Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Lung Neoplasms
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the safety and effectiveness of BIO 300 Oral Suspension when used in combination with standard dose radiation therapy and chemotherapy in patients with non-small cell lung cancer. Based on preclinical data the investigators hypothesize that BIO 300 Oral Suspension will reduce the incidence of radiation-induced pneumonitis and pulmonary fibrosis.

Detailed description:
This is an open-label, single-arm, ascending dose Phase I/II study of BIO 300 Oral Suspension given in combination with paclitaxel/carboplatin and radiotherapy in subjects with stage II, III, or IV NSCLC who are candidates for combined chemoradiotherapy.

A minimum of 6 subjects will be accrued sequentially at each dose level of BIO 300. BIO 300 will be administered daily for the entire course of concurrent chemoradiotherapy, a minimum of 6 weeks; in combination with standard paclitaxel / carboplatin chemotherapy and radiotherapy.

The initial dose of BIO 300 will be administered on Day 1, Visit 2 in which safety data (adverse events, electrocardiograms (ECGs), results of safety laboratory determinations), pharmacokinetic (PK) and pharmacodynamic (PD) data will be collected. PK data will be collected from a minimum of six (6) study subjects from each cohort. PD data will be collected from all subjects in each study cohort. Day 1 of chemotherapy will be scheduled at the discretion of the investigator provided the subject has completed a minimum of 1 day of BIO 300 dosing. BIO 300 will be administered in combination with the chemotherapy components of the protocol (paclitaxel and carboplatin). During the first or second chemotherapy infusion, additional safety, PK and PD data will be collected. Day 1 of radiation therapy (RT) may be scheduled at the discretion of the investigator provided the subject has completed a minimum of 2 days of BIO 300 dosing. BIO 300 will continue to be administered daily; paclitaxel and carboplatin will be administered weekly and radiotherapy will be administered daily until a total dose of 60-70 Gy has been administered. During the period of combined BIO 300 and chemoradiotherapy (6-7 weeks), additional safety, PK and PD data will be collected weekly. An interim data analysis will be completed once the highest dose cohort concludes chemoradiation therapy, in an effort to determine the optimal biological dose. Following analysis, there will be an option to enroll up to an additional 12 subjects at the optimal biological dose. At the conclusion of the study, primary and secondary outcome measures will be evaluated. Data will be analyzed from all cohorts to determine the oncologic response, safety of BIO 300, and a recommended BIO 300 dose.

Arms:
arm 1: Ascending dose evaluation of BIO 300 Oral Suspension (3 dose levels) given in combination with paclitaxel/carboplatin and radiotherapy.

Interventions: intervention 1: BIO 300 Oral Suspension intervention 2: Paclitaxel intervention 3: Carboplatin intervention 4: Radiotherapy
Intervention descriptions: intervention 1: Cohort 1: BIO 300 500 mg Cohort 2: BIO 300 1,000 mg Cohort 3: BIO 300 1,500 mg Cohort 4: BIO 300 Optimal dose (TBD) BIO 300 dose will be given daily, 7 days/week (Week 1, day 1 through week 6) The 2nd and 3rd dosing cohort (1,000 and 1,500 mg/day) will begin following the accrual of a minimum of 6 subjects at the previous dose level, dose escalation to the next BIO 300 dose level will be allowed to occur when a cohort has completed concurrent chemoradiotherapy with fewer than 33% Dose Limiting Toxicities (DLTs) attributed to BIO 300 Oral Suspension. intervention 2: During the Concurrent Therapy period, paclitaxel 45 mg/m2 will be administered by intravenous drip weekly during weeks 1-6.

During the Consolidation Therapy period, paclitaxel 200 mg/m2 will be administered by intravenous drip two times, 21 days apart. intervention 3: During the Concurrent Therapy period, area under the curve (AUC) = 2mg\* min/mL will be administered by intravenous drip weekly during weeks 1-6.

During the Consolidation Therapy period, carboplatin AUC = 6mg\*min/mL will be administered by intravenous drip two times, 21 days apart. intervention 4: Radiation treatment will be scheduled at the discretion of the investigator provided the subject has completed a minimum of 2 days of BIO 300 dosing. Subjects will receive radiation therapy 5 days per week, once daily fractions, 1.8-2.0 Gy per fraction, for 6-7 weeks.

Protocol document:
Prot_SAP_000.pdf: 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
4  
T  A  B  L  E   O F   C  O  N  T  E  N  T S   
C LI  NI C  A  L I  N  V E S TI  G  A T  O R  E  N  D  O  R S E  M E  N T S   ..........................................................  2 
S P  O  N S  O  R  E  N  D  O  R S E  M E  N T S  .........................................................................................  3 
T  A  B L E   O F   C  O  N T E  N T S  ....................................................................................................  4 
LI S T   O F  FI  G  U  R E S  ............................................................................................................  8 
LI S T   O F  T  A  B L E S  ..............................................................................................................  9 
G L  O S S  A  R  Y   .....................................................................................................................  1 0 
P  R  O T  O  C  O L  S  Y  N  O P SI S  .................................................................................................  1 3 
1. 0    
I  N T  R  O  D  U  C TI  O  N ..........................................................................................  2 1 
1. 1    Dis e as e   B a c k gr o u n d   ...........................................................................................  2 1 
1. 2    B a c k gr o u n d  of t h e  St u d y   Dr u g ..........................................................................  2 1   
1. 3    P ot e nti al   Ris ks  a n d   R e p ort e d   A d v ers e  E v e nts fr o  m t h e  St u d y   Dr u g .................  2 2  
1. 4    R ati o n al e f or  Pr o p os e d  T h er a p e uti c  St u d y.........................................................  2 3   
1. 5    R ati o n al e f or   D osi n g ..........................................................................................  2 4   
2. 0    
O  BJ E  C TI  V E S   .................................................................................................  2 6 
2. 1    Pri  m ar y  ...............................................................................................................  2 6 
2. 2    S e c o n d ar y  ...........................................................................................................  2 6 
3. 0    
S T  U  D  Y   D E SI  G  N  ...........................................................................................  2 6 
3. 1    C h e  m ot h er a p y   D os e  L e v els   ...............................................................................  2 7 
3. 2    C o ns oli d ati o n  Tr e at  m e nt ....................................................................................  2 7   
3. 3   
St u d y   O v er vi e  w  - P h as e I/II   D os e  Es c al ati o n  Tri al  ...........................................  2 8 
3. 3. 1    S c h e  m a  of  Tri al   D esi g n  ......................................................................................  2 9 
4. 0    
S  U  BJ E  C T S  .....................................................................................................  3 0 
4. 1    N u  m b er  of  S u bj e cts ............................................................................................  3 0   
4. 2    S u bj e ct  Eli gi bilit y  ...............................................................................................  3 0 
4. 2. 1    I n cl usi o n   Crit eri a ................................................................................................  3 0 
4. 2. 2    E x cl usi o n   Crit eri a  ...............................................................................................  3 1 
4. 3    S u bj e ct   Wit h dr a  w al  a n d   R e pl a c e  m e nt  ...............................................................  3 2 
4. 3. 1    S u bj e ct   Wit h dr a  w al  ............................................................................................  3 2 
4. 3. 2    S u bj e ct   R e pl a c e  m e nt  ..........................................................................................  3 3 
4. 3. 3    P ot e nti al   R e as o ns f or  S u bj e ct   Attriti o n  ..............................................................  3 3 
4. 3. 3. 1    Dr u g  -R el at e d   R e as o ns   .........................................................................  3 3 
4. 3. 3. 2    Cli ni c al  -Tri al -R el at e d   R e as o ns   ............................................................  3 3 
4. 3. 3. 3    S u bj e ct -R el at e d   R e as o ns   D et er  mi n e d  b y t h e I n v esti g at or   ..................  3 3 
4. 3. 3. 4    Ot h er   R e as o ns   ......................................................................................  3 3 
4. 3. 3. 5      L ost t o  F oll o  w- u p ...............................................................................  3 4 
4. 3. 3. 6    D e at h   ....................................................................................................  3 4 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
5  
4. 4    Crit eri a f or   Dis c o nti n u ati o n  of  S u bj e cts fr o  m t h e  Tri al .....................................  3 4   
5. 0   
S T  U  D  Y   D  R  U  G  ..............................................................................................  3 4 
5. 1    D es cri pti o n  of  St u d y   Dr u g .................................................................................  3 4   
5. 2    Dr u g   D os es   .........................................................................................................  3 5 
5. 3    D ur ati o n  of  Tr e at  m e nt ........................................................................................  3 5   
5. 4    C o ntr ai n di c ati o n .................................................................................................  3 5   
5. 5    Crit eri a f or   D os e  Es c al ati o n   ...............................................................................  3 5 
5. 6    Dr u g  St or a g e   ......................................................................................................  3 6 
5. 7    Dr u g   A c c o  u nt a bilit y  ...........................................................................................  3 6 
6. 0    
C  O  N  C  U  R  R E  N T   M E  DI  C  A TI  O  N S   A  N  D  T  R E  A T  M E  N T S   ...........................  3 6 
6. 1    P a clit a x el  ............................................................................................................  3 6 
6. 2    C ar b o pl ati n .........................................................................................................  3 6   
6. 3    R a di ati o n  T h er a p y   ..............................................................................................  3 7 
6. 3. 1    A d v ers e  E v e nts   R e p ort e d   wit h   R a di ati o n  T h er a p y ............................................  3 7   
6. 4    C o n c o  mit a nt  T h er a pi es  a n d   M e di c ati o ns ...........................................................  3 9   
6. 5     G ui d eli n es f or   D os e   D el a y  a n d   D os e   M o difi c ati o n ...........................................  4 0  
6. 5. 1    C o n c urr e nt   C h e  m or a di ati o n  a n d   BI  O  3 0 0  Tr e at  m e nt ........................................  4 0   
6. 5. 1. 1    C h e  m ot h er a p y/  BI  O  3 0 0/  R T   D os e   M o difi c ati o n f or   H e  m at ol o gi c 
T o xi cit y  ........................................................................................................  4 0 
6. 5. 1. 2    C h e  m ot h er a p y/  BI  O 3 0 0   D os e   M o difi  c ati o ns f or  N o  n- H e  m at ol o g  ic 
T o xi cit y ........................................................................................................  4 1  
6. 5. 1. 3    C h e  m ot h er a p y/  R T      D os e    M odifi c ati o ns   f or  R T    Fi el d,     N o n-
H e  m at o  l o gi c  T o xi cit y     D urin g C o n c urr e nt  T h e  r a p y ...................................  4 3 
6. 5. 1. 4    C ar b o pl ati n   D os e   M o difi c ati o ns f or   R e n al  T o xi cit y ...........................  4 4   
6. 5. 1. 5    P a clit a x el  f or N e  u r op at h y  ....................................................................  4 4 
6. 5. 1. 6    C ar b o pl ati n   f or N e  u r op at h y  .................................................................  4 4 
6. 5. 2    D os e   M o difi c ati o ns   D uri n g   C o ns oli d ati o n   C h e  m ot h er a p y ................................  4 4   
6. 5. 2. 1  C o ns oli d ati o n  T  h er a p y   D os e   M o difi c ati o ns f or   H e  m at ol o gi c  T o xi cit y ...  4 5  
6. 5. 2. 2    C o ns oli d ati o n  T h er a p y   D os e   M o difi c ati o ns f or   N o n-  H e  m at ol o gi c 
T o xi cit y  ........................................................................................................  4 6 
6. 5. 3    C ar b o pl  ati n  D os e     M odifi c at i o ns f or R e  n al  T o xi cit y  ..........................................  4 6 
6. 5. 4    P a clit a x el    D os e   M o dific ati o ns f or  N e  u r op at h y  ..................................................  4 6 
6. 5. 5    C ar b o pl ati n   f or N e  u r op at h y  ...............................................................................  4 7 
6. 5. 6   M a n a g e  m e nt  of   Q T c  pr ol o n g ati o n .......................................................................  4 7  
6. 5. 6. 1   A b n or  m al   Q T c i nt er v al  of  ≥  5 0 0   ms e c  or  b as eli n e  c h a n g e  of  >  6 0   ms e c .  4 7  
6. 5. 6. 2   A b n or  m al   Q T c i nt er v al  of  4 8 0- 4 9 9   ms e c .................................................  4 7  


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
6  
6. 5. 7   D os e   M o difi c ati o n  d u e t o   G astr oi nt esti n al (  GI)  T o xi cit y ....................................  4 8  
7. 0    
 S  C  H E  D  U L E   O F   A S S E S S  M E  N T S  ...............................................................  4 8 
7. 1    Ti  m e t o  E v e nt .....................................................................................................  4 8  
7. 2   A d  mi nistr ati o n  of   BI  O  3 0 0   Or al  S us p e nsi o n ..........................................................  5 3  
7. 3  S u bj e ct   Bl o o d  S a  m pli n g f or  S af et y,  P h ar  m a c o ki n eti cs  a n d  P h ar  m a c o d y n a  mi cs ...  5 3  
7. 4    S u bj e ct   Bl o o d   V ol u  m e   R e q uir e  m e nts ................................................................  5 7  
7. 5    S p e ci  m e n   C oll e cti o n  S u  m  m ar y  ..........................................................................  5 8 
7. 6    H e alt h  -R el at e d   Q u alit y  of  Lif e (  H  R  Q  O L)   A n al ysis   ..........................................  5 8 
7. 6. 1    F  A  C T -T  OI  ..........................................................................................................  5 8 
7. 6. 2    U  C S  D  -S  O  B  ........................................................................................................  5 8 
7. 6. 3    S  w all o  wi n g   Di ar y  ...............................................................................................  5 8 
8. 0    
S  A F E T  Y   R E P  O  R TI  N  G  ..................................................................................  5 9 
8. 1    D efi niti o ns   ..........................................................................................................  5 9 
8. 1. 1    A d v ers e  E v e nts   ...................................................................................................  5 9 
8. 1. 2    S eri o us   A d v ers e  E v e nts ......................................................................................  5 9  
8. 1. 3    U n e x p e ct e d   A d v ers e  E v e nts...............................................................................  5 9   
8. 2    D o c u  m e nti n g   A d v ers e  E v e nts ............................................................................  5 9   
8. 2. 1    A d v ers e  E v e nt   D at a  El e  m e nts   ............................................................................  5 9 
8. 2. 2    S e v erit y  of   A Es  ..................................................................................................  6 0 
8. 2. 3    Ass ess  m e nt  of   R el ati o ns hi p  of   A E t o  Tr e at  m e nt ...............................................  6 0   
8. 2. 4    F oll o  w- u p  of   A Es ...............................................................................................  6 0  
8. 3    R e p orti n g   A Es t o I  R  B ........................................................................................  6 0   
8. 4    E x p e dit e d r e p orti n g  of  a d v ers e  e v e nts ...............................................................  6 1  
8. 5    D os e  Li  miti n g  T o xi citi es (  D L Ts)   .......................................................................  6 1 
9. 0    
D  A T  A   M  A  N  A  G E  M E  N T   ...............................................................................  6 3 
9. 1    D at a   C a pt ur e   M et h o ds   ........................................................................................  6 3 
9. 2    D at a  q u alit y  ass ur a n c e   ........................................................................................  6 3 
9. 3    S a  m pl e si z e r ati o n al e  ..........................................................................................  6 4 
9. 4    I nt eri  m  d at a  a n a ylsis........................................................................................... 6 4  
9. 5    St atisti c al  a n a l ysis  of  d at a ..................................................................................  6 4 
1 0. 0    
A  D  MI  NI S T  R  A TI  V E  P  R  O  C E  D  U  R E S   ...........................................................  6 5 
1 0. 1    S u bj e ct i nf or  m e d  c o ns e nt ...................................................................................  6 5  
1 0. 2    I  R  B   A p pr o v al .....................................................................................................  6 5 
1 0. 3    S u bj e ct  c o nfi d e nti alit y ........................................................................................ 6 5  
1 0. 4    Et hi c al  c o n d u ct  of t h e st u d y ...............................................................................  6 5  


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
7  
1 0. 5    Pr ot o c ol  a  m e n d  m e nts .........................................................................................  6 6  
1 0. 6    M o nit ori n g ..........................................................................................................  6 6   
1 0. 6. 1  O n  -sit e   M o nit ori n g .............................................................................................  6 6 
1 0. 6. 2  S af et y   D at a   M o nit ori n g  a n d   R e p orti n g ..............................................................  6 6  
1 0. 6. 3  Pr ot o c ol   D e vi ati o ns ............................................................................................  6 7  
1 0. 7    R e c or ds r et e nti o n  ................................................................................................ 6 8  
1 1. 0    
R E F E  R E  N  C E S   ...............................................................................................  6 9 
1 2. 0    
A P P E  N  DI C E S   ................................................................................................  7 1 
A p p e n di x  1:   C o nt a ct list ...............................................................................................  7 1   
A p p e n di x  2:   Dr u gs t h at   m a y  pr ol o n g   Q T c ...................................................................  8 0   
A p p e n di x  3:   N e  w   Y or k   H e art   Ass o ci ati o n  F u n cti o n al   Cl assifi c ati o n ..........................  8 1   
A p p e n di x  4:   R E  CI S T   Crit eri a .......................................................................................  8 2   
A p p e n di x  5:   C T  C  A E  v ersi o n  4. 0 3 ................................................................................  8 3   
A p p e n di x  6:  E  C  O  G  P erf or  m a n c e st at us .......................................................................  8 4   
A p p e n di x  7:   Dr u gs t o  a v oi d   wit h   BI  O  3 0 0   Or al  S us p e nsi o n........................................  8 5   
A p p e n di x  8:  S o y   Ri c h  F o o ds ........................................................................................  8 6   
A p p e n di x  9:  S u  m  m ar y  of  bl o o d  dr a  ws f or s af et y,  P  K,  a n d  P  D  ass ess  m e nt .................  8 7   
A p p e n di x  1 0:   Crit eri a f or  P at h ol o gi c   R es p o ns e  of  T ar g et  L esi o ns  a n d  E xt e nt  of 
S ur gi c al   R es e cti o n  ........................................................................................................  8 8 
A p p e n di x  1 1:   R a di ati o n  P n e u  m o nitis  q u a ntifi c ati o n  vi a   C T  c h a n g es ..........................  8 9   


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
8  
LI S  T   O F  FI  G  U  R  E S   
Fi g ur e  3. 3. 1  S c h e  m a  of  Tri al   D esi g n  ................................................................................  2 9 
Fi g ur e  6. 5. 6. 1   M a n a g e  m e nt  of   Q T c  pr ol o n g ati o n  or  a b n or  miti es  ....................................  4 8 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
9  
LI S  T   O F   T  A  B  L  E S   
T a bl e  1. 2. 1   BI  O  3 0 0   Or al  S us p e nsi o n  F or  m ul ati o n .........................................................  2 2  
T a bl e  1. 5. 1  T ot al  g e nist ei n:   C  m a x  a n d   A  U  C fr o  m  p h ar  m a c o ki n eti c st u di es  ...................  2 5 
T a bl e  3. 1. 1  P a clit a x el  a n d   C ar b o pl ati n   D osi n g  S c h e  m e ...................................................  2 7  
T a bl e  3. 3. 1  Tr e at  m e nt   O v er vi e  w  ......................................................................................  2 8 
T a bl e  5. 2. 1   BI  O  3 0 0   Or al  S us p e nsi o n   D osi n g ..................................................................  3 5  
T a bl e  6. 3. 1. 1  Es o p h a gitis  gr a di n g s yst e  m ........................................................................  3 8  
T a bl e  6. 3. 1. 2  S u g g esti o ns f or   m a n a g e  m e nt  of r a di ati o n  es o p h a gitis ...............................  3 8   
T a bl e  6. 5. 1. 1. 1    D os e   M o difi c ati o n f or   H e  m at ol o gi c  T o xi cit y   .....................................  4 0 
T a bl e  6. 5. 1. 2. 1    D os e   M o difi c ati o n f or   N o n-  H e  m at ol o gi c  T o xi cit y   .............................  4 1 
T a bl e  6. 5. 1. 3. 1   D os e   M o difi c ati o n f or I n-fi el d  n o n- H e  m at ol o gi c  T o xi cit y   .....................  4 3 
T a bl e  6. 5. 2. 1. 1   C o ns oli d ati o n   D os e   M o difi c ati o n f or   H e  m at ol o gi c  T o xi cit y ..................  4 5   
T a bl e  6. 5. 2. 2. 1   C o ns oli d ati o n   D os e   M o difi c ati o n f or  n o n- H e  m at ol  o gi c  T o xi cit y  ...........  4 6 
T a bl e  7. 1. 1  Ti  m e t o  E v e nt f or  n o n s ur gi c al s u bj e cts ........................................................  4 9  
T a bl e  7. 1. 2  Ti  m e t o  E v e nt f or s ur gi c al s u bj e cts ...............................................................  5 0  
T a bl e  7. 1. 3   Visit   Wi n d o  w  T a bl e .......................................................................................  5 2  
T a bl e  7. 4. 1   Bl o o d  v ol u  m e, s u bj e cts  e nr oll e d f or  P  K  a n d  P  D  a n al ysis .............................  5 7   
T a bl e  7. 4. 2   Bl o o d  v ol u  m e, s u bj e cts  e nr oll e d f or  P  D  a n al ysis ..........................................  5 7  
T a bl e  7. 5. 1  S p e ci  m e n   C oll e cti o n  S u  m  m ar y .....................................................................  5 8  
T a bl e  8. 2. 2. 1   Gr a di n g  a n d   D es cri pti o n  of   A d v ers e  E v e nts ..............................................  6 0  


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
1 0  
G  L  O S S  A  R  Y   
4- D   C T
4  D   C o  m p ut e d  T o  m o gr a p h y 
A E
A d v ers e  E v e nt   
A F  R  RI
Ar  m e d  F or c es   R a di o bi ol o g y   R es e ar c h I nstit ut e 
AI  D S
A c q uir e d I  m  m u n e   D efi ci e n c y  S y n dr o  m e   
A L T
Al a ni n e  Tr a ns a  mi n as e   
A  N  C
A bs ol ut e   N e utr o p hil   C o u nt 
A S T
As p art at e   A  mi n otr a nsf er as e   
A  U  C
Ar e a  u n d er t h e  pl as  m a  c o n c e ntr ati o n  v ers us ti  m e  c ur v e 
B  A  R  D  A
Bi o  m e di c al   A d v a n c e d   R es e ar c h  a n d   D e v el o p  m e nt   A ut h orit y   
B  MI
B o d y   M ass I n d e x   
B P
Bl o o d  Pr ess ur e 
B S  A
B o d y  S urf a c e   Ar e a   
B  U  N
Bl o o d   Ur e a   Nitr o g e n 
C
C e nti gr a d e   
C  B  C
C o  m pl et e   Bl o o d   C o u nt 
c c
c u bi c  c e nti  m et ers  
C F  R
C o d e  of  F e d er al   R e g ul ati o ns   
C  G E
C o b alt   Gr a y  E q ui v al e nt 
C  m a x
M a xi  m u  m ( p e a k)  pl as  m a  c o n c e ntr ati o n   
C  O P  D
C hr o ni c   O bstr u cti v e  P ul  m o n ar  y   Dis e as e  
C  R F
C as e   R e p ort  F or  m   
C T
C o  m p ut e d  T o  m o gr a p h y 
C T  C  A 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 
C T  V
Cli ni c al  T ar g et   V ol u  m e   
D( d)
D a y   
D L T
D os e  Li  miti n g  T o xi cit y   
E  C  G
El e ctr o c ar di o gr a  m  
E  C  O  G
E ast er n   C o o p er ati v e   O n c ol o g y   Gr o u p 
E  R
Estr o g e n   R e c e pt or  
F
F a hr e n h eit  
F  A  C T -T  OI  
F u n cti o n al   Ass ess  m e nt  of   C a n c er  T h er a p y  –  Tri al   O ut c o  m e I n d e x  
F  D  A
F o o d  a n d   Dr u g   A d  mi nistr ati o n 
F  D  G
Fl u d e o x y gl u c os e 
F E  V 1
F or c e d  E x pir ati o n   V ol u  m e i n  1 s e c o n d 
F  V  C
F or c e d   Vit al   C a p a cit y  
G  C P
G o o d   Cli ni c al  Pr a cti  c e  
G T  V
Gr oss  T u  m or   V ol u  m e 
G y
Gr a y   
H( h)
H o ur 
H  G  B
H e  m o gl o bi n 
HI P  A  A
H e alt h I ns ur a n c e  P ort a bilit y  a n d   A c c o u nt a bilit y   A ct 
HI  V
H u  m a n I  m  m u n o d efi ci e n c y   Vir us   
H  R  Q  O L
H e alt h  -R el at e d   Q u alit y  of  Lif e   
I L
I nt erl e u ki n 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
1 1  
I  N  D 
I n v esti g ati o n al   N e  w   Dr u g 
I  R  B 
I nstit uti o n al   R e vi e  w   B o ar d 
I  V 
I ntr a v e n o us 
K g   
Kil o gr a  m   
L 
Lit er  
L  B  B  B  
L eft   B u n dl e   Br a n c h   Bl o c k  
m g   
Milli gr a  m   
MI P   
M a xi  m u  m I nt e nsit y  Pr oj e cti o n   
m L   
Millilit er   
M P S   
M u c o p ol ys a c c h ari d os es 
M  RI   
M a g n eti c   R es o n a n c e I  m a gi n g   
ms e c   
Millis e c o n d   
M T  D   
M a xi  m al   T ol er at e d   D os e  
N  A   
N ot   A v ail a bl e   
N  CI   
N ati o n al   C a n c er I nstit ut e   
N  D  A   
N e  w   Dr u g   A p pli c ati o n   
n g 
N a n o gr a  m   
NI  H   
N ati o n al I nstit ut es  of   H e alt h   
N S  C L C   
N o n  -S  m all   C ell  L u n g   C a n c er  
N  Y  H  A    
N e  w   Y or k   H e art   Ass o ci ati o n   
O  H  R P   
Offi c e  of   H u  m a n   R es e ar c h  Pr ot e cti o n   
O S 
O v er all  S ur vi v al 
P 
P uls e 
P  D  
P h ar  m a c o d y n a  mi c  
P E T  
P ositr o n  E  missi o n  T o  m o gr a p h y 
P F S  
Pr o gr essi o n  Fr e e  S ur vi v al 
P F T  
P ul  m o n ar y  F u n cti o n  T est 
P  K  
P h ar  m a c o ki n eti c  
P L T  
Pl at el et  
P S  A  
Pr ost at e -S p e cifi c   A nti g e n  
P  V  C  
Pr e  m at ur e   V e ntri c ul ar   C o ntr a cti o n s 
Q  C   
Q u alit y   C o ntr ol 
Q  O L   
Q u alit y  of  Lif e   
Q T   
Ti  m e fr o  m  E  C  G   Q   w a v e t o t h e  e n d  of t h e  T   w a v e 
Q T c   
C orr e ct e d   Q T i nt er v al   
R E  CI S T   
R es p o ns e  E v al u ati o n   Crit eri a i n  S oli d  T u  m ors 
R T   
R a di ati o n  T h er a p y   
R T  O  G   
R a di ati o n  T h er a p y   O n c ol o g y   Gr o u p 
S  A E  
S eri o us   A d v ers e  E v e nt  
S  B  R T  
St er e ot a cti c   B o d y   R a di ot h er a p y  
S  O P  
St a n d ar d   O p er ati n g  Pr o c e d ur e 
T 
T e  m p er at ur e  
T  ½  
H alf  -lif e  of  eli  mi n ati o n 
T  A  
T est   Arti cl e  
T  B  D  
T o  b e  d et er  mi n e d  
T  G F  
Tr a nsf or  mi n g   Gr o  wt h  F a ct or  


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
1 2  
T  m a x  
Ti  m e t o   m a xi  m u  m ( p e a k)  pl as  m a  c o n c e ntr ati o n  
T  N F 
T u  m or   N e cr osis  F a ct or 
U  C S  D  -S  O  B    
U ni v ersit y   of     C alif or ni a,    S a n     Di e g o   –   S h ort n ess   of     Br e at h 
Q u esti o n n air e 
U L  N   
U p p er  Li  mit  of   N or  m al   
V #   
Visit   N u  m b er   
W  B  C   
W hit e   Bl o o d   C ell 
β  h  C  G 
B et a   H u  m a n   C h ori o ni c   G o n a d otr o pi n 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
1 3  
P  R  O  T  O  C  O  L  S  Y  N  O P S I S  
P r ot o c ol   Titl e  
A   P  h as e   I/II    Cli ni c al   St u d y    E v al u ati n g   t h e   S af et y   a n d 
Eff e cti v e n ess   of     BI  O   3 0 0     Or al   S us p e nsi o n   i n   P ati e nts 
R e c ei vi n g   C h e  m or a di ati o n  T h er a p y f or   N o n  -S  m all   C ell  L u n g 
C a n c er (  N S  C L C)   
P r ot o c ol   N u  m b e r  
C L - 0 1 0 1- 0 1
S p o ns o r  
H u  m a n eti cs   C or p or ati o n 
 
 
St u d y  P h as e  
P h as e I/II  
N a  m e  of  St u d y   D r u g   
BI  O  3 0 0   Or al  S us p e nsi o n ( 3 2 5   m g/  m L) 
I n v esti g ati o n al  Sit es 
M  ulti pl e  sit es wit hi n t h e   U nit e d  St at es   
St u d y   O bj e cti v es  
Pri  m ar y   O bj e cti v e  
T h e   pri  m ar y   o bj e cti v e   is   t o   d es cri b e   a n y   d os e   li  m  iti n g 
t o xi citi es    of    t h e    c o  m bi n ati o n    of     BI  O    3 0 0     wit h 
c h e  m or a di ot h er a p y i n s u bj e cts   wit h   N S  C L C  a n d t o  d et er  mi n e 
t h e r e c o  m  m e n d e d  d os e (t h e  o pti  m al  d os e)  of t his c o  m bi n ati o n. 
S e c o n d ar y   O bj e cti v es  
•
T o  d es cri b e t h e  o v er all  a d v ers e  e v e nt  pr ofil e  of t h e
c o  m bi n ati o n  of   BI  O  3 0 0  a n d  c h e  m or a di ot h er a p y i n
t h e t ar g et  p ati e nt  p o p ul ati o n
•
T o  d et er  mi n e t h e  p h ar  m a c o ki n eti cs  of   BI  O  3 0 0  a n d
t h e  c h e  m ot h er a p y  c o  m p o n e nts  of t h e r e gi  m e n
( p a clit a x el  a n d  c ar b o pl ati n)   w h e n  gi v e n i n
c o  m bi n ati o n
•
T o  d et er  mi n e t h e  p h ar  m a c o d y n a  mi c  eff e cts  of   BI  O
3 0 0 i n  c o  m bi n ati o n   wit h  c h e  m or a di ot h er a p y  b y t h e
d et er  mi n ati o n  of  c ert ai n s er u  m  pr ot ei n  a n d  c yt o ki n e
l e v els
•
T o r e p ort l o c al  pr o gr essi o n r at e  as  d efi n e d  p er
R E  CI S T ( 1. 1)  crit eri a   (s e e   A p p e n di x  4). S ur gi c al
p ati e nts  p at h ol o gi c al r es p o ns e   will  b e  e v al u at e d  as
d efi n e d i n   A p p e n di x  1 0.
•
P ul  m o n ar y f u n cti o n t est ( P F T )  a n d q u alit y  of lif e
(Q  O L  ) m e as ur es ( F  A  C T  -T  OI,   U S  C  D -S  O  B,  a n d
s  w all o  wi n g  di ar y)
•
T o  st u d y t h e  eff e ct  of   BI  O  3 0 0  o n t h e i n ci d e n c e  of
p ul  m o n ar y fi br osis f oll o  wi n g  c h e  m or a di ot h er a p y i n
t h e t ar g et  p o p ul ati o n  as  ass ess e d  b y  4  D   C T s c a n ni n g
•
T o  d et er  mi n e  o v er all s ur vi v al (  O S)  a n d  pr o gr essi o n
fr e e s ur vi v al ( P F S) i n t h e st u d y  p o p ul ati o n


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
1 4  
St u d y   D esi g n  
T his is  a n  o p e n -l a b el,  si n gl e-ar  m,  as c e n di n g  d os e   P h as e  I/II 
st u d y    of     BI  O    3 0 0    gi v e n    or all y   i n   c o  m bi n ati o n     wit h  
p a clit a x el/ c ar b o pl ati n  a n d r a di ot h er a p y i n  s u bj e cts   wit h  st a g e 
II,  III,   or  I  V    N S  C L C    w h o   ar e   c a n di d at es  f or   c o  m bi n e d 
c h e  m or a di ot h er a p y. 
P h as e I/II  –  As c e n di n g   D os e   E v al u ati o n  of   BI  O  3 0 0 ( 3  d os e 
l e v els) 
A   mi ni  m u  m   of  6  s u bj e cts   will  b e a c cr u e d  s e q u e nti all y a t  e a c h 
d os e  of   BI  O  3 0 0.    BI  O  3 0 0   will  b e  a d  mi nist er e d  d ail y f or  t h e 
e ntir e  c o urs e  of  c o n c urr e nt  c h e  m or a di ot h er a p y,  a   mi ni  m u  m  of 
6   w e e ks  ;  c h e  m ot h er a p y    will  b e  a d  mi nist er e d    w e e kl y   f or  6 
w e e ks   a n d  r a di ot h er a p y   will  b e  a d  mi nist er e d  d ail y (  M-F) f or 
a p pr o xi  m at el y  6- 7  w e e ks  .   T h e i niti al  d os e  of  BI  O  3 0 0   will  b e 
5 0 0    m g/ d;  s u bs e q u e nt  d os es    will  b e  1 0 0 0    m g/ d  a n d   1 5 0 0 
m g/ d  .      P a clit a x el   a n d   c ar b o pl ati n     will   b e   a d  mi nist er e d 
i ntr a v e n o usl y   w e e kl y,  p a clit a x el i n  a  d os e  of  4 5   m g/  m2  a n d 
c ar b o pl ati n  i n  a  d os e  s uffi ci e nt  t o  a c hi e v e  a n    A  U  C   of   2  
m g *  mi n/  m L  .    R a di ot h er a p y    will  b e  a d  mi nist er e d  5  d a ys  a 
w e e k  (  M  -F)  f or  a p pr o xi  m at el y   6- 7 w e e ks i n  a  d ail y  fr a cti o n 
of  1. 8- 2. 0   G y t o  a t ot al  d os e  of  6 0- 7 0  G y.   
T h e i niti al  d os e  of   BI  O  3 0 0   will  b e  a d  mi nist er e d  o n   D a y   1, 
Visit  2, i n   w hi c h   s af et y  d at a ( a d v ers e  e v e nts,  E  C  Gs, r es ults  of 
s af et y l a b or at or y  d et er  mi n ati o ns),  p h ar  m a c o ki n eti c ( P  K ) a n d 
p h ar  m a c o d y n a  mi c ( P  D ) d at a   will  b e  c oll e ct e d.   P  K  d at a   will 
b e  c oll e ct e d  fr o  m  a    mi ni  m u  m  of  si x  ( 6)  st u d y   p arti ci p a nts 
fr o  m  e a c h st u d y  c o h ort.   Bl o o d s a  m pl es f or  P  D  d at a  c oll e cti o n 
will  b e  c oll e ct e d  pri or t o  a n d  p ost   BI  O  3 0 0  d osi n g (  2  hr) fr o  m 
all s u bj e cts i n  e a c h st u d y  c o h ort.  
D a y  1  of   c h e  m ot h er a p y    m a y  b e s c h e d ul e d  at t h e  dis cr eti o n  of 
t h e   i n v esti g at or   pr o vi d e d   t h e   s u bj e ct   h as   c o  m pl et e d   a 
mi ni  m u  m  of   1   d a y  of   BI  O  3 0 0  d osi n g.   BI  O  3 0 0    will  b e 
a d  mi nist er e d    i n    c o  m bi n ati o n    wit h    t h e    c h e  m ot h er a p y 
c o  m p o n e nts    of   t h e   pr ot o c ol    t h er a p y    ( p a clit a x el    a n d 
c ar b o pl ati n).     D uri n g   t h e   first    or   s e c o n d   c h e  m ot h er a p y 
i nf usi o n, as  b ef or e,  a d diti o n al s af et y,  P  K  a n d  P  D  d at a   will  b e 
c oll e ct e d.   Bl o o d   s a  m pl es  f or   P  D   d at a   c oll e cti o n    will   b e 
c oll e ct e d  pri or  t o  a n d  p ost   BI  O  3 0 0  d osi n g  ( 2  hr)  fr o  m  all 
s u bj e cts i n  e a c h st u d y  c o h ort.  
D a y  1  of   r a di ati o n  t h er a p y  (  R T)  m a y  b e  s c h e d ul e d  at  t h e 
dis cr eti o n   of   t h e   i n v esti g at or   pr o vi d e d   t h e   s u bj e ct   h as 
c o m pl et e d  a   mi ni  m u  m  of  2  d a ys  of   BI  O  3 0 0  d osi n g.   BI  O  3 0 0 
will   c o nti n u e   t o   b e   a d  mi nist er e d   d ail y;   p a clit a x el   a n d 
c ar b o pl ati n   will  b e  a d  mi nist er e d   w e e kl y  a n d r a di ot h er a p y   will  
b e  a d  mi nist er e d  d ail y  as  d es cri b e d  a b o v e  u ntil  a t ot al  d os e  of 
6 0 -7 0   G y   h as   b e e n   a d  m  i nist er e d.      D uri n g  t h e   p eri o d   of


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
1 5  
c o  m bi n e d  BI  O  3 0 0  a n d  c h e  m or a di ot h er a p y  (a p pr o xi  m at el y  6 -
7  w e e ks  ),  a d diti o n al s af et y,  P  K  a n d  P  D  d at a   will  b e  c oll e ct e d 
w e e kl y.   Tr o u g h   l e v els    f or     BI  O    3 0 0,    p a clit a x el,    a n d 
c ar b o pl ati n   will  b e  c oll e ct e d   w e e kl y.   Bl o o d  s a  m pl es  f o r  P  D 
d at a  c oll e cti o n   will  b e  c oll e ct e d   w e e kl y  d uri n g t h e  c o  m bi n e d 
BI  O  3 0 0  a n d  c h e  m or a di ot h er a p y  p eri o d  at t h e  s a  m e ti  m e  as 
t h e  tr o u g h  l e v els,  j ust   pri or  t o  t h at    w e e k’s  c h e  m ot h er a p y 
tr e at  m e nt  a n d t h at  d a ys’   BI  O  3 0 0  d os e.  T ot al  d ur ati o n  of   BI  O 
3 0 0 tr e at  m e nt  will  b e  a   mi ni  m u  m  of   6  w e e ks  . Bl o o d  s a  m pl es 
f or   P  D   d at a     will   als o   b e   c oll e ct e d   at   t h e   e n d   of   t h e 
c o ns oli d ati o n  p h as e,  a n d  at  t h e  3  a n d  6    m o nt hs   f oll o  w  u p 
visit s. 
F oll o  wi n g  a c cr u al  of  6  s u bj e cts  at  a  p arti c ul ar   BI  O  3 0 0  d os e 
l e v el,  d os e  es c al ati o n m a y  o c c ur   w h e n  a  c o h ort  h as  c o  m pl et e d 
c o n c urr e nt  c h e  m or a di ot h er a p y    wit h  f e  w er  t h a n   3 3  %    D L Ts  
attri b ut e d t o   BI  O  3 0 0   Or al  S us p e nsi o n . I nt eri  m  d at a  a n al ysis 
will    b e   c o  m pl et e d    o n c e   t h e    hi g h est   c o h ort   c o n cl u d es 
c h e  m or a di ati o n t h er a p y, i n  a n  eff ort t o  d et er  mi n e t h e  o pti  m al  
bi ol o gi c al  d os e.  F oll o  wi n g  a n al ysis, t h er e   will  b e  a n  o pti o n t o 
e nr oll  u p t o  a n  a d diti o n al  1 2 s u bj e ct s at  t h e  o pti  m al  bi ol o gi c al 
d os e. 
At t h e  c o n cl usi o n  of t h e  st u d y,  d at a   will  b e  a n al y z e d fr o  m  all 
c o h orts  t o  d et er  mi n e  t h e  o n c ol o gi c  r es p o ns e,  s af et y  of   BI O 
3 0 0,  a n d  a  r e c o  m  m e n d e d   BI  O  3 0 0  d os e.   R e p orti n g  of  l o c al 
pr o gr essi o n r at e  as  d efi n e d  p er   R E  CI S T ( 1. 1)  crit eri a  will  b e 
d o n e f or  all  s u bj e cts i n  e a c h  of t h e  c o h orts  (s e e   A p p e n di x  4). 
S ur gi c al  p ati e nts  p at h ol o gi c al  r es p o ns e   will  b e  e v al u at e d  as 
d efi n e d i n   A p p e n di x  1 0.     I n  a d diti o n,  q u alit y  of lif e   will  b e 
ass ess e d  usi n g t h e  F u n cti o n al   Ass ess  m e nt  of   C a n c er  T h er a p y 
–  Tri al   O ut c o  m e I n d e x ( F  A  C T -T  OI).  T h e r at e  of  F  A  C T -T  OI
d e cli n e  at  3   m o nt hs  p ost  c o n c urr e nt  c h e  m or a di ati o n t h er a p y
c o  m pl eti o n    will   b e    m e as ur e d.    A d d iti o n al   q u alit y   of  lif e
m e as ur es   will  als o  b e  us e d, i n cl u di n g  a s  w all o  wi n g  di ar y  a n d
t h e   U ni v ersit y  of  C alif or ni a –  S a n   Di e g o (  U  C S  D) s h ort n ess  of
br e at h ( S  O  B)  q u esti o n n air e.  S u bj e cts   will  u n d er g o l o n g -t er  m
f oll o  w-u p  aft er t h e  c o  m pl eti o n  of t h er a p y t o  d et er mi n e  o v er all
s ur vi v al (  O S),  pr o gr essi o n fr e e  s ur vi v al ( P F S),  a n d t h e  eff e ct
of   BI  O  3 0 0  o n  p ul  m o n ar y fi br osis.
I n cl usi o n   C rit e ri a  
S u bj e cts   m ust f ulfill  all  of t h e f oll o  wi n g i n cl usi o n  crit eri a:  
1)  A g e   >  1 8
2)  Hist ol o gi c al  or  c yt ol o gi c al  c o nfir  m ati o n  of
N S  C L C (s p  ut u  m  c yt ol o g y   will  n ot  b e  a d e q u at e
e vi d e n c e  of   m ali g n a n c y)
3)   S u bj e cts  di a g n os e d   wit h st a g e II, III,  or I  V
( oli g o  m et ast ati c) N S  C L  C f or   w h o  m r a di ati o n


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
1 6  
t h er a p y of  6 0 -7 0  G y  a n d  c o n c urr e nt   w e e kl y   
p a clit a x el/ c ar b o pl ati n  is r e c o  m  m e n d e d  as  p art  of 
p ot e nti all y  c ur ati v e t h er a p y  eit h er  al o n e  or 
pr e o p er ati v el y .  
4)  U p t o t hr e e s  m all   ( ≤ 3  c  m  e a c h) l u n g
oli g o  m et ast as es   will  b e  all o  w e d   a n d/ or  o n e
oli g o  m et ast asis  at  a n y   ot h er/ or sit e i n t h e  b o d y.
T h es e  c o ul d  b e tr e at e d   wit h f o c us e d  S  B  R T
( St er e ot a cti c   B o d y   R T).
5)    E  C  O  G  P S  of  0  or  1 (  A p p e n di x  6)
6)  F E  V 1:   b est  v al u e  o bt ai n e d  pr e-  or  p ost-
br o n c h o dil at or   m ust  b e  ≥  1. 0  lit ers/s e c o n d or  >
5 0  %  pr e di ct e d  v al u e
7)  A d e q u at e  b o n e   m arr o  w r es er v e  b as e d  o n
a.  W  B  C   >  3, 0 0 0/ µ L
b.  A  N  C   >  1, 5 0 0/ µ L
c.  P L T  >  1 0 0, 0 0 0/ µ L
d.  H  G  B   >  9  g/ d L
8)  A d e q u at e  h e p ati c r es er v e  as  e vi d e n c e d   b y
A L T/  A S T   <  3  X   U L  N f or t h e r ef er e n c e l a b  a n d
bilir u bi n  <  1. 5   m g/ d L ( e x c e pt i n s u bj e cts   wit h
k n o  w n   Gil b ert’s s y n dr o  m e,   w h er e t h e  bilir u bi n
m a y  b e   <  2. 0   m g/ d L)
9)    A d e q u at e r e n al f u n cti o n  as  e vi d e n c e d  b y  a s er u  m
cr e ati ni n e  ≤   1. 5 X   U L  N f or t h e r ef er e n c e
l a b or at or y   O  R  a  c al c ul at e d  cr e ati ni n e  cl e ar a n c e  of
≥  6 0   m L/  mi n  b y t h e   C o c kr oft- G a ult  e q u ati o n
1 0)  F e  m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al   m ust
h a v e  a  n e g ati v e  pr e g n a n c y t est   wit hi n  7 2  h o urs  of
t h e st art  of tr e at  m e nt
1 1)  F e  m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al  a n d
m al e s u bj e cts   wit h f e  m al e s e x u al  p art n ers  of
c hil d b e ari n g  p ot e nti al   m ust  a gr e e t o  us e  a n
eff e cti v e   m et h o d  of  c o ntr a c e pti o n ( e. g.,  or al
c o ntr a c e pti v es,  d o u bl e- b arri er   m et h o ds s u c h  as  a
c o n d o  m  a n d  a  di a p hr a g  m, i ntr a ut eri n e  d e vi c e)
d uri n g t h e st u d y  a n d f or  9 0  d a ys f oll o  wi n g t h e
l ast  d os e  of st u d y   m e di c ati o n  or t o  a bst ai n fr o  m
s e x u al i nt er c o urs e f or t his ti  m e;  a   w o  m a n  n ot  of
c hil d b e ari n g  p ot e nti al is  o n e   w h o  h as  u n d er g o n e
bil at er al  o o p h or e ct o  mi es  or   w h o is  p ost-
m e n o p a us al,  d efi n e d  as  n o   m e nstr u al  p eri o ds f or
1 2  c o ns e c uti v e   m o nt hs
1 2)   A bilit y t o r e a d  a n d  pr o vi d e   writt e n i nf or  m e d
c o ns e nt
E x cl usi o n   C rit e ri a   
S u bj e cts   m a y  n ot  h a v e  a n y  of t h e f oll o  wi n g  e x cl usi o n  crit eri a:  


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
1 7  
1)  W ei g ht l oss  gr e at er t h a n  1 0  % i n  pri or   4   w e e ks
2)   Pri or   m ali g n a n c y i n   w hi c h t h e y r e c ei v e d  a n y
t h or a ci c r a di ot h er a p y u nl ess t h e tr e ati n g
p h ysi ci a n  c o nsi d ers it  u nli k el y t o i  m p a ct t h e
cli ni c al  o ut c o  m e  of t h e  p ati e nt.
3)   P ati e nts   wit h  c o n c urr e nt i n v asi v e
m ali g n a n c y    ot h er t h a n  n o n-m el a n o  m a s ki n  c a n c er
or  c er vi c al i ntr a e pit h eli al  n e o pl asi a   u nl ess t h e
tr e ati n g  p h ysi ci a n  c o nsi d ers it  u nli k el y t o i  m p a ct
t h e  cli ni c al  o ut c o  m e  of t h e  p ati e nt.
4)    A n  a cti v e i nf e cti o n  or   wit h  a f e v er  ≥  3 8. 5°  C
wit hi n  3  d a ys  of t h e first s c h e d ul e d  d a y  of  d osi n g
5)   P o orl y  c o ntr oll e d i nt er c urr e nt ill n ess es, s u c h  as
u n c o ntr oll e d  h y p ert e nsi o n;  p o orl y  c o ntr oll e d
di a b et es   m ellit us,  d efi n e d  as t h e  n e e d f or
h os pit ali z ati o n  2  or   m or e ti  m es i n t h e  pr e c e di n g
1 2   m o nt hs.  P ati e nt   m a y  n ot  h a v e  h a d  a n y  of t h e
f oll o  wi n g   wit hi n  6   m o nt hs  pri or t o st u d y  e ntr y:
u nst a bl e  a n gi n a;  hist or y  of   m y o c ar di al i nf ar cti o n,
a c ut e  c or o n a r y s y n dr o  m e;  hist or y  of  c o n g esti v e
h e art f ail ur e;  c ar di a c  arr h yt h  mi as r e q uiri n g
m e di c al t h er a p y  or  a  p a c e  m a k er  ; c er e br o v as c ul ar
e v e nts .
6)  P at ie nts  wit h  a    pri or t h or a c ot o  m y wit hi n   1  w e e k
of st u d y r e gistr ati o n .
7)    C hr o ni c   O bstr u cti v e  P ul  m o n ar y  Dis e as e
(  C  O  P  D )  e x a c er b ati o n   or  ot h er r es pir at or y
ill n ess  r e q uiri n g  h os pit ali z ati o n  or  pr e cl u di n g
st u d y t h er a p y wit hi n  3 0  d a ys  b ef or e   r e gistr ati o n
8)  P ati e nts  wit h  a n y  of t h e f oll o  wi n g  ar e  n ot
eli gi bl e;
a.  Pr e vi o us  hist or y  of   Q T c  pr ol o n g ati o n   r es ulti n g  fr o  m
m e di c ati o n   t h at   r e q uir e  d    dis c o nti n u ati o n    of   t h at
m e di c ati o n;
b.  C o n g e nit al l o n g   Q T  s y n dr o  m e,  or  1  st d e gr e e  r el ati v e
wit h  u n e x pl ai n e d s u d d e n  d e at h  u n d er  4 0  y e ars  of  a g e;
c.  Pr es e n c e  of l eft  b u n dl e  br a n c h  bl o c k ( L  B  B  B);
d.  Q T c   wit h   Fri d eri ci a’s  c orr e cti o n t h at is  u n  m e as ur a bl e,
or  ≥  4 8 0   ms e c  o n  s cr e e ni n g   E  C  G.   T h e  a v er a g e   Q T c
fr o  m t h e s cr e e ni n g  E  C  G ( c o  m pl et e d i n tri pli c at e) m ust
b e  <  4 8 0   ms e c i n  or d er f or t h e  p ati e nt t o  b e  eli gi bl e f or
t h e st u d y;
e.  S u bj e cts t a ki n g  a n y  c o n c o  mit a nt   m e di c ati o n t h at   m a y
c a us e   Q T c  pr ol o n g ati o n, i n d u c e   T ors a d es  d e  P oi nt es
(s e e   A p p e n di x  2)  ar e  n ot  eli gi bl e if   Q T c  ≥ 4 6 0  ms e c.


