t h e I D S  at  U N C M C.  
6. 1. 3   R o ut e  of  A d mi nist r ati o n 
Ol a n z a pi n e  t a bl et  will  b e t a k e n  b y  m o ut h as  a   m as k e d  or al  c a ps ul e.  
6. 1. 4   M et h o d  of  A d mi nist r ati o n 
Ol a n z a pi n e  c a n  b e t a k e n  wit h  or  wit h o ut f o o d.   T h e first  d os e  will  b e  gi v e n  pri or t o 
st art  of  c h e m ot h er a p y  ( +/- 1  h o ur)  a n d s u bs e q u e nt  d os es  will  b e   gi v e n ni g htl y  at 
2 1 0 0 ( +/- 2  h o urs).  
6. 1. 5   D r u g  O r d e ri n g  a n d  A c c o u nt a bilit y  
T h e  i n v esti g at or   or  d esi g n e e   is  r es p o nsi bl e  f or  k e e pi n g   a c c ur at e  r e c or ds   of t h e  
cli ni c al s u p pli es .   Dr u g s u p pl y  will  b e  m ai nt ai n e d  b y  U N C I D S  a n d  dis p e ns e d t o 
t h e  p ati e nt fl o or f or  a d mi nistr ati o n t o t h e  p ati e nt  b y  a r e gist er e d  n urs e  
6. 1. 6   R et u r n  a n d  R et e nti o n  of  St u d y  D r u g  
U p o n   c o m pl eti o n   or  t er mi n ati o n   of  t h e  st u d y,   all   u n us e d   a n d/ or   p arti all y   us e d  
pr o d u ct  will  b e  d estr o y e d  at t h e sit e  p er  i nstit uti o n al  p oli c y ( e. g.,  U N C I D S  dr u g 
d estr u cti o n  p oli c y ).  
6. 1. 7   A d v e rs e  E v e nts 
T h e  m ost  c o m m o n  a d v ers e  eff e cts  of  ol a n z a pi n e  of  p arti c ul ar i nt er est i n t his st u d y 
ar e  Q T C  pr ol o n g ati o n  a n d s o m n ol e n c e  
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
1 4 
6. 2   
Pl a c e b o  
6. 2. 1   H o w  S u p pli e d  
Pl a c e b o  will  b e st or e d i n  a n d  dis p e ns e d fr o m  U N C I n v esti g ati o n al  Dr u g  S er vi c e 
(I D S). I D S is  bli n di n g t h e st u d y tr e at m e nt  b y pl a ci n g  ol a n z a pi n e  or  pl a c e b o  i nsi d e 
of  a  m as k e d  or al  c a ps ul e.  S c h e d uli n g  a n d  d osi n g  of st a n d ar d  of  c ar e  CI N V 
pr o p h yl a xis  dr u gs ( o n d a ns etr o n,  a pr e pit a nt,  a n d  d e x a m et h as o n e)  ar e  a d mi nist er e d 
a c c or di n g t o t h e  c o n diti o ni n g r e gi m e n  (A p p e n di x  D ) 
6. 2. 2   St o r a g e  a n d  H a n dli n g  
Pl a c e b o s h o ul d  b e st or e d  at  c o ntr oll e d r o o m t e m p er at ur e,  2 0° t o  2 5° C ( 6 8° t o 
7 7° F) [ 1 0].  Pl a c e b o  will  b e st or e d  a n d  h a n dl e d  b y t h e I D S  at  U N C M C.  
6. 2. 3   R o ut e  of  A d mi nist r ati o n 
Pl a c e b o  t a bl et  will  b e t a k e n  b y  m o ut h as  a  m as k e d  or al  c a ps ul e.   
6. 2. 4   M et h o d  of  A d mi nist r ati o n 
Pl a c e b o  c a n  b e t a k e n  wit h  or  wit h o ut f o o d.   T h e first  d o es  will  b e  gi v e n  pri or t o 
st art  of  c h e m ot h er a p y ( +/ - 1  h o ur)  a n d s u bs e q u e nt  d os es  will  b e  gi v e n  ni g htl y  at 
2 1 0 0 ( +/- 2  h o urs).  
6. 2. 5   D r u g  O r d e ri n g  a n d  A c c o u nt a bilit y  
T h e  i n v esti g at or  or  d esi g n e e   is  r es p o nsi bl e  f or  k e e pi n g   a c c ur at e  r e c or ds   of t h e  
cli ni c al s u p pli es.   Dr u g s u p pl y  will  b e  m ai nt ai n e d  b y  U N C I D S  a n d  dis p e ns e d t o 
t h e  p ati e nt fl o or f or  a d mi nistr ati o n t o t h e  p ati e nt  b y  a r e gist er e d  n urs e  
6. 2. 6   R et u r n  a n d  R et e nti o n  of  Pl a c e b o   
U p o n   c o m pl eti o n   or  t er mi n ati o n   of  t h e  st u d y,   all   u n us e d   a n d/ or   p arti all y   us e d  
pr o d u ct  will  b e  d estr o y e d  at t h e sit e  p er  i nstit uti o n al  p oli c y ( e. g.,  U N C I D S  dr u g 
d estr u cti o n  p oli c y ).  
 
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
1 5 
7. 0   C LI NI C A L  A S S E S S M E N T S  
Cli ni c al  ass ess m e nts  will  b e  p erf or m e d  as  o utli n e d  i n t h e  Ti m e  a n d  E v e nts  T a bl e i n 
S e cti o n  8. 1  
7. 1   
Ass ess m e nt  D es c ri pti o ns  
7. 1. 1   C o n c o mit a nt  M e di c ati o ns 
All   c o n c o mit a nt   m e di c ati o n   a n d   c o n c urr e nt  t h er a pi es   will   b e   d o c u m e nt e d   a t 
B as eli n e/ S cr e e ni n g  a n d t hr o u g h o ut t h e st u d y  as s u m m ari z e d i n t h e  Ti m e  a n d  E v e nts 
T a bl e i n  S e cti o n  8. 0.  D os e , r o ut e,  u nit fr e q u e n c y  of  a d mi nistr ati o n,  a n d i n di c ati o n 
f or a d mi nistr ati o n  a n d  d at es  of  m e di c ati o n  will  b e  c a pt ur e d.  
7. 1. 2   D e m o g r a p hi cs  
D e m o gr a p hi c  i n f or m ati o n  ( d at e   of   birt h,   g e n d er,  r a c e)   will   b e  r e c or d e d   at  
S cr e e ni n g . 
7. 1. 3   M e di c al  Hist o r y   
R el e v a nt   m e di c al   hist or y,  i n cl u di n g   hist or y   of   c urr e nt   dis e as e,   ot h er   p erti n e nt  
hist or y,   a n d  i nf or m ati o n  r e g ar di n g   u n d erl yi n g   dis e as es   will   b e  r e c or d e d   at 
S cr e e ni n g   a n d  a  f o c us e d   ass ess m e nt   o n  s y m pt o ms/t o xi cit y   will   b e   p erf or m e d  
t h er e aft er.  
7. 1. 4   P h ysi c al  E x a mi n ati o n 
A   c o m pl et e   p h ysi c al   e x a mi n ati o n   i n cl u di n g  h ei g ht  ( at  s cr e e ni n g   o nl y),   w ei g ht,  
P erf or m a n c e st at us  E C O G  a n d  vit al si g ns   (i. e., t e m p er at ur e  a n d  bl o o d pr ess ur e) 
will  b e  p erf or m e d  b y  a  c o -i n v esti g at or  w h o is  a  p h ysi ci a n or  a d v a n c e d  pr a cti c e 
pr o vi d er  at  S cr e e ni n g  a n d t h e first  St u d y  Visit  # 1.    
 
Q u alifi e d st aff ( M D,  N P,  R N,  a n d  P A)  m a y  c o m pl et e t h e  a b br e vi at e d  p h ysi c al  e x a m 
at  all  ot h er  visits.    
 
N e w  a b n or m al  p h ysi c al  e x a m fi n di n gs  m ust  b e  d o c u m e nt e d  a n d  will  b e f oll o w e d 
b y  a  p h ysi ci a n  or  ot h er  q u alifi e d st aff  at t h e  n e xt s c h e d ul e d  visit.  
7. 1. 5   A d v e rs e  E v e nts 
E v e nts s h o ul d  b e  ass ess e d  p er  N CI -C T C A E  crit eri a  v 5. 0 . I nf or m ati o n r e g ar di n g 
o c c urr e n c e  of  a d v ers e  e v e nts  will  b e  c a pt ur e d t hr o u g h o ut t h e st u d y.  D ur ati o n (st art 
a n d st o p  d at es), s e v erit y/ gr a d e,  o ut c o m e, tr e at m e nt  a n d r el ati o n t o st u d y  dr u g  will 
b e r e c or d e d i n t h e  c as e r e p ort f or m ( C R F).  
7. 2   
P ati e nt  R e p o rt e d  O ut c o m es ( Q u alit y  of lif e  ass ess m e nt) 
P R O - C T C A E t o ols t o  ass ess fr e q u e n c y  a n d s e v erit y  of  n a us e a i n cl u d e d i n 
A p p e n di x  A .  


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
1 6 
8. 0   E V A L U A TI O N S  A N D  A S S E S S M E N T S  
T h e  N CI  P ati e nt  R e p ort e d  O ut c o m es - C o m m o n  T er mi n ol o g y  Crit eri a f or  A d v ers e  E v e nts (P R O - C T C A E)  will  b e  a d mi nist er e d 
e v er y  m or ni n g st arti n g  wit h t h e first  d os e  of  hi g hl y  or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y  a n d  c o nti n ui n g f or  5 
d a ys  aft er t h e l ast  d os e  of  hi g hl y  or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y (s e e s e cti o n  8 . 1). 
 