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
1 8  
9)  P ati e nts  m ust  n ot  h a v e  h a d  a  cli ni c all y si g nifi c a nt
c ar di a c  e v e nt s u c h  as   m y o c ar di al i nf ar cti o n
(  wit hi n  6   m o nt hs  pri or t o t h e first  d os e  of t h e
st u d y tr e at  m e nt);  u n c o ntr oll e d/s y  m pt o  m ati c
c o n g esti v e  h e art f ail ur e ( N e  w   Y or k   H e art
Ass o ci ati o n (  N  Y  H  A)  cl assifi c ati o n  of  h e art
dis e as e ,   Cl ass III  or I  V, s e e   A p p e n di x  3)   wit hi n  6
m o nt hs  b ef or e  e ntr y;  or t h e  pr es e n c e  of   a n y  ot h er
u n c o ntr oll e d  c ar di o v as c ul ar  c o n diti o ns
( h y p ert e nsi o n  or  arr h yt h  mi a,  u nst a bl e  a n gi n a
p e ct oris,  or s e v er e  v al v ul ar  h e art  dis e as e,  et c.)
t h at, i n t h e  o pi ni o n  of t h e I n v esti g at or, i n cr e as es
t h e ris k  of  v e ntri c ul ar  arr h yt h  mi a.
1 0)  P ati e nts   wit h  a  hist or y  of  arr h yt h  mi a (  m ultif o c al
pr e  m at ur e  v e ntri c ul ar  c o ntr a cti o ns ( P  V  Cs),
bi g e mi n y, tri g  e mi n y,  v e ntri c ul ar t a c h y c ar di a,  or
u n c o ntr oll e d  atri al fi brill ati o n)   w hi c h is
s y  m pt o  m ati c  or r e q uir es tr e at  m e nt (  C T  C  A E
Gr a d e  3)  or  as y  m pt o  m ati c s ust ai n e d  v e ntri c ul ar
t a c h y c ar di a  ar e  n ot  eli gi bl e.   P ati e nts   wit h  atri al
fi brill ati o n wit h   w ell  - c o ntr oll e d  v e ntri c ul ar r at e
o n   m e di c ati o n,  ar e  eli gi bl e.
1 1) Ps y c hi atri c  c o n diti o ns, s o ci al sit u ati o ns  or
s u bst a n c e  a b us e t h at  pr e cl u d es t h e  a bilit y  of t h e
s u bj e ct t o  c o o p er at e   wit h t h e r e q uir e  m e nts  of t h e
tri al  a n d  pr ot o c ol t h er a p y
1 2)  Gr a d e  2  or  hi g h er  p eri p h er al  n e ur o p at h y
1 3)   K n o  w n  hist or y  of   HI  V /  AI  D S,  h e p atitis   B  or   C.
N  ot e,   h o  w e v er, t h at HI  V   or  h e p atitis  t esti n g is
n ot  r e q uir e d f or e ntr y  i nt o t his  pr ot o c ol. T h e
n e e d  t o  e x cl u d e p ati e nts  wit h   AI  D S  ,  h e p atitis   B
or   C  fr o  m t his  pr ot o c ol is n e c ess ar y  b e c a us e  t h e
tr e at  m e nts i n v ol v e d i n t his  pr ot o c ol m a y    b e
si g nifi c a ntl y i  m  m u n os u p pr essi v e.   Pr ot o c ol-
s p e cifi c r e q uir e  m e nts m a y   als o  e x cl u d e  i  m  m u n o-
c o  m pr o  mis e d  p ati e nts.
1 4)  Pr e g n a n c y   or  w o  m e n    of   c hil d b e ari n g   p ot e nti al
a n d   m e n    w h o    ar e   s e x u all y  a cti v e   a n d   n ot
willi n g/ a bl e    t o  us e  m e di c all y    a c c e pt a bl e   f or  ms
of  c o ntr a c e pti o n;   t his  e x cl usi o n  is  n e c ess ar y
b e c a us e  t h e tr e at  m e nt i n v ol v e d i n t his st u d y   m a y
b e t er at o g e ni c.
1 5)  W o  m e n   w h o  ar e  br e astf e e di n g  ar e  n ot  eli gi bl e f or
t his st u d y.
N u  m b e r  of  S u bj e cts   
U p  t o  t  hirt y -si x  (3 6 )    m al e  a n d  f e  m al e  s u bj e cts    w h o   gi v e 
i nf or  m e d  c o ns e nt  a n d  f ulfill  t h e  s el e cti o n  crit eri a    will  b e 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
1 9  
e nr oll e d   i nt o  t h e  tri al.    T hr ee   c o h orts    will   b e   c o  m pl et e d 
s e q u e nti all y; e a c h   will  a c cr u e  a   mi ni  m u  m  of  6  s u bj e cts. O n c e 
t h e  t hir d  c o h ort  h as  c o  m pl et e d  c h e  m or a di ati o n  t h er a p y  a n d 
i nt eri  m  d at a  a n al ysis  h as  d et er  mi n e d  t h e  o pti  m al  bi ol o gi c al 
d os e  of    BI  O  3 0 0 ,  u p  t o   a n  a d d iti o n al  1 2  s u bj e cts  will    b e 
e nr oll e d  at  t h at  d os e.  
D os e   Es c al ati o n 
C rit e ri a   
A   mi ni  m u  m  of  6 s u bj e cts   will  b e tr e at e d  p er  d os e l e v el.   D os e 
es c al ati o n   m a y  o c c ur   w h e n  a  c o h ort  h as  c o  m pl et e d  c o n c urr e nt 
c h e  m or a di ot h er a p y   wit h  l ess t h a n 3 3  %   D L Ts  attri b ut a bl e t o 
BI  O  3 0 0   Or al   S us p e nsi o n  . If  o n e  or  f e  w er   D L Ts  o c c ur,  t h e 
d os e   will  b e  es c al at e d  t o t h e  n e xt  c o h ort  of  6  s u bj e cts.  If  2 
D L Ts  o c c ur  ( 2/ 6  s u bj e cts),  a n  a d diti o n al  2  s u bj e cts   will  b e 
tr e at e d   wit h t h e  s a  m e  d os e. If  n o  a d diti o n al   D L Ts  o c c ur ( 2/ 8 
s u bj e cts),  d os e  es c al ati o n   m a y  pr o c e e d.  If  1  a d diti o n al  D L T 
o c c urs ( 3/ 8  s u bj e cts),  a n  a d diti o n al  2  s u bj e cts   will  b e tr e at e d 
at t h e  s a  m e  d os e  f or  a t ot al  of  1 0  s u bj e cts.   If  n o  a d diti o n al 
D L Ts  o c c ur ( 3/ 1 0 s u bj e cts),  d os e es c al ati o n   m a y  pr o c e e d.   T h e 
st u d y    s p o ns or     will   t e  m p or aril y    c e as e    e nr oll  m e nt    f or 
e v al u ati o n if i n  a n y  gi v e n  c o h ort  4  s u bj e cts ( o ut  of  a t ot al  of 
1 0)  e x p eri e n c e   D L Ts  attri b ut a bl e t o  BI  O  3 0 0   Or al  S us p e n si o n
as t h e   M T  D   will  h a v e  b e e n  e x c e e d e d.
P r ot o c ol   T h e r a p y  
BI  O  3 0 0   will  b e  a d  mi nist er e d  o n c e  d ail y  or all y  as  a n  a q u e o us 
n a n os us p e nsi o n  at t h e  d os e  c urr e ntl y  o p e n t o  e nr oll  m e nt. 
P a clit a x el   will  b e  a d  mi nist er e d i ntr a v e n o usl y   w e e kl y  d uri n g 
r a di ot h er a p y i n  a d os e  of  4 5   m g/  m 2. 
C ar b o pl ati n   will  b e  a d  mi nist er e d i ntr a v e n o usl y   w e e kl y  d uri n g 
r a di ot h er a p y  i n  a  d os e  d esi g n e d  t o  a c hi e v e  a n    A  U  C  of  2 
m g *  mi n/  m L  . 
R a di ot h er a p y   will  b e  a d  mi nist er e d  5  d a ys  a   w e e k  (  M  -F)  i n 
fr a cti o ns   of   1. 8- 2. 0    G y  t o  t ot al   d os e   of   6 0 -7 0   G y   o v er   
a p pr o xi  m at el y   6- 7 w e e ks  . 
F oll o  wi n g    c o  m pl eti o n    of    t h e    pr ot o c ol    pr es cri b e d 
c h e  m or a di ot h er a p y,   s u bj e cts   wit h   u nr es e ct a bl e/  m e di c all y 
i n o p er a bl e  dis e as e will   r e c ei v e  c o ns oli d ati o n  c h e  m ot h er a p y 
c o nsisti n g  of  a n  a d diti o n al  2  c y cl es  of  p a clit a x el  2 0 0   m g/  m 2 
a n d   c a r b o pl ati n   a d  mi nist er e d   t o   a c hi e v e   a n     A  U  C   of   6 
m g *  mi n/  m L    o n    D a y   1   of  a   3 -w e e k  c y cl e.    S u bj e cts    wi t h 
p ot e nti a ll y  r es e ct a bl e  dis e as e    will  b e  e v al u at e d  f or  s ur g er y 
a n d  r est a g e d . If  t h e p ati e nt is  d e e  m e d  fit  a n d  a n  a p pr o pri at e 
c a n di d at e  f or  s ur g er y,  s ur g er y   will o c c ur  a p pr o xi  m at el y   6-1 2  
w e e ks   p ost   c o n c urr e nt   c h e  m or a di ati o n    wit h   c o ns oli d ati o n 
c h e  m ot h er a p y s c h e d ul e d  6 -1 2   w e e ks f oll o  wi n g s ur g er y.  
D u r ati o n  of  St u d y 
T r e at  m e nt   
BI  O    3 0 0  tr e at  m e nt   will   b e   a p pr o xi  m at el y    6- 7  w e e ks  i n 
d ur ati o n , i n  c o  m bi n ati o n   wit h c h e  m or a di ot h er a p y.    BI  O  3 0 0 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
2 0  
tr e at  m e nt   will  b e  gi v e n  d ail y  u ntil  c o n c urr e nt  c h e  m or a di ati o n 
t h er a p y  is  c o  m pl et e d.    S u bj e cts    will  r e c ei v e   c o ns oli d ati o n 
c h e  m ot h er a p y    c o nsisti n g    of    p a clit a x el    a n d    c ar b o pl ati n 
a d  mi nistr ati o n    at    t h e    c o n cl usi o n    of    t h e    c o n c urr e nt 
c h e  m or a di at i o n tr e at  m e nts or  aft er  s ur g er y .   C ar b o pl ati n   will 
b e   gi v e n   aft er   p a clit a x el,   b ot h    will   b e   a d  mi nist er e d   b y 
i ntr a v e n o us  dri p  o n c e  e v er y  2 1  d a ys f or t  w o  c y cl es. 
St u d y  P r o c e d u r es  
S e e  S c h e d ul e  of   Ass ess  m e nts  
C rit e ri a f o r 
E v al u ati o n 
S af et y 
S af et y  of t h e  c o  m bi n ati o n  of  BI  O  3 0 0  a n d  c h e  m or a di ot h er a p y 
will  b e  b as e d  o n  t h e  r e p orti n g  of  a d v ers e  e v e nts  b y  st u d y 
s u bj e cts;  b y  fi n di n gs  o n  p h ysi c al  e x a  m;  b y  d et er  mi n ati o n  of 
vit al si g ns ( bl o o d  pr ess ur e,  p uls e, t e  m p er at ur e, r es pir at or y r at e 
a n d   w ei g ht);  b y  fi n di n gs  o n   E  C  Gs;  a n d t h e  r es ults  of  s af et y 
l a b or at or y  t ests  ( c o  m pl et e  bl o o d  c o u nts,  s er u  m  c h e  mistri es, 
uri n al ys es).  
P h ar  m a c o ki n eti cs 
T h e   p h ar  m a c o ki n eti cs   of    BI  O   3 0 0  a n d  t h e  c h e  m ot h er a p y 
a g e nts   t h at    c o  m p os e    pr ot o c ol   t h er a p y    ( p a clit a x el    a n d 
c ar b o pl ati n)    will  b e  d et er  mi n e d  b y    m e as ur es  of  t h e  s er u  m 
l e v els   of   t ot al   g e nist ei n,   fr e e   g e nist ei n,   p a clit a x el   a n d 
c ar b o pl ati n.    St a n d ar d  p h ar  m a c o ki n eti c  p ar a  m et ers  (  C  m a x, 
T  m a x,    A  U  C,  h alf -lif e,    V d,  et c.)    will  t h e n  b e  d eri v e d  fr o  m 
t h es e   m e as ur e d s er u  m l e v els. 
P h ar  m a c o d y n a  mi cs 
T h e   p h ar  m a c o d y n a  mi c   eff e ct   of    BI  O   3 0 0   al o n e   a n d   i n 
c o  m bi n ati o n   wit h  c h e  m or a di ot h er a p y   will  b e  d et er  mi n e d  b y 
t h e   m e as ur e  m e nt  of  c ert ai n s er u  m pr ot ei n  a n d  c yt o ki n e l e v els. 
C  yt o ki n e   m ar k ers  m a y   i n cl u d e I L- 6, I L- 1α,  I L- 1β,   I L-8, I L -
1 0,   T  N F α,  T  G F β 1,    T  G F β 2,   a n d    T  G F β 3.   P ot e n ti al  ser u  m 
pr ot ei ns  of  i nt er est  i n cl u d e  gr a n ul o c yt e  c ol o n y  sti  m ul ati n g 
f a ct or (  G-C S F),   C  -r e a cti v e  pr ot ei n,  a n d  pr ost a gl a n di n  E 2.  
Effi c a c y  
T h e  l o c al  pr o gr essi o n  r at e  as  d efi n e d  p er  t h e    R E  CI S T  1. 1 
crit eri a  (  A p p e n di x  4)  will  b e  us e d  t o  ass ess  t h e  n e ar  -t er  m 
e ffi c a c y    of    t h e    c o  m bi n ati o n    of     BI  O    3 0 0    a n d 
c h e  m or a di ot h er a p y.  S ur gi c al  p ati e nts  p at h ol o gi c al  r es p o ns e 
will  b e e v al u at e d as  d efi n e d i n   A p p e n di x  1 0. I n a d diti o n,  P F Ts 
a n d  a  s  w all o  wi n g  di ar y   will  b e  us e d t o  ass ess  s af et y  of   BI  O 
3 0 0    Or al   S us p e nsi o n.      T h e  l o n g er -t er  m   effi c a c y   of  t his 
c o  m bi n ati o n   will  b e  b as e d  f or t h e  d et er  mi n ati o n  of o v er all a n d 
pr o gr essi o n- fr e e  s ur vi v al  a n d f or t h e i n ci d e n c e  of  p ul  m o n ar y 
fi br osis  as  d et er  mi n e d  b y  4  D   C T  s c a n ni n g.     Q u alit y  of  lif e 




















P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
3 0  
4. 0   
S  U  B J  E  C  T S  
4. 1   
N u  m b e r  of   S u bj e cts  
U p   t o thirt y -si x ( 3 6)   m al e  a n d f e  m al e  s u bj e cts   w h o  gi v e i nf or  m e d  c o ns e nt  a n d f ulfill t h e 
s el e cti o n  crit eri a    will  b e  r e cr uit e d  a n d   e nr oll e d   i nt o  t h e  tri al.    T hr ee  c o h orts    will  b e 
c o  m pl et e d  s e q u e nti all y ; e a c h   will  a c cr u e  a   mi ni  m u  m  of  6  s u bj e cts. O n c e t h e t hir d   c o h ort 
h as  c o  m pl et e d  c h e  m or a di ati o n  t h er a p y  a n d  i nt eri  m   d at a  a n al ysis   h as   d et er  mi n e d   t h e 
o pti  m al  bi ol o gi c al  BI  O  3 0 0   d os e,  t h er e   will  b e  a n o pti o n t o  e nr oll  u p t o  a n  a d diti o n al  1 2 
s u bj e cts  at t h at  d os e (s e e s e cti o n  9. 4 f or s el e cti o n  of  o pti  m al  d os e) .  
4. 2    
S u bj e ct   Eli gi bilit y  
Pri or t o  e nr oll  m e nt i nt o t h e  st u d y,  s u bj e cts   m ust   m e et  all i n cl usi o n  crit eri a  a n d  n ot   m e et 
a n y  of t h e  e x cl usi o n  crit eri a. If t h e  Pri n ci p al I n v esti g at or  h as  a n y  q u esti o ns  o n  a  s u bj e ct’s 
eli gi bilit y,  t h e  s p o ns or   will  c o nt a ct  t h e    M e di c al    M o nit or  t o  r e vi e  w  a n d  t o    m a k e  a  fi n al 
d et er  mi n ati o n  of  eli gi bilit y.   
4. 2. 1   I n cl usi o n C  rit e ri a  
1)    A g  e  ≥  1 8. 
2)    Hist ol o gi c al  or  c yt ol o gi c al  c o nfir  m ati o n  of   N S  C L  C (s p ut u  m  c yt ol o g y   will  n ot  b e 
a d e q u at e  e vi d e n c e  of   m ali g n a n c y) . 
3)    P ati e nts  di a g n os e d   wit h st a g e II, III,  or I  V ( oli g o  m et ast ati c)   N S  C L C f or   w h o  m 
r a di ati o n t h er a p y of  6 0- 7 0    G y  a n d  c o n c urr e nt w e e kl y   p a clit a x el/ c ar b o pl ati n  is 
r e c o  m  m e n d e d  as  p art  of  p ot e nti all y  c ur ati v e t h er a p y  eit h er  al o n e  or  pr e o p er ati v el y. 
If   a  pl e ur al   eff usi o n   is  pr es e nt,   t h e  f oll o  wi n g  crit eri a     m ust   b e  m et    t o   e x cl u d e   
m ali g n a nt    i n v ol v e  m e nt (i n c ur a bl e   M 1 a dis e as e):  
a)    W h e n    pl e ur al   fl ui d  is  visi bl e  o n  b ot h  t h e  C T    s c a n  a n d   o n  a  c h est   x-r a y,  a 
pl e ur a c e nt esis   is  r e q uir e d  t o  c o nfir  m   t h at  t h e  pl e ur al   fl ui d  is  c yt ol o gi c all y 
n e g ati v e ,  u nl ess t h e  eff usi o n is   mi ni  m al  a n d/ or t o o s  m all t o s af el y t a p. 
4)    P ati e nts  m a y   h a v e  ≤  3 l u n g  oli g o  m et ast as es ( e a c h  ≤  3 c  m)  a n d/ or  1  oli g o m et ast as  is at 
a n y  ot h er  sit e i n t h e  b o d y,  b as e d  u p o n t h e f oll o  wi n g   mi ni  m u  m  a c c e pt a bl e  di a g n osti c 
w or k u p: 
a)    Hist or y/ p h ysi c al  e x a  mi n ati o n   wit hi n  1 0   w e e ks  pri or t o r e gistr ati o n   
b)    C o  m p ut e d t o  m o gr a p hi c (  C T)/  M  RI i  m a gi n g  of t h e l u n g   wit hi n  1 0   w e e ks  pri or 
t o r e gistr ati o n (  N  O T E: If  a w h ol e  b o d y   P E T/  C T   w as  d o n e,  a s e p ar at e   C T  s c a n 
of t h e  c h est is  n ot r e q uir e d) 
c)    W h ol e-  b o d y  F  D  G -P E T  or  P E T/  C T ; or if  n o  P E T is  a v ail a bl e,  a  b o n e  s c a n is 
r e q uir e d   wit hi n  1 0   w e e ks  pri or t o  r e gistr ati o n ( a n d   C T  or   M  RI   m ust i n cl u d e 
t h e li v er) 
d)    M  RI ( or   C T) i  m a gi n g  of t h e  br ai n   wit hi n  1 0   w e e ks  pri or t o r e gistr ati o n   
Oli g o  m et ast as es   m a y  b e tr e at e d  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)    E  C  O  G  P erf or  m a n c e  St at us   0- 1 (  A p p e n di x  6). 
6)    F E  V 1:  b est  v al u e  o bt ai n e d  pr e-  or  p ost- br o n c h o dil at or   m ust   b e ≥  1. 0  lit ers/s e c o n d or  >  
5 0  %  pr e di ct e d  v al u e . 
7)    C  B  C/ diff er e nti al    o bt ai n e d wit hi n    4 w e e ks    pri or t o st arti n g tr e at  m e nt , wit h   a d e q u at e  
b o n e   m arr o  w f u n cti o n  d efi n e d  as  f oll o  ws: 
a)    W  B  C   ≥  3, 0 0 0/  µ L 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
3 1  
b)    A bs ol ut e  n e utr o p hil  c  o u nt (  A  N  C)   ≥  1, 5 0 0  c ells/µ L 
c)    Pl at el ets   ≥  1 0 0, 0 0 0  c ells/µ L 
d)    H e  m o gl o bi n  ≥  9. 0   g/ d L   (  N ot e:  T h e   us e  of  tr a nsf usi o n  or  ot h er   i nt er v e nti o n  t o 
a c hi e v e    HG  B    ≥  9. 0  g/ d L is  a c c e pt a bl e.) 
8)    A d e q u at e  h e p ati c r es er v e  as  e vi d e n c e d  b y   A L T/  A S T   <  3  X   U L  N f or t h e r ef er e n c e l a b 
a n d   bilir u bi n  ≤  1. 5   m g/ d L ( e x c e pt i n s u bj e cts   wit h  k n o  w n   Gil b ert’s s y n dr o  m e,   w h er e 
t h e  bilir u bi n   m a y  b e  <  2. 0   m g/ d L) 
9)    A d e q u at e r e n al f u n cti o n  as  e vi d e n  c e d  b y  a s er u  m  cr e ati ni n e  ≤  1. 5 X   U L  N f or t h e 
r ef er e n c e l a b or at or y   O  R  a  c al c ul at e d  cr e ati ni n e  cl e ar a n c e  of  ≥  6 0 m L/  mi n  b y t h e 
C o c kr oft-  G a ult  e q u ati o n  . 
1 0)  F e  m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al  m ust  h a v e  a  n e g ati v e  pr e g n a n c y t est   wit hi n   7 2 
h o urs  of t h e st art  of tr e at  m e nt.  
1 1)  F e  m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al  a n d   m al e s u bj e cts   wit h f e  m al e s e x u al  p art n ers 
of  c hi l d b e ari n g  p ot e nti al   m ust  a gr e e t o  us e  a n  eff e cti v e   m et h o d  of  c o ntr a c e pti o n ( e. g., 
or al   c o ntr a c e pti v es,   d o u bl e -b arri er    m et h o ds  s u c h   as   a   c o n d o  m   a n d   a   di a p hr a g  m, 
i ntr a ut eri n e  d e vi c e) d uri n g t h e st u d y  a n d f or  9 0  d a ys f oll o  wi n g t h e l ast  d os e  of t h e st u d y 
m e di c  ati o n   or  t o   a bst ai n  fr o  m  s e x u al  i nt er c o urs e  f or  t his  ti  m e;   a    w o  m a n   n ot   of 
c hil d b e ari n g  p ot e nti al  is  o n e   w h o  h as  u n d er g o n e  bil at er al  o o p h or e ct o  mi es  or   w h o  is 
p ost-  m e n o p a us al,  d efi n e d  as  n o   m e nstr u al  p eri o ds f or  1 2  c o ns e c uti v e   m o nt hs. 
1 2)  P ati e nt   m ust  b e  a bl e t o  r e a d  a n d si g n t h e st u d y s p e cifi c i nf or  m e d  c o ns e nt  pri or t o st u d y 
e ntr y.  
 
4. 2. 2   E x cl usi o n   C rit e ri a   
1)    W ei g ht l oss  gr e at er t h a n  1 0  % i n t h e  pri or  4   w e e ks. 
2)    Pri or   m ali g n a n c y i n   w hi c h t h e y r e c ei v e d  a n y t h or a ci c r a di ot h er a p y  u nl ess t h e tr e ati n g 
p h ysi ci a n  c o nsi d ers  it  u nli k el y t o i  m p a ct t h e  cli ni c al  o ut c o  m e  of t h e  p ati e nt.  
3)    P ati e nts   wit h  c o n c urr e nt i n v asi v e   m ali g n a n c y   ot h er t h a n  n o n-m el a n o  m a s ki n  c a n c er 
or  c er vi c al i ntr a e pit h eli al  n e o pl asi a   u nl ess t h e tr e ati n g  p h ysi ci a n  c o nsi d ers it  u nli k el y 
t o i  m p a ct t h e  cli ni c al  out c o  m e  of t h e  p ati e nt . 
4)    A n  a cti v e i nf e cti o n  or   wit h  a f e v er  ≥  3 8. 5°  C   wit hi n  3  d a ys  of t h e first s c h e d ul e d  d a y 
of  d osi n g. 
5)    P o orl y  c o ntr oll e d  i nt er c urr e nt ill n ess es, s u c h  as; 
a)    u n c o ntr oll e d  h y p ert e nsi o n;   
b)    p o orl y  c o ntr oll e d  di a b et es    m ellit us,  d efi n e d  as  t h e  n e e d  f or  h os pit ali z ati o n  2  or 
m or e ti  m es i n t h e  pr e c e di n g  1 2   m o nt hs. 
c)    u nst a bl e  a n gi n a;  hist or y  of    m y o c ar di al  i nf ar cti o n  or  a c ut e  c or o n ar y  s y n dr o  m e 
wit hi n  6   m o nt hs  pri or t o st u d y  e ntr y;  
d)    hist or y  of  c o n g esti v e  h e art f ail ur e   wit hi n  6   m o nt hs  of st u d y  e ntr y ;  
e)    c ar di a c   arr h yt h  mi as  r e q uiri n g    m e di c al  t h er a p y  or  a  p a c e  m a k er;  c er e br o v as c ul ar 
e v e nts   wit hi n  6   m o nt hs  pri or t o st u d y  e ntr y;  
6)    P at ie nts  wit h  a    pri or t h or a c ot o  m y wit hi n   1  w e e k   of st u d y  r e gistr ati o n. 
7)    C hr o ni c   O bstr u cti v e  P ul  m o n ar y   Dis e as e   (  C  O  P  D )  e x a c er b ati o n   or  ot h er 
res pir at or y  ill n ess  r e q uiri n g  h os pit ali z ati o n  or  pr e cl u di n g st u d y t h er a p y wit hi n  3 0 
d a ys  b ef or e  st arti n g tr e at  m e nt. 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
3 2  
8)    P ati e nts   wit h  a n y  of t h e f oll o  wi n g  ar e  n ot  eli gi bl e;  
a)    Pr e vi o us  hist or y  of    Q T c  pr ol o n g ati o n  r es ulti n g  fr o  m    m e di c ati o n  t h at  r e q uir e d 
dis c o nti n u a ti o n  of t h at   m e di c ati o n;  
b)    C o n g e nit al l o n g   Q T s y n dr o  m e,  or  1 st d e gr e e r el ati v e   wit h  u n e x pl ai n e d s u d d e n  d e at h 
u n d er  4 0  y e ars  of  a g e;  
c)    Pr es e n c e  of l eft  b u n dl e  br a n c h  bl o c k ( L  B  B  B);  
d)    Q T c   wit h   Fri d eri ci a’s  c orr e cti o n t h at is  u n  m e as ur a bl e,  or  ≥  4 8 0   ms e c  o n s cr e e ni n g 
E  C  G.  T h e  a v er a g e   Q T c fr o  m t h e s cr e e ni n g  E  C  Gs ( c o  m pl et e d i n tri pli c at e)   m ust  b e 
<   4 8 0   ms e c i n  or d er f or t h e  p ati e nt t o  b e  eli gi bl e f or t h e st u d y;  
e)    S u bj e cts  t a ki n g  a n y  c o n c o  mit a nt    m e di c ati o n  t h at    m a y  c a us e    Q T c  pr ol o n g ati o n, 
i n d u c e  T ors a d es  d e  P oi nt es (s e e   A p p e n di x  2)  ar e  n ot  eli gi bl e if   Q T c  ≥  4 6 0   ms e c.   
9)    P ati e nts   m ust  n ot  h a v e  h a d  a  cli ni c all y si g nifi c a nt  c ar di a c  e v e nt s u c h  as   m y o c ar di al 
i nf ar cti o n (  wit hi n  6   m o nt hs  pri or t o t h e first  d os e  of t h e st u dy tr e at  m e nt); 
u n c o ntr oll e d/s y  m pt o  m ati c  c o n g esti v e  h e art f ail ur e (  N e  w   Y or k   H e art   Ass o ci ati o n 
(  N  Y  H  A)  cl assifi c ati o n  of  h e art  dis e as e,   Cl ass III  or I  V, s e e   A p p e n di x  3)   wit hi n  6 
m o nt hs  b ef or e  e ntr y;  or t h e  pr es e n c e  of  a n y  ot h er  u n c o ntr oll e d  c ar di o v as c ul ar 
c o n diti o ns ( h y p ert e nsi o n  or  arr h yt h  mi a,  u nst a bl e  a n gi n a  p e ct oris,  or s e v er e  v al v ul ar 
h e art  dis e as e,  et c.) t h at, i n t h e  o pi ni o n  of t h e I n v esti g at or, i n cr e as es t h e ris k  of 
v e ntri c ul ar  arr h yt h  mi a.  
1 0)  P ati e nts   wit h  a  hist or y  of  arr h yt h  mi a (  m ultif o c al  pr e  m at ur e  v e ntri c ul ar  c o ntr a cti o ns 
( P  V  Cs),  bi g e  mi n y, tri g e  mi n y,  v e ntri c ul ar t a c h y c ar di a,  or  u n c o ntr oll e d  atri al 
fi brill ati o n)   w hi c h is s y  m pt o  m ati c  or r e q uir es tr e at  m e nt (  C T  C  A E   Gr a d e  3)  or 
as y  m pt o  m ati c s ust ai n e d  v e ntri c ul ar t a c h y c ar di a  ar e  n ot  eli gi bl e.   P ati e nts   wit h  atri al 
fi brill ati o n   wit h   w ell-c o ntr oll e d  v e ntri c ul ar r at e  o n   m e di c ati o n,  ar e  eli gi bl e.  
1 1)  Ps y c hi atri c  c o n diti o ns, s o ci al sit u ati o ns  or s u bst a n c e  a b us e t h at  pr e cl u d es t h e  a bilit y 
of t h e s u bj e ct t o  c o o p er at e   wit h t h e r e q uir e  m e nts  of t h e tri al  a n d  pr ot o c ol t h er a p y 
1 2)  G  r a d e  2  or  hi g h er  p eri p h er al  n e ur o p at h y 
1 3)  K n o  w n  hist or y  of   HI  V  /  AI  D S,  h e p atitis   B  or   C.   Not e,   h o  w e v er, t h at HI  V   o r 
h e p atiti s  t esti n g is  n ot r e q uir e d f or e ntr y  i nt o t his  pr ot o c ol. T h e  n e e d  t o  e x cl u d e 
p ati e nts  wit h   AI  D S    or  h e p atitis   B  or   C fr o  m t his pr ot o c ol  is n e c ess ar y  b e c a us e  t h e 
tr e at  m e nts i n v ol v e d i n t his  pr ot o c ol m a y    b e si g nifi c a ntl y i  m  m u n os u p pr essi v e. 
Pr ot o c ol- s p e cifi c r e q uir e  m e nts m a y   als o  e x cl u d e  i  m  m u n o- c o  m pr o  mis e d  p ati e nts. 
1 4)  Pr e g n a n c y   or  w o  m e n    of   c hil d b e ari n g   p ot e nti al  a n d   m e n    w h o    ar e   s e x u all y  a cti v e  
a n d   n ot   willi n g/ a bl e   t o  us e  m e di c all y    a c c e pt a bl e   f or  ms  of  c o ntr a c e pti o n;  t his 
e x cl usi o n   is  n e c ess ar y  b e c a us e  t h e tr e at  m e nt i n v ol v e d i n t his st u d y   m a y  b e 
t er at o g e ni c. 
1 5)  W o  m e n   w h o  ar e  br e astf e e di n g  ar e  n ot  eli gi bl e f or t his st u d y. 
4. 3    
S u bj e ct  Wit h d r a  w al  a n d   R  e pl a c e  m e nt  
4. 3. 1   S u bj e ct   Wit h d r a  w al  
S u bj e ct r et e nti o n   will  b e  d et er  mi n e d  as t h e  n u  m b er  of s u bj e cts   w h o s u c c essf ull y  c o  m pl et e 
t h e  st u d y  pr ot o c ol  (t his  n u  m b er    will  i n cl u d e  s u bj e cts    w h o  h a v e  i n a d v ert e nt  pr ot o c ol 
d e vi ati o ns) .   S u bj e cts,   w h o  dr o p  o ut,  ar e l ost t o f oll o  w  u p,  or   w h o  n e e d t o  b e   wit h dr a  w n 
fr o  m t h e st u d y,   will  b e i d e ntifi e d  a n d t h e r e as o n   will  b e  c o d e d i n t h e  c as e r e p ort f or  m. 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
3 3  
4. 3. 2   S u bj e ct   R e pl a c e  m e nt  
S u bj e cts  t h at   pr es e nt    wit h   a n   u nr el at e d    m e di c al   c o n diti o n   ( e. g.   str o k e,    m y o c ar di al 
i nf ar cti o n) t h at is  n ot  attri b ut a bl e t o t h e i n v esti g ati o n al  dr u g   will  b e r e pl a c e d.  S u bj e cts t h at 
ar e  u n a bl e  or  u n  willi n g t o  c o  m pl et e  at l e ast  2   w e e ks  of  c o n c urr e nt  c h e  m or a di ati o n t h er a p y 
pl us t h e i n v esti g ati o n al  dr u g  of t h e  st u d y  pr ot o c ol   will  b e r e pl a c e d.  If t h es e  su bj e cts  h a v e 
c o  m pl et e d  t hr o u g h  t h e  BI  O  3 0 0  +    C h e  m o  P  K    visit ,  t h e  r e pl a c e  m e nt  s u bj e cts    will  b e 
assi g n e d t o t h e  n o n -P  K  s u b gr o u p.  A d diti o n al  s u bj e cts   will  b e  e nr oll e d  as  n e e d e d t o f ulfill 
d os e  es c al ati o n  crit eri a (s e e s e cti o n  5. 5   D os e  Es c al ati o n   Crit eri a).  
4. 3. 3   P ot e n ti al R e as o ns f o r  S  u bj e ct  A  tt riti o n 
F or  a n y s u bj e ct l e a vi n g t h e st u d y  e arl y, t h e fi n al st u d y   m e as ur e  m e nts   will  b e  p erf or  m e d  at 
t h e ti  m e  of  d e p art ur e ( or  as s h ortl y t h er e aft er  as  p ossi bl e). 
4. 3. 3. 1  D r u g  -R el at e d   R e as o ns   
1)    S u bj e ct  e x p eri e n c es  a n  a d v ers e r e a cti o n  a n d  d o es  n ot   wis h t o r e  m ai n i n t h e tri al.  
2)    S u bj e ct  e x p eri e n c es  a  s eri o us  a d v ers e  r e a cti o n  or  a  s p e cifi c  a d v ers e  r e a cti o n 
t h at  r e q uir es  dis c o nti n u ati o n  a c c or di n g  t o  t h e  pr ot o c ol  as  d et er  mi n e d  b y  t h e 
i n v esti g at or. 
3)    Cli ni c al tri al is t er  mi n at e d  pr e  m at ur el y  b e c  a us e  of  u n a c c e pt a bl e s af et y c o n c er ns 
(ris ks)  of t h e s u p pl e  m e nt  b ei n g t est e d. 
4. 3. 3. 2  Cli ni c al  -T ri al  -R el at e d   R e as o ns   
1)    S u bj e ct i n di c at es t h e r e q uir e  m e nts ar e t o o  o n er o us,  or t o o l o n g,  or l os es i nt er est; 
or r ef us es t o  p arti ci p at e.  
2)    Cli ni c al tri al is t er  mi n at e d  at  a  pr es et  d at e  a n d s o  m e s u bj e cts  ar e  n ot  c o  m pl et e d.  
4. 3. 3. 3  S u bj e ct -  R el at e d   R e as o ns   D et e r  mi n e d  b y t h e I n v esti g at o r 
1)    S u bj e ct f ails t o   m ai nt ai n  a d e q u at e  c o  m pli a n c e   wit h  o n e  or   m or e  as p e cts  of t h e 
pr ot o c ol  or s u bj e ct f ails t o  c o o p er at e  a d e q u at el y  d uri n g  cli n i c al  visits. 
2)    S u bj e ct f o u n d  n ot t o   m e et  or  n o l o n g er   m e ets t h e  ori gi n al  e ntr y r e q uir e  m e nts. 
3)    S u bj e ct  h as  us e d  a  n o n- a p pr o v e d   m e di ci n e  or tr e at  m e nt  d uri n g t h e tri al. 
4)    S u bj e ct  w h o  at t h e  I n v esti g at or’s  dis cr eti o n  f e els t h at  c o nti n ui n g i n t h e  st u d y 
w o ul d  n ot  b e   i n t h eir  b est i nt er est.  
5)    S u bj e ct  b e c o  m es  pr e g n a nt  ( o bs er v ati o n  a n d  f oll o  w -u p  pr o c e d ur es    m ust  b e 
i niti at e d). 
6)    S u bj e ct   wit h dr a  ws i nf or  m e d  c o ns e nt. 
4. 3. 3. 4  Ot h e r   R e as o ns   
1)    S u bj e ct r ef us es t o st at e r e as o ns f or  dr o p pi n g  o ut. 
2)    S u bj e ct  d e v el o ps  a n i nt er c urr e nt ill n ess  a n d is  u n a bl e  or  u n  willi n g t o  c o nti n u e 
i n  a  cli ni c al tri al;  h o  w e v er, I n v esti g at or  di d  n ot   wis h t o  dis c o nti n u e t h e s u bj e ct. 
3)    S u bj e ct’s  p ers o n al  sit u ati o n  c h a n g es:   e. g.  m or e   w or k  r es p o nsi bilit y/tr a v el  or 
h o  m e  c h a n g es (  m o v es,   m arri es, f a  mil y)  a n d s u bj e ct  h as  l ess ti  m e/  m oti v ati o n t o 
p arti ci p at e.  
4)    Ot h er iss u es r e q uiri n g   wit h dr a  w al  of t h e s u bj e ct fr o  m t h e tri al.   








P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
3 7  
•    Us e  of  c ar b o pl ati n i n  c o  m bi n ati o n   wit h  ot h er  b o n e   m arr o  w s u p pr essi n g t h er a pi es 
m ust  b e  c ar ef ull y   m a n a g e d   wit h r es p e ct t o  d os a g e  a n d ti  mi n g i n  or d er t o   mi ni  mi z e 
a d diti v e  eff e cts  
•    R e n al  eff e cts  of  n e p hr ot o xi c  c o  m p o u n ds   m a y  b e  p ot e nti at e d  b y  c ar b o pl ati n  
•    C o n c o  mit a nt tr e at  m e nt   wit h  a  mi n o gl y c osi d es  h as r es ult e d i n i n cr e as e d r e n al 
a n d/ or  a u di ol o gi c t o xi cit y,  a n d  c a uti o n   m ust  b e  e x e r cis e d   w h e n  a  p ati e nt r e c ei v es 
b ot h  dr u gs 
•    C ar b o pl ati n  c a n i n d u c e  e  m esis,   w hi c h  c a n  b e   m or e s e v er e i n  p ati e nts  pr e vi o usl y 
r e c ei vi n g  e  m et o g e ni c t h er a p y 
•    I n ci d e n c e  of  p eri p h er al  n e ur ot o xi cit y is i n cr e as e d i n  p ati e nts  ol d er t h a n  6 5  y e ars 
a n d i n  p ati e nts  pr e vi o u sl y tr e at e d   wit h  cis pl ati n  
•    I n cr e as e d ris k  of  all er gi c r e a cti o ns i n cl u di n g  a n a p h yl a xis i n  p ati e nts  pr e vi o usl y 
e x p os e d t o  pl ati n u  m t h er a p y ( pl ati ns).  
 
R ef er  t o  t h e   p a c k a g e  i ns ert  f or   d et ail e d   p h ar  m a c ol o gi c,   d osi n g,  st or a g e,   a n d  s af et y 
i nf or  m ati o n. 
6. 3   
R a di a  ti o n T  h e r a p y   
R a di ati o n   t h er a p y   will  b e gi n  d uri n g   w e e k  1  of t h e st u d y  a n d  aft er  a   mi ni  m u  m  of  2  d a ys  of 
BI  O  3 0 0  d osi n g.   T h e t y p e  of r a di ati o n t h er a p y  (3  D  C o nf or  m al  R a di ati o n  T h er a p y, I nt e nsit y 
M o d ul at e d  R a di ati o n  T h er a p y  or  Pr ot o n   B e a  m  R a di ati o n  T h er a p y)  wi  ll  b e at t h e  dis cr eti o n 
of t h e  tr e ati n g i n v esti g at or. P ati e nts   will  r e c ei v e   R T   tr e at  m e nt  5  d a ys  p er   w e ek, i n  o n c e 
d ail y  fr a cti o ns,   1. 8- 2. 0    G y  p er  fr a cti o n.    T h e  t ot al  d os e    will  b e  6 0 - 7 0  G y    (c o b alt    G y 
e q ui v al e nt  ( C  G E  ))  i n  3 0- 3 5  fr a cti o ns.   T h er e  ar e  t y pi c all y n o  fi el d  r e d u cti o ns.   All  fi el ds 
s h o ul d  b e tr e at e d  d ail y  a n d t h e  e ntir e  pl a n ni n g t ar g et  v ol u  m e  s h o ul d  b e tr e at e d  d ail y.   O n 
d a ys   w h e n  c h e  m ot h er a p y is  gi v e n  c o n c urr e ntl y   wit h   R T,  c h e  m ot h er a p y  s h o ul d i d e all y  b e 
a d  mi nist er e d  pri or t o   R T.  
 
6. 3. 1    A d v e rs e   E v e nt  s R e p o rt e d   wit h   R a di ati o n   T h e r a p y   
B  o n e    m arr o  w  t o xi cit y,  s ki n   pi g  m e nt ati o n,  es o p h a gitis   a n d   r a di ati o n   p n e u  m o nitis  ar e 
e x p e ct e d  si d e  eff e cts  of  r a di ati o n  t h er a p y.   R a di ati o n  i n d u c e d    m y o c ar ditis  or  tr a ns v ers e 
m y elitis r ar el y  o c c ur.   R a di o gr a p hi c  e vi d e n c e  of r a di ati o n  c h a n g e  a n d  s u bs e q u e nt fi br osis 
of t h e l u n g   will  o c c ur   wit hi n l u n g  v ol u  m e  of s o  m e  p ati e nts  r e c ei vi n g  ≥ 2 0   G y,  us u all y   wit hi n 
t h e  first  si x    m o nt hs  aft er  i niti ati o n   of  tr e at  m e nt;  t h e  i n ci d e n c e   of  r a di ati o n  i n d u c e d 
p n e u  m o nitis is  a b o ut  1 5 - 2 0  %.  It is  ess enti al t o  s p ar e  as   m u c h  n or  m al l u n g  as  p ossi bl e i n 
or d er t o  a v oi d s y  m pt o  m ati c l u n g i nj ur y. 
R  a d i ati o n  p n e u  m o nitis is  a l u n g t o xi cit y t h at is  a si d e  eff e ct  of  c h e  m or a di ot h er a p y f or l u n g 
c a n c er.  It  is  c h ar a ct eri z e d   b y   e d e  m a,   diff us e  al v e ol ar   d a  m a g e,   d es q u a  m ati o n   of  t h e 
c a pill ar y  e n d ot h eli u  m,  a n d  t h e  d e v el o p  m e nt  of  h y ali n e    m e  m br a n es.  S y  m pt o  ms  i n cl u d e 
s h ort n ess  of  br e at h,  c o u g h,  f ati g u e,  a n d  l oss  of  a p p etit e.    T h e  i n ci d e n c e  of  r a di ati o n 
p n e u  m o nitis  t y pi c all y   p e a ks   b et  w e e n   2   a n d   4    m o nt hs  f oll o  wi n g  t h e   c o  m pl eti o n   of  
r a di ot h er a p y.   T h e  l u n g    m a y  r e c o v er,  b ut  p n e u  m o nitis  i n cr e as es  t h e  ris k  of  d e v el o pi n g 
s u bs e q u e nt  p ul  m o n ar y  c o  m pli c ati o ns, i n cl u di n g  p er  m a n e nt s c ari n g  of t h e l u n gs (fi br osis). 
A    C T  s c a n  is  us e d  t o  d et e ct  t his  t y p e  of  r a di ati o n  -i n d u c e d  l u n g  i nj ur y.    C o  m  m o n    C T 




P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
3 9  
6. 4   
C o n c o  mit a nt   T h e r a pi es  a n d   M e di c ati o ns   
T h o u g h  n o  d at a  h a v e s h o  w n t h at  a n y  c o n c o  mit a nt   m e di c ati o ns   will i nt erf er e   wit h   BI  O  3 0 0 
Or al  S us p e nsi o n, it is  a d vis a bl e t h at  p ati e nts  n ot t a k e  a n y  ot h er   m e di c ati o n(s)  1  h o ur  b ef or e 
or  aft er  a  d os e  of  BI  O  3 0 0   Or al  S us p e nsi o n.  C o n c o  mit a nt   m e di c ati o ns   will  b e  c oll e ct e d f or 
all  s u bj e cts  fr o  m  t h e  s cr e e ni n g  visit   t hr o u g h  c o ns oli d ati o n  c h e  m ot h er a p y.  P ati e nts  o n 
c o n c o  mit a nt  m e di c ati o ns   (s e e   A p p e n di x  2) t h at   m a y  pr ol o n g Q T c   ar e   pr o hi bit e d if   Q T c  ≥ 
4 6 0  ms e c.    
 
C o  -a d  mi nistr ati o n  of  dr u gs  t h at  i n  s o  m e  r e p orts    mi g ht  b e  ass o ci at e d    wit h   T ors a d es  d e 
P oi nt es,  b ut  at  t his  ti  m e  l a c k  s u bst a nti al  e vi d e n c e,  s h o ul d  b e  a v oi d e d  if  p ossi bl e  (s e e 
A p p e n di x  2).    H o  w e v er, t h es e  dr u gs   will  b e  all o  w e d,  at t h e  dis cr eti o n  of t h e i n v esti g at or, 
if  c o nsi d er e d  a bs ol ut el y  n e c ess ar y.  I n  s u c h  c as es, t h e  p ati e nt   m ust  b e  cl os el y   m o nit or e d 
i n cl u di n g  r e g ul ar  c h e c ks  of   Q T c  a n d  el e ctr ol yt es.   T h e   E  C  G   m ust  b e  c h e c k e d   wit hi n  2 4 
h o urs  of  c o  m  m e n ci n g t h e  c o n c o  mit a nt   m e di c ati o n  a n d t h e n  at l e ast  o n c e  p er   w e e k   w hil e 
t h e  p ati e nt r e  m ai ns  o n t h e   m e di c ati o n.   T h e fr e q u e n c y  of  E  C  G   m o nit ori n g  c o ul d r e v ert t o 
t h e st a n d ar d s c h e d ul e if  n o  E  C  G  pr ol o n g ati o n  h as  b e e n  n ot e d  d uri n g t h e first t  w o ( 2) w e e ks 
of  c o -a d  mi nistr ati o n  of  a  dr u g  t h at    m a y  c a us e    Q T c  pr ol o n g ati o n  (s e e    A p p e n di x  2).    
El e ctr ol yt es s h o ul d  b e   m ai nt ai n e d   wit hi n t h e  n or  m al r a n g e  usi n g s u p pl e  m e nts if  n e c ess ar y.   
  
P er  mitt e d s u p p orti v e t h er a p y 
All  s u p p orti v e t h er a p y  f or  o pti  m al   m e di c al  c ar e   will  b e  gi v e n  d uri n g t h e  st u d y  p eri o 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(s)    wit hi n  t h e  p ar a  m et ers  of  t h e  pr ot o c ol  a n d 
d o c u  m e nt e d  o n  e a c h sit e’s s o ur c e  d o c u  m e nts  as  c o n c o  mit a nt   m e di c ati o n. 
 
N a us e a,  v o  miti n g  or  b ot h   m a y  b e  c o ntr oll e d   wit h  a nti e  m eti c t h er a p y.   5  H T  -3  a nt a g o nists 
m a y  pr ol o n g    Q T c  i nt er v al  ris k    wi  t h  t h e  us e  of    O n d a ns etr o n.    I n cr e as e d    m o nit ori n g  is 
s u g g est e d. 
 
T h er a pi es  n ot  p er  mitt e d  
W  B  C  gr o  wt h f a ct ors (  G  -C S F/  G  M  -C S F)   will  n ot  b e  p er  mitt e d  d uri n g r a di ati o n. If  a  p ati e nt 
r e c ei v es   W  B  C  gr o  wt h f a ct ors  d uri n g r a di ati o n, t his  c o nstit ut es  a   m aj or  pr ot o c ol  vi ol ati o n. 
W  B  C  gr o  wt h f a ct ors   m a y  b e  us e d  d uri n g  c o ns oli d ati o n  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  g ui d eli n es,  b ut  s h o ul d  n ot  b e  gi v e n  pr o p h yl a cti c all y.  Er yt hr o p oi eti n   m a y  b e  gi v e n 
at t h e tr e ati n g  p h ysi ci a n’s  dis cr eti o n i n  a c c or d a n c e   wit h  a c c e pt e d  g ui d eli n es.  
Hi g h  d os es  of  gl u c o c orti c oi ds  ( e. g.,   >   2 0    m g  of  Pr e d nis o n e/ d a y  or  e q ui v al e n c e)  a n d 
i  m  m u n os u p pr ess a nts s h o ul d  n ot  b e  us e d. 
 
I  m  m u n ot h er a p y 
I  m  m u n ot h er a pi es (e. g .,  d ur v al u  m a b, p e  m br oli z u  m a b  or  ni v ol u  m a b ) m a y  b e i nit at e d  aft er 
t h e  c o  m pl eti o n  of  c o n c urr e nt  ch e  m or a di ot h er a p y  at t h e  dis cr eti o n  of t h e  tr e ati n g  p h ysi ci a n.  
I  m  m u n ot h er a p e uti cs    will  b e  n ot  b e  c oll e ct e d  o n  t h e   C o nc o  mit a nt    M e di c ati o n   C  R F  b ut 
i nst e a d   will  b e  d o c u  m e nt e d s e p ar at el y  o n t h e I  m  m u n ot h er p y  C  R F.    D at a fr o  m t h e  C  R F   will 
b e  v erifi e d  a g ai nst t h e  s u bje ct   m e di c al  c h art f or  a c c ur a c y.   
 
S o y  pr o d u cts, s u p pl e  m e nts,  a n d  di et 






P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
4 2  
dR a di ati  o n  t h er a p y s ho ul d  c o nti n u e  t o  b e d eli v er e d  f or  ≤  Gr a d e    3  no n - he  m at o l o gi c t o xi citi es i n or  o uts id e 
t h e r a di atio n  tr e at  me nt  fi el d. R T   s ho ul d   b e h el d  f or  all   Gr ad e  4  n o n- h e  m at ol o gi c  to xi cit y  a n d r es u  m e d  o nl y 
w h  e n t o xi cit y is  ≤  Gr a d e  2.   
 
 
 




P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
4 4  
6. 5. 1. 4   C a r b o pl ati n  D os e     M odifi c at i o ns f o r R e  n al   T o xi cit y 
A  >  1 0  %  c h a n g e i n s er u  m  cr e ati ni n e,  b as e d  o n   w e e kl y  c al c ul at e d  cr e ati ni n e  cl e ar a n c e,   will 
w arr a nt  a r e c al c ul ati o n  of t h e  c ar b o pl ati n  d os e. 
6. 5. 1. 5  P a clit a x el  f o r N e  u r o p at h y  
If p a clit a x el   d os es    m ust  b e  wit h h el d   f or gr e at er   t h a n t  w o  c o ns e c uti v e  w e e ks,    t h e  dr u g  
will    b e  h el d  p er  ma n e ntl y f or t h e  d ur ati o n  of  c o n c urr e nt t h er a p y.  
 
If t h er e is  a  de cli n e  i n E  C  O  G   p erf orm a  n c e  st atus  t o gr e at er t h a n  or  e q u al t o   2 f or gr e a ter  
t ha n  2   w e e ks  w hil e    u nd er tr e at  m e nt,  R T    s h o ul d  b e h el d  wit h    n o  f urt h er  c h e  m ot h er ap y  
a d mi nist  e r e d  (  A p p e n di x   6).   R e  -e v al u at e    pati e nt   aft er   o n e    w e e k   f or   r es u  m pti o n   of 
r a di ot h er a p y. 
6. 5. 1. 6   C a r b o pl ati n f o r  N e  u r o p at h y  
D uri n g  c o n c urr e nt  c h e  m or a di ati o n t h er a p y  c ar b o pl ati n  d osi n g   will  b e   m ai nt ai n e d.   Of t h e 
r o uti n el y  us e d  c h e  m ot h er a p e uti cs,  c ar b o pl ati n  is  g e n er all y  c o nsi d er e d  t o  p oss ess  l o  w 
n e ur ot o xi cit y.  Gr a d e   3  p eri p h er al  n e ur o p at h y is  n ot  us u all y  ass o ci at e d   wit h  c ar b o pl ati n, 
b ut r at h er t h e   m or e t o xi c  c h e  m ot h er a p e uti c  p a clit a x el.  
6. 5. 2     D os e   M o difi c ati o ns   D u ri n g   C o ns o li d ati o n   C h e  m ot h e r a p y  
T o   be gi n  c o ns oli d ati o n  c h e m ot h er a p y,    all  pr e vi o us t o xi citi es i ncl u d i ng  n e ur o p at h y    m ust 
h a v e r es ol v e d t o  <  gr a d e  2,   C T  C  A E,  v 4. 0 3. 
 
 






P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
4 7  
6. 5. 5     C a r b o pl ati n f o r  N e  u r o p at h y  
D uri n g  c o ns oli d ati o n t h er a p y  c ar b o pl ati n  d osi n g   will  b e   m ai nt ai n e d.   Of t h e r o uti n el y  us e d 
c h e  m ot h er a p e uti cs, c ar b o pl ati n is  g e n er all y c o nsi d er e d t o  p oss ess l o  w  n e ur ot o xi cit y.  Gr a d e 
3  p eri p h er al  n e ur o p at h y is  n ot  us u all y  ass o ci at e d   wit h c ar b o pl ati n,  b ut  r at h er t h e   m or e t o xi c 
c h e  m ot h er a p e uti c  p a clit a x el.  
 
6. 5. 6   M a n a g e  m e nt  of   Q  T c  p r ol o n g ati o n 
P ati e nts   will  h a v e  E  C  Gs  p erf or  m e d t o   m o nit or   Q T c i nt er v al  usi n g  Fri d eri ci a’s  c orr e cti o n.   
 
F or t his  st u d y,   Q T c  pr ol o n g ati o n is  d efi n e d  as:   A  si n gl e   Q T c i nt er v al  of  ≥  4 8 0   ms e c.  T h e 
Q T c  pr ol o n g ati o n t hr es h ol d f or  h ol di n g   BI  O  3 0 0  h as  b e e n  d efi n e d  as  a   Q T c i nt er v al  of  
≥   5 0 0   ms e c or  a n i n cr e as e  of  >  6 0   ms e c fr o  m  b as eli n e.  
 
T h e  b as eli n e   will  b e t h e  a v er a g e  of t h e s cr e e ni n g  d a y  a n d t h e  pr e  -BI  O  3 0 0   Or al  S us p e nsi o n 
d os e   Q T c i nt er v al  v al u es.  
6. 5. 6. 1   A b n o r  m al   Q  T c i nt e r v al  of  ≥  5 0 0   ms e c  o r  b as eli n e  c h a n g e  of  >  6 0   ms e c 
If t h e   Q T c i nt er v al is ≥  5 0 0   ms e c  or  a n i n cr e as e  of  >  6 0   ms e c  fr o  m  b as eli n e is  o bs er v e d, 
BI  O  3 0 0   will  b e  h el d  a n d  c o n c o  mit a nt   m e di c ati o ns s h o ul d  b e r e  -i ns p e ct e d.   A n y m e di c ati o n 
t h at  c o ul d  c o ntri b ut e t o   Q T c  pr ol o n g ati o n  s h o ul d  b e i d e ntifi e d  a n d r e  m o v e d  as  cli ni c all y 
i n di c at e d.  
 
S er u  m  p ot assi u  m a n d   m a g n esi u  m l e v els s h o ul d  b e c h e c k e d.    A g gr essi v e r e pl a c e  m e nt eit h er 
t hr o u g h  I  V  or  P  O  s h o ul d  b e  att e  m pt e d t o   m ai nt ai n  a l e v el  of  p ot assi u  m  ≥  4. 0   m  m ol/ d L 
a n d/ or   m a g n esi u  m  ≥  2. 0   m g/ d L.  E  C  Gs  a n d  el e ctr ol yt es s h o ul d  b e f oll o  w e d  3 ti  m es  a   w e e k 
u ntil   Q T c i nt er v al f alls  b el o  w  4 8 0   ms e c.    
 
Aft er t h e   Q T c i nt er v al r e c o v ers t o   <  4 8 0   ms e c  or r et ur ns t o   wit hi n  6 0   ms e c  of  b as eli n e  a n d 
f oll o  wi n g r e vi e  w  of t h e  d at a  a n d  c o ns ult ati o n   wit h t h e   m e di c al   m o nit or,  a  d e cisi o n  h o  w t o 
pr o c e e d   wit h   BI  O  3 0 0  d osi n g   will  b e  d et er  mi n e d.  If   BI  O  3 0 0 is  r est art e d  aft er t h e   Q T c 
pr ol o n g ati o n  h as  r es ol v e d,    E  C  Gs  s h o ul d  b e  p erf or  m e d    w e e kl y.    If    BI  O  3 0 0    m ust  b e 
wit h h e  l d f or >  3   w e e ks t o  all o  w f or   Q T c  pr ol o n g ati o n t o r e c o v er t o  <  4 8 0   ms e c  or  b as eli n e, 
t h e  p ati e nt   will  n ot  b e r est art e d  o n t h e st u d y   m e di c ati o n.  
6. 5. 6. 2   A b n o r  m al   Q  T c i nt e r v al  of  4 8 0- 4 9 9   ms e c 
If t h e   Q T c i nt er v al is  4 8 0 -  4 9 9   ms e c,   BI  O  3 0 0 s h o ul d  b e  c o nti n u e d  al o n g   wit h  el e ctr ol yt e 
r e pl a c e  m e nt  as i n di c at e d  b ut  a r e p e at  E  C  G    m ust  b e  o bt ai n e d   wit hi n  4 8  h o urs.  If t h e E  C  G 
r e  m ai ns a b n or  m al it   will  b e  r e p e ate d t  wi c e,  5   mi n ut es  a p art . If t h e   Q T c i nt er v al is <   4 8 0 
ms e c t h e  p ati e nt   will  c o nti n u e tr e at  m e nt  a n d r es u  m e t  h e  E  C  G  s c h e d ul e  as  o utli n e d i n t h e 
S c h e d ul e  of   Ass ess  m e nts (s e e  T a bl e  7. 1. 1). If t h e   Q T c  i nt er v al is  ≥  4 8 0   ms e c,  BI  O  3 0 0   will 
b e  h el d  a n d  t h e  pr o c ess  f or    m o nit ori n g  a n  a b n or  m al   Q T c  i nt er v al  d es cri b e d  i n  s e cti o n 
6. 5. 6. 1   will  b e f oll o  w e d.  
 
 
 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
4 8  
 
Fi g u r e  6. 5. 6. 1   M a n a g e  m e nt  of   Q  T c  p r ol o n g ati o n  o r  a b n o r  miti es   
 
 
6. 5. 7   D os e   M o difi c ati o n  d u e t o   G ast r oi n t esti n al (  GI)   T o xi cit y 
N a us e a,   v o  miti n g,   or   b ot h     m a y   b e   c o ntr oll e d     wit h   a nti e  m eti c   t h er a p y.       R o uti n e 
pr e  m e di c ati o n    f or    c h e  m ot h er a p y    i n    a c c or d a n c e    t o    st a n d ar ds    is    r e c o  m  m e n d e d.  
S y  m pt o  m ati c  p ati e nts  s h o ul d  pr o -a cti v el y  b e tr e at e d   wit h  st a n d ar d  a nti n a us e a/ a nt i e  m eti c 
t h er a p y  as  n e c ess ar y  t o  pr e v e nt  d os e    m o difi c ati o n  or  i nt err u pti o n.      H o  w e v er,  5  H T- 3 
a nt a g o nists   m a y  pr ol o n g   Q T c i nt er v al ris k   wit h  us e  of   O n d a ns etr o n.  I n cr e as e d   m o nit ori n g 
is s u g g est e d. 
 
 
7. 0      S  C  H  E  D  U  L  E   O F   A S S  E S S  M  E  N  T S  
7. 1   
Ti  m e t o   E v e nt   
T h e  Ti  m e t o  E v e nt t a bl e ( T a bl e  7. 1. 1  f or  n o n s ur gi c al s u bj e cts a n d  T a bl e  7. 1. 2 f or c a n di d at e  
s ur gi c al  s u bj e cts ) is  a  r ef er e n c e  of   w h at  st u d y  ass ess  m e nts  n e e d t o  b e  c o  m pl et e d  at  e a c h 
s p e cifi e d  visit.  A    w e e k  is  d efi n e d  as  5  c o ns e c uti v e  b usi n ess  d a ys  e. g.,    W e d n es d a y, 
T h urs d a y,  Fri d a y,   M o n d a y,  T u es d a y.  S e e  T a bl e  7. 1. 3 f or  visit   wi n d o  w  d es cri pti o ns. 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
4 9  
T a bl e  7. 1. 1   Ti  m e t o   E v e nt   f o r  n o n s u r gi c al s u bj e cts 
VI SI  T  #   
1   
2   
3 
4 -
5 a 
6 -
1 0  
1 1 -
3 5 9 
S e   3 6    3 7    3 8    3 9    4 0    4 1    4 2  
P r o c e d u r e  
S cr e e ni n g  
W e e k  1,  d 1   
W e e k  1,  d 2   
W e e k  1,  d 3  - 4a 
W e e k  2   
W ks   3- 6 
D a y  5 9   
D a y  6 6   
D a y  8 7   
P ost  R T   C o  m pl eti o n   
3   m o  
6   m o  
9   m o  
1 1   m o  
1 3  m o   
I nf or  m e d   C o ns e nt 
X   
 
 
   
 
 
   
   
 
   
   
   
   
 
R e vi e  w I/ E   Crit eri a   
X   
X 
 
   
 
 
   
   
 
   
   
   
   
 
M e di c al   Hist or y   
X   
 
 
   
 
 
   
   
 
   
   
   
   
 
P h ysi c al  E x a  m 1  
X 
X b  
X b  
X b  
X   
X  
X  
X   
X  
X 
 
X  
E  C  O  G  S c or e  
X 
X b  
X b    
X b  
X   
X   
X   
X   
X   
X   
   
X 
Vit al  Si g ns  
X 
X b  
X b    
X b  
X   
X   
X   
X   
X   
X   
   
X 
W ei g ht   
X 
X b  
X b    
X b  
X   
X   
X   
X   
X   
X   
   
X 
H ei g ht   
X   
 
 
   
 
 
   
   
 
   
   
   
   
 
E  C  G  
X 2  
X 3  
 
 
X 4 b  
X 4 c 
   
   
 
   
   
   
   
 
C  B  C  
X   
X 
 
 
X b    
X b  
   
X   
X   
X   
 
   
 
 
S er u  m   C h e  mistr y 5 
X   
X 
 
 
X b    
X b  
   
X   
X   
X   
 
   
 
 
Uri n al ysis 6 
X   
 
 
   
   
   
   
   
   
   
 
   
 
 
Pr e g n a n c y  T est 7 
X   
X 
 
   
   
   
   
   
   
   
 
   
 
 
E xt e nt  of   Dis e a s e  
X   
 
 
   
 
X d  
X   
   
X   
X   
X   
X   
X   
X 
P  K s a  m pli n g  
   
X  
X 
X f 
X  
X b  
   
   
 
   
   
   
   
 
P  D s a  m pli n g  
   
X  
 
X f 
X  
X b  
   
   
X   
X   
X 
   
   
 
BI  O  3 0 0   A d  mi n.   
   
X  
X   
X   
X   
X   
   
   
   
   
 
   
 
 
C o n c urr e nt 
C h e  m ot h er a p y  
   
 
X b    
X b    
X b  
   
   
   
   
 
   
 
 
R a di ati o n  T h er a p y   
   
 
 
X   
X   
X   
   
   
   
   
 
   
 
 
C o ns oli d ati o n 
C h e  m ot h e  r a p y 
   
 
 
   
   
   
   
X   
X   
   
 
   
 
 
A d v ers e  E v e nts 1 0  
   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
   
X 
C o n c o  mit a nt 
M e di c ati o ns   
X 
X b  
X b    
X b  
X   
X   
X   
   
   
   
   
 
Q o L   M e as ur es   
X   
 
 
   
   
   
   
   
   
X   
X   
   
   
X 
P ul  m o n ar y   F u n cti o n 
T est  
X   
 
 
   
   
   
X   
   
   
   
X   
   
   
X 
Di a g.   C T  S c a n   
X   
 
 
   
   
   
X   
   
   
X   
X   
   
X   
 
4  D -C T  S c a n   
X   
 
 
   
 
X d  
   
   
X   
   
 
X   
 
X 
S  w all o  wi n g   Di ar y  
X 
X b  
X b    
X b  
   
   
   
X   
X 
   
 
 
Di et   C o u ns eli n g 8 
X 
X b  
X b    
X b  
   
   
   
   
 
   
 
 
aO pti o n al  visit  5 b   as  n e e d e d,   bw e e kl y, cbi -w e e kl y   ( e v er y  ot h er   w e e k), dvisit  2 0  o nl y;  visit   wi n d o  w  all o  w a n c e 
of  +/ - 7  d a ys , eO pti o n al   s ur gi c al  e v al u ati o n, if s u bj e ct is   m e di c all y fit f or  s ur g er y us e t a bl e  7. 1. 2 , f BI  O 3 0 0 
+ c h e  m o  P  K s c h e d uli n g  all o  w e d   w e e k  1  or  2,  S e e  T a bl e  7. 1. 3 f or  d et ails  
 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
5 0  
T a bl e  7. 1. 2   Ti  m e t o   E v e nt f o r s u r gi c al s u bj e cts   
VI SI  T  #   
1   
2   
3 
4 -
5 a 
6 -
1 0  
1 1 -
3 5 9 
S   
3 6    
3 7    
3 8    
3 9    
4 0    
4 1  
P r o c e d u r e  
S cr e e ni n g  
W e e k  1,  d 1   
W e e k  1,  d 2   
W e e k   1,  d 3 - 4a 
W e e k  2   
W ks   3- 6 
D a y  5 9   
6- 1 2   w k  p ost -
s ur g er y 
1 0 -1 6   w k 
p ost -s ur g er y 
P ost  C o ns oli d ati o n   
3   m o  
6   m o  
9   m o  
1 2  m o   
I nf or  m e d   C o ns e nt 
X   
 
 
   
 
 
   
   
 
   
   
   
 
R e vi e  w I/ E   Crit eri a   
X   
X 
 
   
 
 
   
   
 
   
   
   
 
M e di c al   Hist or y   
X   
 
 
   
 
 
   
   
 
   
   
   
 
P h ysi c al  E x a  m 1  
X 
X b  
X b  
X b  
X   
X  
X  
X   
X  
X   
X  
E  C  O  G  S c or e  
X 
X b  
X b    
X b  
X   
X   
X   
X   
X   
X   
X 
Vit al  Si g ns  
X 
X b  
X b    
X b  
X   
X   
X   
X   
X   
X   
X 
W ei g ht   
X 
X b  
X b    
X b  
X   
X   
X   
X   
X   
X   
X 
H ei g ht   
X   
 
 
   
 
 
   
   
 
   
   
   
 
E  C  G  
X 2  
X 3  
 
 
X 4 b  
X 4 c 
   
   
 
   
   
   
 
C  B  C  
X   
X 
 
 
X b    
X b  
   
X   
X   
X   
 
 
 
S er u  m   C h e  mistr y 5 
X   
X 
 
 
X b    
X b  
   
X   
X   
X   
 
 
 
Uri n al ysis 6 
X   
 
 
   
   
   
   
   
   
   
 
 
 
Pr e g n a n c y  T est 7 
X   
X 
 
   
   
   
   
   
   
   
 
 
 
E xt e nt  of   Dis e a s e  
X   
 
 
   
 
X d  
X    
   
   
X   
X   
X   
X 
P  K s a  m pli n g  
   
X  
X 
X f 
X  
X b  
   
   
 
   
   
   
 
P  D s a  m pli n g  
   
X  
 
X f 
X  
X b  
   
   
X   
X   
X 
   
 
BI  O  3 0 0   A d  mi n.   
   
X  
X   
X   
X   
X   
   
   
   
 
 
 
 
C o n c urr e nt 
C h e  m ot h er a p y  
   
 
X b    
X b    
X b  
   
   
   
   
 
 
 
R a di ati o n  T h er a p y   
   
 
 
X   
X   
X   
   
   
   
   
 
 
 
C o ns oli d ati o n 
C h e  m ot h er a p y   
   
 
 
   
   
   
   
X   
X   
   
 
 
 
A d v ers e  E v e nts 1 0 
   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
 
C o n c o  mit a nt 
M e di c ati o ns   
X 
X b  
X b    
X b  
X   
X   
X   
   
   
   
 
Q o L   M e as ur es   
X   
 
 
   
   
   
   
   
   
X   
X   
   
X 
P ul  m o n ar y 
F u n cti o n  T est  
X   
 
 
   
   
   
X   
   
   
   
X   
   
X 
Di a g.   C T  S c a n   
X   
 
 
   
   
   
X   
   
   
X   
X   
X   
X 
4  D -C T  S c a n   
X   
 
 
   
   
   
   
   
   
   
 
 
 
S  w all o  wi n g   Di ar y  
X 
X b  
X b    
X b  
   
   
   
X   
X 
 
 
Di et   C o u ns eli n g 8 
X 
X b  
X b    
X b  
   
   
   
   
 
 
 
aO pti o n al  visit  5 b   as  n e e d e d,   bw e e kl y, cbi -w e e kl y   ( e v er y  ot h er   w e e k), dvisit  2 0  o nl y;  visit   wi n d o  w  all o  w a n c e 
of  +/ - 7  d a ys , f BI  O 3 0 0  + c  h e  m o  P  K s c h e d uli n g  all o  w e d   w e e k  1  o r  2,  S e e  T a bl e  7. 1. 3 f or  d et ails 
 
 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
5 1  
D es c ri pti o n  of s c h e d ul e  of  ass ess  m e nts   
1.    A  c o  m pl et e  p h ysi c al  e x a  m   will  b e  c o  m pl et e d  at s cr e e ni n g.   Ot h er  visits r e q uir e  a 
bri ef  e x a  m, f o c us  o n  ar e as  of t u  m or i n v ol v e  m e nt  or r ef er a bl e t o  a d v ers e  e v e nts. 
2.    E  C  Gs   will  b e  p erf or  m e d  i n tri pli c at e. E a c h r e a di n g   will  b e s e p ar at e d  b y  5 
mi n ut es.  
3.    E  C  G is  utili z e d t o  ass ess  a c ut e  c h a n g es t h at   m a y i  m p a ct  c ar di a c t o xi cit y.   E  C  Gs t o 
b e  o bt ai n e d j ust  pri or t o  a d  mi nistr ati o n  of   BI  O  3 0 0,  a n d  1  h o ur  p ost 
a d  mi nistr ati o n  of   BI  O  3 0 0.  
4.    E  C  G  d at a   will  b e  c oll e ct e d  pri or t o   BI  O  3 0 0  or  c h e  m ot h er a p y  a d  mi nistr ati o n, 
w hi c h e v er  c o  m es first  .  
5.    T o i n cl u d e s o di u  m,  p ot assi u  m,  c hl ori d e,  bi c ar b o n at e,   B  U  N,  cr e ati ni n e,  gl u c os e, 
A S T,   A L T,  al k ali n e  p h os p h at as e, t ot al  bilir u bi n,  al b u  mi n, t ot al  pr ot ei n, 
m a g n esi u  m,  c al ci u  m,    p h os p h or o us  a n d  uri c  a ci d.   A n al ysis  of  p a n cr e ati c  e n z y  m es 
als o t o  b e i n cl u d e d i n  p a n el ( a  m yl as e  a n d li p as e). 
6.    Uri n al ysis t o i n cl u d e  p  H, s p e cifi c  gr a vit y,  di psti c k  d et er  mi n ati o ns  of  gl u c os e, 
k et o n es,  pr ot ei n,  h e  m o gl o bi n,  bilir u bi n. 
7.    Pr e g n a n c y t est   m a y  b e  uri n e  or s er u  m  d et er  mi n ati o n  of  β- H  C  G.   Visit  2 t est is  o nl y 
r e q uir e d if t h e s cr e e ni n g  pr e g n a n c y t est   w as  p erf or  m e d   m or e t h a n  7 2  h o urs  pri or 
t o  visit  2. 
8.    At t h e s cr e e ni n g  visit  p ati e nts   will  b e   c o u ns el e d  a n d  gi v e n i nstr u cti o ns  o n  a  di et 
l o  w i n s o y is ofl a v o n es.    Di et  c o u ns eli n g   will  o c c ur   w e e kl y  d uri n g t h e ti  m e  p eri o d 
w h er e   BI  O  3 0 0 is  a d  mi nist er e d  usi n g t h e i nf or  m ati o n  pr o vi d e d i n   A p p e n di x  8, 
S o y   Ri c h  F o o ds.   
9.    T h e t ot al  n u  m b er  of s u bj e ct  visits  c o  m pl et e d t hr o u g h  c o n c urr e nt 
c h e  m or a di ot h er a p y  ar e fl e xi bl e  a n d  d e p e n d e nt  o n r a di ot h er a p y  a n d  c h e  m ot h er a p y 
s c h e d uli n g.  E a c h s u bj e ct   will  h a v e  a  mi ni  m u  m  of   3 2  visits t hr o u g h t h e  c o n cl usi o n 
of  c o n c urr e nt  c h e  m or a di ot h er a p y ( a p pr o xi  m at el y   6- 7   w e e ks  of  c h e  m ot h er a p y  a n d 
d ail y   R T fr a cti o n s of  1. 8- 2. 0   G y, t ot al  d os e  of  6 0- 7 0  G y)  . 
1 0.  A  ll  a d v ers e  e v e nts   will  b e  c oll e ct e d fr o  m t h e ti  m e t h e s u bj e ct si g ns i nf or  m e d 
c o ns e nt  u ntil  3 0  d a ys  aft er  t h e l ast  a d  mi nistr ati o n  of   BI  O  3 0 0.  Aft er t his ti  m e  ,  
a d v ers e  e v e nt  ass ess  m e nt   will  o c c ur  at  e a c h  visit   b ut  o nl y t h os e  e v e nts t h at  ar e 
c o nsi d er e d s eri o us  a n d  p ossi bl y,  pr o b a bl y  or  d efi nit el y r el at e d t o   BI  O  3 0 0   will  b e 
d o c u  m e nt e d  a n d  r e p ort e d t o t h e s p o ns or   wit hi n  2 4  h o urs  of  a  w ar e n ess (s e e 
s e cti o n  8. 0  S af et y   R e p orti n g f or  d et ails).  
 
 
 
 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
5 2  
T a bl e  7. 1.  3  Visit   Wi n d o  w   T a bl e   
Visit  o r 
P r o c e d u r e  
Visit   Wi n d o  w   
N o  t es 
S cr e e ni n g   Visit    
Wit hi n  2 8 d  pri or t o r e gistr ati o n.
 
P ul  m o n ar y  F u n cti o n 
T est ,   M e di c al   Hist or y, 
P h ysi c al  E x a  m  a n d 
C T s   m a y  b e  c o  m pl et e d 
w  it hi n  10  w ks  pri or   t o 
r e gistr ati o n 
C o n c urr e nt 
C h e  m ot h er a p y   
D a y  1  of  c  h e  m ot h er a p y   m a y  b e s c h e d ul e d  at t h e 
dis cr eti o n  of  t h e i n v esti g at or  pr o vi d e d t h e s u bj e ct  h as 
c o  m pl et e d  a   mi ni  m u  m  of  1  d a ys  of   BI  O  3 0 0  d osi n g . 
S h o ul d  visit s b e 
d el a y e d  d u e t o  a 
h oli d a y, st a n d ar d  of 
c ar e s h o ul d  b e 
f oll o  w e d. 
R a di ati o n 
T h er a p y  
D a y  1  of r a di ati o n t h er a p y   m a y  b e s c h e d ul e d  at t h e 
dis cr eti o n  of  t h e i n v esti g at or  pr o vi d e d t h e s u bj e ct  h as 
c o  m pl et e d  a   mi ni  m u  m  of  2  d a y  of   BI  O  3 0 0  d osi n g . 
S h o ul d  visit s b e 
d el a y e d  d u e t o  a 
h oli d a y, st a n d ar d  of 
c ar e s h o ul d  b e 
f oll o  w e d. 
BI  O  3 0 0  + 
C h e  m o  P  K   
BI  O  3 0 0  +   C h e  m o  p h ar  m a c o ki n eti c s   m a y  b e s c h e d ul e d 
w e e k  1  or   w e e k  2   at t h e  dis cr eti o n  of t h e i n v esti g at or 
pr o vi d e d  t h e s u bj e ct  h as  c o  m pl et e d  at l e ast 4  d a ys  a n d  n o 
m or e t h a n   9  d a ys  of   BI  O  3 0 0  d osi n g . 
 
P  K s a  m pli n g  
F or t h e  pr e -BI  O  3 0 0  a d  mi nistr ati o n ti  m e  p oi nt  a n d t h e  0. 5 
a n d  1  h o ur ti  m e  p oi nts,  bl o o d   will  b e  c oll e ct e d   wit hi n  ±  5 
mi n ut e s  of t h e  d efi n e d  dr a  w ti  m e  p ost   BI  O  3 0 0  d osi n g. 
F or t h e  2,  3,  4  a n d  8  h o ur ti  m e  p oi nts,  bl o o d   will  b e 
c oll e ct e d   wit hi n  ±  1 0   mi n ut es f or t h e  d efi n e d  dr a  w ti  m e 
p ost   BI  O  3 0 0  d osi n g.  T h e  2 4 hr  dr a  w s h o ul d  o c c ur  as 
cl os e t o  2 4  h o urs  aft er t h e  d os e  of   BI  O  3 0 0  a n d  pri or t o 
t h e   m or ni n g  d os e  of   BI  O  3 0 0. 
S e e   A p p e n di x  9, 
s u  m  m ar y  of  bl o o d 
dr a  ws f or s af et y,  P  K, 
a n d  P  D  ass ess  m e nt.  
C  B  C  
M  a y  b e  dr a  w n  u p t o  4 d  pri or t o  visits   w h er e 
c h e  m ot h er a p y is  a d  mi nist er e d  
 
S er u  m   C h e  mistr y  
M  a y  b e  dr a  w n  u p t o  4 d  pri or t o  vi sits   w h er e 
c h e  m ot h er a p y is  a d  mi nist er e d  
 
Visit  S,  S ur gi c al 
E v al u ati o n  
+/ - 7 d  
 
Visit  3 6  -3 7 , 
C o ns oli d ati o n 
C h e  m ot h er a p y  
+/ - 7 d  
+/ - 1 4 d f or   C T  
Visit  3 8  -3 9 ,  3 
a n d  6   m o nt h 
f oll o  w  u p 
+/ - 1 4 d  
 
Visit  4 0  -4 2 ,  9-1 3 
m o nt h f oll o  w  u p   
+/ - 2 1 d  
F or s ur gi c al  s u bj e cts 
vi sit  4 1,  1 2   m o nt h 
f oll o  w  u p ( e n d  of 
st u d y)  
 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
5 3  
7. 2   A d  mi nist r ati o n  of   BI  O  3 0 0   O r al  S us p e nsi o n 
F oll o  wi n g t h e s cr e e ni n g  visit , s u bj e cts   will  b e r e q u est e d t o   m ai nt ai n  a l o  w is ofl a v o n e  di et 
f or t h e  d ur ati o n  of t h e  st u d y.  S u bj e cts   will  b e  pr o vi d e d  a list  of  di et ar y r e q uir e  m e nts f or 
t h e st u d y  a n d  e n c o ur a g e d t o   m ai nt ai n t h eir  di et   wit hi n  a n  a c c e pt a bl e r a n g e. I n  pr e p ar ati o n 
f or t h e   Visit  2 (  D a y  1)  P  K/ P  D st u di es,  all s u bj e cts   will  arri v e  at t h e  cli ni c  aft er  a n o v er ni g ht 
(8  h o ur ) f ast.   T h e first  bl o o d s a  m pl e f or t h es e st u di es   will  b e t a k e n  pri or t o t h e i niti al  d os e 
of   BI  O  3 0 0. (s e e  s e cti o n  7. 3 f or  d et ails  o n  bl o o d  s a  m pli n g f or  P  K/ P  D).    T h e  s u bj e ct   will 
b e  as k e d t o r e  m ai n f asti n g f or  2  h o urs  aft er t his i niti al  d os e  t o  all o  w f or  a d diti o n al  bl o o d 
s a  m pli n g  at   w hi c h ti  m e t h e  s u bj e ct   will  b e  gi v e n  a st a n d ar d   m e al .   Dri n ki n g  of  cl e ar fl ui ds 
( pr ef er a bl y   w at er  o nl y,  8  o u n c es)   will  b e  e n c o ur a g e d f oll o  wi n g  a d  mi nistr ati o n  of   BI  O  3 0 0 
Or al  S us p e nsi o n.   T h e t est  arti cl e   will  b e  c o ns u  m e d  at t h e  b e gi n ni n g  of t h e  d a y i  m  m e di at el y 
aft er t h e i n iti al (ti  m e  0)  bl o o d  s a  m pli n g  o n t h e  d a ys t h at r e q uir e  a  bl o o d  dr a  w.  F oll o  wi n g 
t h e  p h ar  m a c o ki n eti c  p orti o n  of t h e tri al,  a n d t hr o u g h o ut t h e  e ntir e  st u d y,  s u bj e cts will  b e 
e n c o ur a g e d t o t a k e t h e  d ail y  d os e  of   BI  O  3 0 0   Or al  S us p e nsi o n  as  cl os e t o  1  h o ur  pri or  t o 
r a di ati o n  t h er a p y  as  is  l o gisti c all y  f e asi bl e.    O n  d a ys  i n    w hi c h  s u bj e cts  d o  n ot  r e c ei v e 
ra di ati o n t h er a p y, st u d y s u bj e cts  will  b e  e n c o ur a g e d t o t a k e t h e  d ail y  d os e  of  BI  O  3 0 0   Or al 
S us p e nsi o n  as  cl os e t o t h e  s a  m e ti  m e  as t h e y t a k e it  o n  d a ys   w h er e t h e y  r e c ei v e r a di ati o n. 
F or  e x a  m pl e, if t h eir r a di ati o n s essi o ns  ar e s c h e d ul e d f or  1 1: 0 0   A  M, t h e y s h o ul d t a k e t h eir 
d ail y  d os e  of   BI  O  3 0 0   Or al  S us p e nsi o n  at  1 0: 0 0   A  M  e a c h  d a y. 
7. 3  S u bj e ct   Bl o o d  S a  m pli n g f o r  S af et y,  P h a r  m a c o ki n eti cs   a n d  P h a r  m a c o d y n a  mi cs 
Bl o o d    will   b e   c oll e ct e d   o n   all   s u bj e cts   t o     m o nit or   s af et y,   p h ar  m a c o ki n eti cs,   a n d 
p h ar  m a c o d y n a  mi cs  of   BI  O  3 0 0  al o n e  or  i n  c o  m bi n ati o n   wit h  c h e  m ot h er a p y.   BI  O  3 0 0, 
p a clit a x el,  a n d  c ar b o pl ati n  p h ar  m a c o ki n eti cs  a n al ysis   will  b e  c o  m pl et e d  o n  6  s u bj e cts i n 
e a c h  of t h e  d o si n g  c o h orts.  P  K   will  n ot  b e  c o  m pl et e d  o n  c o h ort 4  ( o pti  m al  bi ol o gi c al  d os e). 
 
At  e a c h  visit   w h er e  bl o o d  s a  m pli n g  o c c urs,  bl o o d   will  b e  c oll e ct e d  pri or t o  a n y tr e at  m e nt 
a d  mi nistr ati o n i n cl u di n g t h e  d ail y   BI  O  3 0 0  d osi n g.  
 
A  s u  m  m ar y  of  bl o o d  dr a  ws f or  s af et y,  P  K,  a n d  P  D   ass ess  m e nt  c a n  b e f o u n d i n   A p p e n di x  
9.  B el o  w   is  a n  o v er vi e  w  of t h e  d et ails  of t h e  bl o o d  c oll e cti o n s u  m  m ari z e d  b y  visit.  
 
Visit  1 ( S c r e e ni n g)   
At t h e s cr e e ni n g  visit,  bl o o d   will  b e  c oll e ct e d f or  a   C  B  C  a n d  bl o o d  c h e  mistri es t o  e v al u at e 
t h e  s u bj ect’s  b o n e   m arr o  w  a n d  h e p ati c  r es er v e  a n d  r e n al  f u n cti o n.  If  a  pr e g n a n c y t est is 
r e q uir e d f or t h e  s u bj e ct,  eit h er  a  s er u  m  or  uri n e t est   will  b e  d o n e  at t his ti  m e.   T h es e t est 
r es ults   will  assist i n  d et er  mi ni n g t h e s u bj e ct’s  a bilit y t o  b e i n cl u d e d i n t h e tri al (s e e s e cti o n 
4. 2. 1 I n cl usi o n   Crit eri a).  
 
Visit  2 (  D a y  1)   
F or  s u bj e cts i n t h e  P  K  gr o u p ,  aft er  a n  8-h o ur f ast  a n d  pri or t o t h e i niti al  d os e  of   BI  O  3 0 0, 
t h es e  s u bj e cts   will  h a v e  t h eir  bl o o d  c oll e ct e d  f or  C  B  C,   bl o o d  c h e  mistri es  a n d   BI  O  3 0 0 
p h ar  m a c o d y n a  mi c ( P  K)  a n d  p h ar  m a c o d y n a  mi c  ( P  D)  b as eli n e v al u e s.   T h e   C  B  C  a n d  bl o o d 
c h e  mistri es   m a y  b e  dr a  w n  u p t o  4  d a ys  pri or t o   visits   w h er e  c h e  m ot h er a p y is  a d  mi n ist er e d.  
F or t h os e s u bj e cts   w h o  h a d  a  pr e g n a n c y t est  at  V  isit  1  b ut o c c urr e d   o v er 7 2  h o urs  pri or t o 
t his  visit,  a r e p e at t est is r e q uir e d.  


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
5 4  
 
All s u bj e cts   will r e  m ai n f asti n g  u ntil t h eir  bl o o d s a  m pli n g is  c o  m pl et e d  at   2  h o urs  p ost  BI  O 
3 0 0  d os e ,  at t h at ti  m e t h e s u bj e cts   will  b e  all o  w e d t o  e at  a n d   will  b e  gi v e n  a st a n d ar d   m e al.  
  
F or  t h e   s u bj e cts  i n  t h e   P  K   gr o u p,   bl o o d    will   b e   dr a  w n   f or   p h ar  m a c o ki n eti c   a n d 
p h ar  m a c o d y n a  mi c  s a  m pli n g  of   BI  O  3 0 0  at t h e  f oll o  wi n g ti  m es:  pr e -d os e,  0. 5,  1,  2,  3,  4, 
a n d at 8  h o urs.  F or t h e  0. 5 a n d  1  h o ur  ti  m e  p oi nts, bl o o d   will  b e c oll e ct e d   wit hi n  ±  5   mi n ut es 
of t h e  d efi n e d  dr a  w ti  m e  p ost  BI  O  3 0 0  d osi n g.   F or t h e  2,  3,  4,  a n d  8  h o ur ti  m e  p oi nts,  bl o o d 
will  b e  c oll e ct e d   wit hi n  ±  1 0    mi n ut es  f or  t h e  d efi n e d  dr a  w  ti  m e  p ost   BI  O  3 0 0  d osi n g  . 
N o n cli ni c al   st u di es   d e  m o nstr at e d   t h at   t h e   h alf  -lif e   of   t ot al   g e nist ei n   i n   s er u  m   is 
a p pr o xi  m at el y  7  h o urs.  T h e fi n al  bl o o d  c oll e cti o n f or  P  K  a n al ysis  a s  cl os e t o  2 4  h o urs  p ost 
d osi n g is  c o nstr ai n e d  b y t h e  d osi n g r e gi  m e n,  b ut still  all o  ws f or  P  K s a  m pli n g f or  3- 4  h alf-
li v es.  T his s a  m pli n g r e gi  m e n s h o ul d  pr o vi d e s uffi ci e nt  d at a t o st u d y t h e  eli  mi n ati o n  p h as e 
of t h e st u d y  dr u g.  
 