8. 1   
Ti m e   a nd  E v e nts  T a bl e 
 
S A M P L E   
  
S cr e e ni n g  
Pr e -st u d y1 
E a c h  D a y 
of  C h e m o 
P ost -c h e m o 
D a y  1  
P ost -c h e m o 
D a y  2  
P ost -c h e m o 
D a y  3  
P ost -St u d y  Tr e at m e nt  F oll o w -u p  
P ost -c h e m o 
D a y  4  
P ost -c h e m o 
D a y  5  
E n d  of st u d y 
p eri o d 2 
I nf or m e d  C o ns e nt 
X   
 
 
 
 
 
 
 
D e m o gr a p hi cs  
X   
 
 
 
 
 
 
 
M e di c al  Hist or y  
X   
 
 
 
 
 
 
 
C o n c o mit a nt  M e di c ati o ns   
X   
 
 
 
 
 
 
 
P h ysi c al  E x a m  
X   
 
 
 
 
 
 
 
Fr e q u e n c y 
  of 
  n a us e a 
 
P R O -C T C A E  
  
X 3  
X  
X  
X  
X  
X  
 
S e v erit y   of   n a us e a   P R O -
C T C A E  
  
X 3  
X  
X  
X  
X  
X  
 
P R N   R es c u e   M e di c ati o ns  
d uri n g st u d y  p eri o d   
 
 
 
 
 
 
 
X  
E K G  
X  ( wit hi n  2 
w e e ks  pri or 
t o 
a d missi o n ) 
 
X  
 
 
 
 
X  
Ol a n z a pi n e   or   Pl a c e b o  
A d mi nistr ati o n 4 
  
X  
X  
X  
X  
 
 
 
R e vi e w  n ot es f or s e d ati o n   
  
X  
X  
X  
X  
X  
X  
 
R e vi e w  n ot es f or  e m esis   
  
X  
X  
X  
X  
X  
X  
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
1 7 
Ass ess m e nt  f or A E 5  
  
X  
X  
X  
X  
 
 
X  


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
1 8 
F o ot n ot es t o  Ti m e  a n d  E v e nts  T a bl e  
1.   M e di c al  hist or y  a n d  p h ysi c al  e x a m  m a y  b e  p erf or m e d  wit hi n  2  w e e ks  pri or t o  d a y  1  of 
st u d y  dr u g  tr e at m e nt.   Ot h er  e v al u ati o ns  e x c e pt f or  pr e g n a n c y t est  m ust  b e  p erf or m e d 
wit hi n  2  w e e ks   pri ors  t o   D a y   1  ( D 1)   of   st u d y  tr e at m e nt.   S er u m   B-H C G   m ust   b e  
p erf or m e d  wit hi n  3 0  d a ys  pri or  t o a d missi o n  a n d  m a y  b e r e p e at e d  at t h e  pr e -a d missi o n 
visit  f or  w o m e n  of  c hil d-b e ari n g  p ot e nti al  p er  U N C  H C T  R e ci pi e nt  eli gi bilit y  a n d 
E v al u ati o n  P oli c y  [ P oli c y  St at I D:  6 9 9 4 1 2 5].   
 
2.   T h e  e n d  of tr e at m e nt  visit s h o ul d  o nl y  o c c ur  w h e n  s u bj e cts  p er m a n e ntl y st o p st u d y 
tr e at m e nt  a n d  s h o ul d b e  p erf or m e d   o n tr a ns pl a nt d a y  + 1 0 ( +/ - 2  d a ys).   S u bj e cts  w h o 
h a v e  a n  o n g oi n g  ≥ gr a d e  2  or s eri o us  A E ( S A E)  at t his  visit  will  c o nti n u e t o  b e f oll o w e d 
u ntil t h e  e v e nt is r es ol v e d  or  d e e m e d irr e v ersi bl e  b y t h e i n v esti g at or.    
 
3.   B as eli n e  ass ess m e nt  of  n a us e a s y m pt o ms  usi n g t h e t ar g et e d  P R O -C T C A E i nstr u m e nt 
will   b e   p erf or m e d   pri or  t o   a d mi nistr ati o n   of   c h e m ot h er a p y   o n  t h e  first   d a y   of  
c o n diti o ni n g t h er a p y.  S u bs e q u e nt  ass ess m e nt s  will  o c c ur  e v er y  m or ni n g  u ntil  5  d a ys 
aft er  c o n diti o ni n g t h er a p y. 
 
4.   T h e first  a d mi nistr ati o n  of  Ol a n z a pi n e  or  pl a c e b o  will  b e  pri or t o st art  of  c h e m ot h er a p y 
( +/-  1  h o ur).  S u bs e q u e nt  d os es  will  b e  gi v e n  ni g htl y  at  2 1 0 0 ( +/- 2  h o urs).   
 
5.   T o xi cit y  will  b e  ass ess e d  usi n g  C T C A E  v 5. 0  
 
 
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
1 9 
8. 2   
Ass ess m e nt  of  S af et y  
A n y  s u bj e ct w h o r e c ei v es  at l e ast  o n e  d os e  of st u d y t h er a p y  o n t his  pr ot o c ol  will  b e 
e v al u a bl e f or t o xi cit y.  E a c h  s u bj e ct  will  b e  ass ess e d  d ail y  p er t h e ti m e  a n d  e v e nts 
t a bl e  o utli n e d i n s e cti o n  8. 1 f or t h e  d e v el o p m e nt  of  a n y t o xi cit y  a c c or di n g t o t h e 
Ti m e   a n d   E v e nts  t a bl e.     T o xi cit y   will   b e   ass ess e d   a c c or di n g  t o  t h e   N CI  
C T C A E v 5. 0.   
8. 3   
Ass ess m e nt  of  Effi c a c y 
 
Fr e q u e n c y 
of  n a us e a  
N e v er   
R ar el y   
O c c asi o n all y   Fr e q u e ntl y   
Al m ost 
C o nst a ntl y  
S e v erit y  of 
n a us e a   
N o n e   
Mil d   
M o d er at e   
S e v er e   
V er y  S e v er e  
 
All s u bj e cts  w ill  b e i n cl u d e d i n  a n i nt e nti o n t o tr e at  a n al ysis f or effi c a c y  a n d  CI N V 
pr e v e nti o n.  P R O -C T C A E s c al es  will  b e  a d mi nist er e d  st arti n g  wit h t h e first  d os e  of 
hi g hl y  or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y  a n d  c o nti n ui n g f or  5 
d a ys   aft er  t h e  l ast   d os e   of   hi g hl y   or   m o d er at el y   e m et o g e ni c   c o n diti o ni n g  
c h e m ot h er a p y.  Pl e as e  s e e  ti m e   a n d   e v e nts  t a bl e  i n   s e cti o n   8. 1   f or  s p e cifi c  
i nf or m ati o n 
 
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
2 0 
9. 0   A D V E R S E  E V E N T S  
9. 1   
D efi niti o n s  
9. 1. 1   A d v e rs e  E v e nt ( A E) 
A n  a d v ers e   e v e nt  ( A E)  is  a n y  u nt o w ar d  m e di c al  o c c urr e n c e ( e. g.,  a n  a b n or m al 
l a b or at or y fi n di n g, s y m pt o m,  or  dis e as e t e m p or all y  ass o ci at e d  wit h t h e  us e  of  a 
dr u g  or  st u d y tr e at m e nt ) i n  a s u bj e ct  or  cli ni c al i n v esti g ati o n s u bj e ct  a d mi nist er e d 
a  p h ar m a c e uti c al  pr o d u ct  a n d  w hi c h  d o es  n ot  n e c ess aril y  h a v e  a  c a us al r e l ati o ns hi p 
wit h t his tr e at m e nt.   A n  A E  c a n , t h er ef or e, b e  a n y  u nf a v or a bl e  a n d  u ni nt e n d e d si g n 
(i n cl u di n g   a n   a b n or m al  l a b or at or y  fi n di n g),  s y m pt o m,   or   dis e as e  t e m p or all y  
ass o ci at e d   wit h  t h e   us e   of   a   m e di ci n al   pr o d u ct,   w h et h er   or   n ot  r el at e d  t o  t h e  
m e di ci n al   pr o d u ct.   
 
C o n diti o ni n g   c h e m ot h er a p y  f or  tr a ns pl a nt ati o n  r es ults  i n   ≥   gr a d e   3   a n e mi a, 
t hr o m b o c yt o p e ni a,  l e u k o p e ni a  (i n cl u di n g   n e utr o p e ni a,  l y m p h o p e ni a).  T h es e   ar e  
e x p e ct e d  c o m pli c ati o ns  of tr a ns pl a nt  e x p eri e n c e d  b y  all  p ati e nts  a n d  ar e  n ot  k n o w n 
si d e  effe cts  of  ol a n z a pi n e.   T h us, t h es e  will  n ot  b e  c o nsi d er e d  a d v ers e  e v e nts i n t his 
st u d y.   A d diti o n all y ,  h y p o k al e mi a   a n d   h y p o m a g n es e mi a   ar e  c o m m o n   d u e  t o  
c o n diti o ni n g   c h e m ot h er a p y.     T h er ef or e,   o n l y  ≥  gr a d e  3   f or   h y p o k al e mi a   a n d  
h y p o m a g n es e mi a   will   b e   c o nsi d er e d   a d v ers e   e v e nts.   M u c ositis   a n d  i nf usi o n  
r e a cti o ns  c a n  o c c ur  as  a r es ult  o f  c o n diti o ni n g  c h e m ot h er a p y  a n d s h o ul d  n ot  b e 
attri b ut e d t o  ol a n z a pi n e  as t h es e  ar e  n ot  k n o w n si d e  eff e cts,  e v e n  at  hi g h er  d os es . 
T h e  m ost  c o m m o n  a d v ers e  eff e cts  of  ol a n z a pi n e  of  p arti c ul ar i nt er est i n t his st u d y 
ar e  Q T C  pr ol o n g ati o n  a n d s o m n ol e n c e [ 1 0].  
9. 1. 2   S us p e ct e d  A d v e rs e  R e a cti o n  ( S A R) 
A s us p e ct e d  a d v ers e r e a cti o n ( S A R) is  a n y  A E f or  w hi c h t h er e is  a  r e as o n a bl e 
p ossi bilit y  t h at t h e st u d y tr e at m e nt is t h e  c a us e.    R e as o n a bl e  p ossi bilit y  m e a ns t h at 
t h er e is  e vi d e n c e t o s u g g est  a  c a us al r el ati o ns hi p  b et w e e n t h e  dr u g  a n d t h e  A E.  A 
s us p e ct e d  a d v ers e r e a cti o n i m pli es  a l ess er  d e gr e e  of  c ert ai nt y  a b o ut  c a us alit y t h a n 
a d v ers e r e a cti o n,  w hi c h  m e a ns  a n y  a d v ers e  e v e nt  c a us e d  b y  a st u d y  tr e at m e nt 
 
C a us alit y  ass ess m e nt t o  a st u d y  dr u g  is  a m e di c al j u d g m e nt  m a d e i n  c o nsi d er ati o n 
of  t h e  f oll o wi n g  f a ct ors:  t e m p or al  r el ati o ns hi p   of  t h e   A E  t o  st u d y   tr e at m e nt 
e x p os ur e,  k n o w n  m e c h a nis m  of  a cti o n  or si d e  eff e ct  pr ofil e  of st u d y tr e at m e nt, 
ot h er r e c e nt  or  c o n c o mit a nt  dr u g  e x p os ur es,  n or m al  cli ni c al  c o urs e  of t h e  dis e as e 
u n d er i n v esti g ati o n,  a n d  a n y  ot h er  u n d erl yi n g  or  c o n c urr e nt  m e di c al  c o n diti o ns .  
Ot h er f a ct ors t o  c o nsi d er i n  c o nsi d eri n g  dr u g  as t h e  c a us e  of t h e  A E: 
•   Si n gl e  o c c urr e n c e  of  a n  u n c o m m o n  e v e nt  k n o w n t o  b e str o n gl y  ass o ci at e d 
wit h  st u d y tr e at m e nt  e x p os ur e ( e. g.,  a n gi o e d e m a,  h e p ati c i nj ur y,  St e v e ns -
J o h ns o n  S y n dr o m e) 
•   O n e  or  m or e  o c c urr e n c es  of  a n  e v e nt  n ot  c o m m o nl y  ass o ci at e d  wit h  st u d y 
tr e at m e nt  e x p os ur e,   b ut   ot h er wis e   u n c o m m o n  i n  t h e   p o p ul ati o n  ( e. g.,  


L C C C  2 0 3 7 
 
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PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
2 1 
t e n d o n  r u pt ur e);   oft e n   m or e  t h a n   o n c e   o c c urr e n c e  fr o m   o n e   or  m ulti pl e 
st u di es  w o ul d  b e  n e e d e d  b ef or e t h e s p o ns or  c o ul d  d et er mi n e t h at t h er e is 
r e as o n a bl e  p ossi bilit y  t h at t h e st u d y tr e at m e nt  c a us e d t h e  e v e nt.    
•   A n  a g gr e g at e  a n al ysis  of s p e ci fi c  e v e nts  o bs er v e d i n  a  cli ni c al tri al t h at 
i n di c at es t h e  e v e nts  o c c ur  m or e fr e q u e ntl y i n t h e st u d y tr e at m e nt  gr o u p t h a n 
i n  a  c o n c urr e nt  or  hist ori c al  c o ntr ol  gr o u p 
9. 1. 3   U n e x p e ct e d  A E  o r  S A R  
A n  A E  or  S A R is  c o nsi d er e d  u n e x p e ct e d if  t h e sp e cifi cit y  or s e v erit y  of it is  n ot 
c o nsist e nt  wit h t h e  a p pli c a bl e  pr o d u ct i nf or m ati o n  ( e. g., I n v esti g at or’s  Br o c h ur e 
(I B)  f or   a n  u n a p pr o v e d  st u d y  tr e at m e nt   or   p a c k a g e  i ns ert/s u m m ar y   of   pr o d u ct  
c h ar a ct eristi cs f or  a n  a p pr o v e d  pr o d u ct).   U n e x p e ct e d  als o r ef ers t o  A Es  or  S A Rs 
t h at ar e  m e nti o n e d i n t h e I B  as  o c c urri n g  wit h  a  cl ass  of  dr u g s  or  as  a nti ci p at e d 
fr o m t h e  p h ar m a c ol o gi c al  pr o p erti es  of t h e dr u g ,  b ut  ar e  n ot s p e cifi c all y  m e nti o n e d 
as  o c c urri n g  wit h t h e  p arti c ul ar  dr u g  u n d er i n v esti g ati o n.   
9. 1. 4   S e ri o us  A E  o r   S A R 
A n  A E  or  S A R is  c o nsi d er e d s eri o us if, i n t h e  vi e w  of  eit h er t h e i n v esti g at or  or 
s p o ns or, it r es ults i n  a n y  of t h e f oll o wi n g  o ut c o m es: 
•   D e at h;  
•   Is lif e-t hr e at e ni n g ( pl a c es t h e s u bj e ct  at i m m e di at e ris k  of  d e at h fr o m 
t h e  e v e nt  as it  o c c urr e d); 
•   R e q uir es  i n p ati e nt   h os pit ali z ati o n  ( > 2 4   h o urs)   or   pr ol o n g ati o n   of  
e xisti n g  h os pit ali z ati o n;  *  
•   R es ults i n  c o n g e nit al  a n o m al y/ birt h  d ef e ct;  
•   R es ults i n  a  p ersist e nt  or si g nifi c a nt i n c a p a cit y  or s u bst a nti al  disr u pti o n 
of t h e  a bilit y t o  c o n d u ct  n or m al lif e f u n cti o ns; 
•   I m p ort a nt   m e di c al   e v e nts  t h at   m a y   n ot  r es ult  i n   d e at h,   b e  lif e-
t hr e at e ni n g,   or  r e q uir e   h os pit ali z ati o n   m a y   b e   c o nsi d er e d   a  s eri o us 
a d v ers e  st u d y  tr e at m e nt -r el at e d  e x p eri e n c e   w h e n,   b as e d   u p o n  
a p pr o pri at e   m e di c al  j u d g m e nt,  t h e y   m a y  j e o p ar di z e  t h e   s u bj e ct  or 
s u bj e ct  a n d  m a y r e q uir e  m e di c al  or s ur gi c al i nt er v e nti o n t o  pr e v e nt  o n e 
of t h e  o ut c o m es list e d i n t h e  d efi niti o n.   F or r e p orti n g  p ur p os es,  als o 
c o nsi d er  t h e   o c c urr e n c es   of   pr e g n a n c y   as   a n   e v e nt   w hi c h   m ust   b e  
r e p ort e d  as  a n i m p ort a nt  m e di c al  e v e nt. 
 
* H os pit ali z ati o n  f or   a nti ci p at e d   or   pr ot o c ol  s p e cifi e d   pr o c e d ur es  s u c h   as  
a d mi nistr ati o n  of  c h e m ot h er a p y,  c e ntr al li n e i ns erti o n,  m et ast asis i nt er v e nti o n al 
t h er a p y, r es e cti o n  of  pri m ar y t u m or,  or  el e cti v e s ur g er y,  will  n ot  b e  c o nsi d er e d 
s eri o us  a d v ers e  e v e nts. 
9. 2   
D o c u m e nt ati o n  of  n o n -s e ri o us  A E s o r  S A Rs  
F or  n o n -s eri o us  AE s  or  S A R s,  d o c u m e nt ati o n  m ust  b e gi n  st arti n g  wit h t h e first 
d os e   of   hi g hl y   or   m o d er at el y   e m et o g e ni c   c o n diti o ni n g   c h e m ot h er a p y   a n d  
c o nti n ui n g  f or   5   d a ys   aft er  t h e  l ast   d os e   of   hi g hl y   or   m o d er at el y   e m e t o g e ni c 


L C C C  2 0 3 7 
 
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U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
2 2 
c o n diti o ni n g  c h e m ot h er a p y.  C oll e ct e d  i nf or m ati o n s h o ul d  b e r e c or d e d i n t h e  C as e 
R e p ort  F or ms ( C R F) f or t h at  s u bj e ct.   Pl e as e i n cl u d e  a  d es cri pti o n  of t h e  e v e nt, its 
s e v erit y   or  t o xi cit y   gr a d e,   o ns et   a n d  r es ol v e d   d at es  (if   a p pli c a bl e),   a n d  t h e 
r el ati o ns hi p t o t h e st u d y  dr u g. D o c u m e nt ati o n s h o ul d  o c c ur  at l e ast  m o nt hl y .  
9. 3   
S A E s o r  S e ri o us  S A R s  
9. 3. 1   Ti mi n g 
Aft er i nf or m e d  c o ns e nt   b ut   pri or t o i niti ati o n  of st u d y  m e di c ati o ns,  o nl y  S A Es 
c a us e d  b y  a  pr ot o c ol- m a n d at e d i nt er v e nti o n  will  b e  c oll e ct e d ( e. g.  S A Es r el at e d t o 
i n v asi v e  pr o c e d ur es s u c h as  bi o psi es,  m e di c ati o n  w as h o ut ).  
 