F or  e a c h   BI  O  3 0 0 ti  m e  p oi nt ( P  K  or  P  K  a n d  P  D),  a  3 c c t u b e  of  bl o o d   will  b e  c oll e ct e d i n 
a  3  c c  r e d t o p  bl o o d  c oll e cti o n t u b e.  T h e  bl o o d   will  b e all o  w e d t o  cl ot   2 0-3 0   mi n ut es  a n d 
t h e n  c e ntrif u g e d  at r o o  m t e  m p er at ur e f or  1 0-1 5   mi n ut es.  F or t h e   pr e-d os e  a n d  2 -h o ur  p ost 
d os e  bl o o d  dr a  w (  BI  O  3 0 0  P  K  a n d  P  D), t h e  s er u  m  fr o  m t h e  si n gl e  bl o o d  c oll e cti o n t u b e 
will  b e s e p ar at e d   i nt o t  w o  ali q u ots ( 0. 3  m L f or   BI  O  3 0 0  P  D  a n al ysis  a n d t h e r e  m ai n d er f or 
BI  O  3 0 0  P  K  a n al ysis)  a n d  fr o z e n    at  - 8 0°C  .   T h e  t u b e  f or   BI  O  3 0 0  P  K  a n al ysis   will  b e 
s hi p p e d  t o  t h e  s p o ns or -d esi g n at e d   bi o a n al yti c al   l a b  f or  d et er  mi n ati o n  of    BI  O  3 0 0  P  K 
p ar a  m et ers . 
 
T h e  s e c o n d t u b e fr o  m t h e  pr e -d os e  a n d  2  hr  bl o o d  dr a  w  d es cri b e d  a b o v e ( 0. 3   m L  s er u  m) 
will  b e  us e d f or   BI  O  3 0 0  p h ar  m a c o d y n a  mi c   m ar k er   a n al ysis; t h e t u b e   will  b e  s hi p p e d t o 
t h e s p o ns or-d esi g n at e d l a b f or  a n al ysis.  Bl o o d  s er u  m   will  b e  a n al y z e d f or   P  D  bi o  m ar k er 
e x pr essi o n   l e v el s.    P  D     Bi o  m ar k ers   m a y   i n cl u d e     I L 6,   I L- 1α,  I L- 1β,     I L-8,   I L - 1 0, 
T  N F α,  T  G F β 1,  T  G F β 2,  T  G F β 3,   G- C S F,   C  -r e a cti v e  pr ot ei n  a n d  pr ost a gl a n di n  E 2.  
 
F or  a n y  s u bj e cts  n ot u n d er g oi n g  P  K  t esti n g,  aft er  a n  8-h o ur f ast  a n d  pri or t o t h e i niti al  d os e 
of   BI  O  3 0 0, t h es e s u bj e cts   will  h a v e t h eir  bl o o d  c oll e ct e d  for  C  B  C,   bl o o d  c h e  mistri es  a n d 
BI  O  3 0 0  p h ar  m a c o d y n a  mi c   ( P  D)  b as eli n e v al u e.   F or t h os e s u bj e cts   w h o  h a d  a  pr e g n a n c y 
t est  at V  isit  1  b ut o c c urr e d   o v er  7 2  h o urs  pri or t o t his  visit,  a r e p e at t est is r e q uir e d.  
 
F or t h es e  s u bj e cts,  a  s e c o n d  bl o o d  s a  m pl e   will  b e t a k e n f or  at  2 -h o ur  p ost   BI  O  3 0 0  d os e 
f or  p h ar  m a c o d y n a  mi cs   m ar k er  a n al ysis.  Bl o o d   will  b e  c oll e ct e d   wit hi n  ± 1 0  mi n ut es  of t h e 
d efi n e d  dr a  w ti  m e  p ost   BI  O  3 0 0  d osi n g.  
 
All s u bj e cts   will r e  m ai n f asti n g  u ntil t h eir  bl o o d s a  m pli n g is  c o  m pl et e d  at   2  h o urs  p o st  BI  O 
3 0 0  d os e  at t h at ti  m e t h e s u bj e cts   will  b e  all o  w e d t o  e at  a n d   will  b e  gi v e n  a st a n d ar d   m e al.   
 
Visit  3 (  D a y    2) 
Pri or t o t h e  d a ys  BI  O  3 0 0  d os e, t h os e i n t h e  P  K  gr o u p   will  h a v e t h eir  bl o o d  c oll e ct e d  at t h e 
2 4  hr.  p ost   BI  O  3 0 0  d osi n g f or  P  K  a n al ysis.  T h e s a  m e  a  m o u nt  of  bl o o d   will  b e  dr a  w n  a n d 
t h e s a  m e  pr o c ess   will  b e f oll o  w e d  as  d es cri b e d  a b o v e i n   Visit  2.    B e c a us e t h er e   will  b e  n o 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
5 5  
BI  O  3 0 0  P  D  ass ess  m e nt, t h e  e ntir e  p orti o n  of s er u  m   will  b e fr o z e n i n  a si n gl e t u b e.  T h os e 
n ot i n t h e  P  K  gr o u p   will  n ot  h a v e  bl o o d  dr a  w n t his  d a y. 
  
BI  O  3 0 0  +   C h e  m o  P  K    
Aft er  a n  8  -h o ur  f ast  a n d  pri or  t o  t h e  d ail y   BI  O  3 0 0  d osi n g,  b l o o d   will  b e  c oll e ct e d  as 
d es cri b e d i n   Visit  2  a b o v e   wit h t h e  a d diti o n  of  P  K s a  m pli n g f or  p a clit a x el  a n d  c ar b o pl ati n 
f or t h os e s u bj e cts i n t h e  P  K  gr o u p.  
Bl o o d  s a  m pli n g  f or   p a clit a x el  ti  m e  p oi nts    will  b e :  pr e -d os e,  2,  3,  4,  8,  a n d  2 4  h o urs. 
C ar b o pl ati n ti  m e  p oi nts   will  b e:   pr e -d os e,  2,  4,  8,  a n d  2 4  h o urs . F or t h e  0. 5  a n d  1  h o ur ti  m e 
p oi nts,  bl o o d   will  b e  c oll e ct e d   wit hi n  ±  5   mi n ut es  of t h e  d efi n e d  dr a  w ti  m e  p ost   BI  O  3 0 0 
d osi n g.  F or t h e  2,  3,  4,  a n d  8  h o ur ti  m e  p oi nts,  bl o o d   will  b e  c oll e ct e d   wit hi n  ±  1 0   mi n ut es 
f or t h e  d efi n e d  dr a  w ti  m e  p ost   BI  O  3 0 0  d osi n g. T h e  2 4  h o ur ti  m e  p oi nt,  bl o o d  s h o ul d  b e 
c oll e ct e d  as  cl os e t o  2 4  h o urs  p ost -BI  O  3 0 0  d os e  as  p ossi b  l e. F or  e a c h ti  m e  p oi nt,  a  3  c c 
t u b e  of  bl o o d   will  b e  c oll e ct e d i n  a   K 2   E  D T  A t u b e.   T his  si n gl e  bl o o d  c oll e cti o n  yi el ds 
s uffi ci e nt  pl as  m a f or  b ot h  p a clit a x el  a n d  c ar b o pl ati n  ass ess  m e nt.  T h e  bl o o d  pl as  m a   will  b e 
c oll e ct e d ,  c e ntrif u g e d  at  a p pr o xi  m at el y  4°C   a n d  tr a nsf err e d e q u all y  i nt o t  w o  st eril e t u b es 
a n d   fr o z e n   at    - 8 0°C  .    T h e  t u b e    will   b e   s hi p p e d  t o  t h e   s p o ns or-d esi g n at e d  l a b   f or 
d et er  mi n ati o n  of  p a clit a x el  a n d  c ar b o pl ati n  P  K  p ar a  m et ers.  T h es e ti  m es  ar e r el ati v e t o t h e 
m or ni n g   d os e   of    BI  O   3 0 0    Or al   S us p e nsi o n  .  N o  c ar b o pl ati n   P  K   p ar a  m et ers    will   b e 
m e as ur e d  at t h e   3  hr. ti  m e  p oi nt,  o nl y  p ar a  m et ers f or  p a clit a x el.  
T h e f oll o  wi n g  d a y,  a s  cl os e t o  2 4 h o urs  p ost  BI  O  3 0 0   d osi n g  a n d  pri or t o t h at  d a ys  d os e   of 
BI  O  3 0 0, t h os e i n t h e  P  K  gr o u p   will  h a v e t h eir  bl o o d  c oll e c  t e d f or  P  K  a n al ysis.  T h os e  n ot 
i n t h e   P  K  gr o u p   will  n ot  h a v e  bl o o d  dr a  w n t his  d a y.  F or  p a clit a x el  a n d  c ar b o pl ati n   P  K 
ass ess  m e nt,  a  3  c c t u b e  of  bl o o d   will  b e  c oll e ct e d i n  a   K 2  E  D T  A t u b e.  T h e  pl as  m a   will  b e 
c oll e ct e d ,  c e ntrif u g e d  at  a p pr o xi  m at el y  4°C  a n d   di vi d e d  i nt o t  w o st eril e t u b es  a n d fr o z e n  
at  - 8 0°C.   F or   BI  O  3 0 0  P  K  ass ess  m e nt,  a  3 c c t u b e  of  bl o o d   will  b e  c oll e ct e d i n  a r e d t o p 
bl o o d c oll e cti o n t u b e . T h e  bl o o d   will  b e  all o  w e d t o cl ot   2 0-3 0   mi n ut es a n d t h e n c e ntrif u g e d 
at r o o  m t e  m p er at ur e f or  1 0 -1 5   mi n ut e s.  T h e  s er u  m   will  b e  c oll e ct e d  a n d tr a nsf err e d t o  a 
st eril e t u b e  an d fr o z e n  i n  a - 8 0°C f  re e z er . 
 
W e e ks   2- 6 
I n  a d diti o n t o t h e  bl o o d  s a  m pli n g  f or   C  B  C  a n d  bl o o d  c h e  mistri es, tr o u g h l e v els  f or   BI  O 
3 0 0,   p a clit a x el,   c ar b o pl ati n,   a n d   t h e    BI  O   3 0 0   p h ar  m a c o d y n a  mi c   m ar k ers    will   b e 
d et er  mi n e d     w e e kl y    d uri n g    c o n c urr e nt    c h e  m or a di ot h er a p y,    pri or   t o   t h at     w e e k’s 
c h e  m ot h er a p y tr e at  m e nt  c o urs e  a n d  pri or t o t h at  d a ys   BI  O  3 0 0  d os e.  F or   BI  O  3 0 0 tr o u g h 
l e v els  a n d  P  D  ass ess  m e nt,  o n e  3  c c  t u b e  of  bl o o d   will  b e  c oll e ct e d  i n  a  r e d  t o p  bl o o d 
c oll e cti o n t u b e . T h e  bl o o d   will  b e  all o  w e d t o  cl ot   2 0-3 0   mi n ut es  a n d t h e n  c e ntrif u g e d  at 
r o o  m t e  m p er at ur e f or  1 0-1 5   mi n ut es .  Th e s er u  m  fr o  m t h e si n gl e  bl o o d  c oll e cti o n t u b e will 
b e s e p ar at e d  i nt o t  w o  ali q u ots ( 0. 3  m L f or   BI  O  3 0 0  P  D  a n al ysis  a n d t h e r e  m ai n d er f or   BI  O 
3 0 0  P  K  a n al ysis).  T h e t u b es   will  b e fr o z e n  at - 8 0 °C   a n d s hi p p e d t o t h e s p o ns or -d esi g n at e d 
l a bs f or  a n al ysis.   O n e t u b e   will  b e  s hi p p e d t o t h e s p o ns or-d esi g n at e d  bi o a n al yti c al  l a b f or 
a n al ysis  a n d  d et er  mi n ati o n  of   BI  O  3 0 0 tr o u g h l e v els,  a n d  t h e  s e c o n d t u b e   will  b e s hi p p e d 
t o t h e s p o ns or-d esi g n at e d l a b f or   BI  O  3 0 0  p h ar  m a c o d y n a  mi c   m ar k er  a n al ysis.  
 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
5 6  
I n  a d diti o n, at t h at  s a  m e ti  m e  p oi nt,  a  3  c c t u b e  of  bl o o d   will  b e  c oll e ct e d i n  a   K 2  E  D T  A 
t u b e.  T h e  bl o o d    will  b e  c oll e ct e d,  c e ntrif u g e d  at  a p pr o xi  m at el y  4°C  a n d  di vi d e d   i nt o t  w o 
st eril e t u b es  a n d fr o z e n  at  - 8 0°C.    T h e t u b e   will  b e  s hi p p e d t o t h e  s p o ns or -d esi g n at e d l a b 
f or  d et er  mi n ati o n  of  p a clit a x el  a n d  c ar b o pl ati n tr o u g h l e v els. 
  
Visit    S 
All s u bj e cts   will  h a v e  a  C  B  C  a n d  bl o o d  c h e  mistri es  dr a  w n f or s af et y   m o nit ori n g.    N o  ot h er 
bl o o d s a  m pli n g r e q uir e d.  
 
Visits   3 6 
All s u bj e cts   will  h a v e  a  C  B  C  a n d  bl o o d  c h e  mistri es  dr a  w n f or s af et y   m o nit ori n g.    N o  ot h er 
bl o o d s a  m pli n g r e q uir e d.  
 
Visit  3 7   
All  s u bj e cts    will  h a v e  a   C  B  C  a n d  bl o o d  c h e  mistri es  dr a  w n  f or  s af et y    m o nit ori n g.     I n 
a d diti o n,  bl o o d s er u  m   will  b e  c oll e ct e d f or   BI  O  3 0 0  p h ar  m a c o d y n a  mi c   m ar k er  a n al ysis.  A 
3 c c t u b e  of  bl o o d   will  b e  c oll e ct e d i n  a  r e d t o p  bl o o d  c oll e cti o n t u b e.   T h e  bl o o d   will  b e 
all o  w e d t o  cl ot   2 0-3 0   mi n ut es  a n d t h e n  c e ntrif u g e d  at r o o m t e  m p er at ur e f or  1 0  -1 5   mi n ut es .  
T h e  s er u  m   will  b e  s e p ar at e d  a n d  pl a c e d i nt o  a  st eril e t u b e a n d fr o z e n  at  - 8 0°C  .   T h e t u b e 
will  b e   s hi p p e d t o t h e s p o ns or- d esi g n at e d l a b f or  a n al ysis.  
 
Visit   3 8 
All  s u bj e cts    will  h a v e  a   C  B  C  a n d  bl o o d  c h e  mistri es  dr a  w n  f or  s af et y    m o nit ori n g.     I n 
a d diti o n,  bl o o d s er u  m   will  b e  c oll e ct e d f or   BI  O  3 0 0  p h ar  m a c o d y n a  mi c   m ar k er  a n al ysis.  A 
3 c c t u b e  of  bl o o d   will  b e  c oll e ct e d i n  a  r e d t o p  bl o o d  c oll e cti o n t u b e.   T h e  bl o o d   will  b e 
all o  w e d t o  cl ot   2 0-3 0   mi n ut es  a n d t h e n  c e ntrif u g e d  at r o o  m  t e  m p er at ur e f or  1 0-1 5   mi n ut es .  
T h e  s er u  m   will  b e  s e p ar at e d  a n d  pl a c e d i nt o  a  st eril e t u b e a n d fr o z e n   at - 8 0°C  .   T h e t u b e 
will  b e   s hi p p e d t o t h e s p o ns or- d esi g n at e d l a b f or  a n al ysis.  
 
Visit   3 9 
Bl o o d s er u  m   will  b e  c oll e ct e d f or   BI  O  3 0 0  p h ar  m  a c o d y n a  mi c   m ar k er  a n al ysis.  A  3 c c t u b e 
of  bl o o d   will  b e  c oll e ct e d i n  a r e d t o p  bl o o d  c oll e cti o n t u b e.   T h e  bl o o d   will  b e  all o  w e d t o 
cl ot   2 0-3 0   mi n ut es a n d t h e n c e ntrif u g e d  at r o o  m t e  m p er at ur e f or  1 0 -1 5   mi n ut es .  T h e s er u  m 
will  b e s e p ar at e d   a n d  pl a c e d i nt o a st eril e t u b e a n d fr o z e n  at - 8 0°C  .  T h e t u b e   will  b e s hi p p e d 
t o t h e s p o ns or-d esi g n at e d l a b f or  a n al ysis.  
 
F or  all  ot h er  visits,  n o  pr ot o c ol  bl o o d  c oll e cti o n is r e q uir e d. 
 
( S e e s e cti o n  7. 0  S c h e d ul e  of   Ass ess  m e nts f or  a d diti o n al i nf or  m ati o n.) 
 
 






P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
5 9  
8. 0   
S  A F  E  T  Y   R  E P  O  R  TI  N  G  
8. 1   
D efi niti o ns   
8. 1. 1   A d v e rs e   E v e nts   
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 c al tr e at  m e nt  or  pr o c e d ur e 
r e g ar dl ess  of    w h et h er  it  is  c o nsi d er e d  r el at e d  t o  t h e    m e di c al  tr e at  m e nt  or  pr o c e d ur e 
( attri b uti o n  of  u nr el at e d,  u nli k el y,  p ossi bl e,  pr o b a bl e,  or  d efi nit e).  
8. 1. 2   S e ri o us   A d v e rs e   E v e nts  
S  A  Es t h at fit  a n y  o n e  of t h e  c rit e ri a i n t h e  S  A  E  d efi niti o n  b el o  w   m ust  b e  r e p o rt e d t o 
t h e S p o ns o r   wit hi n  2 4  h o u rs  of  a  w a r e n ess  of t h e  e v e nt.  
 
D efi niti o n  of  a n  S  A  E:   A n y  a d v ers e  dr u g  e x p eri e n c e  o c c urri n g  at  a n y  d os e t h at 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;   
•    A lif e  -t hr e at e ni n g  a d v ers e  dr u g  e x p eri e n c e; 
•    I n p ati e nt  h os pit ali z ati o n  or  pr ol o n g ati o n  of  e xisti n g  h os pit ali z ati o n; 
•    A  p ersist e nt  or si g nifi c a nt  dis a bilit y/i n c a p a cit y;   
•    A  c o n g e nit al  a n o  m al y/ birt h  d ef e ct.   
 
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 n  S  A E  dr u g  e x p eri e n c e,   w h e n,  b as e d  u p o n   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  p ati e nt  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  out c o  m es list e d i n t h e  d efi niti o n.   
8. 1. 3   U n e x p e ct e d   A d v e rs e   E v e nts   
A n y  a d v ers e  e x p eri e n c e t h at ( a) is  n ot i d e ntifi e d i n  n at ur e  or  s e v erit y,  or fr e q u e n c y i n t h e 
c urr e nt i n v esti g at or  br o c h ur e; ( b) t h at is  n ot i d e ntifi e d i n  n at ur e,  s e v erit y,  or fr e q u e n c y i n 
th e ris k i nf or  m ati o n  d es cri b e d i n t h e  g e n er al i n v esti g ati o n al  pl a n  or els e  w h er e i n t h e c urr e nt 
a p pli c ati o n  as  a  m e n d e d; ( c)  or t h at  h as  n ot  b e e n  pr e vi o usl y  o bs er v e d. 
8. 2   
D o c u  m e nti n g   A  d v e rs e  E  v e nts  
All   A Es  , i n cl u di n g cli n ci all y  si g nifi c a nt  l a b or at or y  a b n or  m aliti es will  b e   c oll e ct e d i n t h e 
sit es  s o ur c e  d o c u  m e nt  a n d  r e p ort e d o n t h e   A E  c as e r e p ort f or  m (  C  R F)  fr o  m t h e ti  m e t h e 
s u bj e ct  is  e nr oll e d i n t h e  st u d y u ntil  3 0  d a ys  aft er l a st  a d  mi nistr ati o n  of  st u d y  dr u g.  If t h e 
A E is  a   s eri o us  e v e nt t h at is p ossi bl y,  pr o b a bl y  or  d efi nit el y  r el at e d t o st u d y  dr u g, t h e  e v e nt 
s h o ul d  b e r e p ort e d t o t h e  S p o ns or  e v e n if  o c c urri n g   m or e t h a n  3 0  d a ys  aft er t h e l ast  d os e 
of st u d y  dr u g .   Do c u  m e nt ati o n  of t h e s eri o us  e v e nt  will  b e r e p ort e d  o n t h e  S  eri o us   A d v ers e 
E v e nt  C  R F    a n d s u b  mitt e d t o t h e s p o ns or   wit hi n  2 4  h o urs  of  a  w ar e n ess.  
  
8. 2. 1   A d v e rs e   E v e nt   D at a   E  l e  m e nts 
•    Ass ess  m e nt  p eri o d  
•    A d v ers e  e v e nt t er  m   C T  C  A E  v ersi o n  4. 0 3 
•    S e v erit y   Gr a d e ( 0 - 5)   C T  C  A E  v ersi o n  4. 0 3 
•    Attri b uti o n t o st u d y  a g e nt (r el at e d n ess)   


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
6 0  
•    D at e   A E  o c c urr e d    
•    D at e   A E r es ol v e d    
•    W h et h er  or  n ot t h e  e v e nt   w as r e p ort e d  as  a n  S  A E 
•    W h et h er  or  n ot t h e  p arti ci p a nt  dr o p p e d  d u e t o t h e  e v e nt 
•    A cti o n t a k e n   wit h st u d y  a g e nt 
•    O ut c o  m e  of t h e  e v e nt   
•    C o  m  m e nts   
8. 2. 2   S e v e rit y  of   A Es 
I d e ntif y  t h e  a d v ers e  e v e nt  usi n g  t h e    N  CI    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 (  C T  C  A E)  v ersi o n  4. 0 3.  T h e   C T  C  A E  pr o vi d es  d es cri pti v e t er  mi n ol o g y  a n d  a  s c al e 
f or  e a c h  a d v ers e  e v e nt list e d.   A li n k t o t h e   N  CI  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 (  C T  C  A E)  v ersi o n  4. 0 3  c a n  b e f o u n d i n   A p p e n di x  5.  
T a bl e   8 . 2. 2. 1   Gr a di n g  a n d   D es c ri pti o n  of   A d v e rs e   E v e nts  
Gr a d e     D es cri pti o n   
0    
N o   A E  or   wit hi n  n or  m al li  mits   
1    
Mil d   A E;  a s y  m pt o  m ati c  or   mil d s y  m pt o  ms;  cli ni c al  or  di a g n osti c  o bs er v ati o ns  o nl y; i nt er v e nti o n 
n ot i n di c at e d  
2    
M o d er at e    A E;    mi ni  m al,  l o c al  or  n o ni n v asi v e  i nt er v  e nti o n  ( e. g.,  p a c ki n g,  c a ut er y)  i n di c at e d; 
li  miti n g  a g e-a p pr o pri at e i nstr u  m e nt al  a cti viti es  of  d ail y li vi n g (  A  D L)  
3    
S e v er e   or     m e di c all y   si g nifi c a nt   b ut   n ot   i  m  m e di at el y   lif e -t hr e at e ni n g;   h os pit ali z ati o n   or 
pr ol o n g ati o n  of  h os pit ali z ati o n i n di c at e d;  dis a bli n g; li  miti n g s elf -c ar e   A  D L  
4    
Lif e -t hr e at e ni n g  c o ns e q u e n c es;  ur g e nt i nt er v e nti o n i n di c at e d 
5    
D e at h r el at e d t o   A E   
 
N  O T E:   A  s e v er e   A E,  as  d efi n e d  b y t h e  a b o v e  gr a di n g  s c al e, is   N  O T t h e  s a  m e  as  s eri o us 
A E,   w hi c h is  d efi n e d  a b o v e i n s e cti o n  7. 1. 2. 
8. 2. 3   Ass e  ss  m e nt  of R el ati o ns hi p  of   A  E t o   T  r e at  m e nt  
T h e  p ossi bilit y t h at t h e  a d v ers e  e v e nt is r el at e d t o t h e st u d y  a g e nt   will  b e  cl assifi e d  as  o n e 
of t h e f oll o  wi n g:  u nr el at e d,  u nli k el y,  p ossi bl e,  pr o b a bl e,  d efi nit e.  T h e i n v esti g at or   will  b e 
r es p o nsi bl e f or  d et er  mi ni n g t h e r el at e d n ess  of t h e   A E t o t h e st u d y  a g e nt. 
8. 2. 4     F oll o  w- u p  of   A Es 
F oll o  w- u p  o n  e v e nts,  A Es  a n d  S  A Es  ,  will  b e  d o c u  m e nt e d  a n d s u b  mitt e d t o t h e  S p o ns or  as 
n e  w i nf or  m ati o n is  c oll e ct e d  u ntil   r es ol uti o n  or  u ntil t h eir l ast st u d y  visit.   
8. 3   
R e p o rti n g   A  E  s t o I  R  B 
I n v esti g at ors  ar e  r e q uir e d  t o  r e p ort   pr o  m ptl y  t o  t h e  I R  B  all  u n a nti ci p at e d   pr o bl e  ms 
i n v ol vi n g  ris ks  t o  h u  m a n  s u bj e cts  or  ot h ers,  i n cl u di n g  a d v ers e  e v e nts  t h at  s h o ul d  b e 
c o nsi d er e d   u n a nti ci p at e d   pr o bl e  ms.     T h e   f oll o  wi n g     A E s   s h o ul d   b e   c o nsi d er e d   as 
u n a nti ci p at e d  pr o bl e  ms  t h at   m ust  b e r e p ort e d t o t h e I R  B: 
•    A si n gl e  o c c urr e n c e  of  a s eri o us,  u n e x p e ct e d  e v e nt t h at is  u n c o  m  m o n  a n d str o n gl y 
ass o ci at e d   wit h  dr u g  e x p os ur e. 
•    A si n gl e  o c c urr e n c e,  or   m or e  oft e n  a s  m all  n u  m b er  of  o c c urr e n c es,  of  a s eri o us, 
u n e x p e ct e d  e v e nt t h at is  n ot  c o  m  m o nl y  ass o ci at e d   wit h  dr u g  e x p os ur e,  b ut 
u n c o  m  m o n i n t h e st u d y  p o p ul ati o n. 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
6 1  
•    M ulti pl e  o c c urr e n c es  of  a n   A E t h at,  b as e d  o n  a n  a g gr e g at e  a n al ysis, is  d et er  mi n e d 
t o  b e  a n  u n a nti ci p at e d  pr o bl e  m.  T h er e s h o ul d  b e  a  d et er  mi n ati o n t h at t h e seri es  of 
A E  s r e pr es e nts  a si g n al t h at t h e   A Es   w er e  n ot j ust is ol at e d  o c c urr e n c es  a n d 
i n v ol v e ris k t o  h u  m a n s u bj e cts. 
•    A n   A E t h at is  d es cri b e d  or  a d dr ess e d i n t h e i n v esti g at or’s  br o c h ur e,  pr ot o c ol,  or 
i nf or  m e d  c o ns e nt  d o c u  m e nts,  b ut  o c c urs  at  a s p e cifi cit y  or s e v erit y t h at is 
i n c o nsist e nt   wit h  pri or  o bs er v ati o ns. 
•    A s eri o us   A E t h at is  d es cri b e d  or  a d dr ess e d i n t h e i n v esti g at or’s  br o c h ur e, 
pr ot o c ol,  or i nf or  m e d  c o ns e nt  d o c u  m e nts,  b ut f or   w hi c h t h e r at e  of  o c c urr e n c e i n 
t h e st u d y r e pr es e nts  a  cli ni c all y si g nifi c a nt i n cr e as e i n t h e  e x p e ct e d r at e  of 
o c c urr e n c e.  
•    A n y  ot h er   A E  or s af et y fi n di n g ( e. g.,  b as e d  o n  a ni  m al  or  e pi d e  mi ol o gi c  d at a) t h at 
w o ul d  c a us e t h e s p o ns or t o   m o dif y t h e i n v esti g at or’s  br o c h ur e, st u d y  pr ot o c ol,  or 
i nf or  m e d  c o ns e nt  d o c u  m e nts,  or   w o ul d  pr o  m pt  ot h er  a cti o n  b y t h e I R  B t o  e ns ur e 
t h e  pr ot e cti o n  of  h u  m a n s u bj e cts. 
8. 4   
E x p e dit e d  r e p o rti n g  of  a d v e rs e  e v e nts   
I n v esti g at ors  ar e  r e q uir e d t o  r e p ort  pr o  m ptl y t o t h e  s p o ns or  a n y  a d v ers e  e v e nt  t h at   m a y 
r e as o n a bl y  b e r e g ar d e d  as  c a us e d  b y,  or  pr o b a bl y  c a us e d  b y, t h e st u d y dr u g.   If t h e  a d v ers e 
e v e nt   m e ets t h e s eri o us  a d v ers e  e v e nt  crit eri a, t h e i n v esti g at or s h all r e p ort t h e  e v e nt t o t h e 
s p o ns or   wit hi n  2 4  h o urs  of  a  w ar e n ess . 
 
T h e s p o ns ors   will  n otif y t h e  F  D  A  a n d  all  p arti ci p ati n g i n v esti g at ors i n  a   writt e n I  N  D s  af et y 
r e p ort  of  a n y  a d v ers e  e x p eri e n c e  ass o ci at e d   wit h t h e  us e  of t h e  dr u g t h at is  b ot h  s eri o us 
a n d  u n e x p e ct e d  a n d  a n y fi n di n g fr o  m t ests i n l a b or at or y  a ni  m als t h at s u g g ests  a si g nifi c a nt 
ris k f or  h u  m a n  s u bj e cts.  T h e  s p o ns or   will  s u b  mit  a n I  N  D  s af et y r e p ort t o t h e  F  D  A  a n d  all 
p arti ci p ati n g i n v esti g at ors  n o l at er t h a n  1 5  c al e n d ar  d a ys  aft er t h e s p o ns or  d et er  mi n es t h at 
t h e  s us p e ct e d  a d v ers e  r e a cti o n  or  ot h er  i nf or  m ati o n  q u alifi es  f or  r e p orti n g.  U n e x p e ct e d 
f at al  or lif e-t hr e at e ni n g  s us p e ct e d  a d v ers e  r e a cti o ns will  b e  r e p ort e d t o t h e  F  D  A  n o   l at er 
t h a n  7  c al e n d ar  d a ys  aft er  t h e  s p o ns or’s  i niti al  r e c ei pt  of  t h e  i nf or  m ati o n.  If  t h e  F  D  A 
r e q u ests  a n y  a d diti o n al  d at a  or  i nf or  m ati o n,  t h e  s p o ns or   will  s u b  mit  it  t o  F  D  A  as  s o o n 
as   p ossi bl e,  b ut  n o l at er t h a n  1 5  c al e n d ar  d a ys  aft er r e c ei vi n g t h e r e q u est. 
8. 5   
D os e   Li  miti n g   T o xi citi es (  D  L  Ts)   
Bl o o d s a  m pli n g f or t h e l a b or at or y  p ar a  m et ers   will  b e  p erf or  m e d  d uri n g t h e st u d y a c c or di n g 
t o   t h e   ti  m e   t o   e v e nt   s c h e d ul e   i n   t his   pr ot o c ol.     L a b or at or y   p ar a  m et ers   i n cl u d e 
C  B  C/ diff er e nti al, c  h e  mistr y  pr ofil e (  C  M P),  p h os p h or us,  p a n cr e ati c li p as e   & a  m yl as e.  E  C  G 
a n d  vit al  si g ns   will  als o  b e  p erf or  m e d  a c c or di n g t o t h e  T i  m e t o E v e nt  t a bl e ( T a bl e  7. 1. 1). 
T o xi citi es    will  b e  gr a d e d  a c c or di n g  t o  t h e    V ersi o n  4. 0 3   ( v 4. 0 3)  of  t h e    N  CI   C o  m  m o n 
T er  mi n ol o g y   Cr it eri a f or  A d v ers e  E v e nts (  C T  C A E).    A d v ers e  e v e nt r e p orti n g  a n d  s eri o us 
a d v ers e    e v e nt   r e p orti n g     will   f oll o  w   t h e    g ui d eli n es    d efi n e d    b y    F  D  A    St at ut es. 
Dis c o nti n u ati o n  of  a s u bj e ct  a n d  e arl y st o p pi n g  of  o n e  of t h e tri al  c o h orts   will  b e  b as e d  o n 
t h e   f oll o  wi n g   un a c c e pt a bl e   a d v ers e   e v e nts   (  A E s)   a n d     m ust   b e   attri b ut a bl e   t o   t h e 
i n v esti g ati o n al  dr u g   BI  O  3 0 0   Or al s us p e nsi o n (i. e.  p ossi bl y,  pr o b a bl y  or  d efi nit el y r el at e d 
t o  t h e  st u d y  dr u g)  t o  c o nstit ut e  a   D os e-Li  miti n g   T o xi cit y  (  D L T).     O nl y  a d v ers e  e v e nts 
w hi c h  o c c ur  b ef or e  or  d uri n g  c o n c urr e nt  c h e  m or a di ati o n   will  b e  c o u nt e d  as   D L Ts. 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
6 2  
•    T o xi citi es   m ust  b e  attri b ut a bl e t o t h e st u d y r e gi  m e n (i. e.  p ossi bl y,  pr o b a bl y  or 
d efi nit el y r el at e d t o t h e i n v esti g ati o n al st u d y  dr u g) t o  c o nstit ut e  a   D os e -Li  miti n g 
T o xi cit y (  D L T).    
•    D os e l  i  miti n g t o xi citi es  ar e t o  b e  d efi n e d  as f oll o  ws: 
1)    R a di ati o n  es o p h a gitis   Gr a d e  3 t h at l asts  >  7    c o ns e c uti v e  d a ys  or   Gr a d e  4. 
2)    Gr a d e  4  n e utr o p e ni a f or   m or e t h a n  7  d a ys  or  n e utr o p e ni a f e v er ( d efi n e d  as 
A  N  C  <  5 0 0  a n d  a t e  m p er at ur e  of  3 8. 5°   C  or  a b o v e).   
3)    Gr a d e  3 t  hr o  m b o c yt o p e ni a   wit h  cli ni c all y si g nifi c a nt  bl e e di n g  
4)    Gr a d e  4 t hr o  m b o c yt o p e ni a  >  7  d a ys.   
5)    Gr a d e  4  n a us e a/ v o  miti n g  d es pit e  a p pr o pri at e  a nti e  m eti c t h er a p y.   
6)    Gr a d e  3   A S T/  A L T   el e v ati o ns   >  7  d a ys 
7)    D el a ys  i n  r a di ot h er a p y  or  c h e  m ot h er a p y  d u e  t o  t o xi cit y  of    m or e  t h a n   3 
w e e ks.   D el a ys i n t h e  c urr e nt st a n d ar d  of  c ar e tr e at  m e nt  ar e li k el y t o  h a v e  a 
n e g ati v e  eff e ct  o n  p ati e nt  o ut c o  m e  a n d t h us  ar e t o  b e  d esi g n at e d  as  a   D L T.  
8)    All   ot h er   n o n  -h e  m at ol o gi c  t o xi citi es   of    Gr a d e   3   or   hi g h er,    wit h  t h e 
f oll o  wi n g  e x c e pti o ns: 
a)    a n or e xi a  
b)   f ati g u e 
c)    i nf e cti o n   wit h o ut  n e utr o p e ni a 
d)   Gr a d e  3   A S T/  A L T  el e v ati o ns  ≤  7  d a ys   
e)    I nf usi o n  r e a cti o ns.   P ati e nts   wit h   Gr a d e  3  or   w ors e i nf usi o n  r e a cti o ns 
will  b e r e  m o v e d fr o  m t h e st u d y  a n d r e pl a c e d  a n d   will  n ot  b e  c o nsi d er e d 
e v al u a bl e f or   D L T.  
f)   Gr a d e  3  or  4  el e ctr ol yt e  a b n or  m aliti es t h at  ar e  c orr e ct e d t  o   Gr a d e  2  or 
l ess i n l ess t h a n  4 8  h o urs. 
 
A n y   D L T s h o ul d  b e r e p ort e d t o t h e s p o ns or   wit hi n  4 8  h o urs  of  dis c o v er y   f or r e vi e  w  b y t h e 
m e di c al   m o nit or  . T h e   m e di c al   m o nit or   will   d et er  mi n e   w h e t h er t h e  e v e nt is  a   D L T.   If   a 
D L T  o c c urs, t h e   s p o ns or  will  c o  m  m u ni c a  t e t h e D L T   t o t h e sit es   wit hi n  4 8  h o urs  of t h e 
d et er  mi n ati o n . 
 
A   mi ni  m u  m  of  6  s u bj e cts   will  b e tr e at e d  p er  d os e l e v el.   D os e  es c al ati o n   m a y  o c c ur   w h e n 
a  c o h ort  h as  c o  m pl et e d  c o n c urr e nt  c h e  m or a di ot h er a p y   wit h  l ess t h a n 3 3  %   D L Ts.  If o n e  or 
f e  w er D L Ts   o c c ur , th e  d os e   will  b e  es c al at e d  t o t h e  n e xt  c o h ort  of  6  s u bj e cts. If  2   D L Ts 
o c c ur  ( 2/ 6  s u bj e cts),  a n  a d diti o n al  2  s u bj e cts   will  b e  tr e at e d   wit h  t h e  s a  m e  d os e.  If  n o 
a d diti o n al   D L Ts  o c c ur  ( 2/ 8  s u bj e cts),  d os e  es c al ati o n   m a y  pr o c e e d.  If  1  a d diti o n al  D L T 
o c c urs  ( 3/8 s u bj e cts),  a n  a d diti o n al  2 s u bj e cts   will  b e tr e at e d  at t h e s a  m e  d os e f or  a t ot al  of 
1 0 s u bj e cts.  If  n o  a d diti o n al   D L Ts  o c c ur ( 3/ 1 0 s u bj e cts),  d os e  es c al ati o n   m a y  pr o c e e d. 
 
T h e st u d y s p o ns or   will t e  m p or aril y  c e as e  e nr oll  m e nt   i n  a n y  gi v e n  c o h ort  if  4 s u bj e cts ( o ut 
of  a t ot al  of  1 0),  e x p eri e n c e   D L Ts  attri b ut a bl e t o   BI  O  3 0 0   Or al  S us p e nsi o n  as t h e   M T  D 
will  h a v e  b e e n  e x c e e d e d.    T h e  s p o ns or’s    m e di c al    m o nit or    will  ass ess  t h e  s af et y  d at a 
c oll e ct e d t o  d at e t o  d et er  mi n e if  e nr oll  m e nt  s h o ul d  p er  m a n e ntl y  c e as e  at t h at  d os e.  If t h e 
d e cisi o n  is    m a d e  t o  c e as e  e nr oll  m e nt,  t h e  s p o ns or  a n d  t h e  pri n ci p al  i n v esti g at or    will 
d et er  mi n e if t h e  d os e  s h o ul d  c e as e  or  b e   m o difi e d  f or t h os e  s u bj e cts i n t h at  c o h ort   w h o 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
6 3  
h a v e   n ot  e x p eri e n c e d    D L Ts.  T h e  st u d y  s p o ns or,  t o g et h er    wit h  t h e   PI ,  m a y  c o nsi d er 
a  m e n di n g t h e  pr ot o c ol t hr o u g h  a   m o difi c ati o n  of t h e  d osi n g r e gi  m e n.  
9. 0   
D  A  T  A   M  A  N  A  G  E  M  E  N  T   
D at a  c oll e cti o n   will st art  at st u d y  b as eli n e  a n d t h e n  c o nti n u e  d uri n g t h e st u d y f oll o  wi n g t h e 
ti  m e t o  e v e nt t a bl e i n t h e  pr ot o c ol.    D at a   will  b e r e c or d e d o n  a  c as e r e p ort f or  m f or  e a c h 
s ubj e ct.      T his  d at a b as e    will  b e  2 1    C F  R  P art  1 1  c o  m pli a nt.  S u bj e ct  d at a    will  b e  k e pt 
c o nfi d e nti al .   At   Visit 2 ,  e a c h  s u bj e ct   will  b e  assi g n e d  a  S u bj e ct I  D #. T h e first  n u  m b er i n 
t h e  S u bj e ct  I  D #  is  t h e  sit e  n u  m b er.    Sit e  n u  m b ers will  st art    wit h  1 0 0  a n d  i n cr e as e  b y 
i n cr e  m e nts  of  1 0 0 (i. e.,  1 0 0,  2 0 0,  3 0 0),  as  n e e d e d.  T h e  s e c o n d  n u  m b er   will  b e t h at  of t h e 
s u bj e ct i n t h e  or d er t h e y  ar e  s cr e e n e d  st arti n g   wit h  0 1;  a d diti o n al  n u  m b ers  b ei n g  assi g n e d 
s e q u e nti all y ( 1 0 1,  1 0 2,  1 0 3,  et c.).  I n a d diti o n,  o nl y t h e s u bj e ct i niti als (first,   mi d dl e   & l ast) 
will  b e  us e d  o n st u d y  d o c u  m e nts.   All   m e di c al r e c or ds  ar e r e q uir e d t o  b e  d e  -i d e ntifi e d  pri or 
t o  s u b  missi o n t o t h e  s p o ns or.  St u d y r e c or ds   will  b e  st or e d i n  a l o c k e d  a n d  s e c ur e  st or a g e 
ar e a  at t h e  st u d y  a n d  s p o ns or  f a ciliti es.  T h e i n v esti g at or(s)/i nstit uti o n(s)   will  p er  mit tri al-
r el at e d    m o nit ori n g,  a u dits,  I R  B/I E  C  r e vi e  w,  a n d  r e g ul at or y  i ns p e cti o n(s)  b y  pr o vi di n g 
dir e ct  a c c ess t o  all  s o ur c e  d at a/ d o c u  m e nts  i n cl u di n g  el e ctr o ni c   m e di c al r e c or ds.  
 
T h er e   will  b e  n o i  m p ut ati o n f or   missi n g   Q  O L  o bs er v ati o ns.   T h e  c a us e  of   missi n g  d at a is 
ass u  m e d t o  b e   missi n g  c o  m pl et el y  at r a n d o  m.  
 
D  at a  r e q uir e d  f or  t h e  I nt eri  m   A n al ysis   will  b e   m o nit or e d a n d  cl e a n e d  pri or  t o  d at a b as e 
fr e e z e  a n d  n o  n e  w  d at a    will  b e  a d d e d  t o  t h e   d at a b as e  u ntil  t h e   Pr oj e ct    M a n a g er   or 
St atisti ci a n   gi v es  a p pr o v al.  
 
T h e  tri al   d at a b as e    will   b e  a u dit e d,  cl e a n e d  a n d   l o c k e d  aft er  c o  m pl eti o n  of  t h e  tri al  
a c c or di n g  t o  t h e  st u d y  s p e cifi c    D at a    M a n a g e  m e nt  Pl a n  (  D  M P) .    A  c o p y  of  t his  l o c k e d 
d at a b as e   will  b e  b u r n e d  o nt o  a   C  D-R  O  M  a n d   m a d e  a v ail a bl e f or  st atisti c al  a n al ysis.   D at a 
will  b e  a n al y z e d f or  a d v ers e  e v e nts,  pri  m ar y  o ut c o  m es,  a n d s e c o n d ar y  o ut c o  m es.    
9. 1     
D at a   C a pt u r e   M et h o ds 
T h e  d at a t h at   will  b e  us e d t o  c o  m pl et e t h e  C  R F  s   will  b e  d eri v e d fr o  m t h e  s u bj e cts  s o ur c e 
d o c u  m e nts   ( E  M  R  a n d/ or  p a p er  d o c u  m e nts).     T h e  r es e ar c h  sit e’s  st u d y  p ers o n n el   will 
c o  m pl et e  t h e   C  R Fs  a n d r et ai n t h e  m f or   m o nit ori n g  b y t h e  s p o ns or. O n c e   m o nit ori n g  h as 
b e e n  c o  m pl et e d  a n d t h e  C  R Fs  h a v e  b e e n r e vi e  w e d  a n d si g n e d  b y t h e i n v esti g at or, t h e y   will 
b e  s u b  mitt e d t o t h e  s p o ns or.   D at a  e ntr y  ,  v erifi c ati o n  a n d  cl e a ni n g will  b e  d o n e   a c c or di n g 
t o t h e s p o ns or’s st u d y s p e cifi c   D at a  M  a n a g e  m e nt  P l a n.  
 
All  p h ar  m a c o ki n eti c  c al c ul ati o ns   will  b e  p erf or  m e d  usi n g  v ali d at e d  s oft  w ar e   as  arr a n g e d 
b y  t h e  S p o ns or .  I n di vi d u al  ti  m e-c o n c e ntr ati o n  d at a   will  b e  us e d  i n  all  p h ar  m a c o ki n eti c 
a n al ys es.   T h e ar e a  u n d er t h e s er u  m ( or  pl as  m a) c o n c e ntr ati o n -ti  m e c ur v e,   will  b e esti  m at e d 
usi n g t h e li n e ar tr a p e z oi d al r ul e.  T m a x ,  h alf-lif e  a n d r ati os   will  b e list e d t o t  w o  si g nific a nt 
fi g ur es.    All  ot h er  p ar a  m et ers   will  b e list e d t o t hr e e si g nifi c a nt fi g ur es. 
9. 2     
D at a  q u alit y  ass u r a n c e 
Q u alit y  c o ntr ol  a n d  q u alit y  ass ur a n c e   will  b e  pr o vi d e d  as s p e cifi e d i n t h e s p o ns or’s  S  O P’s 
t o  e ns ur e  a p pr o pri at e  cli ni c al  c ar e  a n d  d at a i nt e grit y. 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
6 4  
9. 3   
S a  m pl e si z e  r ati o n al e  
W e  h a v e  c h os e n  a  s a  m pl e  si z e  of   6  p ati e nts  p er  c o h ort , wit h t h e  o pti o n t o  e nr oll  u p t o   a n 
a d diti o n al  1 2  at  a  si n gl e  d os e l e v el  ( o pti  m al  bi ol o gi c al d os e) .   T his is  a  s uffi ci e nt  n u  m b er 
of  p ati e nts t o i d e ntif y   D L Ts.   
9. 4   
I nt e ri  m  d at a  an a ylsis 
At t h e  c o  m pl eti o n  of  d os e  es c al ati o n, i nt eri  m  d at a  a n al ysis   will  b e  c o  m pl et e d t o  ass ess  BI  O 
3 0 0 s af et y  a n d t o r e vi e  w s e c o n d ar y  o ut c o  m e   m e as ur es.  D at a   tr e n ds   will  b e  us e d t o  c h o os e 
a  si n gl e   BI  O  3 0 0  d os e ( 5 0 0,  1 0 0 0  or  1 5 0 0  m g/ d)  as t h e  o pti  m al  b i ol o gic al  d os e.    U p t o  a n 
a d diti o n al  1 2  s u bj e cts  will  b e  e nr oll e d  at t h e   o pti  m al  b i ol o gi c al  d os e t o f urt h er  e v al u at e 
BI  O  3 0 0  ’s  s af et y  a n d effi c a c y.   T h e   m a xi  m u  m t ol er at e d  d os e   will  b e  us e d  f or  c o h ort  4  if 
t h er e  ar e  n o  a p p ar e nt  diff er e n c es i n  effi c a c y. 
9. 5   
St atist i c al  a n al ysis  of  d at a 
A n i n d e p e n d e nt st atisti ci a n  usi n g st a n d ar d st atisti c al t e c h ni q u es   will  d et er  mi n e st atisti c all y 
si g nifi c a nt   diff er e n c es  i n  t h e  tri al    m e as ur e  m e nt   d at a   at  t h e   n o  mi n al   0. 0 5  l e v el   of 
si g nifi c a n c e.          D at a    will  b e  s u  m  m ari z e d  b y  d es cri pti v e  st atisti cs  (  m e a n/  m e di a ns  a n d 
st a n d ar d  err ors/ c o nfi d e n c e  i nt er v als  f or  c o nti n u o us  r es p o ns e  v ari a bl es  a n d  distri b uti o n 
t a bl es  or  hist o gr a  ms  f or  dis cr et e  r es p o ns e  v ari a bl es).  I n  a d diti o n,  r el ati o ns hi ps  b et  w e e n 
t h es e r es p o ns e  v ari a bl es   will  b e e x pl or e d  usi n g  no n -p ar a  m etri c  a p pr o a c h es ( e. g.,  S p e ar  m a n 
r a n k  c orr el ati o n),  p ar a  m etri c  c orr el ati o n  a n al ysis   m et h o ds ( e. g.,  c orr el ati o n  c o effi ci e nt),  or 
a p pr o pri at e   st atisti c al   t ests   ( e. g.,   t h e     C hi -s q u ar e   tr e n d   t est   f or   c at e g ori c al   d at a). 
F urt h er  m or e,  a p pr o pri at e r e gr essi o n t e c h ni q u es f or t h es e r es p o ns e  v ari a bl es ( e. g.,  a n al ysis 
of   v ari a n c e/ c o v ari a n c e  (  A  N  O  V  A/  A  N  C  O  V  A)),  li n e ar  r e gr essi o n,   pr o p orti o n al   h a z ar ds 
r e gr essi o n, l o gisti c r e gr essi o n,   G E E  a n d   mi x e d  eff e cts   m o d els)   will  b e  e  m pl o y e d t o f urt h er 
e x a  mi n e t h eir r el ati o ns hi p  wit h  o n e  a n ot h er.  C o nfi d e n c e i nt er v als   will  b e  c al c ul at e d f or t h e 
diff er e n c es.   T h e  c o  m p ut e d  c h a n g e  fr o  m  b as eli n e    will  b e  c al c ul at e d  f or  all    m e as ur e d 
v ari a bl es  a n d  e x pr ess e d  as t h e   m e a n  c h a n g e fr o  m  b as eli n e  + st a n d ar d  d e vi ati o n ( S  D)  of t h e 
c h a n g e fr o  m  b as el i n e.    A t  w o-s a  m pl e t-t est   will  b e  us e d t o t est t h e t u  m or si z e r e d u cti o n  a n d 
a l o g -r a n k t est   will  b e  us e d t o  c o  m p ar e ti  m e t o  e v e nt  o ut c o  m es. 
 
St atisti c al a n al ys es  of t h e  F  A  C T -T  OI  d at a   will  b e  p erf or  m e d   wit h t h e  us e  of  S P S S s oft  w ar e, 
v ersi o n  1 6. 0 ;  e a c h  p ati ent    will  b e  us e d  as  his/ h er  o  w n  c o ntr ol.   A n al ysis  of  v ari a n c e 
(  A  N  O  V  A)   will  b e  us e d t o  c o  m p ar e   m e a n   U  C S  D-S  O  B  c h a n g e s c or es l o n git u di n all y (fr o  m 
b as eli n e t o f oll o  w -u p  visits).   T h e   A  N  O  V  As  c a n  b e f oll o  w e d   wit h  p - v al u e-a dj ust e d,  p air -
wis e ( p ar a  m etri c  a n d t h e n  n o  n- p ar a  m etri c)  c o  m p aris o ns  of t h e   m e a n   U  C S  D -S  O  B  c h a n g e 
s c or es.   M ulti v ari at e li n e ar r e gr essi o n  a n al ys es,  a dj ust e d f or  b as eli n e s c or es,   will  b e  us e d t o 
e x a  mi n e t h e  p ati e nt  r e p ort e d  o ut c o  m es  ( P  R  O).  T h e  s  w all o  wi n g  di ar y   will  b e  s c or e d  a n d 
a n al y z e d  as  pr e vi o usl y  d es cri b e d  [ 2 6]. 
 
Usi n g  k n o  w n  p h ar  m a c o ki n eti c  p ar a  m et ers  of  p a clit a x el  a n d  c ar b o pl ati n, t h e  ar e a  u n d er t h e 
s er u  m  ( or  pl as  m a)  c o n c e ntr ati o n -ti  m e  c ur v e  (  A  U  C  i n   m g *  mi n/  m L)  will  b e  us e d   b y  t h e 
s p o ns or t o  ass ess t h e  effe ct  of   BI  O  3 0 0   Or al  S us p e nsi o n  o n t h e  p h ar  m a c o ki n eti c  pr ofil e  of 
t h e i n di vi d u al  c h e  m ot h er a p e uti cs.  A  si  mil ar   m et h o d   will  b e  us e d t o  ass ess t h e  eff e ct  of 
p a clit a x el a n d c ar b o pl ati n  o n t h e  p h ar  m a c o ki n eti cs  of  BI  O  3 0 0   Or al  S us p e nsi o n.   F oll o  wi n g 
a  si n gl e  d os e  of   BI  O  3 0 0   Or al  s us p e nsi o n  (t h e  first   w e e k  of t h e  st u d y) t h e   A  U  C   will  b e 
d et er  mi n e d.  T h e f oll o  wi n g   w e e k  c h e  m ot h er a p y   will  b e  a d d e d t o t h e tr e at  m e nt r e gi  m e n  a n d 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
6 5  
A  U  C  v al u es   will  b e  d et er  mi n e d f or  e a c h  of t h e  dr u gs ( p a clit a x el,  c ar b o pl ati n,  a n d  BI  O  3 0 0 
Or al  S  us p e nsi o n).  T h e   A  U  C  v al u es  at t his ti  m e p oi nt   will  b e  c o  m p ar e d t o t h at  o bt ai n e d aft er 
a   BI  O  3 0 0  d os e  o nl y  a n d  t o  t h e  pr e d et er  mi n e d  pl a n n e d   A  U  C  v al u es  of  p a clit a x el  a n d 
c ar b o pl ati n.  T his   m et h o d ol o g y   will  d et er  mi n e  p ot e nti al  BI  O  3 0 0  -m e di at e d   eff e cts  o n  dr u g 
e x p os ur e  of t h e c h e  m ot h er a p e uti cs a n d a n y c h e  m ot h er a p e uti c -m e di at e d eff e cts  o n  BI  O  3 0 0 
dr u g  e x p os ur e.  Pr o vi d e d t h at t h e i n ci d e n c e  of   D L Ts  h as  n ot  e x c e e d e d t h e t hr es h ol d f or tri al 
dis c o nti n u ati o n  a n d  d os e  es c al ati o n t h e tri al   will  b e  all o  w e d t o  c o nti n u e. 
 
I n a d diti o n t o t h e  d at a  a n d   m et h o ds  d es cri b e d  a b o v e,  a d diti o n al tri al  d at a t o  b e  a n al y z e d 
fr e q u e n c y  of   D L Ts,  p h ar  m a c o d y n a  mi cs,  p ul  m o n ar y f u n cti o n t est, a n d  E  C  O  G  p erf or  m a n c e. 
P ot e nti al  p h ar  m a c o d y n a  mi cs  m ar k ers i n cl u d e t h e  c yt o ki n es   I L-6, I L - 1β,  I L- 1α,  I L-8, I L-
1 0,   T  N F α,  T  G F β 1,   T  G F β 2,  a n d   T  G F β 3.  S er u  m  pr ot ei ns  of i nt er est i n cl u d e  gr a n ul o c yt e 
c ol o n y  sti  m ul ati n g  f a ct or  (  G -C S F),    C  -r e a cti v e  pr ot ei n,  a n d  pr ost a gl a n di n    E 2.  Fi n all y, 
p ul  m o n ar y f u n cti o n ( b y  s pir o  m etr y)   will  b e   m e as ur e d i n t h e  st u d y.  F or c e d   Vit al   C a p a cit y 
( F  V  C)   a n d   F or c e d    E x pir at or y    V ol u  m e  i n  t h e   first   s e c o n d   ( F E  V 1)    will   b e   s c or e d 
l o n git u di n all y f or i n di vi d u al s u bj e cts i n t h e st u d y  as  d es cri b e d  a b o v e. 
1 0. 0   A  D  MI  NI S  T  R  A  TI  V  E  P  R  O  C  E  D  U  R  E S   
1 0. 1   S u bj e ct i nf o r  m e d  c o ns e nt  
All  p ot e nti al st u d y  p arti ci p a nts   will  b e  gi v  e n a c o p y  of t h e I R  B -a p pr o v e d I nf or  m e d  C o ns e nt 
t o r e vi e  w.  T h e i n v esti g at or   will  e x pl ai n  all  as p e cts  of t h e st u d y i n l a y l a n g u a g e  a n d  a ns  w er 
all  q u esti o ns  r e g ar di n g  t h e  st u d y.  If  t h e  p arti ci p a nt  d e ci d es  t o  p arti ci p at e  i n  t h e  st u d y, 
h e/s h e    will  b e  as k e d  t o  s i g n  t h e  I nf or  m e d    C o ns e nt  d o c u  m e nt.    A  c o p y  of  t h e  si g n e d 
I nf or  m e d   C o ns e nt   will  b e  gi v e n t o t h e st u d y  p arti ci p a nt  a n d t h e  ori gi n al I nf or  m e d   C o ns e nt 
d o c u  m e nt  will  b e  k e pt  o n fil e  .  T h e st u d y  a g e nt(s)   will  n ot  b e r el e as e d t o  a  p arti ci p a nt   w h o 
h as  n ot  si g n e d t h e  I nf or  m e d   C o ns e nt  d o c u  m e nt.  P ati e nts   w h o r ef us e t o  p arti ci p at e  or   w h o 
wit h dr a  w fr o  m t h e st u d y   will  b e tr e at e d   wit h o ut  pr ej u di c e.    
T h e i nf or  m e d  c o ns e nt  d o c u  m e nt   m ust  b e r e vi e  w e d  a n d  a p pr o v e d  b y t h e I  R  B,  a n y  c h a n g es 
t o t h e i nf or  m e d  c o ns e nt   m ust  b e s u b  mitt e d t o t h e I  R  B f or  a p pr o v al  pri or t o i niti ati o n.   
1 0. 2    I  R  B   A p p r o v al 
Pri or  t o  i niti ati n g  t h e  st u d y  a n d  r e c ei vi n g  a g e nt,  t h e   r es e ar c h  sit e  m ust  o bt ai n    writt e n 
a p pr o v al t o c o n d u ct t h e st u d y fr o  m t h e a p pr o pri at e I  R  B  a n d s u b  mit t h e a p pr o v al  d o c u  m e nts 
t o t h e s p o ns or.  
1 0. 3   S u bj e ct  c o nfi d e nti alit y  
I n  or d er t o   m ai nt ai n  s u bj e ct  c o nfi d e nti alit y,  a  s u bj e ct  n u  m b er  a n d i niti als   will i d e ntif y  all 
st u d y s u bj e cts  o n   C  R Fs  a n d  ot h er  d o c u  m e nt ati o n s u b  mitt e d t o t h e  S p o ns or.   
1 0. 4   Et hi c al  c o n d u ct  of t h e st u d y   
Pri or t o i niti ati n g  t his  st u d y, t h e Pri n ci p al I n v esti g at or  at  e a c h r es e ar c h  sit e  will  pr o vi d e  a 
si g n e d  F or  m  F  D  A  1 5 7 2  st ati n g  t h at  t h e  st u d y    will  b e  c o n d u ct e d  i n  c o  m pli a n c e    wit h 
r e g ul ati o ns f or  cli ni c al i n v esti g ati o ns  a n d listi n g t h e i n v esti g at ors t h at   will  b e  p arti ci p ati n g 
i n t h e  pr ot o c ol. 
 
T his  st u d y    will  b e  p erf or  m e d  as  o utli n e d  u n d er  I  N  D  1 1 9 3 2 2  i n  c o  m pli a n c e    wit h  t his 
pr ot o c ol   a n d   all   a p pli c a bl e  r e g ul ati o ns   a n d   g ui d eli n es  ( e. g.    G o o d    Cli ni c al   Pr a cti c e 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
6 6  
G ui d eli n es, t h e   D e cl ar ati o n  of   H elsi n ki,  2 1   C F  R 5 0  – Pr ot e cti o n  of   H u  m a n  S u bj e cts,  a n d  2 1 
C  F  R 5 6 –I nstit uti o n al   R e vi e  w   B o ar ds).   
1 0. 5   P r ot o c ol  a  m e n d  m e nts  
S h o ul d  c h a n g es  b e c o  m e  n e c ess ar y,  pr ot o c ol  a  m e n d  m e nts   will  b e  s u b  mitt e d  a n d  a p pr o v e d 
b y t h e I  R  B  pri or t o i  m pl e  m e nt ati o n.  
1 0. 6   M o nit o ri n g   
1 0. 6. 1   O n  -sit e   M o nit o ri n g 
T h e s p o ns or  will     mo nit or t h e  pr o gr ess  of  all  cli ni c al i n v esti g ati o ns  b ei n g  c o n d u ct e d  u n d er 
its  I  N  D b as e d  o n  t h e  st u d y  s p e cifi c    M o nit ori n g  Pl a n . M o nit ori n g  visits  ar e  i nt e n d e d  t o 
e ns ur e  t h e   pr ot o c ol   a n d   a p pli c a bl e  r e g ul at or y  r e q uir e  m e nts   ar e   b ei n g  f oll o  w e d,  t h e 
i n v esti g at or is  a d e q u at el y  o v ers e ei n g t h e  c o n d u ct  of t h e  st u d y,  s u bj e cts’ ri g hts  a n d  s af et y 
ar e  pr ot e ct e d  a n d  t o  c o nfir  m  d at a  i nt e grit y  a n d  q u alit y.   Aft er  t h e  r es e ar c h  sit e  h as  b e e n 
q u alifi e d, r e c ei v es I  R  B  a p pr o v al  a n d  h as  b e e n tr ai n e d  a n d i nti at e d t h e   m o nit or   will  p er f or  m 
r o uti n e i nt eri  m  visits. I nt eri  m  visits   will o c c ur  o n  a n  o n g oi n g  b asis,  as  d es cri b e d   b el o  w.  At 
a   mi ni  m u  m,  p eri o di c   m o nit ori n g   will  o c c ur  o n  a n  a n n u al  b asis f or  a n y  i n v esti g ati o n al sit e 
wit h  at l e ast  1 s u bj e ct  e nr oll e d.    
 
F r e q u e n c y  of  O n  -Sit e   M o nit o ri n g   Visits  
P h as e  of  St u d y  
Esti  m at e d   M o nit o ri n g   Visit  F r e q u e n c y   
I niti al  E nr oll  m e nt 
Aft er e nr oll  m e nt  of t h e first  1  or  2 s u bj e cts at e a c h 
sit e.  
 
Tr e at  m e nt   &  F oll o  w -u p  
E v er y   6 -8   w e e ks    d e p e n di n g  o n  t h e  n u  m b er  of 
s u bj e cts  e nr oll e d  a n d  visits t o  b e   m o nit or e d  
P ri or t o  d os e  es c al ati o n t o  n e xt  c o h ort 
Aft er   s u c c e ssf ul   c o  m pl eti o n   (l ess   t h a n   3 3  % 
D L T s) i n t h e  c o n c urr e nt  c h e  m or a di ati o n  p eri o d    
E n d  of  f oll o  w u p 
Aft er l ast  s u bj e ct l ast  visit i n  e a c h   sit e  
Cl os e  -o ut  
Aft er  all  d at a  q u eri es  h a v e  b e e n  cl os e d   
 
I n  a d diti o n t o t h e   m o nit ori n g fr e q u e n c y list e d  a b o v e, i nt eri  m  visits   m a y  n e e d t o  b e   m or e 
fr e q u e nt if t h er e is 
1)    A  c h a n g e i n st u d y  p ers o n n el (t o  all o  w f or tr ai ni n g  a n d  a d diti o n al s p o ns or 
o v ersi g ht) 
2)    A  pr ot o c ol  a  m e n d  m e nt/s af et y iss u e t h at si g nifi c a ntl y  aff e cts st u d y  pr o c e d ur  es 
or  d esi g n 
3)    A  d o c u  m e nt e d  or s us p e ct e d l a c k  of st u d y  c o  m pli a n c e  or i n v esti g at or  o v ersi g ht 
4)    A n iss u e   wit h r e cr uit  m e nt  or  e nr oll  m e nt   
 
If t h e  st u d y  s p o ns or  dis c o v ers t h at  a  p arti ci p ati n g  i n v esti g at or is  n ot  c o  m pl yi n g   wit h t h e 
si g n e d   a gr e e  m e nt   ( F or  m    F  D  A - 1 5 7 2),   t h e    g e n er al   i n v esti g ati o n al    pl a n,    or   ot h er 
r e q uir e  m e nts t h e st u d y s p o ns or s h all  pr o  m ptl y  eit h er s e c ur e  c o  m pli a n c e  or  dis c o nti n u e t h e 
i n v esti g at or’s  p arti ci p ati o n i n t h e i n v esti g ati o n.  
1 0. 6. 2   S af et y   D at a   M o nit o ri n g  a n d   R e p o rti n g 
T h e s p o ns or  will   r e vi e  w  a n d e v al u at e t h e  e vi d e n c e r el ati n g t o t h e s af et y  a n d  eff e cti v e n ess 
of t h e  dr u g  as it is  o bt ai n e d fr o  m t h e  p arti ci p ati n g  i n v esti g at or. F or r e vi e  wi n g  a n d r e p orti n g 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
6 7  
of s af et y  d at a, t h e s p o ns or   will f oll o  w  F  D  A r e g u l ati o ns,  I C  H   G  C P E 6,  a p pli c a bl e s p o ns or 
S  O Ps  a n d  t h e st u d y s p e cifi c   Cli ni c al  S af et y  Pl a n.   
T h e  n otifi c ati o n  pr o c ess t o t h e st u d y s p o ns or  of  all s af et y  d at a  b e gi ns   wit h  t h e  c o  m pl eti o n 
a n d  s u b  missi o n  of t h e  a p pr o pri at e   C  R F s  or i n t h e  c as e  of  a  i niti al s eri o us  e v e nt r e p orti n g,  
b y  p h o n e . I n v esti g at ors ar e  r e q uir e d t o r e p ort  pr o  m ptl y t o t h e  s p o ns or  a n y  a d v ers e  e v e nts 
t h at    m a y  r e as o n a bl y  b e  r e g ar d e d  as  c a us e d  b y,  or  pr o b a bl y  c a us e d  b y,  t h e  dr u g.  If  t h e 
A  d v ers e  E v e nt   (  A E) m e ets t h e   S eri o us   A d v ers e  E v e nt   ( S  A E) crit eri a, t h e i n v esti g at or is 
r e q uir e d t o r e p ort t h e  e v e nt t o t h e s p o ns or   wit hi n  2 4  h o urs  of a  w ar e n ess .   
 
T o   R e p o rt  a  S  A  E   c all t h e  H u  m a n eti cs   A d v e rs e   E v e nt   R e p o rti n g    li n e: 
 or  b y  c o nt a cti n g t h e   m e di c al   m o nit or  
 
M e di c al   M o nit o r   
Mi c h a el   K ur  m a n,   M  D   
 
 
 
 
Pr o  m pt  r e vi e  w  of t h e  S  A E  b y t h e   m e di c al   m o nit or   will  b e  c o  m pl et e d t o  d et er  mi n e if t h e 
e v e nt   m e ets  a n y  of t h e  crit eri a f or  r e p orti n g t o t h e  F  D  A , I n v esti g at ors,  a n d/ or I nstit uti o n al 
R e vi e  w   B o ar ds (I R  B).    S h o ul d  a n  S  A E  b e  d et er  mi n e d t o   m e et t h e  crit eri a f or  a  7  or  1 5  d a y 
r e p ort a bl e  e v e nt, t h e  F  D  A   will  b e  n otifi e d  a c c or di n gl y.  
T h e   m e di c al   m o nit or   will  assist i n   writi n g t h e  I  N  D  s af et y  r e p ort   wit h t h  e  st u d y  s p o ns or. 
T h e s p o ns or  will   s u b  mit  all  n e c ess ar y r e p orts t o  F  D  A r e g ar di n g i nf or  m ati o n r ele v a nt t o t h e 
s af et y  of t h e  dr u g.  
N o   D at a  S af et y   M o nit ori n g   B o ar d (  D S  M  B) is r e q uir e d f or t his st u d y  h o  w e v er, s af et y  d at a 
will  b e r e vi e  w e d  b y t h e s p o ns or  o n  a n  o n g oi n g  b asis  a n d  q u art erl y f or tr e n di n g  of  a d v ers e 
e v e nts  a n d  cli ni c all y r el e v a nt  s af et y  d at a  o v er ti  m e t o i d e ntif y  p ot e nti al  s af et y  si g n als  a n d 
t h e n  d et er  mi n e if  a n y  a cti o n is  n e e d e d t o  e ns ur e t h e s af et y  of s u bj e cts.  
T h e  s p o ns or   will  n otif y  t h e  PIs  at  e a c h  sit e  r e g ar di n g  a n y  d os e  li  miti n g  t o xi cit y  (  D L T) 
a n d/ or  S  A E r el at e d t o   BI  O  3 0 0.  S h o ul d t h e  s p o ns or d et er  mi n e  t h at t h e i n v esti g ati o n al  dr u g 
pr es e nts  a n  u nr e as o n a bl e  a n d si g nifi c a nt ris k t o s u bj e cts  t h e st u d y s h all  b e  dis c o nti n u e d. I n 
t his  c as e, t h e  st u d y  s po ns or   will  n otif y  t h e F  D  A,  all i nstit uti o n al  r e vi e  w  b o ar ds,  a n d  all 
i n v esti g at ors   w h o  h a v e  at  a n y ti  m e  p arti ci p at e d i n t h e i n v esti g ati o n  of t h e  dis c o nti n u a n c e 
a n d  ass ur e t h e  dis p ositi o n  of  all  st o c ks  of t h e  dr u g  o utst a n di n g,  a n d  f ur nis h  F  D  A   wit h  a 
f ull r e port  of t h e s p o ns or’s  a cti o ns.  
 
1 0. 6. 3    P r ot o c ol   D e vi ati o ns 
C  o  m pli a n c e   wit h t h e  st u d y  pr ot o c ol  a n d  all  st u d y  pr o c e d ur es   will  b e  ass ess e d  at  e a c h   o n-
sit e   m o nit ori n g  visit.   A  pr ot o c ol  d e vi ati o n f or t his st u d y is  d efi n e d  as  a n y  d e p art ur e fr o  m 
t h e  pr ot o c ol   w h et h er  pr e-a p pr o v e d  b y t h e  s p o ns or  or  u n pl a n n e d.  Pr ot o c ol  d e vi ati o ns   m a y 
b e i d e ntifi e d  d uri n g   m o nit ori n g  visits  or  b y t h e sit e  eit h er i n  a nti ci p ati o n  of  a  d e v ai ati o n  or 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
6 8  
u p o n  dis c o v er y.  T h e r es e ar c h  sit e  s h o ul d  c o  m pl et e  a  Pr ot o c ol   D e vi ati o n   C  R F  a n d  s u b  mit 
it t o t h e s p o ns or  aft er r e vi e  w  a n d  si g n at ur e  b y t h e i n v esti g at or. 
O n  a  q u art erl y  b as  is,  t h e  s p o ns or   will  r e vi e  w  pr ot o c ol  d e vi ati o ns b y  sit e  a n d  o v er all  t o 
d et er  mi n e if t h er e  ar e  a n y tr e n ds i d e ntifi e d  t h at   m a y  aff e ct  p ati e nt s af et y,  d at a i nt e grit y  a n d 
t h e i  mp a ct  o n  a n al ysis  a n d t o  d et er  mi n e if  a n y  a cti o ns  n e e d t o  b e t a k e n  pr e v e nt  c o nti n u e d 
d e vi ati o ns.  
1 0. 7   R e c o r ds  r et e nti o n   
Cli ni c al  r e c or ds  f or   all   p arti ci p a nts,  i n cl u di n g   all  s o ur c e   d o c u  m e nt ati o n  ( c o nt ai ni n g 
e vi d e n c e  t o  st u d y  eli gi bilit y,  hist or y  a n d  p h ysi c a l  fi n di n gs,  l a b or at or y  d at a,  r es ults  of 
c o ns ult ati o ns,  et c.),  as   w ell  as  I R  B  r e c or ds  a n d  ot h er  r e g ul at or y  d o c u  m e nt ati o n   will  b e 
r et ai n e d  b y t h e  Pr ot o c ol  L e a d I n v esti g at or i n  a  s e c ur e  st or a g e f a cilit y i n  c o  m pli a n c e   wit h 
HI P  A  A,   O  H  R P,  F  D  A  r e g ul ati o ns  a n d  g ui d  a n c e,  u nl ess  t h e  st a n d ar d  at  t h e  sit e  is    m or e 
stri n g e nt.   T h e  r e c or ds  f or  all  st u di es  p erf or  m e d  u n d er  a n  I  N  D   will  b e    m ai nt ai n e d,  at  a 
mi ni  m u  m,  f or t  w o  ( 2)  y e ars  aft er t h e  a p pr o v al  of  a n   N  D  A.   T h e  s p o ns or   will  b e  n otifi e d 
pri or  t o  t h e  pl a n n e d  d estr u cti o n  of  a n y    m at eri als.   T h e  r e c or ds  s h o ul d  b e  a c c essi bl e  f or 
i ns p e cti o n  a n d  c o p yi n g  b y  a ut h ori z e d  p ers o ns  of t h e  F o o d  a n d   Dr u g   A d  mi nistr ati o n.  
 
 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
6 9  
1 1. 0   R  E F  E  R  E  N  C  E S   
1.   
C a n c er  of t h e  L u n g  a n d  Br o n c h us  - S E E R  St at  F a ct  S h e ets .   2 0 1 7- 0 6-2 1];   A v ail a bl e 
fr o  m: htt p://s e er. c a n c er. g o v/st atf a cts/ ht  ml/l u n g b. ht  ml . 
2.   
C a n c er     
F a cts    
a n d     
Fi g ur es    
2 0 1 4  .    
2 0 1 4;     
A v ail a bl e    
fr o  m: 
htt p://  w  w  w. c a n c er. or g/r es e ar c h/ c a n c erf a ctsst atisti cs/ c a n c erf a ctsfi g ur es 2 0 1 4/ . 
3.   
P ol k o  ws ki,   K.  a n d   A. P.   M a z ur e k,  Bi ol o gi c al  pr o p erti es  of  g e nist ei n.  A r e vi e  w  of i n 
vitr o  a n d i n  vi v o  d at a.    A ct a  P ol  P h ar  m,  2 0 0 0. 5 7 ( 2):  p.  1 3 5- 5 5. 
4.   
P a v es e, J.  M .,   R. L.  F ar  m er,  a n d   R.  C.   B er g a n, I n hi biti o n  of  c a n c er  c ell i n v asi o n  a n d 
m et ast asis  b y  g e nist ei n.     C a n c er   M et ast asis   R e v,  2 0 1 0. 2 9 ( 3):  p.  4 6 5- 8 2. 
5.   
Ki  m,   K.  H.,  et  al.,   Hi g h  d os e  g e nist ei n  a gl y c o n e  t h er a p y  is  s af e  i n  p ati e nts   wit h 
m u c o p ol ys a c c h ari d os es i n v ol vi n g t h e  c e ntr al  n er v o us  s yst e  m.   M ol   G e n et    M et a b, 
2 0 1 3.  1 0 9 ( 4):  p.  3 8 2- 5. 
6.   
Fis c h er,   L.,  et  al.,   Cli ni c al  c h ar a ct eristi cs  a n d  p h ar  m a c o ki n eti cs  of  p urifi e d  s o y 
is ofl a v o n es:    m ulti pl e-d os e  a d  mi nistr ati o n  t o    m e n    wit h  pr ost at e  n e o pl asi a.   N utr 
C a n c er,  2 0 0 4.   4 8 ( 2):  p.  1 6 0- 7 0. 
7.   
P o p,   E.  A.,  et  al.,  Eff e cts  of  a  hi g h  d ail y  d os e  of  s o y is ofl a v o n es  o n   D  N A  d a  m a g e, 
a p o pt osis,  a n d  estr o g e ni c  o ut c o  m es i n  h e alt h y  p ost  m e n o p a us al   w o  m e n:  a  p h as e I 
cli ni c al tri al.    M e n o p a us e,  2 0 0 8. 1 5 ( 4  Pt  1):  p.  6 8 4- 9 2. 
8.   
Pl ass  m a n n,  S.,  R o  2 4 -2 0 7 6/ 0 0 0  S e g  m e nt II:   Or al  st u d y f or  eff e cts  o n  e  m br y o -f et al  
d e v el o p  m e nt i n t h e r at.   1 9 9 7,   H off  m a n - L a   R o c h e  Lt d.,   B asl e (  C  H).  
9.   
W ol z,   E.  R.,   D.;  S c h  mi d,   H.;   H o  w al d,   M.;   K n u p p e,   C.,   R o  2 4 -2 0 7 6/ 0 0 0:  1 3 -W e e k 
or al t o xi cit y  (f e e d  a d  mi x)  st u d y i n t h e  r at.   2 0 01,   H off  m a n -L a   R o c h e,   B asl e (  C  H) 
( T esti n g I nstit uti o n:   R  C  C  Lt d., Iti n g e n,  S  wit z erl a n d). 
1 0.   
Kir c h n er,   S.,   M o us e  l y  m p h o  m a  c ell    m ut ati o n  t est  (  M L/ T  K)  ( 2 1 3    M 0 0).    2 0 0 0, 
H off  m a n   - L a   R o c h e  Lt d.,   B asl e (  C  H).  
1 1.   
M ust er,    W.,   R o  2 4 -2 0 7 6/ 0 0 0:    Mi cr o n u cl e us  T est  (  M  N T)  i n   P eri p h er al   Bl o o d  of 
Mi c e  aft er  R e p e at e d   Or al  A d  mi nistr ati o n (  G a v a g e) ( 1 3 8  M 9 6)  .  1 9 9 9,   H off  m a n - L a 
R o c h e  Lt d.,   B asl e (  C  H).   
1 2.   
W ol z,  E.  D.,   B.;   C h et el at,   A.;   M att h es,   B.;  Fl a d e,   D.,   R o  2 4 -2 0 7 6/ 0 0 0 (  G e nist ei n): 
Mi cr o n u cl e us   Ass a y i n   B o n e   M arr o  w   C ells  of t  h e   R at  aft er   Or al   A d  mi nistr ati o n 
(  G a v a g e).  2 0 0 4,   R o c h e   Vit a  mi ns   Lt d.,   B asl e  (  C  H)    ( T esti n g  F a cilit y:   R  C  C   Lt d., 
Iti n g e n,  S  wit z erl a n d). 
1 3.   
Milt y k,    W.,  et  al.,   L a c k  of  si g nifi c a nt  g e n ot o xi cit y  of  p urifi e d  s o y  is ofl a v o n es 
( g e nist ei n,  d ai dz ei n,  a n d  gl y cit ei n) i n  2 0  p ati e nts   wit h  pr ost at e  c a n c er. A  m  J   Cli n 
N utr,  2 0 0 3.   7 7 ( 4):  p.  8 7 5- 8 2. 
1 4.   
S c h  mitt,    G.,   T h e  t er at o g e ni c  p ot e nti al  of   R o  2 4 -2 0 7 6/ 0 0 0  (    G e nist ei n):    W h ol e 
e  m br y o  c ult ur e  ass a y.   1 9 9 7,   H off  m a n -  L a   R o c h e  Lt d.,   B asl e (  C  H). 
1 5.   
M c  Cl ai n,  R.  M.,  et  al.,   S u b c h r o ni c  a n d  c hr o ni c s af et y st u di es  wit h  g e nist ei n i n  d o gs.  
F o o d   C h e  m  T o xi c ol,  2 0 0 5.  4 3 ( 1 0):  p.  1 4 6 1- 8 2. 
1 6.   
H u  m a n eti cs,   BI  O  3 0 0:  2 8 -D a y  I ntr a v e n o us  I nj e cti o n  T o xi cit y  St u d y i n   M al e  a n d 
F e  m al e  B e a gl e   D o gs  R e p ort .  2 0 1 3.  p.  7 1 1. 
1 7.   
H u  m a n eti cs,   BI  O  3 0 0:   A  I ntr a  m us c ul ar  Si n gl e   M a xi  m u  m  T ol er at e d   D os e  a n d  7  -
D a y   R e p e at   D os e   R a n g e  -Fi n di n g  T o xi cit y  St u d y i n   B e a gl e   D o gs   R e p ort .  2 0 1 3.  p. 
1 7 9. 
1 8.   
H u  m a n eti cs,   BI  O  3 0 0:   A  7 -D a y  I ntr a v e n o us  I nj e cti o n  T o xi cit y  St u d y  i n   B e a gl e 
D o gs  R e p ort  .  2 0 1 3.  p.  2 0 5. 


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
 
C  O  N FI  D  E  N  TI  A  L  I  N F  O  R  M  A  TI  O  N   O F   H  U  M  A  N  E  TI  C S   C  O  R P  O  R  A  TI  O  N   
7 0  
1 9.   
H u  m a n eti cs,   D e v el o  p  m e nt  of  BI  O  3 0 0  As  A  R a di ati o n   M o d ul at or  F or   Us e   D uri n g 
R a di ot h er a p y   Of  L u n g   C a n c er -   N  CI  P h as e I  Fi n al  R e p ort .  2 0 1 4. 
2 0.   
K ari  m,    N.  A.,  et  al.,   P h as e  II    Cli ni c al  Tri al  of    G efiti ni b  f or  t h e  Tr e at  m e nt  of 
C h e  m o n ai v e    P ati e nts    wit h    A d v a n c e d    N o n  -s  m all    C ell   L u n g    C a n c er    wit h    P o or 
P erf or  m a n c e  St at us.    Cli n   M e d I nsi g hts   O n c ol,  2 0 1 4. 8 :  p.  1 2 1- 8. 
2 1.    
S e ki n e, I.,  et  al.,  Q u alit y  of lif e  a n d  dis e as e  -r el at e d s y  m pt o  ms i n  pr e vi o usl y tr e at e d 
J a p a n es e  p ati e nts   wit h  n o n -s  m all-c ell l u n g  c a n c er:  r es ults  of  a  r a n d o  miz e d  p h as e 
III st u d y ( V- 1 5- 3 2)  of  g efiti ni b  v ers us  d o c et a x el.   A n n   O n c ol,  2 0 0 9. 2 0 ( 9):  p.  1 4 8 3-
8. 
2 2.   
C ell a,    D.,   et   al.,   W h at  is   a   cli ni c all y    m e a ni n gf ul   c h a n g e   o n  t h e    F u n cti o n al 
Ass ess  m e nt   of    C a n c er   T h er a p y -L u n g  ( F A  C T -L)    Q u esti o n n air e ?    R es ults  fr o  m 
E ast er n    C o o p er ati v e    O n c ol o g y    Gr o u p  ( E  C  O  G)  St u d y  5 5 9 2.    J    Cli n    E pi d e  mi ol, 
2 0 0 2.  5 5 ( 3):  p.  2 8 5- 9 5. 
2 3.   
C ell a,   D. F.,  et  al.,   R eli a bilit y  a n d  v ali dit y  of t h e  F u n cti o n al  Ass ess  m e nt  of   C a n c er 
T h er a p y- L u n g  ( F A  C T -L)  q u alit y  of lif e i nstr u  m e nt.  L u n g   C a n c er,  1 9 9 5.   1 2 ( 3):  p. 
1 9 9- 2 2 0. 
2 4.    
S wi gris,  J.J.,  et  al.,   T h e   U  C S  D  s h ort n ess  of  br e at h  q u esti o n n air e  h as l o n git u di n al 
c o nstr u ct  v ali dit y i n i di o p at hi c  p ul  m o n ar y fi br osis.  R es pir   M e d,  2 0 1 2.   1 0 6 ( 1 0):  p. 
1 4 4 7- 5 5. 
2 5.   
F a y ers,  P.  M.,  et  al.,  Ass ess  m e nt  of  q u alit y  of lif e i n  s  m all -c ell l u n g  c a n c er  usi n g  a 
D ail y    Di ar y    C ar d  d e v el o p e d  b y  t h e    M e di c al    R es e ar c h    C o u n cil   L u n g    C a n c er 
W or ki n g  P art y.     Br J   C a n c er,  1 9 9 1. 6 4 ( 2):  p.  2 9 9- 3 0 6. 
2 6.   
M o vs as,   B.,  et  al.,   R a n d o  miz e d tri al  of  a  mif osti n e i n l o c all y  a d v a n c e d  n o n -s  m all-
c ell l u n g  c a n c er  p ati e nts r e c ei vi n g  c h e m ot h er a p y  a n d  h y p erfr a cti o n at e d r a di ati o n: 
r a di ati o n t h er a p y  o n c ol o g y  gr o u p tri al  9 8 - 0 1. J  Cli n   O n c ol,  2 0 0 5. 2 3 ( 1 0):  p.  2 1 4 5-
5 4. 
 
 




















P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
8 0  
A p p e n di x  2  : D r u gs   t h at   m a y  p r ol o n g   Q  T c 
T o  d et er  m i n e if  a  dr u g   m a y  pr ol o n g t h e   Q T  C i nt er val,  a c c ess  t h e f oll o  wi n g li n k f or  a 
c urr e nt listi n g  of  dr u gs   wit h  a  k n o  w n  or  p ossi bl e ris k  of  pr ol o n gi n g t h e   Q T c i nt er v al  or 
i n d u ci n g  T ors a d es  d e  P oi nt es ( T d P),   or  c o nt a ct t h e st u d y s p o ns or. T h e  us e  of t h es e  dr u gs 
s h o ul d  b e  c ar ef ull y  e v al u at e d f or t his st u d y.  
htt ps:// cr e di bl e  m e ds. or g/  




P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
8 2  
A p p e n di x   4 :   R  E  CI S  T   C rit e ri a 
R es p o ns  e   Ass ess  m e nt (  R  E  CI S  T   C rit e ri a)  
 M e as ur e  m e nt  of  R es p o ns e 
T h e  r at e  of  pr o gr essi v e  dis e as e   will  b e  e v al u at e d  i n  t his  st u d y  usi n g  t h e  i nt er n ati o n al 
crit e ri a   pr o p os e d   b y  t h e    R es p o ns e    E v al u ati o n    Crit eri a  i n   S oli d    T u  m ors   (  R E  CI S T) 
C o  m  mitt e e [
]  S e e  htt p:// ct e p.i nf o. ni h. g o v/ g ui d eli n es/r e cist. ht  ml 
f or f urt h er  d et ails. 
R es p o ns e   C rit e ri a:   E v al u ati o n  of t a r g et l esi o ns   
*  C o  m pl et e   R es p o ns e ( C  R):   Dis a p p e ar a n c e  of  all t ar g et l esi o ns
* P arti al   R es p o ns e ( P  R):   At l e ast  a  3 0  %  d e cr e as e i n t h e s u  m  of t h e  L  D  of t ar g et l esi o ns,
t a ki n g  as r ef er e n c e t h e  b as eli n e s u  m  L  D
* Pr o gr essi v e    Dis e as e  ( P  D):    At  l e ast  a  2 0  %  i n cr e as e  i n  t h e  s u  m  of  t h e   L  D  of  t ar g et
l esi o ns, t a ki n g  as r ef er e n c e t h e s  m all est s u  m  L  D r e c or d e d si n c e t h e tr e at  m e nt st art e d  or
t h e  a p p e ar a n c e  of  o n e  or   m or e  n e  w
L esi o ns
* St a bl e    Dis e as e  ( S  D):    N eit h er  s uffi ci e nt  s hri n k a g e  t o  q u alif y  f or  P  R  n or  s uffi ci e nt
i n cr e as e t o  q u alif y f or  P  D, t a ki n g  as r ef er e n c e t h e  s  m all est  s u  m  L  D  si n c e t h e tr e at  m e nt
st art e d


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
8 3  
A p p e n di x   5:   C  T  C  A  E  v e rsi o n  4. 0 3 
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 (  C T  C  A E) 
T h e    m ost  r e c e nt  v ersi o n  of  t h e    C T  C  A E  ( v 4. 0 3)  c a n  b e  f o u n d  a n d  d o  w nl o a d e d  at  t h e 
f oll o  wi n g li n k. 
htt p:// e vs. n ci. ni h. g o v/ft p 1/  C T  C  A E/  C T  C  A E _ 4. 0 3 _ 2 0 1 0- 0 6-
1 4 _  Q ui c k  R ef er e n c e _ 8. 5 x 1 1. p df  


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
8 4  
A p p e n di x   6 :   E  C  O  G  P e rf o r  m a n c e st at us 
T o   m o nit or  a n d  f oll o  w t h e  p ati e nt’s  g e n er al   w ell - bei n g  a n d  a cti viti es  of  n or  m al lif e t h e 
E  C  O  G/ Z u br o d  p erf or  m a n c e st at us   will  b e  d et er  mi n e d t hr o u g h o ut t h e  c o urs e  of t h e  cli ni c al 
st u d y.  T h e  p erf or  m a n c e st at us s c or e   will  b e r e c or d e d  at  b as eli n e,   w e e kl y  d uri n g t h e  8 -w e e k 
st u d y,  at t h e f oll o  w  u p  visits f or  c o n s oli d ati o n t h er a p y,  at t h e first f oll o  w -u p ( 3   m o nt hs), 
a n d  at  6  a n d  1 2   m o nt hs. 
E  C  O  G  P e rf o r  m a n c e  St at us   
Gr a d e     E  C  O  G  
0    
F ull y  a cti v e,  a bl e t o  c arr y  o n  all  pr e -dis e as e  p erf or  m a n c e   wit h o ut r estri cti o n  
1    
R estri ct e d i n  p h ysi c all y str e n u o us  a cti vit y  b ut  a  m b ul at  or y  a n d  a bl e t o  c arr y  o ut 
w or k  of  a li g ht  or s e d e nt ar y  n at ur e,  e. g., li g ht  h o us e   w or k,  offi c e   w or k   
2    
A  m b ul at or y  a n d  c a p a bl e  of  all  s elf c ar e  b ut  u n a bl e  t o  c arr y  o ut  a n y    w or k 
a cti viti es.   U p  a n d  a b o ut   m or e t h a n  5 0  %  of   w a ki n g  h o urs  
3    
C a p a bl e  of  o nl y  li  mit e d   s elf c ar e,  c o nfi n e d  t o  b e d  or  c h air   m or e  t h a n  5 0  %  of 
w a ki n g  h o urs   
4    
C o  m pl et el y  dis a bl e d.   C a n n ot  c arr y  o n  a n y  s elf c ar e.   T ot all y  c o nfi n e d t o  b e d  or 
c h air  
5    
D e a d   


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
8 5  


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
8 6  
A p p e n di x   8:  S o y   Ri c h  F o o ds 
T h e f oll  o  wi n g is  a list  of s o y  ri c h f o o ds t h at st u d y  p a rti ci p a nts s h o ul d  b e  c o u ns el e d t o 
a v oi d   w hil e  p a rti ci p ati n g i n t h e st u d y:  
E d a  m a  m e  
M e at     Alt er n ati v es  c o nt ai ni n g s o y  pr ot ei n  or t of u,  e. g. n o   m e at  h ot  d o gs 
Mis o   
N att o   
N utriti o n al  dri n ks  a n d  b ars   wit h  a d d e d s o y  pr ot ei n 
S o y  mil k  
S o y  c h e es e  
S o y i c e  cr e a  m  
S o y  y o g urt  
S o y   N uts  
T e  m p e h  
T e xt ur e d  S o y  Pr ot ei n  
T of u  
W h ol e  S o y b e a ns   
Us e t o t h e   f oll o  wi n g li n ks f or  a d diti o n al i nf or  m ati o n  o n s o y ri c h f o o ds: 
htt p://  w w  w. u csf h e alt h. or g/ e d u c ati o n/ a _ g ui d e _t o _f o o ds _ri c h _i n _s o y/   
htt p://  w w  w. ars. us d a. g o v/ S P 2  Us er Fil es/ Pl a c e/ 8 0 4 0 0 5 2 5/  D at a/is ofl a v/Is ofl a v    R 2. p df   




P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
8 8  
A p p e n di x   1 0:   C rit e ri a  f o r    P at h ol o gi c    R es p o ns e  of    T a r g et    L esi o ns    a n d   E xt e nt  of 
S u r gi c al   R es e cti o n  
C rit e ri a f o r  P at h ol o gi c   R es p o ns e  of   T a r g et   L esi o ns   
•  P at h ol o gi c   C o  m pl et e   R es p o ns e ( P  C  R):   C o  m pl et e r es e cti o n (  R 0 r es e cti o n)
a c hi e v e d  a n d  n o  e vi d e n c e  of  vi a bl e t u  m or i n t h e  e ntir e r es e cti o n s p e ci  m e n;
•  M e di asti n al  P at h ol o gi c   C o  m pl et e   R es p o ns e (  M  C  R) (t o  b e  ass ess e d  o nl y if t h er e
w er e   m e di asti n al  L  Ns (  N 2  dis e as e)  pr es e nt  at  di a g n osis):   C o  m pl et e r es e cti o n
a c hi e v e d   wit h  n o  e vi d e n c e  of r esi d u al  vi a bl e t u  m or i n t h e   m e di asti n al l y  m p h
n o d es, r e g ar dl ess  of t h e  pri  m ar y t u  m or st at us;
•  Pr o gr essi v e   Dis e as e ( P  D):   N e  w sit es  of  dis e as e i d e ntifi e d  p at h ol o gi c all y ( e. g.,
m ali g n a nt  pl e ur al st u d di n g,   m ulti pl e  p ul  m o n ar y   m et ast as es,  et c.);
•  St a bl e   Dis e as e ( S  D):   N ot   m e eti n g t h e  crit eri a  of  a n y  of t h e t hr e e  c at e g ori es  a b o v e.
E xt e nt  of  S u r gi c al   R es e cti o n   
•  R 0:   C o  m pl et e r es e cti o n  of  all  dis e as e   wit h  n e g ati v e   m ar gi ns  a n d t h e  hi g h est
l y  m p h  n o d e r es e ct e d  n e g ati v e f or r esi d u al t u  m or;
•  R 1:   C o  m pl et e r es e cti o n  of  all  gr oss  d  is e as e   wit h  p at h ol o gi c all y  p ositi v e   m ar gi ns
a n d/ or  p at h ol o gi c  e vi d e n c e  of t u  m or  c ells i n t h e  hi g h est l y  m p h  n o d e r es e ct e d i n
t h e   m e di asti n u  m  a n d/ or  e xtr a c a ps ul ar  n o d al s pr e a d;
•  R 2:   Gr oss r esi d u al  dis e as e l eft  b e hi n d  aft er s ur gi c al r es e cti o n.