F or  a n y  ot h er  e x p eri e n c e  or  c o n diti o n t h at  m e ets t h e  d efi niti o n  of  a n  S A E  or  a  
s eri o us  S A R, r e c or di n g  of t h e  e v e nt m ust  b e gi n  st arti n g  wit h t h e first  d os e  of  hi g hl y 
or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y  a n d  c o nti n ui n g f or  5  d a ys 
aft er t h e l ast  d os e  of  hi g hl y  or  m o d er at el y  e m et o g e ni c  c o n diti o ni n g  c h e m ot h er a p y.   
9. 3. 2   D o c u m e nt ati o n  a n d  N otifi c ati o n 
S A Es  or  S eri o us  S A Rs  m ust  b e r e c or d e d i n  t h e  S A E  c o ns ol e wit hi n  O n C or e ® f or 
t h at s u bj e ct wit hi n  2 4  h o urs  of l e ar ni n g  of its  o c c urr e n c e .  A d diti o n all y, t h e  p r oj e ct 
m a n a g er  m ust  als o  b e  n otifi e d  vi a  e m ail  of  all  S A Es  wit hi n  2 4  h o urs  of l e ar ni n g  of 
its  o c c urr e n c e.  
9. 4   
A d v e rs e  E v e nt  R e p o rti n g  
9. 4. 1   I R B  R e p o rti n g  R e q ui r e m e nts:  
U N C : 
•  
T h e  U N C -I R B  will  b e  n otifi e d  of  all  S A Es t h at  q u alif y  as  a n  U n a nti ci p at e d 
Pr o bl e m  as  p er t h e  U N C I R B  P oli ci es  usi n g t h e I R B’s  w e b -b as e d r e p orti n g 
s yst e m  wit hi n  7  d a ys  of t h e I n v esti g at or  b e c o mi n g  a w ar e  of t h e  pr o bl e m.  
9. 5   
D at a  a n d  S af et y  M o nit o ri n g  Pl a n 
T h e  Pr i n ci p al I n v esti g at or  will  pr o vi d e  c o nti n u o us  m o nit ori n g  of s u bj e ct  s af et y i n 
t his tri al  wit h  p eri o di c r e p orti n g t o t h e  D at a a n d  S af et y  M o nit ori n g  C o m mitt e e 
( D S MC).  
 
M e eti n gs/t el e c o nf er e n c es  will  b e  h el d  at  a fr e q u e n c y  d e p e n d e nt  o n st u d y  a c cr u al.  
T h es e  m e eti n gs  will i n cl u d e  t h e i n v esti g at ors as  w ell  as  pr ot o c ol  n urs e s,  cli ni c al 
r es e ar c h  ass o ci at es, r e g ul at or y  ass o ci ate s,  d at a  m a n a g ers,  bi ost atisti ci a ns,  a n d  a n y 
ot h er r el e v a nt  p ers o n n el t h e  pri n ci p al i n v esti g at ors  m a y  d e e m  a p pr o pri at e.  At t h es e 
m e eti n gs,  t h e  r es e ar c h  t e a m   will   dis c uss   all  iss u es  r el e v a nt  t o  st u d y   pr o gr ess,  
i n cl u di n g  e nr oll m e nt, s af et y, r e g ul at or y,  d at a  c oll e cti o n,  et c. 
 
T h e t e a m  will  pr o d u c e s u m m ari es  or  mi n ut es  of t h es e  m e eti n gs.  T h es e s u m m ari es 
will  b e  a v ail a bl e f or i ns p e cti o n  w h e n r e q u est e d  b y  a n y  of t h e r e g ul at or y  b o di es 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
2 3 
c h ar g e d  wit h t h e s af et y  of  h u m a n s u bj e cts  a n d t h e i nt e grit y  of  d at a i n cl u di n g,  b ut 
n ot  li mit e d  t o,   t h e   o v ersi g ht  of  Offi c e   of   H u m a n   R es e ar c h   Et hi cs  ( O H R E)  
Bi o m e di c al   I R B, t h e  O n c ol o g y  Pr ot o c ol  R e vi e w  C o m mitt e e ( P R C)  or t h e  N ort h 
C ar oli n a  Tr a C S I nstit ut e  D at a   a n d S af et y  M o nit ori n g  B o ar d  ( D S M B).   
 
T h e  U N C  L C C C  D at a  a n d  S af et y   M o nit ori n g C o m mitt e e ( D S M C)  will r e vi e w t h e 
st u d y  o n  a  r e g ul ar ( q u art erl y t o  a n n u all y)  b asis,  wit h t h e fr e q u e n c y  of r e vi e w  b as e d 
o n ris k  a n d  c o m pl e xit y  as  d et er mi n e d  b y t h e  U N C  Pr ot o c ol  R e vi e w  C o m mitt e e .  
T h e   U N C   PI   will   b e  r es p o nsi bl e  f or  s u b mitti n g  t h e  f oll o wi n g  i nf or m ati o n  f or  
r e vi e w:   1) s af et y  a n d  a c cr u al  d at a i n cl u di n g t h e  n u m b er  of  s u bj e cts tr e at e d;  2) 
si g nifi c a nt  d e v el o p m e nts r e p ort e d i n t h e lit er at ur e t h at  m a y  aff e ct t h e s af et y  of 
p arti ci p a nts   or  t h e   et hi cs   of  t h e  st u d y;   3 )   pr eli mi n ar y  r es p o ns e   d at a;   a n d  4 ) 
s um m ari es  of t e a m  m e eti n gs t h at  h a v e  o c c urr e d si n c e t h e l ast r e p ort.  Fi n di n gs  of 
t h e  D S M C r e vi e w  will  b e  diss e mi n at e d  b y  m e m o t o t h e  U N C  PI,  P R C, t h e  U N C 
I R B a n d  D S M B .   


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
2 4 
1 0. 0   S T A TI S TI C A L  C O N SI D E R A TI O N S  
1 0. 1   St u d y  D esi g n  
 
T his  is   a  si n gl e   c e nt er,  r a n d o mi z e d,   d o u bl e   bli n d,   pl a c e b o   c o ntr oll e d  st u d y  
e v al u ati n g  ol a n z a pi n e’s r ol e i n  CI N V  pr o p h yl a xis i n  H C T  p ati e nts.   E a c h  p ati e nt 
will  r e c ei v e   ol a n z a pi n e   or   pl a c e b o  st arti n g   wit h  t h e  first   d os e   of   hi g hl y   or  
m o d er at el y  e m et o g e ni c   c o n diti o ni n g c h e m ot h er a p y (t y pi c all y l asti n g  1-7  d a ys)  a n d 
c o nti n ui n g   3   d a ys   b e y o n d  t h e  l ast   d os e   of   hi g hl y   or   m o d er at el y   e m et o g e ni c  
c o n diti o ni n g  c h e m ot h er a p y.  Pri m ar y  a n d s e c o n d ar y  o bj e cti v es  ar e list e d i n s e cti o ns 
3. 1  a n d  3. 2.  
 
1 0. 2   S a m pl e  Si z e,  A c c r u al   a n d  D u r ati o n  of  A c c r u al 
 
T h e f oll o wi n g  d esi g n  will  b e  us e d:   Ass u mi n g t h e r at e  of  c o m pl et e r es p o ns e i n t h e 
pl a c e b o  ar m  is 2 4 %  a n d t h at t h e r at e i n t h e  ol a n z a pi n e  ar m  will  b e  hi g h er ( 5 5 %) , 
w e   will   n e e d   6 8  t ot al   p ati e nts  i n   e a c h   ar m  ( 3 4  i n   e a c h   c o h ort   of   a ut ol o g o us  
r e ci pi e nts  a n d  all o ge n ei c r e ci pi e nts)  f or  a t ot al  of 1 3 6  [ 7] .   Wit h t his  n u m b er  of 
p ati e nts,  w e  will  h a v e  8 0 %  p o w er t o  d et e ct  a  diff er e n c e,  usi n g  a  c hi -s q u ar e d t est 
wit h t w o -si d e d  al p h a  of  0. 0 5, if t h e r at e i n t h e  ol a n z a pi n e  ar m  is  8 0 %.   T o  a c c o u nt 
f or  dr o p o ut,  w e  pl a n t o  e nroll  1 5 0 .   Si n c e  ol a n z a pi n e is  a n  F D A  a p pr o v e d  dr u g 
c o m m o nl y  us e d f or  CI N V,  w e  a nti ci p at e  a  hi g h  a c cr u al r at e  of  a p pr o xi m at el y  5 0 %. 
W e  a nti ci p at e s cr e e ni n g  a b o ut  3 0 0  p ati e nts t o r e a c h  o ur t ar g et  a c cr u al  of  1 5 0  t ot al 
p ati e nts.   Si n c e   w e   d o   a b o ut   1 6 5  a d ult  tr a ns pl a nts   p er   y e ar   w e   esti m at e  t h at  
e nr oll m e nt  will l ast  a b o ut  1. 5 - 2  y e ars.  
1 0. 3   D at a  A n al ysi s  Pl a ns  
 
All  a n al ys es  will  b e r e p ort e d s e p ar at el y f or t h os e r e c ei vi n g  all o g e ni c  a n d 
a ut ol o g o us tr a ns pl a nts.   
 