P r ot o c ol  #  C  L 0 1 0 1 -0 1  
P h as e I/II   BI  O  3 0 0   N S  C  L  C  St u d y    
V e rsi o n  8. 0,   2 6  F e b  2 0 1 8  
8 9  
A p p e n di x  1  1:   R a di ati o n  P n e u  m o nitis  q u a ntifi c ati o n  vi a   C  T  c h a n g es 
Q u a ntif yi n g   C  T   C h a n g es   
S c o r e    
D es c ri pti o n   
0    
N o  c h a n g e   
1    
Sli g ht  h o  m o g e n e o us i n cr e as e i n r a di o gr a p hi c  d e nsit y ( e g,  gr o u n d  gl ass  a p p e ar a n c e)  
2    
P at c h y   or     m ultif o c al   c o ns oli d ati o n   t h at   d o es   n ot   c o nf or  m   t o   i rr a di at e d   ar e a 
( pr es u  m a bl y  as t o o  p at c h y) 
3    
S e v er e  c o nfl u e nt  c o ns oli d ati o n t h at  c o nf or  ms t o s h a p e  of irr a di at e d  ar e a  b ut  d o es  n ot 
u nif or  ml y i n v ol v e it  


BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
P a g e  1  of  4 3 
St atisti c al   A n al ysis  Pl a n 
( S  A P) 
P  R  O T  O  C  O L   N  U  M  B E  R: 
C L 0 1 0 1- 0 1 
S  A P   V E  R SI  O  N: 
Dr aft  6 
S  A P   D  A T E: 
9- O ct  - 2 0 1 7
P  R  O T  O  C  O L   D  A T E: 
Ori gi n al:  7   A pr  2 0 1 5 
V ersi o n  3. 0:  1 8   A u g  2 0 1 5 
V ersi o n  3. 0:  1 6  F e b  2 0 1 6 
V ersi o n  4. 0:  2   M a y  2 0 1 6 
V ersi o n  5. 0:  1 5   A u g  2 0 1 6 
V ersi o n  6. 0:  2 0   D e c  2 0 1 6 
V ersi o n  7. 0:  1 5   A u g  2 0 1 7 
S P  O  N S  O  R: 
H u  m a n eti cs 
P  R E P  A  R E  D   B  Y: 
H u  m a n eti cs 
A  U T  H  O  R( S): 
M eliss a I n gr a  m,  P h.  D. 
A P P  R  O  V E  D: 
N a  m e   
Titl e,   C o  m p a n y  
D at e   
N a  m e   
Titl e,   C o  m p a n y  
D at e   


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  2  of  4 3 
 
T  A  B  L  E   O F   C  O  N  T  E  N  T S 
1    I  N T  R  O  D  U  C TI  O  N ...................................................................................................................  5 
2    S T  U  D  Y   O  BJ E  C TI  V E S,  T  R E  A T  M E  N T S   A  N  D  E  N  D P  OI  N T S ..............................................  5  
2. 1    S T  U  D  Y   O  BJ E  C TI  V E S ....................................................................................................  5  
2. 1. 1    
Pri  m ar y   O bj e cti v es ....................................................................................................  5  
2. 1. 2    
S e c o n d ar y   O bj e cti v es ................................................................................................  5  
2. 2    T  R E  A T  M E  N T   G  R  O  U P S .................................................................................................  5  
2. 3    S T  U  D  Y  E  N  D P  OI  N T S .....................................................................................................  6  
2. 3. 1    
Pri  m ar y  E n d p oi nts ....................................................................................................  6  
2. 3. 2    
S e c o n d ar y  E n d p oi nts ................................................................................................  6  
3    S T  U  D  Y   D E SI  G  N ....................................................................................................................  6  
3. 1    O  V E  R  A L L  S T  U  D  Y   D E SI  G  N .........................................................................................  6   
3. 2    D  O S E  LI  MI TI  N  G  T  O  XI  CI TI E S .....................................................................................  7   
3. 3    E  A  R L  Y  T E  R  MI  N  A TI  O  N ................................................................................................  8  
3. 3. 1    
P ot e nti al   R e as o ns f or  S u bj e ct   Attriti o n .....................................................................  8  
3. 3. 2    
Crit eri a f or   Dis c o nti n u ati o n  of  S u bj e cts fr o  m t h e  Tri al ............................................  9   
3. 4    S  C  H E  D  U L E   O F  S T  U  D  Y   A S S E S S  M E  N T S ....................................................................  9  
4    S  A  M P L E  SI Z E   C  O  N SI  D E  R  A TI  O  N S ..................................................................................  1 5  
5    A  N  A L  Y SI S  P  O P  U L  A TI  O  N S ...............................................................................................  1 5   
5. 1    F  U L L   A  N  A L  Y SI S  S E T .................................................................................................  1 5  
5. 2    E F FI  C  A  C  Y   A  N  A L  Y SI S  S E T ........................................................................................  1 5  
5. 3    P  H  A  R  M  A  C  O  KI  N E TI  C ( P  K)  P  O P  U L  A TI  O  N ..............................................................  1 5  
5. 4    P  H  A  R  M  A  C  O  D  Y  N  A  MI  C S ( P  D)  P  O P  U L  A TI  O  N .........................................................  1 5  
6    C  O  N SI  D E  R  A TI  O  N S  F  O  R   D  A T  A   A  N  A L  Y SI S ...................................................................  1 5   
6. 1    P  R  O  G  R  A  M  MI  N  G  E  N  VI  R  O  N  M E  N T ...........................................................................  1 5  
6. 2    S T  R  A T  A   A  N  D   C  O  V  A  RI  A T E S ....................................................................................  1 5  
6. 3    S  U  B  G  R  O  U P S ................................................................................................................  1 5  
6. 4    M  U L TI P L E   C  O  M P  A  RI S  O  N S   A  N  D   M  U L TI P LI  C T  Y .................................................  1 5   
6. 5    SI  G  NI FI  C  A  N  C E  L E  V E L ..............................................................................................  1 6  
6. 6    S T  A TI S TI  C  A L   N  O T  AI  O  N   A  N  D   M E T  H  O  D  O L  O  G  Y ..................................................  1 6  
7    D  A T  A   H  A  N  D LI  N  G   M E T  H  O  D S ..........................................................................................  1 6   
7. 1    MI S SI  N  G   D  A T  A ...........................................................................................................  1 6   
7. 1. 1    
F  A  C T- T  OI   H a n dli n g  of   Missi n g It e  ms ..................................................................  1 6  
7. 2    VI SI T   WI  N  D  O  W S .........................................................................................................  1 7   
7. 3    D  A T  A   D E  RI  V  A TI  O  N S   A  N  D   D E FI  NI TI  O  N S .............................................................  1 7   
8    S T  U  D  Y  P  O P  U L  A TI  O  N ........................................................................................................  1 7  
8. 1    A  N  A L  Y SI S  P  O P  U L  A TI  O  N ..........................................................................................  1 7   
8. 2    S  U  BJ E  C T   DI S P  O S TI TI  O  N ...........................................................................................  1 8  
8. 3    I  N  C L  U SI  O  N/ E  X  C L  U SI  O  N   C  RI T E  RI  A .......................................................................  1 8 
8. 4    P  R  O T  O  C  O L   D E  VI  A TI  O  N S ..........................................................................................  1 8  
8. 5    D E  M  O  G  R  A P  HI  C   C  H  A  R  A  C T E  RI S TI  C S .....................................................................  1 8   
8. 6    C  O  N  C  O  MI T  A  N T   M E  DI  C  A TI  O  N S ..............................................................................  1 8   
8. 7    M E  DI  C  A L   HI S T  O  R  Y ...................................................................................................  1 8   
9    E F FI  C  A  C  Y   A  N  A L  Y SI S .......................................................................................................  1 8  


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  3  of  4 3 
9. 1    O  BJ E  C TI  V E   R E S P  O  N S E S ...........................................................................................  1 8   
9. 2    D  U  R  A TI  O  N   O F   R E S P  O  N S E (  D  O  R) ............................................................................  1 9   
9. 3    P  R  O  G  R E S SI  O  N  F  R E E  S  U  R  VI  V  A L ............................................................................  1 9  
9. 4    P  U L  M  O  N  A  R  Y  F  U  N  C TI  O  N  T E S T ...............................................................................  2 0  
9. 5    S  W  A L L  O  WI  N  G   DI  A  R  Y ...............................................................................................  2 0  
9. 6    S  O  B  Q .............................................................................................................................  2 0  
9. 7    F  A  C T- T  OI  ......................................................................................................................  2 0 
1 0    S  A F E T  Y  ................................................................................................................................  2 0 
1 0. 1    E  X P  O S  U  R E  T  O  S T  U  D  Y   D  R  U  G ..................................................................................  2 0  
1 0. 2    D L T   A  N  D   M T  D .............................................................................................................  2 1   
1 0. 3    A  D  V E  R S E  E  V E  N T S .....................................................................................................  2 1   
1 0. 4    S E  RI  O  U S   A  D  V E  R S E  E  V E  N T S   A  N  D   D E  A T  H ...........................................................  2 1  
1 0. 5    L  A  B  O  R  A T  O  R  Y  E  V  A L  U  A TI  O  N S ...............................................................................  2 1  
1 0. 6    P  R E  G  N  A  N  C  Y  T E S T .....................................................................................................  2 1  
1 0. 7    P  H  Y SI  C  A L  E  X  A  MI  N  A TI  O  N S .....................................................................................  2 2  
1 0. 8    E L E  C T  R  O  C  A  R  DI  O  G  R  A  M S ........................................................................................  2 2  
1 0. 9    E  C  O  G .............................................................................................................................  2 2  
1 0. 1 0    VI T  A L  SI  G  N S ............................................................................................................  2 2   
1 1    P  H  A  R  M  A  C  O  KI  N E TI  C S   A  N  A L  Y S E S ................................................................................  2 2  
1 2    P  H  A  R  M  A  C  O  D  Y  N  A  MI  C   A  N  A L  Y S E S ...............................................................................  2 2  
1 3    I  N T E  RI  M   A  N  A L  Y SI S ..........................................................................................................  2 2 
1 4    E  N  D -O F  - S T  U  D  Y   A  N  A L  Y SI S .............................................................................................  2 2 
1 5    T  A  B L E   O F   C  O  N T E  N T S  F  O  R   D  A T  A   DI S P L  A  Y S .............................................................  2 4  
1 5. 1    D E  M  O  G  R  A P  HI S  C  S  U  M  M  A  R  Y  FI  G  U  R E S   A  N  D  T  A  B L E S .......................................  2 4   
1 5. 2    E F FI  C  A  C  Y  S  U  M  M  A  R  Y  FI  G  U  R E S   A  N  D  T  A  B L E S ...................................................  2 4  
1 5. 3    S  A F E T  Y  S  U  M  M  A  R  Y  FI  G  U  R E S   A  N  D  T  A  B L E S ........................................................  2 5  
1 5. 3. 1    A d v ers e  E v e nts .......................................................................................................  2 5   
1 5. 3. 2    S eri o us   A d v ers e  E v e nts,   D e at hs  a n d   Ot h er  Si g nifi c a nt   A d v ers e  E v e nts  ................  2 5 
1 5. 3. 3    N arr ati v es ................................................................................................................  2 5   
1 5. 3. 4    L a b or at or y   R es ults ..................................................................................................  2 5  
1 5. 3. 5    Ot h er  S af et y   R es ults ...............................................................................................  2 5   
1 5. 4    LI S TI  N  G S ......................................................................................................................  2 6  
1 5. 4. 1    Dis c o nti n u e d  P ati e nts ..............................................................................................  2 6   
1 5. 4. 2    Pr ot o c ol   D e vi ati o ns .................................................................................................  2 6  
1 5. 4. 3    S u bj e cts  E x cl u d e d fr o  m t h e  Effi c a c y   A n al ysis .......................................................  2 6  
1 5. 4. 4    D e  m o gr a p hi c   D at a ..................................................................................................  2 6   
1 5. 4. 5    C o  m pli a n c e  a n d/ or   Dr u g   C o n c e ntr ati o n   D at a .........................................................  2 6   
1 5. 4. 6    I n di vi d u al  Effi c a c y   R es p o ns e   D at a .........................................................................  2 6 
1 5. 4. 7    A d v ers e  E v e nt  Listi n gs ...........................................................................................  2 6   
1 5. 4. 8    Listi n gs  of I n di vi d u al  L a b or at or y   M e as ur e  m e nts ...................................................  2 7  
1 5. 4. 9    Listi n gs  of   Ot h er  S af et y  E n d p oi nts .........................................................................  2 7  
1 6    R E F E  R E  N  C E S ......................................................................................................................  2 8   
 
 
 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  4  of  4 3 
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 
A L T           
Al a ni n e  Tr a ns a  mi n as e 
A  N  C           
A bs ol ut e   N e utr o p hil   C o u nt 
A S T           
As p art at e   A  mi n otr a nsf er as e 
A  U  C           
Ar e a   U n d er   C ur v e 
B  U  N         
Bl o o d   Ur e a   Nitr o g e n 
C  B  C         
C o  m pl et e   Bl o o d   C o u nt 
C  m a x       
M a xi  m u  m  S er u  m  or  Pl as  m a   C o n c e ntr ati o n 
C  R         
C o  m pl et e   R es p o ns e 
C  R Fs        
C as e   R e p ort  F or  ms 
C T         
C o  m p ut e d  T o  m o gr a p h y 
C T  C  A E     
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 
D L  C  O      
Diff usi n g  c a p a cit y  of t h e l u n gs f or  c ar b o n   m o n o xi d e  
D L T           
D os e  Li  miti n g  T o xi cit y 
E  C  G         
El e ctr o c ar di o gr a  m 
E  C  O  G      
E ast er   C o o p er ati v e   O n c ol o g y   Gr o u p 
F  A  C T- T  OI     F u n cti o n al   Ass ess  m e nt  of   C a n c er  T h er a p y- Tri al   O ut c o  m e I n d e x (l u n g  c a n c er) 
F  A S         
F ull   A n al ysis  S et 
F E  V 1     
F or c e d  e x pir at or y  v ol u  m e i n  1 s e c o n d  
F  V  C         
F or c e d  vit al  c a p a cit y 
G y           
Gr a y  u nit  of  a bs or b e d i o ni zi n g-r a di ati o n  d os e 
M- F         
M o n d a y- Fri d a y 
M T  D          
M a xi  m u  m  T ol er at e d   D os e 
N S  C L  C     
N o n- S  m all   C ell  L u n g   C a n c er 
O S           
O v er all  S ur vi v al 
P  D         
P h ar  m a c o d y n a  mi cs 
P E T         
P ositr o n  E  missi o n  T o  m o gr a p h y 
P F S         
Pr o gr essi o n  Fr e e  S ur vi v al 
P F T         
P ul  m o n ar y  F u n cti o n  Test   
P  K         
P h ar  m a c o ki n eti cs 
P L T        
Pl at el et  
P  R         
P arti al   R es p o ns e 
Q  O L           
Q u alit y  of  Lif e 
Q T           
Ti  m e fr o  m  E  C  G   Q   w a v e t o t h e  e n d  of t h e  T   w a v e 
Q T c           
C orr e ct e d   Q T i nt er v al 
R E  CI S T     
R es p o ns e  E v al u ati o n   Crit eri a i n  S oli d  T u  m ors 
R T         
R a di ati o n  T h er a p y 
S  A E         
S eri o us   A d v ers e  E v e nt 
S  A P         
St atisti c al   A n al ysis  Pl a n 
S  D         
St a bl e   Dis e as e 
S  O  B  Q      
T h e   U ni v ersit y  of   C alif or ni a,  S a n   Di e g o  S h ort n ess  of   Br e at h   Q u esti o n n air e 
S  O  C         
S yst e  m   Or g a n   Cl ass 
S T  D         
St a n d ar d   D e vi ati o n 
T 1/ 2        
S er u  m  or  Pl as  m a  h alf-lif e 
T  m a x         
Ti  m e  at  P e a k  S er u  m  or  Pl as  m a   C o n c e ntr ati o n 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  5  of  4 3 
1    I  N  T  R  O  D  U  C  TI  O  N  
T his  d o c u  m e nt  d es cri b es t h e st atisti c al   m et h o ds  a n d  d at a  pr es e nt ati o ns t o  b e  us e d i n t h e s u  m  m ar y 
a n d  a n al ysis  of st u d y  d at a fr o  m  Pr ot o c ol   C L 0 1 0 1- 0 1.   B a c k gr o u n d i nf or  m ati o n is  pr o vi d e d f or t h e 
o v er all  st u d y  d esi g n  a n d  o bj e cti v es.   T h e r e a d er is r ef err e d t o t h e  st u d y  pr ot o c ol  a n d  c as e r e p ort 
f or  ms (  C  R Fs) f or  d et ails  of st u d y  c o n d u ct  a n d  d at a  c oll e cti o n. 
2    S  T  U  D  Y  O  B J  E  C  TI  V  E S,   T  R  E  A  T  M  E  N  T S   A  N  D   E  N  D P  OI  N  T S   
2. 1    S  T  U  D  Y   O  B J  E  C  TI  V  E S 
2. 1. 1    P ri  m a r y   O bj e cti v es 
T h e  pri  m ar y  o bj e cti v e is t o  d es cri b e  a n y  d os e li  miti n g t o xi citi es  of t h e  c o  m bi n ati o n  of   BI  O  3 0 0 
wit h  c h e  m or a di ot h er a p y i n  s u bj e cts   wit h  n o n-s  m all  c ell l u n g  c a n c er (  N S  C L  C)  a n d t o  d et er  mi n e 
t h e r e c o  m  m e n d e d  d os e (t h e  o pti  m al  d os e)  of t his  c o  m bi n ati o n.  
2. 1. 2    S e c o n d a r y   O bj e cti v es 
S e c o n d ar y  o bj e cti v es  of t his st u d y  ar e: 
•    T o   d es cri b e  t h e   o v er all   a d v ers e   e v e nt   pr ofil e   of  t h e   c o  m bi n ati o n   of    BI  O   3 0 0   a n d 
c h e  m or a di ot h er a p y i n t h e t ar g et  p ati e nt  p o p ul ati o n 
•    T o  d et er  mi n e t h e  p h ar  m a c o ki n eti cs  of   BI  O  3 0 0  a n d t h e  c h e  m ot h er a p y  c o  m p o n e nts  of t h e 
r e gi  m e n ( p a clit a x el  a n d  c ar b o pl ati n)   w h e n  gi v e n i n  c o  m bi n ati o n 
•    T o    d et er  mi n e   t h e    p h ar  m a c o d y n a  mi c    eff e cts    of     BI  O    3 0 0   i n    c o  m bi n ati o n     wit h 
c h e  m or a di ot h er a p y  b y t h e  d et er  mi n ati o n  of  c ert ai n s er u  m  pr ot ei n  a n d  c yt o ki n e l e v els  
•    T o r e p ort l o c al  pr o gr essi o n r at e as  d efi n e d  p er  R E  CI S T ( 1. 1) crit eri a  or f or s ur gi c al  p ati e nts 
p at h ol o gi c al r es p o ns e. 
•    P ul  m o n ar y  f u n cti o n t est  ( P F T)  a n d  q u alit y  of lif e  (  Q  O L)   m e as ur es  ( F  A  C T- T  OI,   U S  C  D-
S  O  B,  a n d s  w all o  wi n g  di ar y) 
•    T o  st u d y  t h e   eff e ct   of    BI  O   3 0 0   o n  t h e  i n ci d e n c e   of   p ul  m o n ar y  fi br osis  f oll o  wi n g 
c h e  m or a di ot h er a p y i n t h e t ar g et  p o p ul ati o n  as  ass ess e d  b y  4  D   C T s c a n ni n g  
•    T o  d et er  mi n e  o v er all  s ur vi v al  (  O S)  a n d  pr o gr essi o n  fr e e  s ur vi v al  ( P F S)  i n  t h e  st u d y 
p o p ul ati o n 
2. 2    T  R  E  A  T  M  E  N  T   G  R  O  U P S 
A   mi ni  m u  m  of  6 s u bj e cts   will  b e  a c cr u e d s e q u e nti all y  at  e a c h  d os e  of   BI  O  3 0 0.    BI  O  3 0 0   will  b e 
a d  mi nist er e d  d ail y f or t h e  e ntir e  c o urs e  of  c o n c urr e nt  c h e  m or a di ot h er a p y,  a   mi ni  m u  m  of  6   w e e ks; 
c h e  m ot h er a p y   will  b e  a d  mi nist er e d   w e e kl y  f or  6   w e e ks  a n d  r a di ot h er a p y   will  b e  a d  mi nist er e d 
d ail y (  M- F) f or  a  p eri o d  of  6   w e e ks.    T h e i niti al  d os e  of   BI  O  3 0 0   will  b e  5 0 0   m g/ d;  s u bs e q u e nt 
d os es    will  b e  1 0 0 0    m g/ d  a n d  1 5 0 0    m g/ d.     P a clit a x el  a n d  c ar b o pl ati n    will  b e  a d  mi nist er e d 
i ntr a v e n o usl y   w e e kl y,  p a clit a x el  i n  a  d os e  of  4 5   m g/  m2  a n d  c ar b o pl ati n  i n  a  d os e  s uffi ci e nt  t o 
a c hi e v e  a n   A  U  C  of  2   m g *  mi n/  m L.    R a di ot h er a p y   will  b e  a d  mi nist er e d  5  d a ys  a   w e e k (  M- F) f or  6 
w e e ks i n  a  d ail y fr a cti o n  of  2. 0   G y t o  a t ot al  d os e  of  6 0   G y. 
F oll o  wi n g a c cr u al  of  6 s u bj e cts at a  p arti c ul ar  BI  O  3 0 0  d os e l e v el,  d os e es c al ati o n   m a y  o c c ur   w h e n 
a  c o h ort  h as  c o  m pl et e d  c o n c urr e nt  c h e  m or a di ot h er a p y   wit h  f e  w er t h a n  3 3  %   D L Ts  attri b ut e d t o 
BI  O  3 0 0    Or al  S us p e nsi o n.  I nt eri  m  d at a  a n al ysis    will  b e  c o  m pl et e d  o n c e  t h e  hi g h est  c o h ort 
c o n cl u d es c h e  m or a di ati o n t h er a p y, i n a n eff ort t o  d et er  mi n e t h e  o pti  m al  bi ol o gi c al  d os e.  F oll o  wi n g 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  6  of  4 3 
a n al ysis, t h er e   will  b e  a n  o pti o n t o  e nr oll  u p t o  a n  a d diti o n al  1 2  s u bj e cts  at t h e  o pti  m al  bi ol o gi c al 
d os e. 
2. 3    S  T  U  D  Y   E  N  D P  OI  N  T S 
2. 3. 1    P ri  m a r y   E n d p oi nts 
T h e  pri  m ar y  e n d p oi nt  of  o pti  m al   BI  O  3 0 0  d os e is  d et er  mi n e d  b y   D L T  a n d   M T  D.  Pl e as e r ef er t o 
S e cti o n  3. 1 f or  d et ails i n t h e  d et er  mi n ati o n  of t h e  o pti  m al  d os e.  
 
2. 3. 2    S e c o n d a r y   E n d p oi nts 
A d v ers e  e v e nts  a n d  s eri o us  a d v ers e  e v e nts  c o d e d  a c c or di n g  t o   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 ersi o n  4. 0 3. 
P n e u  m o nitis/fi br osis i n ci d e n c e  a c c or di n g t o  d o c u  m e nt e d   A Es  a n d  q u a ntifi c ati o n  vi a   C T.  
•    P h ar  m a c o ki n eti c  e n d p oi nts f or   BI  O  3 0 0,  p a clit a x el  a n d  c ar b o pl ati n  ar e: 
o    M a xi  m u  m  c o n c e ntr ati o n (  C
m a x ) 
o    Ti  m e  at   m a x  c o n c e ntr ati o n ( T m a x ) 
o    Ar e a  u n d er t h e  c o n c e ntr ati o n-ti  m e  c ur v e (  A  U  C)   
o    H alf  -lif e ( T1/ 2) 
o    Cl e ar a n c e (  Cl) 
•    P h ar  m a c o d y n a  mi c  e n d p oi nts  ar e: 
o    C yt o ki n es I L- 6, I L- 1  b , I L- 1a , I L- 8, I L- 1 0,  T  N Fa , T  G F b 1,  T  G F b 2,  a n d  T  G F b 3  
o    Gr a n ul o c yt e  c ol o n y sti  m ul ati n g f a ct or (  G-  C S F) 
o    C-r e a cti v e  pr ot ei n,  a n d  
o    Pr ost a gl a n di n  E 2 
•    Dis e as e  pr o gr essi o n/ T u  m or r es p o ns e: 
o    O bj e cti v e t u  m or r es p o ns e  T u  m or  di a  m et er 
o    O bj e cti v e t u  m or r es p o ns e  a c c or di n g t o   R E  CI S T  1. 1   Crit eri a 
o    Pr o gr essi o n  Fr e e  S ur vi v al  
•    Q u alit y  of  Lif e   M e as ur es: 
o    S  O  B  Q 
o    F  A  C T- T  OI  
o    S  w all o  wi n g  di ar y 
•    P ul  m o n ar y  F u n cti o n: 
o    F  V  C/ F E  V 1 
o    D L  C  O 
3    S  T  U  D  Y   D  E SI  G  N  
3. 1    O  V  E  R  A  L  L  S  T  U  D  Y   D  E SI  G  N 
T his st u d y is  a n  o p e n l a b el,  d os e  es c al ati o n tri al   wit h s e q u e nti al  c o h orts  of s u bj e cts r e c ei vi n g   BI  O 
3 0 0   Or al  S us p e nsi o n  a n d  c h e  m or a di ati o n t h er a p y.  T hr e e  d os es  of   BI  O  3 0 0   Or al  S us p e nsi o n ( 5 0 0 
m g/ d,   1 0 0 0    m g/ d,   a n d   1 5 0 0    m g/ d)    will   b e   a d  mi nist er e d   d uri n g  t h e   c o urs e   of   c o n c urr e nt 
c h e  m or a di ati o n t h er a p y.  E a c h  c o h ort   will  b e gi n   wit h  a st u d y  of t h e  p h ar  m a c o ki n eti cs  of   BI  O  3 0 0 
Or al  S us p e nsi o n f oll o  w e d  b y a  p h ar  m a c o ki n eti c st u d y  of  BI  O  3 0 0   Or al  S us p e nsi o n i n c o  m bi n ati o n 
wit h  p a clit a x el  a n d  c ar b o pl ati n.  T his is t o  d es cri b e  a n y  p ot e nti al  dr u g- dr u g i nt er a cti o ns  of  BI  O  3 0 0 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  7  of  4 3 
Or al   S us p e nsi o n    wit h  t h e  c h e  m ot h er a p e uti cs.    T h e  s u bj e cts    will  c o  m pl et e  si x  ( 6)    w e e ks   of 
c o n c urr e nt  c h e  m or a di ati o n  t h er a p y    w hil e  c o nti n ui n g  d ail y    BI  O  3 0 0    Or al  S us p e nsi o n  d osi n g. 
F oll o  wi n g  c h e  m or a di ati o n  t h er a p y  p ati e nts    will  c o  m pl et e  c o ns oli d ati o n  t h er a p y  as  d es cri b e d. 
D uri n g  c o ns oli d ati o n t h er a p y  p ati e nts   will  n ot  b e  d os e d   wit h t h e st u d y  dr u g.   
A   mi ni  m u  m  of  6 s u bj e cts   will  b e  a c cr u e d s e q u e nti all y  at  e a c h  d os e  of   BI  O  3 0 0.    BI  O  3 0 0   will  b e 
a d  mi nist er e d  d ail y f or t h e  e ntir e  c o urs e  of  c o n c urr e nt  c h e  m or a di ot h er a p y,  a   mi ni  m u  m  of  6   w e e ks; 
c h e  m ot h er a p y   will  b e  a d  mi nist er e d   w e e kl y  f or  6   w e e ks  a n d  r a di ot h er a p y   will  b e  a d  mi nist er e d 
d ail y (  M- F) f or  a  p eri o d  of  6   w e e ks.    T h e i niti al  d os e  of   BI  O  3 0 0   will  b e  5 0 0   m g/ d;  s u bs e q u e nt 
d os es    will  b e  1 0 0 0    m g/ d  a n d  1 5 0 0    m g/ d.     P a clit a x el  a n d  c ar b o pl ati n    will  b e  a d  mi nist er e d 
i ntr a v e n o usl y   w e e kl y,  p a clit a x el  i n  a  d os e  of  4 5   m g/  m2  a n d  c ar b o pl ati n  i n  a  d os e  s uffi ci e nt  t o 
a c hi e v e  a n   A  U  C  of  2   m g *  mi n/  m L.    R a di ot h er a p y   will  b e  a d  mi nist er e d  5  d a ys  a   w e e k (  M- F) f or  6 
w e e ks i n  a  d ail y fr a cti o n  of  2. 0   G y t o  a t ot al  d os e  of  6 0   G y. 
T h e i niti al  d os e  of   BI  O  3 0 0   will  b e  a d  mi nist er e d  o n   D a y  1,   Visit  2, i n   w hi c h  s af et y  d at a ( a d v ers e 
e v e nts,     E  C  Gs,   r es ults    of   s af et y   l a b or at or y    d et er  mi n ati o ns),    p h ar  m a c o ki n eti c   ( P  K)    a n d 
p h ar  m a c o d y n a  mi c ( P  D)  d at a   will  b e  c oll e ct e d.   P  K  d at a   will  b e  c oll e ct e d fr o  m  a   mi ni  m u  m  of  si x 
( 6)  st u d y  p arti ci p a nts  fr o  m  e a c h  st u d y  c o h ort.    Bl o o d  s a  m pl es  f or  P  D  d at a  c oll e cti o n    will  b e 
c oll e ct e d  pri or t o  a n d  p ost   BI  O  3 0 0  d osi n g ( 2  hr) fr o  m  all s u bj e cts i n  e a c h st u d y  c o h ort.   
D a y  1  of   c h e  m ot h er a p y    m a y  b e s c h e d ul e d  at t h e  dis cr eti o n  of t h e i n v esti g at or  pr o vi d e d t h e s u bj e ct 
h as  c o  m pl et e d  a    mi ni  m u  m  of  1  d a y  of    BI  O  3 0 0  d osi n g.    BI  O  3 0 0    will  b e  a d  mi nist er e d  i n 
c o  m bi n ati o n     wit h   t h e   c h e  m ot h er a p y   c o  m p o n e nts   of   t h e   pr ot o c ol   t h er a p y   ( p a clit a x el   a n d 
c ar b o pl ati n).   D uri n g t h e  first  or  s e c o n d  c h e  m ot h er a p y i nf usi o n,  as  b ef or e,  a d diti o n al  s af et y,  P  K 
a n d  P  D  d at a   will  b e  c oll e ct e d.   Bl o o d s a  m pl es f or  P  D  d at a  c oll e cti o n   will  b e  c oll e ct e d  pri or t o  a n d 
p ost   BI  O  3 0 0  d osi n g ( 2  hr) fr o  m  all s u bj e cts i n  e a c h st u d y  c o h ort.  
D a y  1  of   r a di ati o n t h er a p y  (  R T)   m a y  b e  s c h e d ul e d  at t h e  dis cr eti o n  of t h e i n v esti g at or  pr o vi d e d 
t h e  s u bj e ct  h as  c o  m pl et e d  a   mi ni  m u  m  of  2  d a ys  of   BI  O  3 0 0  d osi n g.   BI  O  3 0 0   will  c o nti n u e t o  b e 
a d  mi nist er e d  d ail y;  p a clit a x el  a n d  c ar b o pl ati n   will  b e  a d  mi nist er e d   w e e kl y  a n d r a di ot h er a p y   will 
b e a d  mi nist er e d  d ail y as  d es cri b e d a b o v e  u ntil a t ot al  d os e  of  6 0   G y  h as  b e e n a d  mi nist er e d.    D uri n g 
t h e  p eri o d  of  c o  m bi n e d   BI  O  3 0 0  a n d  c h e  m or a di ot h er a p y ( 6   w e e ks),  a d diti o n al s af et y,  P  K  a n d  P  D 
d at a    will  b e  c oll e ct e d    w e e kl y.   Tr o u g h  l e v els  f or   BI  O  3 0 0,  p a clit a x el,  a n d  c ar b o pl ati n    will  b e 
c oll e ct e d    w e e kl y.    Bl o o d  s a  m pl es  f or  P  D  d at a  c oll e cti o n    will  b e  c oll e ct e d    w e e kl y  d uri n g  t h e 
c o  m bi n e d   BI  O  3 0 0  a n d  c h e  m or a di ot h er a p y  p eri o d  at t h e s a  m e ti  m e  as t h e tr o u g h l e v els, j ust  pri or 
t o t h at   w e e k’s  c h e  m ot h er a p y tr e at  m e nt  a n d t h at  d a ys’   BI  O  3 0 0  d os e.   T ot al  d ur ati o n  of   BI  O  3 0 0 
tr e at  m e nt   will  b e  a   mi ni  m u  m  of  6   w e e ks.   Bl o o d  s a  m pl es f or  P  D  d at a   will  als o  b e  c oll e ct e d  at t h e 
e n d  of t h e  c o ns oli d ati o n  p h as e,  a n d  at t h e  3  a n d  6   m o nt hs f oll o  w  u p  visits.  
F oll o  wi n g a c cr u al  of  6 s u bj e cts at a  p arti c ul ar  BI  O  3 0 0  d os e l e v el,  d os e es c al ati o n   m a y  o c c ur   w h e n 
a  c o h ort  h as  c o  m pl et e d  c o n c urr e nt  c h e  m or a di ot h er a p y   wit h  f e  w er t h a n  3 3  %   D L Ts  attri b ut e d t o 
BI  O  3 0 0    Or al  S us p e nsi o n.  I nt eri  m  d at a  a n al ysis    will  b e  c o  m pl et e d  o n c e  t h e  hi g h est  c o h ort 
c o n cl u d es c h e  m or a di ati o n t h er a p y, i n a n eff ort t o  d et er  mi n e t h e  o pti  m al  bi ol o gi c al  d os e.  F oll o  wi n g 
a n al ysis, t h er e   will  b e  a n  o pti o n t o  e nr oll  u p t o  a n  a d diti o n al  1 2  s u bj e cts  at t h e  o pti  m al  bi ol o gi c al 
d os e. 
3. 2    D  O S  E   LI  MI  TI  N  G   T  O  XI  CI  TI  E S 
D os e li  miti n g t o xi citi es  ar e  d efi n e d  b y  a n y  of t h e f oll o  wi n g   BI  O  3 0 0 r el at e d  e v e nts   w hi c h  o c c ur 
b ef or e  or  d uri n g  c o n c urr e nt  c h e  m or a di ati o n  a n d is  c oll e ct e d i n t h e   A E   C  R Fs:  


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  8  of  4 3 
1)    R a di ati o n  es o p h a gitis   Gr a d e  3 t h at l asts  >  7  c o ns e c uti v e  d a ys  or   Gr a d e  4. 
2)    Gr a d e  4  n e utr o p e ni a f or   m or e t h a n  7  d a ys  or  n e utr o p e ni a f e v er ( d efi n e d  as   A  N  C  <  5 0 0  a n d 
a t e  m p er at ur e  of  3 8. 5°   C  or  a b o v e). 
3)    Gr a d e  3 t hr o  m b o c yt o p e ni a   wit h  cli ni c all y si g nifi c a nt  bl e e di n g 
4)    Gr a d e  4 t hr o  m b o c yt o p e ni a  >  7  d a ys. 
5)    Gr a d e  4  n a us e a/ v o  miti n g  d es pit e  a p pr o pri at e  a nti e  m eti c t h er a p y. 
6)    Gr a d e  3   A S T/  A L T  el e v ati o ns  >  7  d a ys 
7)    D el a ys i n r a di ot h er a p y  or  c h e  m ot h er a p y  d u e t o t o xi cit y  of   m or e t h a n  3   w e e ks.   D el a ys i n 
t h e c urr e nt st a n d ar d  of c ar e tr e at  m e nt ar e li k el y t o  h a v e a  n e g ati v e eff e ct  o n  p ati e nt  o ut c o  m e 
a n d t h us  ar e t o  b e  d esi g n at e d  as  a   D L T. 
8)    All  ot h er  n o n- h e  m at ol o gi c t o xi citi es  of   Gr a d e  3  or  hi g h er,   wit h t h e f oll o  wi n g  e x c e pti o ns:   
a.    a n or e xi a 
b.    f ati g u e 
c.    i nf e cti o n   wit h o ut  n e utr o p e ni a 
d.    Gr a d e  3   A S T/  A L T  el e v ati o ns  ≤  7  d a ys 
e.    I nf usi o n  r e a cti o ns.    P ati e nts    wit h    Gr a d e  3  or    w ors e  i nf usi o n  r e a cti o ns    will  b e 
r e  m o v e d fr o  m t h e st u d y a n d r e pl a c e d a n d   will  n ot  b e c o nsi d er e d e v al u a bl e f or   D L T. 
f.   Gr a d e  3  or  4  el e ctr ol yt e  a b n or  m aliti es t h at  ar e  c orr e ct e d t o   Gr a d e  2  or l ess i n l ess 
t h a n  4 8  h o urs. 
3. 3    E  A  R  L  Y   T  E  R  MI  N  A  TI  O  N 
3. 3. 1    P ot e nti al   R e as o ns f o r  S u bj e ct   Att riti o n 
F or  a n y s u bj e ct l e a vi n g t h e st u d y  e arl y, t h e fi n al st u d y   m e as ur e  m e nts   will  b e  p erf or  m e d  at t h e ti  m e 
of  d e p art ur e ( or  as s h ortl y t h er e aft er  as  p ossi bl e).  
1)    Dr u g-  R el at e d   R e as o ns 
a.    S u bj e ct  e x p eri e n c es  a n  a d v ers e r e a cti o n  a n d  d o es  n ot   wis h t o r e  m ai n i n t h e tri al.  
b.    S u bj e ct  e x p eri e n c es  a  s eri o us  a d v ers e  r e a cti o n  or  a  s p e cifi c  a d v ers e  r e a cti o n t h at 
r e q uir es    dis c o nti n u ati o n   a c c or di n g   t o   t h e    pr ot o c ol   as    d et er  mi n e d    b y   t h e 
i n v esti g at or. 
c.    Cli ni c al  tri al  is  t er  mi n at e d  pr e  m at ur el y  b e c a us e  of  u n a c c e pt a bl e  s af et y  c o n c er ns 
(ris ks)  of t h e s u p pl e  m e nt  b ei n g t est e d. 
2)    Cli ni c al- Tri al-  R el at e d   R e as o ns 
a.    S u bj e ct i n di c at es t h e r e q uir e  m e nts  ar e t o o  o n er o us,  or t o o l o n g,  or l os es i nt er est;  or 
r ef us es t o  p arti ci p at e. 
b.    Cli ni c al tri al is t er  mi n at e d  at  a  pr es et  d at e  a n d s o  m e s u bj e cts  ar e  n ot  c o  m pl et e d.   
3)    S u bj e ct-  R el at e d   R e as o ns   D et er  mi n e d  b y t h e I n v esti g at or 
a.    S u bj e ct  f ails  t o    m ai nt ai n  a d e q u at e  c o  m pli a n c e    wit h  o n e  or    m or e  as p e cts  of  t h e 
pr ot o c ol  or s u bj e ct f ails t o  c o o p er at e  a d e q u at el y  d uri n g  cli ni c al  visits.  
b.    S u bj e ct f o u n d  n ot t o   m e et  or  n o l o n g er   m e ets t h e  ori gi n al  e ntr y r e q uir e  m e nts.  
c.    S u bj e ct  h as  us e d  a  n o n- a p pr o v e d   m e di ci n e  or tr e at  m e nt  d uri n g t h e tri al.  
d.    S u bj e ct   w h o  at t h e I n v esti g at or’s  dis cr eti o n f e els t h at  c o nti n ui n g i n t h e st u d y   w o ul d 
n ot  b e i n t h eir  b est i nt er est.  
e.    S u bj e ct   b e c o  m es   pr e g n a nt   ( o bs er v ati o n   a n d   f oll o  w- u p   pr o c e d ur es     m ust   b e 
i niti at e d). 
f.   S u bj e ct   wit h dr a  ws i nf or  m e d  c o ns e nt. 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  9  of  4 3 
4)    Ot h er   R e as o ns 
a.    S u bj e ct r ef us es t o st at e r e as o ns f or  dr o p pi n g  o ut. 
b.    S u bj e ct  d e v el o ps  a n i nt er c urr e nt ill n ess  a n d is  u n a bl e  or  u n  willi n g t o  c o nti n u e i n  a 
cli ni c al tri al;  h o  w e v er, I n v esti g at or  di d  n ot   wis h t o  dis c o nti n u e t h e s u bj e ct.  
c.    S u bj e ct’s  p ers o n al sit u ati o n  c h a n g es:  e. g.   m or e   w or k r es p o nsi bilit y/tr a v el  or  h o  m e 
c h a n g es   (  m o v es,     m arri es,   f a  mil y)   a n d   s u bj e ct   h as   l ess   ti  m e/  m oti v ati o n   t o 
p arti ci p at e. 
d.    Ot h er iss u es r e q uiri n g   wit h dr a  w al  of t h e s u bj e ct fr o  m t h e tri al.   
5)    L ost t o  F oll o  w- u p 
6)    D e at h   
 
3. 3. 2    C rit e ri a f o r   Dis c o nti n u ati o n  of  S u bj e cts f r o  m t h e   T ri al 
Pr ot o c ol tr e at  m e nt   m a y  b e  dis c o nti n u e d f or  a n y  of t h e f oll o  wi n g r e as o ns:  
1)    At t h e  dis cr eti o n  of t h e I n v esti g at or,  at y pi c al  pr o gr essi o n  of  dis e as e;   
2)    If  4 0  %  or   m or e  of s u bj e cts ( 4  o ut  of  a t ot al  of  1 0) i n  a  c o h ort  e x p eri e n c e  a   D L T  attri b ut a bl e 
t o   BI  O  3 0 0   Or al  S us p e nsi o n, t h e   M T  D   will  h a v e  b e e n  e x c e e d e d  a n d  e nr oll  m e nt i nt o t h at 
c o h ort  a n d  a n y  hi g h er- d os e  c o h ort  c urr e ntl y  o p e n t o  e nr oll  m e nt   will  c e as e (s e e s e cti o n  8. 5, 
D os e  Li  miti n g  T o xi citi es (  D L Ts).  
3)    A  d el a y i n  pr ot o c ol tr e at  m e nt  of  gr e at er t h a n  3   w e e ks  d uri n g t h e c o n c urr e nt  p h as e a n d   m or e 
t h a n  4   w e e ks i n t h e  c o ns oli d ati o n  c h e  m ot h er a p y  p h as e. 
4)    A n y  o n e  of t h e   D os e   Li  miti n g   T o xi citi es list e d i n  s e cti o n  8. 5,   D os e   Li  miti n g   T o xi citi es 
(  D L Ts).  
5)    If  pr ot o c ol tr e at  m e nt is  dis c o nti n u e d  d u e t o  d el a y  or  d os e li  miti n g t o xi cit y (  D L T),  at t h e 
dis c o nti n u ati o n  visit,   C  B  C   wit h  diff er e nti al  a n d  s er u  m  c h e  mistri es   will  b e  c o  m pl et e d f or 
s af et y r e p orti n g.   At t h e  dis cr eti o n  of t h e I n v esti g at or, a d diti o n al f oll o  w- u p  bl o o d   w or k   m a y 
b e r e q u est e d.  
6)    If   pr ot o c ol  tr e at  m e nt  is   dis c o nti n u e d  f or   a n y   ot h er  r e as o n,   at  t h e   dis cr eti o n   of  t h e 
I n v esti g at or,   C  B  C   wit h  diff er e nti al  a n d  s er u  m  c h e  mistri es    m a y  b e  r e q u est e d  f or  s af et y 
r e p orti n g  p ur p os es.  
 
3. 4    S  C  H  E  D  U  L  E   O F  S  T  U  D  Y   A S S  E S S  M  E  N  T S 
T a bl e   3- 1 :   Ti  m e t o   E v e nt f o r  n o n s u r gi c al s u bj e cts 
VI SI  T  #   
1   
2   
3   
4- 5 a 
6-
1 0  
1 1 -
3 5 9 
S e   
3 6    
3 7    
3 8    
3 9    
4 0    
4 1    
4 2  
P r o c e d u r e  
S cr e e ni n g  
W e e k  1,  d 1   
W e e k  1,  d 2   
W e e k  1,  d 3  - 4a 
W e e k  2   
W ks   3- 6 
D a y  5 9   
D a y  6 6   
D a y  8 7   
P ost  R T   C o  m pl eti o n   
3   m o  
6   m o  
9   m o  
1 1   m o  
1 3  m o   
I nf or  m e d 
C o ns e nt   
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R e vi e  w    I/ E 
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Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  1 0  of  4 3 
M e di c al 
Hist or y   
X   
 
 
   
 
 
   
   
 
   
   
   
   
 
P h ysi c al 
E x a  m 1  
X 
X b  
X b  
X b  
X   
X  
X  
X   
X  
X 
 
X  
E  C  O  G  S c or e  
X 
X b  
X b    
X b  
X   
X   
X   
X   
X   
X   
   
X 
Vit al  Si g ns  
X 
X b  
X b    
X b  
X   
X   
X   
X   
X   
X   
   
X 
W ei g ht   
X 
X b  
X b    
X b  
X   
X   
X   
X   
X   
X   
   
X 
H ei g ht   
X   
 
 
   
 
 
   
   
 
   
   
   
   
 
E  C  G  
X 2  
X 3  
 
 
X 4 b  
X 4 c 
   
   
 
   
   
   
   
 
C  B  C  
X   
X 
 
 
X b    
X b  
   
X   
X   
X   
 
   
 
 
S er u  m 
C h e  mistr y 5 
X   
X 
 
 
X b    
X b  
   
X   
X   
X   
 
   
 
 
Uri n al ysis 6 
X   
 
 
   
   
   
   
   
   
   
 
   
 
 
Pr e g n a n c y 
T est 7 
X   
X 
 
   
   
   
   
   
   
   
 
   
 
 
E xt e nt    
of 
Dis e as e   
X   
 
 
   
 
X d  
X   
   
X   
X   
X   
X   
X   
X 
P  K s a  m pli n g  
   
X  
X 
X f 
X  
X b  
   
   
 
   
   
   
   
 
P  D s a  m pli n g  
   
X  
 
X f 
X  
X b  
   
   
X   
X   
X 
   
   
 
BI  O    
3 0 0 
A d  mi n.   
   
X  
X   
X   
X   
X   
   
   
   
 
 
   
 
 
C o n c urr e nt 
C h e  m ot h er a
p y  
   
 
X b    
X b    
X b  
   
   
   
   
 
   
 
 
R a di ati o n 
T h er a p y  
   
 
 
X   
X   
X   
   
   
   
   
 
   
 
 
C o ns oli d ati o
n 
C h e  m ot h er a
p y  
   
 
 
   
   
   
   
X   
X   
   
 
   
 
 
A d v ers e 
E v e nts 1 0  
   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
   
X 
C o n c o  mit a nt 
M e di c ati o ns   
X 
X b  
X b    
X b  
X   
X   
X   
   
   
   
   
 
Q o L 
M e as ur es   
X   
 
 
   
   
   
   
   
   
X   
X   
   
   
X 
P ul  m o n ar y 
F u n cti o n 
T est  
X   
 
 
   
   
   
X   
   
   
   
X   
   
   
X 
Di a g.     
C T 
S c a n  
X   
 
 
   
   
   
X   
   
   
X   
X   
   
X   
 
4  D -C T  S c a n   
X   
 
 
   
 
X d  
   
   
X   
   
 
X   
 
X 
S  w all o  wi n g 
Di ar y   
X 
X b  
X b    
X b  
   
   
   
X   
X 
   
 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  1 1  of  4 3 
Di et 
C o u ns eli n g 8 
X 
X b  
X b    
X b  
   
   
   
   
 
   
 
 
aO pti o n al  visit  5 b   as  n e e d e d,   bw e e kl y, cbi -w e e kl y   ( e v er y  ot h er   w e e k), dvisit  2 0  o nl y;  visit   wi n d o  w  all o  w a n c e  of  +/ - 7 
d a ys , eO pti o n al   s ur gi c al  e v al u ati o n,  if  s u bj e ct  is    m e di c all y  fit  f or  s ur g er y  us e  t a bl e  7. 1. 2, f BI  O 3 0 0  + c  h e  m o   P  K 
s c h e d uli n g  all o  w e d   w e e k  1  or  2,  S e e  T a bl e  7. 1. 3 f or  d et ails  
 
T a bl e   3- 2 :   Ti  m e t o   E v e nt f o r s u r gi c al s u bj e cts 
VI SI  T  #   
1   
2   
3   
4- 5 a   6- 1 0  
1 1 -
3 5 9 
S   
3 6    
3 7    
3 8    
3 9    
4 0    
4 1  
P r o c e d u r e  
S cr e e ni n g  
W e e k  1,  d 1   
W e e k  1,  d 2   
W e e k  1,  d 3  - 4a 
W e e k  2   
W ks   3- 6 
D a y  5 9   
6- 1 2   w k  p ost -
s ur g er y 
1 0 -1 6   w k 
p ost -s ur g er y 
P ost  C o ns oli d ati o n   
3   m o  
6   m o  
9   m o  
1 2  m o   
I nf or  m e d 
C o ns e nt   
X   
 
 
   
 
 
   
   
 
   
   
   
 
R e vi e  w    I/ E 
Crit eri a   
X   
X 
 
   
 
 
   
   
 
   
   
   
 
M e di c al 
Hist or y   
X   
 
 
   
 
 
   
   
 
   
   
   
 
P h ysi c al 
E x a  m 1  
X 
X b  
X b  
X b  
X   
X  
X  
X   
X  
X   
X  
E  C  O  G  S c or e  
X 
X b  
X b    
X b  
X   
X   
X   
X   
X   
X   
X 
Vit al  Si g ns  
X 
X b  
X b    
X b  
X   
X   
X   
X   
X   
X   
X 
W ei g ht   
X 
X b  
X b    
X b  
X   
X   
X   
X   
X   
X   
X 
H ei g ht   
X   
 
 
   
 
 
   
   
 
   
   
   
 
E  C  G  
X 2  
X 3  
 
 
X 4 b  
X 4 c 
   
   
 
   
   
   
 
C  B  C  
X   
X 
 
 
X b    
X b  
   
X   
X   
X   
 
 
 
S er u  m 
C h e  mistr y 5 
X   
X 
 
 
X b    
X b  
   
X   
X   
X   
 
 
 
Uri n al ysis 6 
X   
 
 
   
   
   
   
   
   
   
 
 
 
Pr e g n a n c y 
T est 7 
X   
X 
 
   
   
   
   
   
   
   
 
 
 
E xt e nt    
of 
Dis e as e   
X   
 
 
   
 
X d  
X    
   
   
X   
X   
X   
X 
P  K s a  m pli n g  
   
X  
X 
X f 
X  
X b  
   
   
 
   
   
   
 
P  D s a  m pli n g  
   
X  
 
X f 
X  
X b  
   
   
X   
X   
X 
   
 
BI  O    
3 0 0 
A d  mi n.   
   
X  
X   
X   
X   
X   
   
   
   
 
 
 
 
C o n c urr e nt 
C h e  m ot h er a p
y  
   
 
X b  
X b    
X b  
   
   
   
   
 
 
 
R a di ati o n 
T h er a p y  
   
 
 
X   
X   
X   
   
   
   
   
 
 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  1 2  of  4 3 
C o ns oli d ati o n 
C h e  m ot h er a p
y 
   
 
 
   
   
   
   
X   
X   
   
 
 
 
A d v ers e 
E v e nts 1 0 
   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
 
C o n c o  mit a nt 
M e di c ati o ns   
X 
X b  
X b    
X b  
X   
X   
X   
   
   
   
 
Q o L 
M e as ur es   
X   
 
 
   
   
   
   
   
   
X   
X   
   
X 
P ul  m o n ar y 
F u n cti o n  T est  
X   
 
 
   
   
   
X   
   
   
   
X   
   
X 
Di a g.     
C T 
S c a n  
X   
 
 
   
   
   
X   
   
   
X   
X   
X   
X 
4  D -C T  S c a n   
X   
 
 
   
   
 
   
   
   
   
 
 
 
S  w all o  wi n g 
Di ar y   
X 
X b  
X b    
X b  
   
   
   
X   
X 
 
 
Di et 
C o u ns eli n g 8 
X 
X b  
X b    
X b  
   
   
   
   
 
 
 
aO pti o n al  visit  5 b   as  n e e d e d,   bw e e kl y, cbi -w e e kl y   ( e v er y  ot h er   w e e k), dvisit  2 0  o nl y;  visit   wi n d o  w  all o  w a n c e  of  +/ - 7 
d a ys , f BI  O 3 0 0  + c  h e  m o  P  K s c h e d uli n g  all o  w e d   w e e k  1  or  2,  S e e  T a bl e  7. 1. 3 f or  d et ails  
 
 
D es c ri pti o n  of s c h e d ul e  of  ass ess  m e nts 
1.    A c o  m pl et e  p h ysi c al e x a  m   will  b e c o  m pl et e d at s cr e e ni n g.   Ot h er  visits r e q uir e a  bri ef e x a  m, 
f o c us  o n  ar e as  of t u  m or i n v ol v e  m e nt  or r ef er a bl e t o  a d v ers e  e v e nts. 
2.    E  C  Gs   will  b e  p erf or  m e d i n tri pli c at e.  E a c h r e a di n g   will  b e s e p ar at e d  b y  5   mi n ut es.    
3.    E  C  G  is  utili z e d  t o  ass ess  a c ut e  c h a n g es  t h at    m a y  i  m p a ct  c ar di a c  t o xi cit y.   E  C  Gs  t o  b e 
o bt ai n e d j ust  pri or t o  a d  mi nistr ati o n  of   BI  O  3 0 0,  a n d  1  h o ur  p ost  a d  mi nistr ati o n  of   BI  O 
3 0 0.  
4.    E  C  G  d at a   will  b e  c oll e ct e d  pri or t o   BI  O  3 0 0  or  c h e  m ot h er a p y  a d  mi nistr ati o n,   w hi c h e v er 
c o  m es first.  
5.    T o  i n cl u d e  s o di u  m,  p ot assi u  m,  c hl ori d e,  bi c ar b o n at e,    B  U  N,  cr e ati ni n e,  gl u c os e,    A S T, 
A L T,  al k ali n e  p h os p h at as e,  t ot al  bilir u bi n,  al b u  mi n,  t ot al  pr ot ei n,    m a g n esi u  m,  c al ci u  m, 
p h os p h or o us  a n d  uri c  a ci d.   A n al ysis  of  p a n cr e ati c  e n z y  m es  als o t o  b e i n cl u d e d i n  p a n el 
( a  m yl as e  a n d li p as e). 
6.    Uri n al ysis  t o  i n cl u d e  p  H,  s p e cifi c  gr a vit y,  di psti c k  d et er  mi n ati o ns  of  gl u c os e,  k et o n es, 
pr ot ei n,  h e  m o gl o bi n,  bilir u bi n. 
7.    Pr e g n a n c y t est   m a y  b e  uri n e  or s er u  m  d et er  mi n ati o n  of  β-  H  C  G.   Visit  2 t est is  o nl y r e q uir e d 
if t h e s cr e e ni n g  pr e g n a n c y t est   w as  p erf or  m e d   m or e t h a n  7 2  h o urs  pri or t o  visit  2. 
8.    At t h e s cr e e ni n g  visit  p ati e nts   will  b e  c o u ns el e d  a n d  gi v e n i nstr u cti o ns  o n  a  di et l o  w i n s o y 
is ofl a v o n es.    Di et  c o u ns eli n g   will  o c c ur   w e e kl y  d uri n g t h e ti  m e  p eri o d   w h er e   BI  O  3 0 0 is 
a d  mi nist er e d.   
9.    T h e t ot al  n u  m b er  of  s u bj e ct  visits  c o  m pl et e d t hr o u g h  c o n c urr e nt  c h e  m or a di ot h er a p y  ar e 
fl e xi bl e  a n d  d e p e n d e nt  o n  r a di ot h er a p y  a n d  c h e  m ot h er a p y  s c h e d uli n g.   E a c h  s u bj e ct   will 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  1 3  of  4 3 
h a v e  a   mi ni  m u  m  of  3 2  visits t hr o u g h t h e  c o n cl usi o n  of  c o n c urr e nt  c h e  m or a di ot h er a p y ( 6 
w e e ks  of  c h e  m ot h er a p y  a n d  d ail y   R T fr a cti o ns  of  2. 0   G y, t ot al  d os e  of  6 0   G y). 
1 0.  All  a d v ers e  e v e nts   will  b e  c oll e ct e d fr o  m t h e ti  m e t h e s u bj e ct si g ns i nf or  m e d  c o ns e nt  u ntil 
3 0  d a ys  aft er t h e l ast  a d  mi nistr ati o n  of  BI  O  3 0 0.    Aft er t his ti  m e,  a d v ers e  e v e nt  ass ess  m e nt 
will  o c c ur  at  e a c h  visit  b ut  o nl y  t h os e  e v e nts  t h at  ar e  c o nsi d er e d  s eri o us  a n d  p ossi bl y, 
pr o b a bl y  or  d efi nit el y r el at e d t o   BI  O  3 0 0   will  b e  d o c u  m e nt e d  a n d  r e p ort e d t o t h e s p o ns or 
wit hi n  2 4  h o urs  of  a  w ar e n ess.  
 
 
 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  1 4  of  4 3 
T a bl e  7. 1. 3   Visit   Wi n d o  w   T a bl e   
Visit  o r 
P r o c e d u r e  
Visit   Wi n d o  w   
N ot es   
S cr e e ni n g   Visit    
Wit hi n  2 8 d  pri or t o r e gistr ati o n.
 
P ul  m o n ar y  F u n cti o n 
T est ,   M e di c al   Hist or y, 
P h ysi c al  E x a  m  a n d   C Ts  
m a y  b e  c o  m pl et e d   w  it hi n 
1 0  w ks  pri or   t o 
r e gistr ati o n 
C o n c urr e nt 
C h e  m ot h er a p y   
D a y  1  of  c  h e  m ot h er a p y   m a y  b e s c h e d ul e d  at t h e  dis cr eti o n  of t h e 
i n v esti g at or  pr o vi d e d t h e s u bj e ct  h as  c o  m pl et e d  a   mi ni  m u  m  of 1 
d a ys  of   BI  O  3 0 0  d osi n g . 
S h o ul d  visit s b e  d el a y e d 
d u e t o  a  h oli d a y, 
st a n d ar d  of  c ar e s h o ul d 
b e f oll o  w e d.  
R a di ati o n 
T h er a p y  
D a y  1  of r a di ati o n t h er a p y   m a y  b e s c h e d ul e d  at t h e  dis cr eti o n  of 
t h e i n v esti g at or  pr o vi d e d t h e s u bj e ct  h as  c o  m pl et e d  a   mi ni  m u  m 
of  2  d a y  of   BI  O  3 0 0  d osi n g . 
S h o ul d  visit s b e  d el a y e d 
d u e t o  a  h oli d a y, 
st a n d ar d  of  c ar e s h o ul d 
b e f oll o  w e d.  
BI  O  3 0 0  + 
C h e  m o  P  K   
BI  O  3 0 0  +   C h e  m o  p h ar  m a c o ki n eti cs   m a y  b e s c h e d ul e d   w e e k  1 
or   w e e k  2  at t h e  dis cr eti o n  of t h e i n v esti g at or  pr o vi d e d  t h e 
s u bj e ct  h as  c o  m pl et e d  at l e ast  4  d a ys  a n d  n o   m or e t h a n  9  d a ys  of 
BI  O  3 0 0  d osi n g  . 
 
P  K s a  m pli n g  
F or t h e  pr e -BI  O  3 0 0  a d  mi nistr ati o n ti  m e  p oi nt  a n d t h e  0. 5  a n d  1 
h o ur ti  m e  p oi nts,  bl o o d   will  b e  c oll e ct e d   wit hi n  ±  5   mi n ut es  of 
t h e  d efi n e d  dr a  w ti  m e  p ost   BI  O  3 0 0  d osi n g.  F or t h e  2,  3,  4  a n d  8 
h o ur ti  m e  p oi nts,  bl o o d   will  b e  c oll e ct e d   wit hi n  ±  1 0   mi n ut es f or 
t h e  d efi n e d  dr a  w ti  m e  p ost   BI  O  3 0 0  d osi n g. T h e  2 4 hr  dr a  w 
s h o ul d  o c c ur as  cl os e t o  2 4  h o urs  aft er t h e  d os e  of   BI  O  3 0 0  a n d 
pri or t o t h e   m or ni n g  d os e  of   BI  O  3 0 0 . 
 
C  B  C  
M  a y  b e  dr a  w n  u p t o  4 d  pri or t o  visits   w h er e  c h e  m ot h er a p y is 
a d  mi nist er e d  
 
S er u  m  C h e  mistr y  
M  a y  b e  dr a  w n  u p t o  4 d  pri or t o  visits   w h er e  c h e  m ot h er a p y is 
a d  mi nist er e d  
 
Visit  S,  S ur gi c al 
E v al u ati o n  
+/ - 7 d  
 
Visit  3 6  -3 7, 
C o ns oli d ati o n 
C h e  m ot h er a p y  
+/ - 7 d  
+/ - 1 4 d f or   C T  
Visit  3 8  -3 9,  3  a n d 
6   m o nt h f oll o  w 
u p  
+/ - 1 4 d  
 
Visit  4 0  -4 2,  9 -1 3 
m o nt h f oll o  w  u p   
+/ - 2 1 d  
F or s ur gi c al s u bj e cts 
visit  4 1,  1 2   m o nt h f oll o  w 
u p ( e n d  of st u d y)  
 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  1 5  of  4 3 
4    S  A  M P  L  E  SI  Z  E   C  O  N SI  D  E  R  A  TI  O  N S  
N o  f or  m al  s a  m pl e  si z e  c al c ul ati o n    will  b e  p erf or  m e d  as  t his  st u d y  is    m e a nt  t o  b e  h y p ot h esis 
g e n er ati n g. 
5    A  N  A  L  Y SI S  P  O P  U  L  A  TI  O  N S   
5. 1    F  U  L  L   A  N  A  L  Y SI S  S  E  T 
T h e  F ull   A n al ysis  S et ( F  A S)   will i n cl u d e  all  s u bj e cts   w h o r e c ei v e  at l e ast  o n e  d os e  of   BI  O  3 0 0. 
T his  a n al ysis s et   will  b e  us e d t o s u  m  m ari z e  all s af et y  e n d p oi nts.  
5. 2    E F FI  C  A  C  Y   A  N  A  L  Y SI S  S  E  T 
T h e   Effi c a c y   A n al ysis  S et ( E  A S)   will i n cl u d e  all  s u bj e cts   w h o r e c ei v e  at l e ast  o n e  d os e  of   BI  O 
3 0 0  a n d  h a v e  at  l e ast  o n e  e xt e nt  of  dis e as e  ass ess  m e nt  f oll o  wi n g  t h e  c o n cl usi o n  of  c o n c urr e nt 
t h er a p y. 
5. 3    P  H  A  R  M  A  C  O  KI  N  E  TI  C ( P  K)  P  O P  U  L  A  TI  O  N 
T h e  P  K  P o p ul ati o n   will  i n cl u d e  all  s u bj e cts   w h o  r e c ei v e  at  l e ast  1  d os e  of   BI  O  3 0 0  a n d  h a v e 
s uffi ci e nt,  v ali d  P  K s a  m pl es t o  esti  m at e  k e y  p ar a  m et ers f or  at l e ast  1  of t h e  d a ys  of s a  m pli n g.  P  K 
s u  m  m ari es   will  b e  b as e d  o n t h e  P  K  p o p ul ati o n. 
5. 4    P  H  A  R  M  A  C  O  D  Y  N  A  MI  C S ( P  D)  P  O P  U  L  A  TI  O  N 
T h e  P  D  P o p ul ati o n   will  i n cl u d e  all  s u bj e cts   w h o  r e c ei v e  at  l e ast  1  d os e  of   BI  O  3 0 0  a n d  h a v e 
s uffi ci e nt,  v ali d  P  D s a  m pl es t o  esti  m at e  k e y  p ar a  m et ers f or  at l e ast  1  of t h e  d a ys  of s a  m pli n g.  P  D 
s u  m  m ari es   will  b e  b as e d  o n t h e  P  D  p o p ul ati o n. 
6    C  O  N SI  D  E  R  A  TI  O  N S  F  O  R   D  A  T  A   A  N  A  L  Y SI S   
6. 1    P  R  O  G  R  A  M  MI  N  G   E  N  VI  R  O  N  M  E  N  T 
D at a   will  b e  e x p ort e d fr o  m t h e  st u d y  s p e cifi c  v ali d at e d  cli ni c al tri al  d at a b as e  a n d i  m p ort e d i nt o 
t h e   R s oft  w ar e  e n vir o n  m e nt f or st atisti c al  c o  m p uti n g  a n d  gr a p hi cs  g e n er ati o n [ 1]. 
6. 2    S  T  R  A  T  A   A  N  D   C  O  V  A  RI  A  T  E S 
T h er e  ar e  n o str at a  or  c o v ari at es f or t his st u d y. 
6. 3    S  U  B  G  R  O  U P S 
S u b gr o u ps    will  n ot  b e  a n al y z e d  i n  t his  st u d y.  F ut ur e  st u di es    will  i n cl u d e  s u b gr o u p  a n al ys es, 
s u b gr o u ps   m a y i n cl u d e: 
•    G e n d er 
•    C a n c er st a g e  at  e nr oll  m e nt 
•    Hist ol o g y ( e. g. s u bt y p e  of   N S  C L  C) 
•    T u  m or l o c ati o n 
 
6. 4    M  U  L  TI P  L  E   C  O  M P  A  RI S  O  N S   A  N  D   M  U  L  TI P  LI  C  T  Y 
T h er e  ar e  n o  pl a n n e d  a dj ust  m e nts f or   m ulti pli cit y. 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  1 6  of  4 3 
6. 5    SI  G  NI FI  C  A  N  C  E   L  E  V  E  L 
A n  i n d e p e n d e nt  st atisti ci a n   usi n g  st a n d ar d  st atisti c al  t e c h ni q u es    will   d et er  mi n e  st atisti c all y 
si g nifi c a nt  diff er e n c es i n t h e tri al   m e as ur e  m e nt  d at a  at t h e  n o  mi n al  0. 0 5 l e v el  of si g nifi c a n c e.       
6. 6    S  T  A  TI S  TI  C  A  L   N  O  T  AI  O  N   A  N  D   M  E  T  H  O  D  O  L  O  G  Y 
U nl ess st at e d  ot h er  wis e, t h e t er  m “ d es cri pti v e st atisti cs ” r ef ers t o t h e  n u  m b er  of s u bj e cts ( n),   m e a n, 
m e di a n,   st a n d ar d   d e vi ati o n   ( S T  D),     mi ni  m u  m   (  mi n),   a n d     m a xi  m u  m   (  m a x)   a n d   st a n d ar d 
err ors/ c o nfi d e n c e i nt er v als f or  c o nti n u o us r es p o ns e  v ari a bl es  a n d  distri b uti o n t a bl es  or  hist o gr a  ms 
f or  dis cr et e r es p o ns e  v ari a bl es.   Mi n  a n d   m a x  v al u es   will  b e r o u n d e d t o t h e  pr e cisi o n  of t h e  ori gi n al 
v al u e,   m e a ns  a n d   m e di a ns   will  b e  r o u n d e d t o  1  d e ci  m al  pl a c e  gr e at er t h a n t h e  pr e cisi o n  of t h e 
ori gi n al  v al u e,  a n d   S T  Ds   will  b e  r o u n d e d t o  2  d e ci  m al  pl a c es  gr e at er t h a n t h e  pr e cisi o n  of t h e 
ori gi n al  v al u e.  P er c e nt a g es   will  b e r o u n d e d t o t h e  n e ar est   w h ol e  n u  m b er ( z er os  ar e  n ot  dis pl a y e d) 
wit h  v al u es  of  “ <  1  % ”  a n d  “ >  9 9  % ” s h o  w n  as  n e c ess ar y f or  v al u es f alli n g  n e ar t h e  b o u n d ari es.   
I n  a d diti o n, r el ati o ns hi ps  b et  w e e n t h es e r es p o ns e  v ari a bl es   will  b e  e x pl or e d  usi n g  n o n- p ar a  m etri c 
a p pr o a c h es  ( e. g.,   S p e ar  m a n  r a n k  c orr el ati o n),   p ar a  m etri c  c orr el ati o n  a n al ysis    m et h o ds  ( e. g., 
c orr el ati o n   c o effi ci e nt),   or   a p pr o pri at e   st atisti c al  t ests   ( e. g.,  t h e    C hi-s q u ar e  tr e n d  t est   f or 
c at e g ori c al  d at a).  F urt h er  m or e,  a p pr o pri at e  r e gr essi o n  t e c h ni q u es  f or  t h es e  r es p o ns e  v ari a bl es 
( e. g.,  a n al ysis  of  c o v ari a n c e  (  A  N  C  O  V  A)),  li n e ar  r e gr essi o n,  pr o p orti o n al  h a z ar ds  r e gr essi o n, 
l o gisti c  r e gr essi o n,  g e n er ali z e d  esti  m ati n g  e q u ati o n  (  G E E)  a n d    mi x e d  eff e cts    m o d els)    will  b e 
e  m pl o y e d  t o  f urt h er  e x a  mi n e  t h eir  r el ati o ns hi p   wit h  o n e  a n ot h er.   C o nfi d e n c e  i nt er v als   will  b e 
c al c ul at e d  f or  t h e  diff er e n c es.   T h e  c o  m p ut e d  c h a n g e  fr o  m  b as eli n e    will  b e  c al c ul at e d  f or  all 
m e as ur e d  v ari a bl es  a n d  e x pr ess e d  as t h e   m e a n  c h a n g e fr o  m  b as eli n e  +  st a n d ar d  d e vi ati o n ( S T  D) 
of t h e  c h a n g e fr o  m  b as eli n e.    A t  w o-s a  m pl e t-t est   will  b e  us e d t o t est t h e t u  m or si z e r e d u cti o n  a n d 
a l o g-r a n k t est   will  b e  us e d t o  c o  m p ar e ti  m e t o  e v e nt  o ut c o  m es.    A n al ysis  of  c o v ari a n c e   will  b e 
us e d t o  c o  m p ar e  d os a g e  gr o u ps  o n  “ c h a n g e fr o  m  b as eli n e ”   m e as ur es (  wit h  b as eli n e   m e as ur e  m e nt 
c o nsi d er e d  as  a n  a dj ust  m e nt  c o v ari at e).  
U nl ess  ot h er  wis e  n ot e,  all  d at a  c oll e ct e d  d uri n g t h e st u d y   will  b e i n cl u d e d i n  d at a listi n gs  a n d   will 
b e s ort e d  b y tr e at  m e nt  gr o u p, s u bj e ct  n u  m b er  a n d t h e n  b y  visit f or  e a c h s u bj e ct  n u  m b er. 
7    D  A  T  A   H  A  N  D  LI  N  G   M  E  T  H  O  D S   
7. 1    MI S SI  N  G   D  A  T  A 
Gi v e n t h e  s  m all  s a  m pl e  si z e,  d es cri pti v e  st atisti cs  a n d  ot h er  a n al ys es   will  b e  c o  m pl et e d   wit h o ut 
r e pl a ci n g  or i  m p uti n g   missi n g  v al u es,   wit h t h e  e x c e pti o n  of t h e  F  A  C T- T  OI   w hi c h   will  b e  pr or at e d 
as  d es cri b e d  b el o  w. 
7. 1. 1    F  A  C  T -  T  OI   H a n dli n g  of   Missi n g It e  ms   
F  A  C T s c ori n g   will  b e  c o  m pl et e d  as  d es cri b e d i n t h e   A d  mi nistr ati o n  a n d  S c ori n g   G ui d eli n es i n t h e 
m a n u al  or  o n-li n e  at   w  w  w.f a cit. or g  .   Bri efl y, if t h er e  ar e   missi n g it e  ms,  s u bs c al e  s c or es will    b e 
pr or at e d.     T his  is  d o n e  b y    m ulti pl yi n g  t h e  s u  m  of  t h e  s u bs c al e  b y  t h e  n u  m b er  of  it e  ms  i n  t h e 
s u bs c al e, t h e n  di vi di n g  b y t h e  n u  m b er  of it e  ms  a ct u all y  a ns  w er e d.   T his  c a n  b e  d o n e  o n t h e s c ori n g 
g ui d e  or  b y  usi n g t h e f or  m ul a  b el o  w: 
P r o r at e d  s u bs c al e  s c o r e   =   [ S u  m  of  it e  m  s c or es]  x   [  N  of  it e  ms  i n  s u bs c al e]  ÷   [  N  of  it e  ms 
a ns  w er e d] 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  1 7  of  4 3 
W h e n t h er e  ar e   missi n g  d at a,  pr or ati n g  b y s u bs c al e i n t his   w a y is  a c c e pt a bl e  as l o n g  as     m o r e t h a n 
5 0  %  of t h e it e  ms   w er e  a ns  w er e d ( e. g.,  a   mi ni  m u  m  of  4  of  7 it e  ms,  4  of  6 it e  ms,  et c. ).    T h e t ot al 
s c or e  is  t h e n  c al c ul at e d  as  t h e  s u  m  of  t h e  u n-  w ei g ht e d  s u bs c al e  s c or es.     T h e  F  A  C T  s c al e  is 
c o nsi d er e d t o  b e  a n  a c c e pt a bl e i n di c at or  of  p ati e nt  q u alit y  of lif e  as l o n g  as  o v e r all it e  m  r es p o ns e 
r at e   is  gr e at er  t h a n  8 0  %  ( e. g.,  at  l e ast  2 2  of  2 7  F  A  C T-  G  it e  ms  c o  m pl et e d).     T his  is  n ot  t o  b e 
c o nf us e d   wit h i n di vi d u al s u bs c al e it e  m r es p o ns e r at e,   w hi c h  all o  ws  a s u bs c al e s c or e t o  b e  pr or at e d 
f or   missi n g it e  ms if  gr e at er t h a n  5 0  %  of it e  ms  ar e  a ns  w er e d. I n  a d diti o n,  a t ot al s c or e s h o ul d  o nl y 
b e  c al c ul at e d if   A L L  of t h e  c o  m p o n e nt s u bs c al es  h a v e  v ali d s c or es.    
7. 2    VI SI  T   WI  N  D  O  W S 
V al u es   will  b e  pr es e nt e d  f or  all  s c h e d ul e d  st u d y  visits  a c c or di n g t o t h e  n o  mi n al  v al u e  o bt ai n e d 
fr o  m  t h e   C  R F.  If  a n  u ns c h e d ul e d  visit  f alls  i n  a  visit    wi n d o  w    wit h  a n  e xisti n g  n o  mi n al  visit 
ass ess  m e nt, t h e  n o  mi n al  ass ess  m e nt   will  b e  us e d  f or  s u  m  m ar y  pr es e nt ati o n.  If  n o  n o  mi n al  visit 
ass ess  m e nt  e xists f or  a  visit   wi n d o  w   wit h  u ns c h e d ul e d  visit(s), t h e n t h e l at est  u ns c h e d ul e d  visit 
wit hi n  t h e  visit   wi n d o  w   will  b e  us e d.  If   m ulti pl e  n o  mi n al  ass ess  m e nts  ar e  c oll e ct e d   wit hi n  t h e 
s a  m e  visit, t h e l at est  v al u e  a n d  c orr es p o n di n g  d at e   will  b e  us e d f or s u  m  m ar y  pr es e nt ati o n. 
7. 3    D  A  T  A   D  E  RI  V  A  TI  O  N S   A  N  D   D  E FI  NI  TI  O  N S 
B as eli n e   will  b e  c o nsi d er e d  as t h e l ast  n o n-  missi n g  ass ess  m e nt  pri or t o t h e first  a d  mi nistr ati o n  of 
BI  O  3 0 0.    
C h a n g es  fr o  m  b as eli n e    will  b e  c al c ul at e d  as  diff er e n c es  b et  w e e n  ass ess  m e nt  v al u es  a n d  t h eir 
c orr es p o n di n g  b as eli n e  v al u es. 
P er c e nt  c h a n g es  fr o  m  b as eli n e   will  b e  c al c ul at e d  as  diff er e n c es  b et  w e e n  ass ess  m e nt  v al u es  a n d 
t h eir  c orr es p o n di n g  b as eli n e  v al u es  di vi d e d  b y t h e  c orr es p o n di n g  b as eli n e  v al u es. 
A g e   will  b e  c al c ul at e d fr o  m t h e  d at e  of  birt h t o s cr e e ni n g  visit  d at e.   
If   m ulti pl e  d at es  o c c ur f or t h e s cr e e ni n g  visit, t h e  c o n v e nti o n  as  d es cri b e d  at t h e  e n d  of  S e cti o n  7. 2 
will  b e  us e d. 
T h e f oll o  wi n g   will  d efi n e  pri or   m e di c ati o n  us e  v ers us  c o n c o  mit a nt   m e di c ati o n  us e:   
•    Pri or  us e  e n d e d  b ef or e t h e first  a d  mi nistr ati o n  of   BI  O  3 0 0 
•    C o n c o  mit a nt  us e is  o n  or  aft er t h e first  a d  mi nistr ati o n  of  BI  O  3 0 0  a n d  pri or t o  3 0  d a ys  p ost 
t h e l ast  a d  mi nistr ati o n  of   BI  O  3 0 0 
8    S  T  U  D  Y  P  O P  U  L  A  TI  O  N  
U nl ess  ot h er  wis e  st at e d,  all  st u d y  p o p ul ati o n  a n al ys es   will  b e  p erf or  m e d  o n t h e  F ull   A n al ysis  S et 
( F  A S). 
8. 1    A  N  A  L  Y SI S  P  O P  U  L  A  TI  O  N 
T h e  a n al ysis  p o p ul ati o n listi n g   will i n cl u d e, f or  e a c h  p o p ul ati o n  d et ail e d i n  S e cti o n  5,   w h et h er  or 
n ot  t h e  s u bj e ct    w as  i n cl u d e d  i n  t h e  p o p ul ati o n  a n d  t h e  r e as o n  f or  b ei n g  e x cl u d e d  fr o  m  t h e 
p o p ul ati o n.   N u  m b er  of  s u bj e cts i n  e a c h  a n al ysis  p o p ul ati o n   will  b e  s u  m  m ari z e d  b ot h  o v er all  a n d 
b y tr e at  m e nt  gr o u p. 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  1 8  of  4 3 
8. 2    S  U  B J  E  C  T   DI S P  O S  TI  TI  O  N 
S u bj e ct  dis p ositi o n   will  b e  pr es e nt e d f or  all s u bj e cts.  T h e  c o  m p ositi o n  of t h e  a n al ysis  p o p ul ati o ns 
a n d  t h os e    w h o  e nr oll e d,  c o  m pl et e d  or  dis c o nti n u e d  fr o  m  t h e  st u d y    will  b e  s u  m  m ari z e d  b y 
tr e at  m e nt  gr o u p  a n d  o v er all   wit h  d es cri pti v e st atisti cs.  R e as o ns f or  dis c o nti n u ati o n   will  b e  pr es e nt 
wit h  fr e q u e n ci es  a n d  p er c e nt a g es  f or  all  c at e g ori es.   A  c o  m pr e h e nsi v e  d at a  listi n g   will  als o  b e 
i n cl u d e d. 
8. 3    I  N  C  L  U SI  O  N/  E  X  C  L  U SI  O  N   C  RI  T  E  RI  A 
I n cl usi o n  a n d  e x cl usi o n  crit eri a f ail ur es   will  b e i n cl u d e d i n  a  d at a listi n g. 
8. 4    P  R  O  T  O  C  O  L   D  E  VI  A  TI  O  N S 
Pr ot o c ol  d e vi ati o ns   will  b e  s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  c at e g or y  a n d i n cl u d e d i n  a  d at a 
listi n g. 
M aj or  pr ot o c ol  d e vi ati o ns i n cl u d e,  b ut  ar e  n ot li  mit e d t o t h e f oll o  wi n g:   
•    N o n-f ulfill  m e nt  of  all i n cl usi o n  crit eri a  or f ulfill  m e nt  of  at l e ast  o n e  e x cl usi o n  crit eri a;   
•    I  m pr o p er I nf or  m e d   C o ns e nt  pr o c ess; 
•    N o n- d el e g at e d st u d y  p ers o n n el  dis p e nsi n g i n v esti g ati o n al  pr o d u ct; 
•    Ot h er r el e v a nt  vi ol ati o ns, t o  b e j u d g e d  o n  a n i n di vi d u al  b asis. 
 
Mi n or  pr ot o c ol  d e vi ati o ns i n cl u d e,  b ut  ar e  n ot li  mit e d t o: 
•    M e as ur e  m e nts  o bt ai n e d  o utsi d e t h e  visit   wi n d o  w t o  a li  mit e d  d e gr e e;   
•    Miss e d  visit  ass ess  m e nts; 
•    L a c k  of s o ur c e  d o c u  m e nt ati o n; 
•    Ot h er  d e vi ati o ns   will  b e j u d g e d  o n  a n i n di vi d u al  b asis. 
 
8. 5    D  E  M  O  G  R  A P  HI  C   C  H  A  R  A  C  T  E  RI S  TI  C S 
D e  m o gr a p hi c  a n d  b as eli n e  c h ar a ct eristi c  d at a   will  b e  s u  m  m ari z e d   wit h  d es cri pti v e  st atisti cs  f or 
a g e,  g e n d er, r a c e,  et h ni cit y,  h ei g ht,   w ei g ht, i niti al t u  m or  st a g e, t u  m or  hist ol o g y, t u  m or l o c ati o n, 
a n d   m arit al st at us.   A  c o  m pr e h e nsi v e listi n g   will  als o  b e i n cl u d e d. 
8. 6    C  O  N  C  O  MI  T  A  N  T   M  E  DI  C  A  TI  O  N S  
A  d at a listi n g   will  b e i n cl u d e d t h at s h o  ws  all   m e di c ati o ns  b y  v er b ati  m  n a  m e.     
8. 7    M  E  DI  C  A  L   HI S  T  O  R  Y 
A  c o  m pr e h e nsi v e  d at a listi n g  of   m e di c al  hist or y   will    b e i n cl u d e d. 
9    E F FI  C  A  C  Y   A  N  A  L  Y SI S   
9. 1    O  B J  E  C  TI  V  E   R  E S P  O  N S  E S 
O bj e cti v e  r es p o ns es  of  t h e  t ar g et  l esi o n  b as e d  o n   m e as ur e  m e nts  fr o  m  a  c o n v e nti o n al   C T  s c a n, 
P E T/  C T,  4  D-  C T  or  ot h er   will  b e  d et er  mi n e d i n  all  s u bj e cts  at  b as eli n e  a c c or di n g t o t h e   R E  CI S T 
1. 1  crit eri a (s e e   A p p e n di x  4  of t h e  pr ot o c ol).  T h e  pr o p orti o n  of  p ati e nts  e x p eri e n ci n g  pr o gr essi v e 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  1 9  of  4 3 
dis e as e,   st a bl e   dis e as e   ( S  D),   p arti al   r es p o ns es   ( P  R)   or   c o  m pl et e   r es p o ns es   (  C  R)    will   b e 
s u  m  m ari z e d i n t a b ul ar f or  m at. 
P er   R E  CI S T  1. 1,  o v er all r es p o ns e r at e (  O  R  R)   will  b e  c al c ul at e d  usi n g  b est  o v er all r es p o ns e   wit h 
c o nfir  m ati o n  of   C  R  a n d  P  R.  T h e  c orr es p o n di n g  9 5  %  e x a ct  c o nfi d e n c e i nt er v al   will  b e  c al c ul at e d 
b as e d  o n t h e  bi n o  mi al  distri b uti o n. 
B est  o v er all r es p o ns e ( pr o gr essi v e  dis e as e, st a bl e  dis e as e,  P  R,  C  R,  or  n ot a p pli c a bl e/ n ot e v al u a bl e) 
will  b e  t a b ul at e d.  If  S  D  is  b eli e v e d  t o  b e  b est  r es p o ns e,    m e as ur e  m e nts    m ust  h a v e    m et  t h e  S  D 
crit eri a  at l e ast  o n c e  aft er  st u d y  e ntr y  at  a   mi ni  m u  m i nt er v al  of  4 2  d a ys. If t h e   mi ni  m u  m ti  m e is 
n ot    m et    w h e n  S  D  is  t h e  b est  ti  m e  p oi nt  r es p o ns e,  t h e  p ati e nt’s  b est  r es p o ns e  d e p e n ds  o n  t h e 
s u bs e q u e nt  ass ess  m e nts ( a c c or di n g t o   R E  CI S T  1. 1). 
T u  m or  di a  m et er    m e as ur e  m e nts  a n d  c h a n g e  fr o  m  b as eli n e   will  b e  s u  m  m ari z e d   wit h  d es cri pti v e 
st atisti cs  b y  visit   wit h r es p e ct t o tr e at  m e nt  gr o u p.   A  pl ot  of t u  m or  di a  m et er  o v er ti  m e   will  als o  b e 
i n cl u d e d. 
9. 2    D  U  R  A  TI  O  N   O F   R  E S P  O  N S  E (  D  O  R) 
D ur ati o n  of r es p o ns e (  D  O  R) is  d efi n e d  as t h e ti  m e fr o  m t h e first t u  m or r es p o ns e  of   C  R  or  P  R t o 
d o c u  m e nt e d t u  m or  pr o gr essi o n  or  d e at h,   w hi c h e v er is t h e  e arli est.  
D  O  R   will  b e s u  m  m ari z e d f or t h e r es p o n d ers  o nl y.  R es p o n d er is  d efi n e d  as t h os e s u bj e cts   w h o  h a d 
t u  m or r es p o ns e  of   C  R  or  P  R. 
A   K a pl a n-  M ei er  a n al ysis  of   D  O  R   will  b e  p erf or  m e d t o g et h er   wit h its  9 5  %  c o nfi d e n c e i nt er v al.   
T h e   D  O  R   will  b e  c e ns or e d i n t h e f oll o  wi n g s c e n ari os: 
1)    S u bj e cts   w h o  g o  off tr e at  m e nt f or r e as o ns  ot h er t h a n  pr o gr essi o n  a n d  b e gi n tr e at  m e nt   wit h 
ot h er  a nti- n e o pl asti c t h er a pi es   will  als o  b e  c e ns or e d  at t h e  d at e  of l ast t u  m or  ass ess  m e nt 
b ef or e st arti n g  ot h er  a nti- n e o pl asti c t h er a pi es. 
2)    If s u bj e ct  h a d  pr o gr essi v e  dis e as e  or  d e at h  o c c urr e d  aft er   missi n g t  w o t u  m or  ass ess  m e nts, 
t h e  p ati e nt   will  b e  c e ns or e d  at t h e  d at e  of t h e  pr e vi o us t u  m or  ass ess  m e nt   wit h   C  R,  P  R  or 
S  D.  
3)    If s u bj e ct  d o es  n ot  h a v e  p ost  b as eli n e t u  m or  ass ess  m e nt  or   wit h  n o  P  D  or  d e at h   wit hi n t  w o 
ass ess  m e nts aft er e nr oll  m e nt, t h e   D  O  R   will  b e c e ns or e d at t h e  d at e  of t h e first  d os e  of st u d y 
dr u g. 
4)    If   a   s u bj e ct    wit h dr a  ws  fr o  m  t h e   st u d y   pr e  m at ur el y  f or  r e as o ns   ot h er  t h a n   dis e as e 
pr o gr essi o n  or  d e at h,   D  O  R   will  b e  c e ns or e d  at t h e  s u bj e ct’s l ast  d at e  k n o  w n  ali v e  a n d  n ot 
P  D.  
D  O  R   will  b e  pr es e nt e d i n  a  b y-s u bj e ct listi n g. 
9. 3    P  R  O  G  R  E S SI  O  N  F  R  E  E  S  U  R  VI  V  A  L 
Pr o gr essi o n fr e e  s ur vi v al ( P F S)   will  b e  c al c ul at e d fr o  m t h e first  a d  mi nistr ati o n  of   BI  O  3 0 0  u ntil 
d e at h  or  u ntil  t h e  crit eri a  f or  dis e as e  pr o gr essi o n  ar e    m et  ( a c c or di n g  t o   R E  CI S T  1. 1  or  i n  t h e 
o pi ni o n  of t h e tr e ati n g  p h ysi ci a n).   A   K a pl a n-  M ei er  a n al ysis  of  P F S   will  b e  p erf or  m e d  a n d   m e di a n 
s ur vi v al ti  m e  a n d its  9 5  %  c o nfi d e n c e i nt er v al   will  b e  c o  m p ut e d  b y tr e at  m e nt  c o h ort  a n d  o v er all. 
A   K a pl a n-  M ei er  c ur v e   will  b e  pr es e nt e d. 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  2 0  of  4 3 
If t h e  s u bj e ct  h as  n ot  pr o gr ess e d  or  di es  at t h e ti  m e  of t h e fi n al  d at a  c ut off,  P F S   will  b e  c e ns or e d 
usi n g t h e s a  m e r ul es  d es cri b e d i n  9. 2. 
P F S (i n  d a ys) is  c al c ul at e d  as: 
(  D at e  of  d e at h  of  d o c u  m e nt e d  pr o gr essi o n)  – (  D at e  of first  a d  mi nistr ati o n  of  BI  O  3 0 0)  +  1, if  e v e nt 
(  D at e  of l ast t u  m or  ass ess  m e nt   wit h   C  R,  P  R,  or  S  D)  – (  D at e  of first  a d  mi nistr ati o n  of   BI  O  3 0 0)  + 
1, if  c e ns or 
A  c o  m pr e h e nsi v e  d at a listi n g   will  als o  b e i n cl u d e d. 
9. 4    P  U  L  M  O  N  A  R  Y  F  U  N  C  TI  O  N   T  E S  T 
T h e    m e as ur e  m e nts  of  P F T  i n cl u di n g  f or c e d  vit al  c a p a cit y  ( F  V  C),  f or c e d  e x pir at or y  v ol u  m e 
( FE  V 1),  F E  V 1/ F  V  C,  diff usi o n  c a p a cit y  (  D L  C  O)  a n d  c h a n g e  fr o  m  b as eli n e   will  b e  s u  m  m ari z e d 
wit h  d es cri pti v e st atisti cs  b y ti  m e  p oi nt   wit h r es p e ct t o tr e at  m e nt  gr o u p.   
A  d at a listi n g  of  all r es ults   will  als o  b e i n cl u d e d. 
9. 5    S  W  A  L  L  O  WI  N  G   DI  A  R  Y 
T h e  p ati e nt s elf- ass ess e d  d ail y s  w all o  wi n g s c or e (t h e s  w all o  wi n g  q u esti o n n air e) fr o  m  0 t o  5,  1    n o 
pr o bl e  ms s  w all o  wi n g;  2   mil d s or e n ess  o nl y;  3 s o  m e  diffi c ult y s  w all o  wi n g s oli ds;  4 c a n n ot s  w all o  w 
s oli ds;  a n d  5  c a n n ot  s  w all o  w li q ui ds.   T h e   m e as ur e  m e nts   will  b e  a n al y z e d  usi n g  ar e a  u n d er t h e 
c ur v e (  A  U  C)   m et h o d ol o g y,   w hi c h i n c or p or at es  b ot h t h e  gr a d e  a n d  d ur ati o n  of t h e   m e as ur e d  e n d 
p oi nt.  T h e  a v er a g e s c or e fr o  m t h e s  w all o  wi n g  di ar y   will  b e  pl ott e d  b y tr e at  m e nt  gr o u p.  
A  c o  m pr e h e nsi v e  d at a listi n g   will  als o  b e i n cl u d e d. 
9. 6    S  O  B Q 
T h e  S  O  B  Q   will  b e s c or e d  b y s u  m  mi n g r es p o ns es  a cr oss t h e  2 4 it e  ms t o f or  m  a t ot al s c or e, r a n gi n g 
fr o  m  0 t o  1 2 0.  T h e   m e as ur e  m e nts  a n d  c h a n g e fr o  m  b as eli n e   will  b e  s u  m  m ari z e d   wit h  d es cri pti v e 
st atisti cs  a n d ti  m e  p oi nt   wit h r es p e ct t o tr e at  m e nt  gr o u p. 
9. 7    F  A  C  T -  T  OI 
T h e   F  A  C T- T  OI    will   b e  s c or e d   a c c or di n g  t o   F  A  C T- L   S c ori n g    G ui d eli n es    V ersi o n   4.    T h e 
m e as ur e  m e nts  a n d  c h a n g e fr o  m  b as eli n e   will  b e  s u  m  m ari z e d   wit h  d es cri pti v e  st atisti cs  a n d ti  m e 
p oi nt   wit h r es p e ct t o tr e at  m e nt  gr o u p. 
1 0    S  A F  E  T  Y  
T h e f ull  a n al ysis  s et   will  b e  us e d f or  all t h e  a n al ys es  of  s af et y  d at a.  S af et y  d at a   will i n cl u d e   A Es, 
s af et y   l a b or at or y   (  C  B  C/ h e  m at ol o g y,   s er u  m   c h e  mistr y   a n d   uri n al ysis),   pr e g n a n c y   t est   (if 
a p pli c a bl e),  p h ysi c al  e x a  m,  E  C  G,  E  C  O  G  a n d  vit al si g ns.  T h e  pr o p orti o n  of s u bj e cts  e x p eri e n ci n g 
a d v ers e  e v e nts,  s eri o us  a d v ers e  e v e nts,  a n d  d os e li  miti n g t o xi citi es   will  b e  s u  m  m ari z e d f or  e a c h 
d osi n g  c o h ort.   A  d at a listi n g  of s u bj e cts  e x p eri e n ci n g tr e at  m e nt  d el a ys   will  als o  b e i n cl u d e d.  
1 0. 1   E  X P  O S  U  R  E   T  O  S  T  U  D  Y   D  R  U  G 
BI  O  3 0 0    will  b e  or all y  a d  mi nist er e d  d ail y  t hr o u g h  c o n c urr e nt  c h e  m or a di ot h er a p y  f or  u p  t o  8 
w e e ks.   T ot al  d os e  a d  mi nist er e d  (  m g),  d ur ati o n  of  e x p os ur e  (  w e e ks)  a n d  st u d y tr e at  m e nt  d osi n g 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  2 1  of  4 3 
c o  m pli a n c e   will  b e  s u  m  m ari z e d   wit h  d es cri pti v e  st atisti cs  b y tr e at  m e nt  gr o u p.   A  c o  m pr e h e nsi v e 
d at a listi n g f or   BI  O  3 0 0  a d  mi nistr ati o n   will  als o  b e  pr o vi d e d. 
1 0. 2   D  L  T   A  N  D   M  T  D 
T h e  pri  m ar y  o bj e cti v e  of t h e st u d y is t o  d es cri b e  a n y  d os e li  miti n g t o xi citi es  a n d t o  d et er  mi n e t h e 
r e c o  m  m e n d e d  d os e (t h e  o pti  m al  d os e)  of t his  c o  m bi n ati o n.  
T h e  d efi niti o n  of    D L T  is  s p e cifi e d  i n  S e cti o n  3. 2.    M et h o d ol o g y  f or  d et er  mi ni n g  t h e    M T  D  is 
s p e cifi e d i n  S e cti o n  3. 1. 
T h e  d os e s el e ct e d  as t h e   M T  D  or t h e  o pti  m al  d os e  of   BI  O  3 0 0   will  b e s u  m  m ari z e d.   D L T   will  als o 
b e s u  m  m ari z e d f or t h e  d os e l e v els. 
1 0. 3   A  D  V  E  R S  E   E  V  E  N  T S 
T h e   C T  C  A E   V ersi o n  4. 0 3   will  b e  us e d t o  gr a d e  all   A Es.   All r e p ort e d t er  ms  a n d  d es cri pti o ns f or 
A Es   will  b e  c o d e d  usi n g   C T  C  A E   V ersi o n  4. 0 3  a n d s u  m  m ari z e d   wit h fr e q u e n ci es  a n d  p er c e nt a g es 
b y tr e at  m e nt  gr o u p, s yst e  m  or g a n  cl assifi c ati o n ( S  O  C)  a n d  pr ef err e d t er  m. 
A d diti o n all y,   A E s u  m  m ari es   will  b e  pr o vi d e d f or t h e f oll o  wi n g: 
•    D L T   
•    A Es   
•    A Es l e a di n g t o  dis c o nti n u ati o n fr o  m t h e st u d y 
•    A Es  b y r el ati o ns hi p t o   BI  O  3 0 0 
•    A Es  b y s e v erit y  usi n g   C T  C  A E  gr a d e 
•    A Es   wit h  1 0  %  or  hi g h er i n ci d e n c e r at es 
F or  all   A E s u  m  m ari es,  e v e nts   will  b e  c o u nt e d  o nl y  o n c e  p er s u bj e ct  b y  pri  m ar y  S  O  C  a n d  pr ef err e d 
t er  m.   W h e n  a n   A E  o c c urs   m or e t h a n  o n c e f or  a  s u bj e ct, t h e   m a xi  m u  m  s e v erit y  a n d  c a us alit y will 
b e  us e d. 
All   A Es   will  b e i n cl u d e d i n  c o  m pr e h e nsi v e  d at a listi n gs.  S e p ar at e listi n gs   will  b e  pr o vi d e d f or   A Es 
of   D L Ts,  all   A Es r el at e d t o   BI  O  3 0 0,  all   Gr a d e  3  or  4   A Es,   A Es l e a di n g t o  dis c o nti n u ati o n fr o  m 
st u d y,  a n d    A Es  c oll e ct e d    m or e  t h a n  3 0 d a ys  p ost  fi n al    BI  O  3 0 0  a d  mi nistr ati o n  t h at    w er e  n ot 
i n cl u d e d i n   A E s u  m  m ari es  or  a n al ysis. 
1 0. 4   S  E  RI  O  U S   A  D  V  E  R S  E   E  V  E  N  T S   A  N  D   D  E  A  T  H 
S e p ar at e  d at a listi n gs  a n d s u  m  m ari es   will  b e  pr es e nt f or  all  S  A Es  a n d  d e at hs.  
1 0. 5   L  A  B  O  R  A  T  O  R  Y   E  V  A  L  U  A  TI  O  N S 
L a b or at or y  ass ess  m e nts   will  b e  s u  m  m ari z e d   wit h  d es cri pti v e  st ati cs,  b y   t est a n d tr e at  m e nt  gr o u p. 
A d diti o n all y,  a b n or  m al r es ults  of   C T  C  A E  gr a d e  3  or  hi g h er   will  b e s u  m  m ari z e d. 
A  d at a listi n g   will  dis pl a y  all l a b or at or y t est r es ults  a n d fi n di n gs.   
1 0. 6   P  R  E  G  N  A  N  C  Y   T  E S  T 
A  d at a listi n g  of  pr e g n a n c y t est r es ults   will  b e  pr o vi d e d. 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  2 2  of  4 3 
1 0. 7   P  H  Y SI  C  A  L   E  X  A  MI  N  A  TI  O  N S 
T h e r es ults  of  p h ysi c al  e x a  mi n ati o ns   will  b e i n  a  d at a listi n g. 
1 0. 8   E  L  E  C  T  R  O  C  A  R  DI  O  G  R  A  M S 
E  C  G   Q T c   m e as ur e  m e nts   will  b e s u  m  m ari z e d   wit h  d es cri pti v e st atisti cs a n d ti  m e  p oi nt   wit h r es p e ct 
t o tr e at  m e nt  gr o u p.   All  E  C  G  d at a   will  b e  dis pl a y e d i n  a  d at a listi n g. 
1 0. 9   E  C  O  G 
T h e  E  C  O  G  p erf or  m a n c e  st at us is  a  p h ysi ci a n  assi g n e d r ati n g  s c al e  us e d t o  ass ess  h o  w  a  p ati e nt’s 
dis e as e is  pr o gr essi n g i n  a d diti o n t o  h o  w t h e  dis e as e  aff e cts t h e  d ail y li vi n g  a biliti es  of t h e  p ati e nt. 
T h e  s c or e  v al u es  ar e  0  t o  5,    w h er e  0  i n di c at es  “f ull y  a cti v e,  a bl e  t o  c arr y  o n  all  pr e- dis e as e 
p erf or  m a n c e    wit h o ut  r estri cti o n ”  a n d  5  i n di c at es  t h e  s u bj e ct  h as  di e d.  It    will  b e  c o n d u ct e d  at 
s cr e e ni n g,   w e e kl y  d uri n g  c o n c urr e nt  c h e  m or a di ot h er a p y,  a n d  e v er y  visit t h er e aft er  e x c e pt  visit  4 1, 
1 1   m o nt h  p ost-  R T c o  m pl eti o n f or  n o n-s ur gi c al s u bj e cts.  Listi n gs  of  E  C  O  G  p erf or  m a n c e st at us   will 
b e  pr o vi d e d. 
1 0. 1 0  VI  T  A  L  SI  G  N S 
T h e r es ults  of  vit al si g ns (i n cl u di n g t e  m p er at ur e, r es pir at or y r at e,  h e art r at e, s yst oli c  a n d  di ast oli c 
bl o o d  pr ess ur e,  h ei g ht  a n d   w ei g ht)   will  b e  s u  m  m ari z e d   wit h  d es cri pti v e  st atisti cs  b y  tr e at  m e nt 
gr o u p.   A  d at a listi n g  of  all  vit al si g ns  d at a   will  b e i n cl u d e d. 
1 1    P  H  A  R  M  A  C  O  KI  N  E  TI  C S   A  N  A  L  Y S  E S  
A  d et ail e d  P  K  a n al ysis  pl a n  a n d r es ults   will  b e i n cl u d e d i n  a s e p ar at e  P  K  a n al ysis r e p ort.   
1 2    P  H  A  R  M  A  C  O  D  Y  N  A  MI  C   A  N  A  L  Y S  E S  
P ot e nti al  p h ar  m a c o d y n a  mi cs   m ar k ers i n cl u d e t h e  cir c ul ati n g l e v els  of  c yt o ki n es I L- 6, I L- 1 b , I L-
1 a , I L- 8, I L- 1 0,  T  N Fa , T  G F b 1,  T  G F b 2,  a n d  T  G F b 3.  Si  mil arl y, s er u  m  pr ot ei ns  of i nt er est i n cl u d e 
gr a n ul o c yt e  c ol o n y sti  m ul ati n g f a ct or (  G-  C S F),   C-r e a cti v e  pr ot ei n,  a n d  pr ost a gl a n di n  E 2.  T h e  P  D 
r es ults  a n d  c h a n g e fr o  m  b as eli n e   will  b e  s u  m  m ari z e d   wit h  d es cri pti v e  st atisti cs,  b y t est  a n d ti  m e 
p oi nt   wit h r es p e ct t o tr e at  m e nt  gr o u p.   A  d at a listi n g   will  dis pl a y  all  P  D r es ults.  
1 3    I  N  T  E  RI  M   A  N  A  L  Y SI S  
T  w o i nt eri  m a n al ys es ar e  pl a n n e d.  T h e first   will  b e c o  m pl et e d at t h e c o n cl usi o n  of t h e   N  CI c o ntr a ct 
1 9  S e pt e  m b er  2 0 1 7.  S e c o n d,  at t h e  c o  m pl eti o n  of  d os e  es c al ati o n, i nt eri  m  d at a  a n al ysis   will  b e 
c o  m pl et e d t o  ass ess   BI  O  3 0 0  s af et y  a n d t o r e vi e  w  s e c o n d ar y  o ut c o  m e   m e as ur es.   D at a tr e n ds   will 
b e  us e d t o  c h o os e  a si n gl e   BI  O  3 0 0  d os e ( 5 0 0,  1 0 0 0  or  1 5 0 0  m g/ d)  as t h e  o pti  m al  bi ol o gi c al  d os e.  
U p t o  a n  a d diti o n al  1 2  s u bj e cts   will  b e  e nr oll e d  at t h e  o pti  m al  bi ol o gi c al  d os e t o f urt h er  e v al u at e 
BI  O  3 0 0’s s af et y  a n d  effi c a c y.  T h e   m a xi  m u  m t ol er at e d  d os e   will  b e  us e d f or  c o h ort  4 if t h er e  ar e 
n o  a p p ar e nt  diff er e n c es i n  effi c a c y. 
1 4    E  N  D  -O F  -S  T  U  D  Y   A  N  A  L  Y SI S  
A fi n al  a n al ysis   will  b e  c o n d u ct e d  aft er t h e l ast  s u bj e ct  c o  m pl et es  or  dis c o nti n u es t h e  st u d y  a n d 
t h e r es ulti n g  cli ni c al  d at a b as e  h as  b e e n  cl e a n e d,  q u alit y  c h e c k e d  a n d l o c k e d. 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  2 3  of  4 3 
 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  2 4  of  4 3 
1 5    T  A  B  L  E   O  F  C  O  N  T  E  N  T S  F  O  R   D  A  T  A   DI S P  L  A  Y S   
1 5. 1   D  E  M  O  G  R  A P  HI S  C  S  U  M  M  A  R  Y  FI  G  U  R  E S   A  N  D   T  A  B  L  E S 
St u d y  P o p ul ati o n   T a bl es 
T a bl e     
Titl e   
P o p ul ati o n  
1 4. 1. 1    
S u  m  m ar y  of   A n al ysis  P o p ul ati o ns  
F  A S  
1 4. 1. 2   
S u  m  m ar y  of   D e  m o gr a p hi c  a n d  B as eli n e   C h ar a ct eristi cs   
F  A S  
1 4. 1. 3   
S u  m  m ar y  of  Pr ot o c ol   D e vi ati o ns  
F  A S  
1 4. 1. 4   
S u  m  m ar y  of  T ot al   D os e  of   BI  O  3 0 0   A d  mi nistr ati o n  
F  A S  
 