 
•   Pri m ar y  e n d p oi nt:  C o m pl et e r es p o ns e - n o  e m esis  a n d  n o  m or e t h a n  mi ni m al 
n a us e a  as  d efi n e d  b y  a s c or e  of ‘ R ar el y’  or l ess  o n t h e  P R O -C T C A E  wit hi n 
t h e first  5  d a ys  of  c h e m ot h er a p y (s e e s e cti o n  3. 1).  A  c hi-s q u ar e d t est  will 
b e  us e d t o  c o m p ar e t h e r at es  of  c o m pl et e r es p o ns e  b et w e e n  ol a n z a pi n e  a n d 
pl a c e b o  ar ms.     
•   S e c o n d ar y  e n d p oi nts:  
o   N u m b er  of r es c u e  m e di c ati o ns t hr o u g h first  5  d a ys  aft er l ast  c h e m o 
a d mi nistr ati o n.   A  Wil c o x o n  R a n k  S u m t est  will  b e  us e d t o 
c o m p ar e t h e  diff er e n c e i n  n u m b er  of r es c u e  m e di c ati o ns  b et w e e n 
t h e  ol a n z a pi n e  a n d  pl a c e b o  ar ms.  
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
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U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
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2 5 
P er c e nt a g es  will  b e r e p ort e d  a n d  C hi -s q u ar e d t ests ( or  Fis h er’s  e x a ct t ests if  c ell 
si z es  ar e s m all)  will  b e  us e d t o  c o m p ar e  p er c e nt a g es  b et w e e n  ar ms .   
o   P er c e nt  a c hi e vi n g  mi ni m al  n a us e a (s c or e  of ‘ R a r el y’  or l ess  o n t h e 
P R O - C T C A E).  
o   M a xi m u m   p ati e nt  r e p ort e d  fr e q u e n c y   of   n a us e a  ( P R O - C T C A E 
S c al e:  N e v er,  R ar el y,  O c c asi o n all y,  Fr e q u e ntl y,  Al m ost  c o nst a ntl y)  
d uri n g t h e  a c ut e  a n d  d el a y e d  p h as es 
o   M a xi m u m  p ati e nt r e p ort e d s e v erit y  of  n a us e a ( P R O -C T C A E  S c al e: 
N o n e,  Mil d,  M o d er at e,  S e v er e,  V er y s e v er e)  d uri n g t h e  a c ut e  a n d 
d el a y e d  p h as es  
o   N u m b er  of  e pis o d es  of  e m esis  d uri n g t h e  a c ut e  a n d  d el a y e d  p h as es 
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
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1 1. 0   S T U D Y  M A N A G E M E N T  
1 1. 1   I nstit uti o n al  R e vi e w  B o a r d (I R B)  A p p r o v al  a n d  C o ns e nt 
It is  e x p e ct e d t h at t h e I R B  will  h a v e t h e  pr o p er r e pr es e nt ati o n  a n d f u n cti o n i n 
a c c or d a n c e   wit h  f e d er all y   m a n d at e d  r e g ul ati o ns.     T h e  I R B  s h o ul d   a p pr o v e  t h e  
c o ns e nt f or m  a n d  pr ot o c ol. 
 
I n  o bt ai ni n g  a n d  d o cu m e nti n g i nf or m e d  c o ns e nt, t h e i n v esti g at or  s h o ul d  c o m pl y 
wit h t h e  a p pli c a bl e r e g ul at or y r e q uir e m e nt(s),  a n d s h o ul d  a d h er e t o  G o o d  Cli ni c al 
Pr a cti c e ( G C P)  a n d t o  et hi c al  pri n ci pl es t h at  h a v e t h eir  ori gi n i n t h e  D e cl ar ati o n  of 
H elsi n ki.  
   
   
 
B ef or e r e cr uit m e nt  a n d  e nr oll m e nt  o nt o t his st u d y, t h e  s u bj e ct  will  b e  gi v e n  a f ull 
e x pl a n ati o n  of t h e st u d y  a n d  will  b e  gi v e n t h e  o p p ort u nit y t o r e vi e w t h e  c o ns e nt 
f or m.  E a c h  c o ns e nt f or m  m ust i n cl u d e  all t h e r el e v a nt  el e m e nts  c urr e ntl y r e q uir e d 
b y  t h e   F D A   R e g ul ati o ns   a n d   l o c al   or  st at e  r e g ul ati o ns.   O n c e  t his   ess e nti al  
i nf or m ati o n  h as  b e e n  pr o vi d e d t o t h e s u bj e ct a n d t h e i n v esti g at or is  ass ur e d t h at t h e 
s u bj e ct u n d erst a n ds t h e i m pli c ati o ns  of  p arti ci p ati n g i n t h e st u d y, t h e  s u bj e ct  will 
b e  as k e d t o  gi v e  c o ns e nt t o  p arti ci p at e i n t h e st u d y  b y si g ni n g  a n I R B - a p pr o v e d 
c o ns e nt f or m. 
 
Pri or t o  a  s u bj e ct ’s  p arti ci p ati o n i n t h e tri al, t h e  writt e n i nf or m e d  c o ns e nt f or m 
s h o ul d   b e  si g n e d   a n d   p ers o n all y   d at e d   b y  t h e   s u bj e ct  a n d   b y  t h e   p ers o n   w h o  
c o n d u ct e d t h e i nf or m e d  c o ns e nt  dis c ussi o n.  
1 1. 2   R e q ui r e d  D o c u m e nt ati o n  
B ef or e t h e st u d y  c a n  b e i niti at e d  at  a n y sit e, t h e f oll o wi n g  d o c u m e nt ati o n  m ust  b e 
pr o vi d e d t o t h e  Cli ni c al  Pr ot o c ol  Offi c e ( C P O)  at t h e  U ni v ersit y  of  N ort h  C ar oli n a.  
•   A  c o p y  of t h e  offi ci al I R B  a p pr o v al l ett er f or t h e  pr ot o c ol  a n d i nf or m e d 
c o ns e nt 
•   I R B  m e m b ers hi p list or  F e d er al wi d e  Ass ur a n c e ( F W A)  n u m b er  
•   C Vs  a n d  m e di c al li c e ns ur e f or t h e  pri n ci p al i n v esti g at or  a n d  a n y s u b -
i n v esti g at ors  w h o  will  b e i n v ol v e d i n t h e st u d y. 
  
•   T h e I n v esti g at or’s si g n at ur e  d o c u m e nti n g  u n d erst a n di n g  of t h e  pr ot o c ol 
a n d  pr o vi di n g  c o m mit m e nt t h at t his tri al  will  b e  c o n d u ct e d  a c c or di n g t o 
all sti p ul ati o ns  of t h e  pr ot o c ol is s uffi ci e nt t o  e ns ur e  c o m pli a n c e   
•   C A P   a n d   C LI A   L a b or at or y   c ertifi c ati o n  n u m b ers   a n d  i nstit uti o n  l a b 
n or m al  v al u es 
•   E x e c ut e d  cli ni c al r es e ar c h  c o ntr a ct  
 


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1 1. 3   R e gist r ati o n  P r o c e d u r es  
All   p ati e nts   m ust   b e  r e gist er e d   b y  t h e   B M T  st u d y   c o or di n at or   at   U N C   b ef or e  
e nr oll m e nt t o st u d y.   Pri or t o r e gistr ati o n,  eli gi bilit y  crit eri a  m ust  b e  c o nfir m e d  wit h 
t h e  B M T st u d y  c o or di n at or.   
 
1 1. 4   D at a  M a n a g e m e nt  a n d  M o nit o ri n g / A u diti n g 
T h e  B M T  cli ni c al  r es e ar c h  gr o u p of t h e  U N C  L C C C  will s er v e  as t h e  c o or di n ati n g 
c e nt er f or t his tri al.  A c cr u al  will  b e tr a c k e d i n  O n C or e ® .  All  d at a  will  b e  c oll e ct e d 
a n d  e nt er e d t hr o u g h  a  w e b  b as e d  cli ni c al r es e ar c h  pl atf o r m, R e d c a p ® .   
1 1. 5   A d h e r e n c e t o t h e  P r ot o c ol  
E x c e pt f or  a n  e m er g e n c y sit u ati o n i n  w hi c h  pr o p er  c ar e f or t h e  pr ot e cti o n, s af et y, 
a n d  w ell -b ei n g  of t h e st u d y  s u bj e ct  r e q uir es  alt er n ati v e tr e at m e nt, t h e st u d y s h all 
b e  c o n d u ct e d  e x a ctl y  as  d es cri b e d i n t h e  a p pr o v e d  pr ot o c ol.   
1 1. 5. 1   E m e r g e n c y  M o difi c ati o ns  
U N C  a n d  Affili at e i n v esti g at ors  m a y i m pl e m e nt  a  d e vi ati o n fr o m,  or  a  c h a n g e  of, 
t h e  pr ot o c ol t o  eli mi n at e  a n i m m e di at e  h a z ar d(s) t o tri al s u bj e cts  wit h o ut  pri or  U N C 
or t h eir r es p e cti v e i nstit uti o n’s I R B/I E C  a p pr o v al/f a v or a bl e  o pi ni o n. 
 
F or  a n y s u c h  e m er g e n c y  m o difi c ati o n i m pl e m e nt e d,  a  U N C I R B  m o difi c ati o n f or m 
m ust  b e  c o m pl et e d  b y  U N C  R es e ar c h  P ers o n n el  wit hi n fi v e ( 5)  b usi n ess  d a ys  of 
m a ki n g t h e  c h a n g e . 
1 1. 5. 2   Si n gl e  S u bj e ct  E x c e pti o ns  
F or I nstit uti o ns  R el yi n g  o n  U N C’s I R B:  
Eli gi bilit y  si n gl e  s u bj e ct   e x c e pti o ns   ar e   n ot   p er mitt e d  f or   Li n e b er g er  
C o m pr e h e nsi v e   C a n c er   C e nt er  I n v esti g at or  I niti at e d   Tri als   u n d er   a n y  
cir c u mst a n c es.  Ot h er t y p es  of si n gl e s u bj e ct  e x c e pti o ns  m a y  b e  all o w e d if  pr o p er 
r e g ul at or y  r e vi e w   h as   b e e n   c o m pl et e d  i n   a c c or d a n c e   wit h   Li n e b er g er  
C o m pr e h e nsi v e  C a n c er  C e nt er’s  Si n gl e  S u bj e ct  E x c e pti o ns  P oli c y.  
1 1. 5. 3   Ot h e r  P r ot o c ol  D e vi ati o ns/ Vi ol ati o ns  
A c c or di n g t o  U N C’s I R B,  a  pr ot o c ol  d e vi ati o n is  a n y  u n pl a n n e d  v ari a n c e fr o m  a n 
I R B  a p pr o v e d  pr ot o c ol t h at:  
•   Is  g e n er all y  n ot e d  or r e c o g ni z e d  aft er it  o c c urs 
•   H as  n o s u bst a nti v e  eff e ct  o n t h e ris ks t o r es e ar c h  p arti ci p a nts  
•   H as  n o s u bst a nti v e  eff e ct  o n t h e s ci e ntifi c i nt e grit y  of t h e r es e ar c h  pl a n 
or t h e  v al u e  of t h e  d at a  c oll e ct e d   
•   Di d  n ot r es ult fr o m  willf ul  or  k n o wi n g  mis c o n d u ct  o n t h e  p art  of t h e 
i n v esti g at or(s).  
 
A n  u n pl a n n e d  pr ot o c ol  v ari a n c e is  c o nsi d er e d  a  vi ol ati o n if t h e  v ari a n c e  m e ets  a n y 
of t h e f oll o wi n g  crit eri a:  


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•   H as   h ar m e d   or  i n cr e as e d  t h e  ris k   of   h ar m  t o   o n e   or   m or e   r es e ar c h 
p arti ci p a nts.  
•   H as  d a m a g e d t h e s ci e ntifi c i nt e grit y  of t h e  d at a  c oll e ct e d f or  t h e st u d y. 
•   R es ults  fr o m   willf ul   or   k n o wi n g   mis c o n d u ct   o n  t h e   p art   of  t h e  
i n v esti g at or(s). 
•   D e m o nstr at es  s eri o us   or   c o nti n ui n g   n o n c o m pli a n c e   wit h  f e d er al 
r e g ul ati o ns,  St at e l a ws,  or  U ni v ersit y  p oli ci es. 
 
If  a  d e vi ati o n  or  vi ol ati o n  o c c urs, pl e as e f oll o w t h e  g ui d eli n es  b el o w:  
 
Pr ot o c ol   D e vi ati o ns:   U N C  or  Affili at e  p ers o n n el  will  r e c or d  t h e   d e vi ati o n  i n  
O n C or e ® ,  a n d r e p ort t o  a n y s p o ns or  or  d at a  a n d s afet y  m o nit ori n g  c o m mitt e e i n 
a c c or d a n c e  wit h t h eir  p oli ci es.   D e vi ati o ns s h o ul d  b e s u m m ari z e d  a n d r e p ort e d t o 
t h e I R B  at t h e ti m e  of  c o nti n ui n g r e vi e w. 
 
Pr ot o c ol  Vi ol ati o ns:  Vi ol ati o ns  s h o ul d  b e r e p ort e d  b y  U N C  p ers o n n el  wit hi n  o n e 
( 1)  w e e k  of t h e i n v esti g at or  b e c o mi n g  a w ar e  of t h e  e v e nt  usi n g t h e s a m e I R B  o nli n e 
m e c h a nis m  us e d t o r e p ort  U n a nti ci p at e d  Pr o bl e ms.    
1 1. 6   A m e n d m e nts t o t h e  P r ot o c ol 
S h o ul d  a m e n d m e nts t o t h e  pr ot o c ol  b e r e q uir e d, t h e  a m e n d m e nts  will  b e  ori gi n at e d 
a n d  d o c u m e nt e d  b y t h e  Pri n ci p al I n v esti g at or  at  U N C.  It s h o ul d  als o  b e  n ot e d t h at 
w h e n  a n  a m e n d m e nt t o t h e  pr ot o c ol s u bst a nti all y  alt ers t h e st u d y  d esi g n  or t h e 
p ot e nti al ris k t o t h e  s u bj e ct,  a r e vis e d  c o ns e nt f or m  mi g ht  b e r e q uir e d.   
 
T h e  writt e n  a m e n d m e nt,  a n d if r e q uir e d t h e  a m e n d e d  c o ns e nt f or m,  m ust  b e s e nt t o 
U N C’s I R B f or  a p pr o v al  pri or t o i m pl e m e nt ati o n.   
1 1. 7   R e c o r d  R et e nti o n  
St u d y  d o c u m e nt ati o n i n cl u d es  all  e C R Fs ,  d at a c orr e cti o n f or ms  or  q u eri es, s o ur c e 
d o c u m e nts,  S p o ns or  c orr es p o n d e n c e t o I n v esti g at ors,  m o nit ori n g l o gs/l ett ers,  a n d 
r e g ul at or y  d o c u m e nts ( e. g.,  pr ot o c ol  a n d  a m e n d m e nts, I R B  c orr es p o n d e n c e  a n d 
a p pr o v al, si g n e d s u bj e ct  c o ns e nt f or ms). 
 
S o ur c e  d o c u m e nts i n cl u d e  all r e c or di n gs  of  o bs er v ati o ns  or  n ot ati o ns  of  cli ni c al 
a cti viti es  a n d  all r e p orts  a n d r e c or ds  n e c ess ar y f or t h e  e v al u ati o n  a n d r e c o nstr u cti o n 
of t h e  cli ni c al r es e ar c h st u d y.  
 
G o v er n m e nt  a g e n c y r e g ul ati o ns  a n d  dir e cti v es r e q uir e t h at  all st u d y  d o c u m e nt ati o n 
p ert ai ni n g  t o  t h e   c o n d u ct   of   a   cli ni c al  tri al   m ust   b e  r et ai n e d   b y  t h e  st u d y  
i n v esti g at or.  I n t h e  c as e  of  a st u d y  wit h  a dr u g /i n v esti g ati o n al  pr o d u ct s e e ki n g 
r e g ul at or y  a p pr o v al  a n d  m ar k eti n g, t h es e  d o c u m e nts s h all  b e r et ai n e d f or  at l e ast 
t w o   y e ars   aft er  t h e  l ast   a p pr o v al   of   m ar k eti n g   a p pli c ati o n  i n   a n  I nt er n ati o n al  
C o nf er e n c e  o n  H ar m o ni z ati o n (I C H) r e gi o n.  I n  all  ot h er  c as es, st u d y  d o c u m e nts 


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PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
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s h o ul d  b e  k e pt  o n fil e  u ntil t hr e e  y e ars  aft er t h e  c o m pl eti o n  a n d fi n al st u d y r e p ort 
of t his i n v esti g ati o n al  st u d y. 
1 1. 8   O bli g ati o ns  of I n v esti g at o rs 
T h e  Pri n ci p al I n v esti g at or is r es p o nsi bl e f or t h e  c o n d u ct  of t h e  cli ni c al tri al  at t h e 
sit e i n  a c c or d a n c e  wit h  Titl e  2 1  of t h e  C o d e  of  F e d er al  R e g ul ati o ns  a n d/ or t h e 
D e cl ar ati o n  of  H elsi n ki.   T h e  Pri n ci p al I n v esti g at or  is r es p o nsi bl e f or  p ers o n all y 
o v ers e ei n g t h e tr e at m e nt  of  all st u d y  s u bj e cts.   T h e  Pri n ci p al I n v esti g at or  m ust 
ass ur e t h at  all st u d y sit e  p ers o n n el, i n cl u di n g s u b -i n v esti g at ors  a n d  ot h er st u d y st aff 
m e m b ers,   a d h er e  t o  t h e  st u d y   pr ot o c ol   a n d   all   F D A/ G C P/ N CI   r e g ul ati o ns   a n d  
g ui d eli n es r e g ar di n g  cli ni c al tri als  b ot h  d uri n g  a n d  aft er st u d y  c o m pl eti o n.  
 
T h e  Pri n ci p al I n v esti g at or  at  e a c h i nstit uti o n  or sit e  will  b e r es p o nsi bl e f or  ass uri n g 
t h at  all t h e r e q uir e d  d at a  will  b e  c oll e ct e d  a n d  e nt er e d i nt o t h e e C R Fs.  P eri o di c all y, 
a u diti n g  a n d  m o nit ori n g  of tri als  will  b e  c o n d u ct e d  a n d t h e  Pri n ci p al I n v esti g at or 
will  pr o vi d e  a c c ess t o  his/ h er  ori gi n al r e c or ds t o  p er mit  v erifi c ati o n  of  pr o p er  e ntr y 
of  d at a.  At t h e  c o m pl eti o n  of t h e st u d y,  all  e C R Fs  will  b e r e vi e w e d  b y t h e  Pri n ci p al 
I n v esti g at or  a n d  will r e q uir e  his/ h er fi n al si g n at ur e t o  v erif y t h e  a c c ur a c y  of t h e 
d at a.  
 


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PI:  J.  Pt a c h ci ns ki  
  
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V e rsi o n  #  1. 0    
 
 
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3 0 
1 2. 0   R E F E R E N C E S  
1.    
M o ns o n,  T.,  et  al.,  Ol a nz a pi n e  as  a r es c u e  a nti e m eti c i n  h e m at o p oi eti c st e m  c ell 
tr a ns pl a nt. J o ur n al  of  O n c ol o g y  P h ar m a c y  Pr a cti c e. 0 ( 0):  p.  1 0 7 8 1 5 5 2 1 9 8 7 9 2 1 5. 
2.    
N a v ari,  R. M.,  et  al.,  Ol a nz a pi n e f or t h e  Pr e v e nti o n  of  C h e m ot h er a p y-I n d u c e d 
N a us e a  a n d  V o miti n g.   N e w  E n gl a n d J o ur n al  of  M e di ci n e,  2 0 1 6. 3 7 5 ( 2):  p.  1 3 4-
1 4 2. 
3.  
N ati o n al  C o m pr e h e nsi v e  C a n c er  N et w or k  ( N C C N).  A nti e m esis  g ui d eli n es 
v 2. 2 0 1 7. 
4.    
H es k et h,  P.J.,  et  al.,  A nti e m eti cs:  A m eri c a n  S o ci et y  of  Cli ni c al  O n c ol o g y  Cli ni c al 
Pr a cti c e  G ui d eli n e  U p d at e.  J  Cli n  O n c ol,  2 0 1 7. 3 5 ( 2 8):  p.  3 2 4 0- 3 2 6 1. 
5.    
N a v ari,  R. M.  a n d  M.  A a pr o,  A nti e m eti c  Pr o p h yl a xis f or  C h e m o t h er a p y-I n d u c e d 
N a us e a  a n d  V o miti n g.   N  E n gl J  M e d,  2 0 1 6. 3 7 4 ( 1 4):  p.  1 3 5 6- 6 7. 
6.    
Trifili o,  S.,  et  al.,  Ol a nz a pi n e  R e d u c es  C h e m ot h er a p y-i n d u c e d  N a us e a  a n d 
V o miti n g  C o m p ar e d  Wit h  A pr e pit a nt i n  M y el o m a  P ati e nts  R e c ei vi n g  Hi g h - d os e 
M el p h al a n  B ef or e  St e m  C ell  T r a ns pl a nt ati o n:  A  R etr os p e cti v e  St u d y.   Cli n 
L y m p h o m a  M y el o m a  L e u k,  2 0 1 7.  1 7 ( 9):  p.  5 8 4- 5 8 9. 
7.      
Cl e m m o ns  A B,  Orr J,  A n dri c k  B,  G a n d hi  A,  S p ort es  C,  D e R e m er  D. 
R a n d o mi z e d,  Pl a c e b o- C o ntr oll e d,  P h as e III  Tri al  of  F os a pr e pit a nt,  O n d a ns etr o n, 
D e x a m et h as o n e ( F O N D)  V ers us  F O N D  Pl us  Ol a n z a pi n e ( F O N D - O) f or t h e 
Pr e v e nti o n  of  C h e m ot h er a p y- I n d u c e d  N a us e a  a n d  V o miti n g i n  P ati e nts  wit h 
H e m at ol o gi c  M ali g n a n ci es  R e c ei vi n g  Hi g hl y  E m et o g e ni c  C h e m ot h er a p y  a n d 
H e m at o p oi eti c  C ell  Tr a ns pl a nt ati o n  R e gi m e ns:  T h e  F O N D -O  Tri al.  Bi ol  Bl o o d 
M arr o w  Tr a n s pl a nt .  2 0 1 8; 2 4( 1 0): 2 0 6 5- 2 0 7 1 
8.    
B as c h,  E.,  et  al.,  F e asi bilit y  of I m pl e m e nti n g t h e  P ati e nt -R e p ort e d  O ut c o m es 
V ersi o n  of t h e  C o m m o n  T er mi n ol o g y  Crit eri a f or  A d v ers e  E v e nts i n  a  M ulti c e nt er 
Tri al:  N C C T G  N 1 0 4 8.  J o ur n al  of  Cli ni c al  O n c ol o g y,  2 0 1 8. 3 6 ( 3 1):  p.  3 1 2 0- 3 1 2 5. 
9.     
Y a n g,  T.,  et  al.,  Effi c a c y  of  ol a nz a pi n e f or t h e  pr o p h yl a xis  of  c h e m ot h er a p y -
i n d u c e d  n a us e a  a n d  v o miti n g:  a  m et a-a n al ysis.   Br J  Cli n  P h ar m a c ol,  2 0 1 7. 8 3 ( 7): 
p.  1 3 6 9- 1 3 7 9. 
1 0.     
Z y pr e x a ( ol a n z a pi n e) [ pr es cri bi n g i nf or m ati o n]. I n di a n a p olis, I N:  Eli  Lill y; 
O ct o b er  2 0 1 9.  
  
 
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
3 1 
1 3. 0   A P P E N DI C E S  
1 3. 1. 1   A p p e n di x  A.  P R O -C T C A E  
F r e q u e n c y  of  n a us e a : “I n t h e l ast  2 4  h o u rs,  h o w  oft e n  di d  y o u  h a v e  n a us e a ? ”  
 
S e v e rit y  of  n a us e a:  “I n t h e l ast  2 4  h o u r s,  w h at  w a s t h e s e v e rit y  of  y o u r  n a us e a 
at its  w o rst ? ”  
 
 
Fr e q u e n c y 
of  n a us e a 
s c or es:  
N e v er   
R ar el y   
O c c asi o n all y   Fr e q u e ntl y   
Al m ost 
C o nst a ntl y 
S e v erit y  of 
n a us e a 
s c or es:   
N o n e   
Mil d   
M o d er at e   
S e v er e   
V er y  S e v er e  
 
 
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
3 2 
 
1 3. 1. 2   A p p e n di x  B.  P r o hi bit e d  M e di c ati o ns  o r  T h os e t o  b e  us e d  wit h  C a uti o n 
 
O n e  of t h e  m e di c ati o ns  y o u  ar e r e c ei vi n g  d uri n g t his  cli ni c al tri al is  Ol a n z a pi n e.  
Ol a n z a pi n e  i nt er a cts wit h s o m e  dr u gs t h at  ar e  pr o c ess e d  b y  y o ur li v er.  B e c a us e  of 
t his, it is  v er y i m p ort a nt t o t ell  y o ur st u d y  d o ct ors  a b o ut  all  of  y o ur  m e di ci n e  b ef or e 
y o u st art t his st u d y. It is  als o  v er y  i m p ort a nt t o t ell t h e m if  y o u st o p t a ki n g  a n y 
r e g ul ar  m e di ci n e,  or if  y o u st art t a ki n g  a  n e w  m e di ci n e  w hil e  y o u t a k e  p art i n t his 
st u d y.  W h e n  y o u t al k  a b o ut  y o ur  m e di ci n e  wit h  y o ur  st u d y  d o ct or, i n cl u d e  m e di ci n e 
y o u   b u y   wit h o ut   a   pr es cri pti o n   at  t h e   dr u g  st or e  ( o v er -t h e   c o u nt er  r e m e d y),  or 
a n yt hi n g  t h at   y o u   b u y  fr o m  t h e   h e alt h  f o o d  st or e   or   gr o c er y  st or e  ( h er b al  
s u p pl e m e nt).  M a n y  h e alt h  c ar e  pr es cri b ers  c a n  writ e  pr es cri pti o ns.  Y o u  m ust  als o 
t ell  yo ur  ot h er  pr es cri b ers ( d o ct ors,  p h ysi ci a ns’  assist a nts  or  n urs e  pr a ctiti o n ers) 
t h at  y o u  ar e t a ki n g  p art i n  a  cli ni c al tri al. B ri n g t his  p a p e r  wit h  y o u .  
 
•   Ol a n z a pi n e  is  pr o c ess e d  b y  a  c ert ai n  e n z y m e i n t h e li v er  c all e d  C Y P2 D 6 .  
Dr u gs t h at i n cr e as e t h e  a cti vit y  of t his  e n z y m e  ar e  c all e d  “i n d u c ers ”,  a n d 
dr u gs  t h at   d e cr e as e  t h e   a cti vit y   of  t his   e n z y m e   ar e   c all e d   “i n hi bit ors ”.   
Ol a n z a pi n e   m ust   b e   us e d   v er y   c ar ef ull y   wit h   ot h er   m e di ci n es  t h at   ar e  
i n d u c e rs  or i n hi bit o rs  of  C Y P2 D 6 .   
•   Y o u  a n d  h e alt h c ar e  pr o vi d ers  w h o  pr es cri b e  dr u gs f or  y o u  m ust  b e  c ar ef ul 
a b o ut  a d di n g  or  r e mo vi n g  a n y  dr u g i n t his  c at e g or y 
•   B ef or e  y o u st art t h e st u d y,  y o ur st u d y  d o ct or  will  w or k  wit h  y o ur r e g ul ar 
pr es cri b er  t o  s wit c h   t h e  f oll o wi n g   m e di c ati ons  if   y o u   ar e  t a ki n g  t h e m:  
Fl u v o x a mi n e  a n d/ o r  ci p r ofl o x a ci n  
•   Y o ur  r e g ul ar   pr es cri b ers  s h o ul d  l o o k   at 
 t his   w e b  sit e : 
htt p:// m e di ci n e.i u p ui. e d u/ cli n p h ar m/ d dis/t a bl e. as p  t o  s e e  if   a n y   m e di ci n e 
t h e y  w a nt t o  pr es cri b e is  o n  a list  of  dr u gs t o  a v oi d.   Y o ur st u d y  d o ct or  m a y 
als o  h a v e  a list  of  m e di c ati o ns f or  y o u  t o s h o w  y o ur r e g ul ar  pr es cri b ers 
i nst e a d  of,  or i n  a d diti o n t o, t his  w e bsit e.   
•   Ot h er  m e di ci n es  c a n  b e  a  pr o bl e m  wit h  y o ur st u d y  dr u gs. 
o   Y o u s h o ul d  c h e c k  wit h  y o ur  d o ct or  or  p h ar m a cist  w h e n e v er  y o u 
n e e d t o  us e  a n  o v er- t h e- c o u nt er m e di ci n e  or  h er b al s u p pl e m e nt.  
o   Y o ur r e g ul ar  pr es cri b er s h o ul d  c h e c k  a  m e di c al r ef er e n c e  or  c all 
y o ur  st u d y   d o ct or  b ef or e   pr es cri bi n g   a n y   n e w   m e di ci n e  f or   y o u. 
Y o ur st u d y  d o ct or’s  n a m e is  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  a n d  h e  or  s h e  c a n 
b e  c o nt a ct e d  at  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _. 
 
 
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
3 3 
1 3. 1. 3   A p p e n di x  C.  F r e d e ri ci a’s  F o r m ul a  
 
Q T c  =  Q T/( R R ^ 0. 3 3) 
 
Q T C =  C orr e ct e d  Q T c 
Q T =  Q T i nt er v al   
R R =  6 0/ h e art r at e 
 
 
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
3 4 
1 3. 1. 4   A p p e n di x   D.  C o n diti o ni n g R e gi m e ns  
 
T h e list  b el o w  e n c o m p ass es t h e  m aj orit y  of  pl a n n e d  c o n diti o ni n g r e gi m e ns f or  p ati e nts 
u n d er g oi n g  H C T.   F or  a n y  n ot i n cl u d e d  b el o w,  p ati e nts  will r e c ei v e  ol a n z a pi n e  o n  a n y 
d a ys  of  hi g hl y  or  m o d er at el y  e m et o g e ni c  c h e m ot h er a p y  pl us  a n  a d diti o n al t hr e e  d a ys 
aft er.   D ail y  m o nit ori n g f or s af et y  a n d  effi c a c y i n  a c c or d a n c e  wit h t h e ti m e  a n d  e v e nts 
t a bl e i n  s e cti o n 8. 1  will  o c c ur f or  a n  a d diti o n al  2  d a ys f oll o wi n g t h e l ast  d os e  of 
ol a n z a pi n e.  
 
St u d y  dr u g  pl a n f or  c h e m ot h er a p y r e gi m e n  B E A M ( a ut ol o g o us) 
 
T r a ns pl a nt  d a y   
-6   
-5   
-4   
-3   
-2   
-1   
0   
+ 1   + 2   + 3   + 4  
C h e m ot h e r a p y 
a g e nt  
B C N U   
V P 1 6  + 
C yr ar a bi n e  
V P 1 6  + 
C yr ar a bi n e  
V P 1 6  + 
C yr ar a bi n e  
V P 1 6  + 
C yr ar a bi n e  
M el p h al a n   
  
  
  
  
 
St u d y  d r u g  
Gi v e n  
X   
X  
X  
X  
X   
X   
X   
X   
X   
  
 
M o nit o ri n g   
X   
X  
X  
X  
X   
X   
X   
X   
X   
X   
X  
 
St u d y  dr u g  pl a n f or  c h e m ot h er a p y r e gi m e n  m el p h al a n ( a ut ol o g o us) 
 
T r a ns pl a nt  d a y   
-1   
0   
+ 1   + 2   + 3   + 4  
C h e m ot h e r a p y 
a g e nt  
M el p h al a n     
  
  
  
 
St u d y  d r u g  
Gi v e n  
X   
X   
X   
X   
  
 
M o nit o ri n g   
X   
X   
X   
X   
X   
X  
 
St u d y  dr u g  pl a n f or  c h e m ot h er a p y r e gi m e n  B e n d a- E A M ( a ut ol o g o us) 
 
T r a ns pl a nt 
d a y  
-7  
-6  
-5   
-4   
-3   
-2   
-1   
0   
+ 1   + 2   + 3   + 4  
C h e m ot h e r a p y 
a g e nt 
B e n d a m usti n e   B e n d a m usti n e   V P 1 6  + 
C yr ar a bi n e 
V P 1 6  + 
C yr ar a bi n e 
V P 1 6  + 
C yr ar a bi n e 
V P 1 6  + 
C yr ar a bi n e 
M el p h al a n     
  
  
  
 
St u d y  d r u g  
Gi v e n  
X  
X  
X   
X   
X   
X   
X   
X   X   
X   
  
 
M o nit o ri n g   
X  
X  
X   
X   
X   
X   
X   
X   X   
X   
X   
X  
 
St u d y  dr u g  pl a n f or  c h e m ot h er a p y r e gi m e n  c ar m usti n e  + t hi ot e p a ( a ut ol o g o us) 
 
T r a ns pl a nt  d a y   
-6  
-5  
-4  
-3  
-2   
-1   
0   
+ 1  
C h e m ot h e r a p y 
a g e nt  
C ar m usti n e   
T hi ot e p a   
T hi ot e p a   
 
  
  
  
 
St u d y  d r u g  
Gi v e n  
X  
X  
X  
X  
X   
X   
  
 
M o nit o ri n g   
X  
X  
X  
X  
X   
X   
X   
X  
 
 
 
 
 
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
3 5 
St u d y  dr u g  pl a n f or  c h e m ot h er a p y r e gi m e n  C E ( a ut ol o g o us) 
 
T r a ns pl a nt  d a y   
-4   
-3   
-2   
-1   
0   
+ 1   + 2   + 3  
C h e m ot h e r a p y 
a g e nt 
C ar b o pl ati n 
+ 
Et o p osi d e  
C ar b o pl ati n 
+ 
Et o p osi d e  
C ar b o pl ati n 
+ 
Et o p osi d e  
 
  
  
  
 
St u d y  d r u g  
Gi v e n  
X  
X  
X  
X   
X   
X   
  
 
M o nit o ri n g   
X  
X  
X  
X   
X   
X   
X   
X  
 
St u d y  dr u g  pl a n f or  c h e m ot h er a p y r e gi m e n  RI C fl u d ar a bi n e/ m el p h al a n ( all o g e n ei c)  
 
T r a ns pl a nt  d a y   
-5  
-4  
-3  
-2  
-1   
0   
+ 1   + 2   + 3   + 4  
C h e m ot h e r a p y 
a g e nt  
Fl u d ar a bi n e *  Fl u d ar a bi n e *  
Fl u d ar a bi n e *  
Fl u d ar a bi n e *  
M el p h al a n     
  
  
  
 
St u d y  d r u g  
Gi v e n  
 
 
 
 
X   
X   
X   
X   
  
 
M o nit o ri n g   
 
 
 
 
X   
X   
X   
X   
X   
X  
 
St u d y  dr u g  pl a n f or  c h e m ot h er a p y r e gi m e n  RI C fl u d ar a bi n e/ b us ulf a n ( all o g e n ei c) 
 
T r a ns pl a nt 
d a y  
-6  
-5  
-4   
-3  
-2  
-1   
0   
+ 1  
C h e m ot h e r a p y 
a g e nt  
Fl u d ar a bi n e *  
Fl u d ar a bi n e 
+  b us ulf a n  
Fl u d ar a bi n e 
+  b us ulf a n  
Fl u d ar a bi n e *  
Fl u d ar a bi n e *  
  
  
 
St u d y  d r u g  
Gi v e n  
 
X  
X  
X  
X  
X   
  
 
M o nit o ri n g   
 
X  
X  
X  
X  
X   
X   
X  
 
St u d y  dr u g  pl a n f or  c h e m ot h er a p y r e gi m e n  N M A fl u d ar a bi n e/ c y cl o p h os p h a mi d e/ T BI 
( all o g e n ei c) 
 
T r a ns pl a nt 
d a y  
-6  
-5  
-4  
-3  
-2  
-1  
C h e m ot h e r a p y 
a g e nt  
Fl u d ar a bi n e  + 
C y cl o p h os p h a mi d e  
Fl u d ar a bi n e *  
Fl u d ar a bi n e *  
Fl u d ar a bi n e *  
Fl u d ar a bi n e *  
T BI  
St u d y  d r u g  
Gi v e n  
X  
X  
X  
X  
 
 
M o nit o ri n g   
X  
X  
X  
X  
X  
X  
 
St u d y  dr u g  pl a n f or  c h e m ot h er a p y r e gi m e n  N M A fl u d ar a bi n e/ c y cl o p h os p h a mi d e 
( all o g e n ei c) 
 
T r a ns pl a nt 
d a y  
-5  
-4  
-3  
-2  
-1  
0   
+ 1  
C h e m ot h e r a p y 
a g e nt  
Fl u d ar a bi n e  + 
C y cl o p h os p h a mi d e  
Fl u d ar a bi n e  + 
C y cl o p h os p h a mi d e  
Fl u d ar a bi n e *  
Fl u d ar a bi n e *  
Fl u d ar a bi n e *  
  
 
St u d y  d r u g  
Gi v e n  
X  
X  
X  
X  
X  
  
 
M o nit o ri n g   
X  
X  
X  
X  
X  
X   
X  
 
 
 
 
 
 


L C C C  2 0 3 7 
 
C O N FI D E N TI A L  
PI:  J.  Pt a c h ci ns ki  
  
U NI V E R S I T Y  O F  N O R T H  C A R O LI N A  
V e rsi o n  #  1. 0    
 
 
A p ril  1 6,  2 0 2 0  
 
3 6 
St u d y  dr u g  pl a n f or  c h e m ot h er a p y r e gi m e n  M A C fl u d ar a bi n e/ b us ulf a n ( all o g e n ei c) 
 
T r a ns pl a nt  d a y   
-5  
-4  
-3  
-2  
-1  
0   
+ 1   
+ 2   
+ 3  
C h e m ot h e r a p y 
a g e nt  
Fl u d ar a bi n e  + 
b us ulf a n  
Fl u d ar a bi n e 
+  b us ulf a n  
Fl u d ar a bi n e 
+  b us ulf a n  
Fl u d ar a bi n e 
+  b us ulf a n  
 
  
  
  
 
St u d y  d r u g  
Gi v e n  
X  
X  
X  
X  
X  
X   
X   
  
 
M o nit o ri n g   
X  
X  
X  
X  
X  
X   
X   
X   
X  
 
St u d y  dr u g  pl a n f or  c h e m ot h er a p y r e gi m e n  M A C  b us ulf a n/ c y cl o p h os p h a mi d e 
( all o g e n ei c) 
 
T r a ns pl a nt  d a y   
-7   
-6   
-5   
-4   
-3  
-2  
-1   
0   
+ 1   
+ 2   
+ 3  
C h e m ot h e r a p y 
a g e nt  
B us ulf a n   
B us ulf a n   
B us ulf a n   
B us ulf a n    
C y cl o p h os p h a mi d e   
C y cl o p h os p h a mi d e   
  
  
  
  
 
St u d y  d r u g  
Gi v e n  
X   
X   
X   
X   
X  
X  
X   
X   
X   
  
 
M o nit o ri n g   
X   
X   
X   
X   
X  
X  
X   
X   
X   
X   
X  
 
St u d y  dr u g  pl a n f or  c h e m ot h er a p y r e gi m e n  M A C  c y cl o p h os p h a mi d e/ T ot al  B o d y 
Irr a di ati o n ( T BI) 
 
T r a ns pl a nt  d a y   
-6   
-5   
-4   
-3  
-2  
-1   
0   
+ 1   
+ 2   
+ 3  
C h e m ot h e r a p y 
a g e nt  
T BI   
T BI   
T BI   
C y cl o p h os p h a mi d e   
C y cl o p h os p h a mi d e   
  
  
  
  
 
St u d y  d r u g  
Gi v e n  
  
  
  
X  
X  
X   
X   
X   
  
 
M o nit o ri n g   
  
  
  
X  
X  
X   
X   
X   
X   
X  
 
 
* -  Fl u d ar a bi n e is  mi ni m all y  e m et o g e ni c  a n d  d o es  n ot  w arr a nt r o uti n e  pr o p h yl a xis  w h e n 
gi v e n  as  a si n gl e  a g e nt.