St u d y  P o p ul ati o n  Fi g u r es 
Fi g u r e    
Titl e   
P o p ul ati o n  
1 4. 1. 1    
Dis p ositi o n  of  S u bj e cts   
F  A S  
 
1 5. 2   E F FI  C  A  C  Y  S  U  M  M  A  R  Y  FI  G  U  R  E S   A  N  D   T  A  B  L  E S 
Effi c a c y   T a bl es 
T a bl e     
Titl e   
P o p ul ati o n  
1 4. 2. 1    
S u  m  m ar y  of   O v er all   R es p o ns e   R at e  a n d   B est   O v er all   R es p o ns e  p er   R E  CI S T  1. 1    E  A S  
1 4. 2. 2    
S u  m  m ar y  of   O v er all   R es p o ns e   R at e  a n d   B est   O v er all   R es p o ns e  p er   R E  CI S T  1. 1    E v al u a bl e  
1 4. 2. 3    
S u  m  m ar y  of  T u  m or   Di a  m et er  
E v al u a bl e  
1 4. 2. 4    
S u  m  m ar y  of   D ur ati o n  of   R es p o ns e  
E  A S  
1 4. 2. 5    
S u  m  m ar y  of   D ur ati o n  of   R es p o ns e  
E v al u a bl e  
1 4. 2. 6    
S u  m  m ar y  of  Pr o gr essi o n  Fr e e  S ur vi v al  p er   R E  CI S T  1. 1  
F  A S  
1 4. 2. 7    
S u  m  m ar y  of  Pr o gr essi o n  Fr e e  S ur vi v al  p er   R E  CI S T  1. 1  
E v al u a bl e  
1 4. 2. 8    
S u  m  m ar y  of   A bs ol ut e   V al u e  a n d  c h a n g e  fr o  m  b as eli n e i n  P ul  m o n ar y  F u n cti o n 
T esti n g   M e as ur e  m e nts  
E  A S  
1 4. 2. 9    
S u  m  m ar y  of  S  w all o  wi n g   D air y   A  U  C  
E  A S  
1 4. 2. 1 0    
S u  m  m ar y  of  S  O  B  Q  Fi n di n gs  
E  A S  
1 4. 2. 1 1   
S u  m  m ar y  of  F  A  C T -T  OI  Fi n di n gs  
E  A S  
 
Effi c a c y  Fi g u r es 
Fi g u r es    
Titl e   
P o p ul ati o n  
1 4. 2. 1    
Pl ot  of   N or  m ali z e d  T u  m or   Di a  m et er  
E  A S  
1 4. 2. 2    
K a pl a n  -M ei er   C ur v e f or  Pr o gr essi o n  Fr e e  S ur vi v al   
E v al u a bl e  
1 4. 2. 3    
K a pl a n  -M ei er   C ur v e f or  Pr o gr essi o n  Fr e e  S ur vi v al   
E v al u a bl e  


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  2 5  of  4 3 
1 4. 2. 4    
K a pl a n  -M ei er   C ur v e f or   D ur ati o n  of   R es p o ns e   
F  A S  
1 4. 2. 5    
K a pl a n  -M ei er   C ur v e f or   D ur ati o n  of   R es p o ns e   
E v al u a bl e  
1 4. 2. 6    
Pl ot  of t h e   A v er a g e  S c or es f or  S  w all o  wi n g   Di ari es  
E  A S  
 
1 5. 3   S  A F  E  T  Y  S  U  M  M  A  R  Y  FI  G  U  R  E S   A  N  D   T  A  B  L  E S 
1 5. 3. 1   A d v e rs e   E v e nts 
T a bl e     
Titl e   
P o p ul ati o n  
1 4. 3. 1. 1    
S u  m  m ar y  of   D os e  Li  miti n g  T o xi cit y  
F  A S  
1 4. 3. 1. 2    
S u  m  m ar y  of  Fr e q u e n c y  a n d   R e as o ns f or   D os e I nt err u pti o ns  
F  A S  
1 4. 3. 1. 3    
S u  m  m ar y  of   A d v ers e  E v e nts  
F  A S  
1 4. 3. 1. 4    
S u  m  m ar y  of   A d v ers e  E v e nts  L e a di n g t o   Dis c o nti n u ati o n fr o  m t h e  St u d y    
F  A S  
1 4. 3. 1. 5    
S u  m  m ar y  of   A d v ers e  E v e nts  b y   R el ati o ns hi p t o   BI  O  3 0 0  
F  A S  
1 4. 3. 1. 6    
S u  m  m ar y  of   A d v ers e  E v e nts  b y  S e v erit y   Usi n g   C T  C  A E   Gr a d e  
F  A S  
1 4. 3. 1. 7    
S u  m  m ar y  of   A d v ers e  E v e nts   wit h  1 0  %  or   Hi g h er I n ci d e nt   R at e  
F  A S  
 
1 5. 3. 2   S e ri o us   A d v e rs e   E v e nts,   D e at hs  a n d   Ot h e r  Si g nifi c a nt   A d v e rs e   E v e nts 
T a bl e     
Titl e   
P o p ul ati o n  
1 4. 3. 2. 1    
S u  m  m ar y  of  S eri o us   A d v ers e  E v e nts  
F  A S  
1 4. 3. 2. 2    
S u  m  m ar y  of  S eri o us   A d v ers e  E v e nts  b y r el ati o ns hi p t o   BI  O  3 0 0  
F  A S  
1 4. 3. 2. 3    
S u  m  m ar y  of   D e at hs  
F  A S  
 
1 5. 3. 3   N a r r ati v es 
N ot  a p pli c a bl e. 
 
1 5. 3. 4   L a b o r at o r y   R es ults 
T a bl e     
Titl e   
P o p ul ati o n  
1 4. 3. 4. 1    
S u  m  m ar y  of  Cli ni c al  L a b or at or y   R es ults   
F  A S  
1 4. 3. 4. 2    
S u  m  m ar y  of   A b n or  m al  Cli ni c al  L a b or at or y   R es ults   
F  A S  
1 4. 3. 4. 3   
S u  m  m ar y  of   Uri n al ysis/ Pr e g n a n c y   R es ults  
F  A S  
 
1 5. 3. 5   Ot h e r  S af et y   R es ults 
T a bl e     
Titl e   
P o p ul ati o n  
1 4. 3. 5. 1    
S u  m  m ar y  of  El e ctr o c ar di o gr a  m   Q T c   R es ults  
F  A S  
1 4. 3. 5. 2    
S u  m  m ar y  of   Vit al  Si g ns  
F  A S  


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  2 6  of  4 3 
 
1 5. 4   LI S  TI  N  G S 
1 5. 4. 1   Dis c o nti n u e d  P ati e nts 
1 5. 4. 1. 1  S u bj e ct   Dis p ositi o n 
 
1 5. 4. 2   P r ot o c ol   D e vi ati o ns 
1 5. 4. 2. 1  I n cl usi o n/ E x cl usi o n   Crit eri a   D e vi ati o ns 
1 5. 4. 2. 2  Pr ot o c ol   D e vi ati o ns 
 
1 5. 4. 3   S u bj e cts   E x cl u d e d f r o  m t h e   Effi c a c y   A n al ysis 
1 5. 4. 3. 1  A n al ysis  P o p ul ati o ns 
 
1 5. 4. 4   D e  m o g r a p hi c   D at a 
1 5. 4. 4. 1  D e  m o gr a p hi c   C h ar a ct eristi cs 
1 5. 4. 4. 2  B as eli n e   C h ar a ct eristi cs 
1 5. 4. 4. 3  C o n c o  mit a nt   M e di c ati o ns 
1 5. 4. 4. 4  M e di c al   Hist or y 
 
1 5. 4. 5   C o  m pli a n c e  a n d/ o r   D r u g   C o n c e nt r ati o n   D at a 
1 5. 4. 5. 1  BI  O  3 0 0   A d  mi nistr ati o n  a n d  E x p os ur e 
1 5. 4. 5. 2  BI  O  3 0 0  Pl as  m a   C o n c e ntr ati o n 
1 5. 4. 5. 3  P a clit a x el  Pl as  m a   C o n c e ntr ati o n 
1 5. 4. 5. 4  C ar b o pl ati n  Pl as  m a   C o n c e ntr ati o n 
 
1 5. 4. 6   I n di vi d u al   Effi c a c y   R es p o ns e   D at a 
1 5. 4. 6. 1  T u  m or   R es p o ns es  P er   R E  CI S T  1. 1 
1 5. 4. 6. 2  T u  m or   Di a  m et er  Fi n di n gs 
1 5. 4. 6. 3  R es p o ns e   Crit eri a:  E v al u ati o n  of  T ar g et  L esi o ns  Fi n di n gs 
1 5. 4. 6. 4  P at h ol o gi c   R es p o ns e  of  T ar g et  L esi o ns  a n d  E xt e nt  of  S ur gi c al   R es e cti o n   Fi n di n gs 
1 5. 4. 6. 5  U ni v ersit y  of  S a n   Di e g o  S h ort n ess  of   Br e at h   Q u esti o n n air e (  U  C S  D- S  O  B)   R es ults 
1 5. 4. 6. 6  F  A  C T- T  OI  Fi n di n gs 
1 5. 4. 6. 7  S  w all o  wi n g   Di ar y  Fi n di n gs 
1 5. 4. 6. 8  P ul  m o n ar y  F u n cti o n  T esti n g  Fi n di n gs 
 
1 5. 4. 7   A d v e rs e   E v e nt   Listi n gs 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  2 7  of  4 3 
1 5. 4. 7. 1  All   A d v ers e  E v e nts 
1 5. 4. 7. 2  A d v ers e  E v e nts  c oll e ct e d  3 0  d a ys  p ost-  BI  O  3 0 0 
1 5. 4. 7. 3  D os e  Li  miti n g  T o xi cit y   A d v ers e  E v e nts 
1 5. 4. 7. 4  A d v ers e  E v e nts  L e a di n g t o   Wit h dr a  w al fr o  m  St u d y 
1 5. 4. 7. 5  S eri o us   A d v ers e  E v e nts 
1 5. 4. 7. 6  A d v ers e  E v e nts   R el at e d t o   BI  O  3 0 0 
1 5. 4. 7. 7  C T  C  A E   Gr a d e  3  or  4   A d v ers e  E v e nts 
1 5. 4. 7. 8  D e at hs 
 
1 5. 4. 8   Listi n gs  of I n di vi d u al   L a b o r at o r y   M e as u r e  m e nts 
1 5. 4. 8. 1  D efi niti o ns  of   N or  m al   R a n g es f or  L a b or at or y   V al u es 
1 5. 4. 8. 2  Cli ni c al  L a b or at or y   R es ults 
1 5. 4. 8. 3  Uri n al ysis/ Pr e g n a n c y   R es ults 
 
1 5. 4. 9   Listi n gs  of   Ot h e r  S af et y   E n d p oi nts 
1 5. 4. 9. 1  P h ysi c al  E x a  mi n ati o ns 
1 5. 4. 9. 2  El e ctr o c ar di o gr a  m  Fi n di n gs 
1 5. 4. 9. 3  E ast er n   C o o p er ati v e   O n c ol o g y   Gr o u p ( E  C  O  G)  P erf or  m a n c e  St at us 
1 5. 4. 9. 4  Vit al  Si g ns  T est   R es ults 
 
 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  2 8  of  4 3 
1 6    R  E F  E  R  E  N  C  E S   
1.     
R    C or e    T e a  m,   R:    A  l a n g u a g e   a n d   e n vir o n  m e nt  f or  st atisti c al   c o  m p uti n g.    2 0 1 7,    R 
F o u n d ati o n f or  St atisti c al   C o  m p uti n g:   Vi e n n a,   A ustri a. 
2.     
M o vs as,   B.,  et  al.,  R a n d o  miz e d tri al  of  a  mif osti n e i n l o c all y  a d v a n c e d  n o n-s  m all- c ell l u n g 
c a n c er   p ati e nts   r e c ei vi n g   c h e  m ot h er a p y   a n d   h y p erfr a cti o n at e d   r a di ati o n:   r a di ati o n 
t h er a p y  o n c ol o g y  gr o u p tri al  9 8- 0 1. J   Cli n   O n c ol,  2 0 0 5. 2 3 ( 1 0):  p.  2 1 4 5- 5 4. 
 
 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  2 9  of  4 3 
S h ell   T a bl es  a n d  Fi g u r es 
T a bl e  1 4. 1. 1  S u  m  m ar y  of   A n al ysis  P o p ul ati o n 
A n al ysis  S et   
All     
5 0 0   m g     
1 0 0 0   m g     1 5 0 0   m g   
F ull   A n al ysis  S et ( F  A S)    
N     
N     
N     
N   
Effi c a c y   A n al ysis  S et ( E  A S)    N     
N     
N     
N   
P  K  P o p ul ati o n  
N     
N     
N     
N   
P  D  P o p ul ati o n  
N     
N     
N     
N   
 
T a bl e  1 4. 1. 2  S u  m  m ar y  of   D e  m o gr a p hi c  a n d   B as eli n e   C h ar a ct eristi cs   
P ati e nt   C h a r a ct e risti c  
All (  N)     
5 0 0   m g (  N)    
1 0 0 0   m g (  N)    
1 5 0 0   m g (  N)  
M/ F   
 
 
 
 
M e di a n  a g e (r a n g e)   
 
 
 
 
R a c e   
 
 
 
 
A  m eri c a n I n di a n  or  Al as k a n   N ati v e    
 
 
 
 
Asi a n  
 
 
 
 
Bl a c k  or  Afri c a n  A  m eri c a n  
 
 
 
 
N ati v e   H a  w aii a n  or   Ot h er  P a cifi c 
Isl a n d er 
 
 
 
 
W hit e  or   C a u c asi a n   
 
 
 
 
U n k n o  w n  or   N ot  R e p ort e d   
 
 
 
 
Et h ni cit y  
 
 
 
 
His p a ni c   
 
 
 
 
N o n  -His p a ni c   
 
 
 
 
U n k n o  w n  or   N ot  R e p ort e d   
 
 
 
 
I niti al  St a g e 
 
 
 
 
II 
 
 
 
 
III 
 
 
 
 
I V 
 
 
 
 
Hist ol o g y   
 
 
 
 
S q u a  m o us  
 
 
 
 
A d e n o c ar ci n o  m a  
 
 
 
 
L ar g e   C ell  
 
 
 
 
Mi x e d   
 
 
 
 
Ot h er   
 
 
 
 
Pri  m ar y t u  m or l o c ati o n  
 
 
 
 
L eft  u p p er l o b e  
 
 
 
 
L eft l o  w er l o b e  
 
 
 
 
L eft li n g ul a  
 
 
 
 
Ri g ht  u p p er l o b e  
 
 
 
 
Ri g ht   mi d dl e l o b e  
 
 
 
 
Ri g ht l o  w er l o b e  
 
 
 
 
U n k n o  w n   
 
 
 
 
M arit al st at us   
 
 
 
 
M arri e d/ ot h er li v e  -i n  p art n er   
 
 
 
 
Si n gl e/ di v or c e d/  wi d o  w e d/s e p ar at e d    
 
 
 
 
U n k n o  w n  or   N ot  R e p ort e d   
 
 
 
 
 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  3 0  of  4 3 
T a bl e  1 4. 1. 3  S u  m  m ar y  of  Pr ot o c ol   D e vi ati o ns 
D e vi ati o n   C at e g o r y   
F r e q u e n c y (  M aj o r/  Mi n o r)  
5 0 0   m g    1 0 0 0   m g    1 5 0 0   m g  
C o n c urr e nt   M e di c ati o n   &   Tr e at  m e nt   D e vi ati o n    
   
 
 
Eli gi bilit y  
   
 
 
St u d y   Dr u g   A d  mi nistr ati o n  
   
   
 
Visit   Ass ess  m e nt   
   
   
 
Visit   Wi n d o  w   
   
   
 
Ot h er   
   
   
 
T ot al     
   
   
 
 
T a bl e  1 4. 1. 4  S u  m  m ar y  of  T ot al   D os e  of   BI  O  3 0 0   A d  mi nistr ati o n 
D r u g   E x p os u r e   
5 0 0   m g    
1 0 0 0   m g    1 5 0 0   m g    All   
M e a n   T ot al   D os e ( r a n g e)  
   
   
   
 
M e a n   D ur ati o n  of  e x p os ur e (  r a n g e) 
   
   
   
 
Fr e q u e n c y   miss e d  d os es (r a n g e)  
   
   
   
 
 
 
 




Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  3 2  of  4 3 
T a bl e  1 4. 2. 1  S u  m  m ar y  of   O v er all   R es p o ns e   R at e  a n d   B est   O v er all   R es p o ns e  p er   R E  CI S T  1. 1 
( E  A S) 
R es p o ns e   
5 0 0   m g    
1 0 0 0   m g    
1 5 0 0   m g    
All   
R es p o ns e  T y p e,   N o. (  %)   
 
 
 
 
C o  m pl et e       
 
 
 
P arti al     
 
 
 
St a bl e   Dis e as e     
 
 
 
Pr o gr essi v e  dis e as e     
 
 
 
O v er all   R es p o ns e   R at e   
 
 
 
 
O v er all   R es p o ns e,   N o. (  %)      
 
 
 
9 5  %   CI,   %     
 
 
 
 
T a bl e  1 4. 2. 2  S u  m  m ar y  of   O v er all   R es p o ns e   R at e  a n d   B est   O v er all   R es p o ns e  p er   R E  CI S T  1. 1 
( E v al u a bl e) 
R es p o ns e   
5 0 0   m g    
1 0 0 0   m g    
1 5 0 0   m g    
All   
R es p o ns e  T y p e,   N o. (  %)   
 
 
 
 
C o  m pl et e       
 
 
 
P arti al     
 
 
 
St a bl e   Dis e as e     
 
 
 
Pr o gr essi v e  dis e as e     
 
 
 
O v er all   R es p o ns e   R at e   
 
 
 
 
O v er all   R es p o ns e,   N o. (  %)      
 
 
 
9 5  %   CI,   %     
 
 
 
 
T a bl e  1 4. 2. 3  S u  m  m ar y  of  T u  m or  Di a  m et er   
T u  m o r   Di a  m et e r   
5 0 0   m g    
1 0 0 0   m g    
1 5 0 0   m g    
All   
B as eli n e   
 
 
 
 
n      
 
 
 
M e a n      
 
 
 
S T  D     
 
 
 
M e di a n      
 
 
 
R a n g e      
 
 
 
Visit   
 
 
 
 
n      
 
 
 
M e a n      
 
 
 
S T  D     
 
 
 
M e di a n      
 
 
 
R a n g e      
 
 
 
C h a n g e fr o  m   B as eli n e t o   Visit     
 
 
 
 
n      
 
 
 
M e a n      
 
 
 
S E     
 
 
 
9 5  %   CI     
 
 
 
 
 
 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  3 3  of  4 3 
T a bl e  1 4. 2. 4  S u  m  m ar y  of   D ur ati o n  of   R es p o ns e ( E  A S) 
 
S u bj e ct    D os e   
D u r ati o n  of   R es p o ns e (  m o nt hs)   
#    
5 0 0   m g  
 
#    
5 0 0   m g  
 
M e di a n   D  O  R,   m o nt hs ( 9 5  %   CI)     
 
#    
1 0 0 0   m g  
 
#    
1 0 0 0   m g  
 
M e di a n   D  O  R,   m o nt hs ( 9 5  %   CI)     
 
#    
1 5 0 0   m g  
 
 
T a bl e  1 4. 2. 5  S u  m  m ar y  of   D ur ati o n  of   R es p o ns e ( E v al u a bl e) 
 
S u bj e ct    D os e   
D u r ati o n  of   R es p o ns e (  m o nt hs)   
#    
5 0 0   m g  
 
#    
5 0 0   m g  
 
M e di a n   D  O  R,   m o nt hs ( 9 5  %   CI)     
 
#    
1 0 0 0   m g  
 
#    
1 0 0 0   m g  
 
M e di a n   D  O  R,   m o nt hs ( 9 5  %   CI)     
 
#    
1 5 0 0   m g  
 
#    
1 5 0 0   m g  
 
M e di a n   D  O  R,   m o nt hs ( 9 5  %   CI)     
 
 
T a bl e  1 4. 2. 6  S u  m  m ar y  of  Pr o gr essi o n  Fr e e  S ur vi v al ( F  A S) 
 
5 0 0   m g  
1 0 0 0   m g  
1 5 0 0   m g  
All   
M e di a n  Pr o gr essi o n 
Fr e e  S ur vi v al  
(  M o nt hs) 
 
 
 
 
9 5  %   CI  
 
 
 
 
 
T a bl e  1 4. 2. 7  S u  m  m ar y  of  Pr o gr essi o n  Fr e e  S ur vi v al ( E v al u a bl e) 
 
5 0 0   m g  
1 0 0 0   m g  
1 5 0 0   m g  
All   
M e di a n  Pr o gr essi o n 
Fr e e  S ur vi v al  
(  M o nt hs) 
 
 
 
 
9 5  %   CI  
 
 
 
 
 
 
 
 
 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  3 4  of  4 3 
T a bl e  1 4. 2. 8  S u  m  m ar y  of    A bs ol ut e    V al u e  a n d  c h a n g e  fr o  m  b as eli n e  i n  P ul  m o n ar y  F u n cti o n 
M e as ur e  m e nts 
V a ri a bl es   
5 0 0   m g    
1 0 0 0   m g    
1 5 0 0   m g    
p- v al u e  
B as eli n e   
F E  V 1 ( L)    X   ±  S T  D    
 
 
 
F  V  C ( L)     
 
 
 
F E  V 1/ F  V  C     
 
 
 
D L  C  O   (m L/  m  m  H g/  mi n  )    
 
 
 
Visit   X,   m o nt h   X   
F E  V 1 ( L)    X   ±  S T  D    
 
 
 
F  V  C ( L)     
 
 
 
F E  V 1/ F  V  C     
 
 
 
D L  C  O   (m L/  m  m  H g/  mi n  )    
 
 
 
P F T  c h a n g es  aft er   X   m o nt hs  
F E  V 1  c h a n g e  ( L)   X   ±  S T  D    
 
 
 
F  V  C  c h a n g e  ( L)    
 
 
 
F E  V 1/ F  V  C  c h a n g e     
 
 
 
D L  C  O   (m L/  m  m  H g/  mi n  ) 
c h a n g e  
 
 
 
 
 
T a bl e  1 4. 2. 9  S u  m  m ar y  of  S  w all o  wi n g   Di ar y  Fi n di n gs 
 
5 0 0   m g  
1 0 0 0   m g  
1 5 0 0   m g  
p- v al u e  
S  w all o  wi n g     Di ar y 
A  U  C   
X   ±  S T  D  
 
 
 
 
 
T a bl e  1 4. 2. 1 0  S u  m  m ar y  of  S  O  B  Q  Fi n di n gs 
S  O  B  Q  
5 0 0   m g    
1 0 0 0   m g    
1 5 0 0   m g    
All   
B as eli n e   
 
 
 
 
n      
 
 
 
M e a n      
 
 
 
S T  D     
 
 
 
M e di a n      
 
 
 
R a n g e      
 
 
 
Visit   
 
 
 
 
n      
 
 
 
M e a n      
 
 
 
S T  D     
 
 
 
M e di a n      
 
 
 
R a n g e      
 
 
 
C h a n g e fr o  m   B as eli n e t o   Visit     
 
 
 
 
n      
 
 
 
M e a n      
 
 
 
S E     
 
 
 
9 5  %   CI     
 
 
 
 
 






Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  3 7  of  4 3 
T a bl e  1 4. 3. 1. 3  S u  m  m ar y  of   A d v ers e  E v e nts 
C  T  C  A  E  v 4  S  O  C/  A  E   
N u  m b e r  of  S u bj e cts   E x p e ri e n ci n g   E v e nt   (  %) 
5 0 0  m g     
1 0 0   m g    
1 5 0 0   m g    
T ot al   
C a r di a c   Dis o r d e rs   
 
 
 
 
     A c ut e   C or o n ar y  S y n dr o  m e   
 
 
 
 
     C ar di a c   Arr est   
 
 
 
 
     S yst oli c   M ur  m ur  
 
 
 
 
E y e  dis o r d e rs   
 
 
 
 
     Bl e p h aritis   
 
 
 
 
     S u b c o nj u n cti v al  h e  m orr h a g e  
 
 
 
 
G ast r oi nt esti n al  dis o r d e rs   
 
 
 
 
     A b d o  mi n al  P ai n   
 
 
 
 
     C o nsti p ati o n   
 
 
 
 
     Di arr h e a   
 
 
 
 
     D ys p e psi a   
 
 
 
 
     D ys p h a gi a   
 
 
 
 
     Fl at ul e n c e  
 
 
 
 
     M u c ositis   Or al   
 
 
 
 
     N a us e a   
 
 
 
 
G e n e r al  dis o r d e rs  a n d 
a d  mi nist r ati o n sit e  c o n diti o ns  
 
 
 
 
     E d e  m a  Li  m bs  
 
 
 
 
     F ati g u e  
 
 
 
 
I nf e cti o ns  a n d i nf est ati o ns  
 
 
 
 
     L u n g I nf e cti o n  
 
 
 
 
     Ot h er, s p e cif y:   Or al   C a n di di asis   
 
 
 
 
     S ki n I nf e cti o n  
 
 
 
 
     Uri n ar y tr a ct i nf e cti o n   
 
 
 
 
     U p p er r es pir at or y i nf e cti o n   
 
 
 
 
I nj u r y,  p ois o ni n g,  a n d  p r o c e d u r al 
c o  m pli c ati o ns  
 
 
 
 
     Br uisi n g   
 
 
 
 
     Ot h er, s p e cif y:  S ki n  a br asi o n   
 
 
 
 
I n v esti g ati o ns 
 
 
 
 
     A n e  mi a   
 
 
 
 
     N e utr o p hil  c o u nt  d e cr e as e d   
 
 
 
 
     Ot h er, s p e cif y:   H e  m at o crit 
d e cr e as e d  
 
 
 
 
     Pl at el et  c o u nt  d e cr e as e d  
 
 
 
 
     W hit e  bl o o d  c ell  d e cr e as e d   
 
 
 
 
M et a b olis  m  a n d  n ut riti o n  dis o r d e rs     
 
 
 
 
     A n or e xi a   
 
 
 
 
     H y p o  m a g n es e  mi a   
 
 
 
 
     H y p o n atr e  mi a   
 
 
 
 
     H y p o k al e  mi a   
 
 
 
 
M us c ul os k el et al  a n d  c o n n e cti v e 
tiss u e  dis o r d e rs 
 
 
 
 
     B a c k  P ai n   
 
 
 
 
     B o n e  p ai n   
 
 
 
 
     M y al gi a   
 
 
 
 
     Ot h er, s p e cif y:   G e n er ali z e d   m us cl e 
w e a k n ess   
 
 
 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  3 8  of  4 3 
C  T  C  A  E  v 4  S  O  C/  A  E   
N u  m b e r  of  S u bj e cts   E x p e ri e n ci n g   E v e nt   (  %) 
5 0 0  m g     
1 0 0   m g    
1 5 0 0   m g    
T ot al   
     Ot h er, s p e cif y: J oi nt  p ai n i n  hi ps   
 
 
 
 
N e r v o us s yst e  m  dis o r d e rs   
 
 
 
 
     Di z zi n ess   
 
 
 
 
     P ar est h esi a  
 
 
 
 
     P eri p h er al  S e ns or y   N e ur o p at h y  
 
 
 
 
R es pi r at o r y,    
t h o r a ci c    
a n d 
m e di asti n al  dis o r d e rs   
 
 
 
 
     C o u g h   
 
 
 
 
     D ys p n e a   
 
 
 
 
     E pist a xis  
 
 
 
 
     L ar y n g e al i nfl a  m  m ati o n  
 
 
 
 
     N as al   C o n g esti o n   
 
 
 
 
     Ot h er,    
s p e cif y:     
R a di ati o n 
p n e u  m o nitis  
 
 
 
 
V as c ul a r  dis o r d e rs   
 
 
 
 
     H y p ot e nsi o n   
 
 
 
 
     T hr o  m b o e  m b oli c  e v e nt  
 
 
 
 
 
T a bl e  1 4. 3. 1. 4  S u  m  m ar y  of   A d v ers e  E v e nts  L e a di n g t o   Dis c o nti n u ati o n  of  St u d y 
   
 
P r ef e r r e d   T e r  m  
5 0 0   m g  
(  N  =   X  X)  
n (  %)  
1 0 0 0   m g  
(  N  =   X  X)  
n (  %)  
1 5 0 0   m g  
(  N  =   X  X)  
n (  %)    
P- v al u e  
N u  m b er  of  S u bj e cts r e p orti n g  a d v ers e  e v e nts l e a di n g t o  dis c o nti n u ati o n     x x ( x x x)    x x ( x x x)    x x ( x x x)    
x x   
[ S yst e  m   Or g a n   Cl ass   Cl ass  # 1] 
   
   
   
 
  [ Pr ef err e d  T er  m  # 1] 
x x ( x x x)    x x ( x x x)    x x ( x x x)    
x x   
  [ Pr ef err e d  T er  m  # 2] 
x x ( x x x)    x x ( x x x)    x x ( x x x)    
x x   
… 
   
   
   
 
 
   
   
   
 
 
 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  3 9  of  4 3 
T a bl e  1 4. 3. 1. 5  S u  m  m ar y  of   A d v ers e  E v e nts  b y   R el ati o ns hi p t o   BI  O  3 0 0 
 
 
P r ef e r r e d   T e r  m  
R el ati o ns hi p     
5 0 0   m g  
(  N  =   X  X)  
n (  %)  
1 0 0 0   m g  
(  N  =   X  X)  
n (  %)  
1 5 0 0   m g  
(  N  =   X  X)  
n (  %)  
N u  m b er  of s u bj e cts r e p orti n g  a d v ers e  e v e nts     
P ossi bl e  
Pr o b a bl e  
D efi nit el y   
T ot al  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x. x)  
 [ S yst e  m   Or g a n   Cl ass   Cl ass  # 1] 
 
 
 
 
  [ Pr ef err e d  T er  m  # 1]  
P ossi bl e  
Pr o b a bl e  
D efi nit el y   
T ot al  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x. x)  
  [ Pr ef err e d  T er  m  # 2] 
P ossi bl e  
Pr o b a bl e  
D efi nit el y   
T ot al  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x.)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x.)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x.)  
 
T a bl e  1 4. 3. 1. 6  S u  m  m ar y  of   A d v ers e  E v e nts  b y  S e v erit y   Usi n g   C T  C  A E   Gr a d e 
   
 
P r ef e r r e d   T e r  m  
M a xi  m u  m 
G r a d e   
5 0 0   m g  
(  N  = 
X  X)    
n (  %)  
1 0 0 0   m g  
(  N  = 
X  X)    
n (  %)  
1 5 0 0   m g  
(  N  = 
X  X)    
n (  %)  
P-
v al u e  
N u  m b er    of    s u bj e cts    r e p orti n g    tr e at  m e nt  -e  m er g e nt 
a d v ers e  e v e nts  
Mil d   
M o d er at e   
S e v er e  
T ot al  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x. x)  
-- 
-- 
x x  
x x  
 [ S yst e  m   Or g a n   Cl ass   Cl ass  # 1] 
 
   
   
   
 
  [ Pr ef err e d  T er  m  # 1]  
Mil d   
M o d er at e   
S e v er e  
T ot al  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x. x)  
--  
-- 
x x  
x x  
  [ Pr ef err e d  T er  m  # 2] 
Mil d   
M o d er at e   
S e v er e  
T ot al  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x.)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x.)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x .) 
--  
-- 
x x  
x x  


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  4 0  of  4 3 
T a bl e  1 4. 3. 1. 7  S u  m  m ar y  of   A d v ers e  E v e nts   wit h  1 0  %  or   Hi g h er I n ci d e nt   R at e 
S u bj e ct  
I  D 
C  T  C  A  E  v 4  S  O  C     A  E   T e r  m     D os e (  m g)      S e v e rit y  
   
 
 
 
 
   
 
 
 
 
   
 
 
 
 
   
 
 
 
 
T a bl e  1 4. 3. 2. 1  S u  m  m ar y  of  S eri o us   A d v ers e  E v e nts 
   
 
P r ef e r r e d   T e r  m  
5 0 0   m g  
(  N  =   X  X)  
n (  %)  
1 0 0 0   m g  
(  N  =   X  X)  
n (  %)  
1 5 0 0   m g  
(  N  =   X  X)  
n (  %)    
P- v al u e  
N u  m b er  of s u bj e cts r e p orti n g s eri o us  a d v ers e  e v e nts     x x ( x x. x)    x x ( x x x)    
   
x x   
[ S yst e  m   Or g a n   Cl ass   Cl ass  # 1] 
   
   
   
 
  [ Pr ef err e d  T er  m  # 1] 
x x ( x x. x)    x x ( x x x)    
   
x x   
  [ Pr ef err e d  T er  m  # 2] 
x x ( x x. x)    x x ( x x x)    
   
x x   
… 
   
   
   
 
 
   
   
   
 
 
T a bl e  1 4. 3. 2. 2  S u  m  m ar y  of  S eri o us   A d v ers e  E v e nts  b y   R el ati o ns hi p t o   BI  O  3 0 0 
 
 
P r ef e r r e d   T e r  m  
R el ati o ns hi p     
5 0 0   m g  
(  N  =   X  X)  
n (  %)  
1 0 0 0   m g  
(  N  =   X  X)  
n (  %)  
1 5 0 0   m g  
(  N  =   X  X)  
n (  %)  
N u  m b er  of s u bj e cts r e p orti n g   S eri o us  a d v ers e  e v e nts    
P ossi bl e  
Pr o b a bl e  
D efi nit el y   
T ot al  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x. x)  
 [ S yst e  m   Or g a n   Cl ass   Cl ass  # 1] 
 
 
   
 
  [ Pr ef err e d  T er  m  # 1]  
P ossi bl e  
Pr o b a bl e  
D efi nit el y   
T ot al  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x. x)  
  [ Pr ef err e d  T er  m  # 2] 
P ossi bl e  
Pr o b a bl e  
D efi nit el y   
T ot al  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x.)  
x x ( x x x)  
x x ( x x x)  
x x ( x x x)  
x x ( x x.)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x. x)  
x x ( x x.)  
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  4 1  of  4 3 
T a bl e  1 4. 3. 2. 3  S u  m  m ar y  of   D e at hs 
S u bj e ct  
I  D 
A g e     
D at e  of 
D e at h   
A  E 
T e r  m   
D at e  of  Fi n al  St u d y 
D r u g/  D os e (  m g)  
PI 
Att ri b uti o n   
M e di c al   M o nit o r 
Att ri b uti o n   
   
 
 
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
 
T a bl e  1 4. 3. 4. 1  S u  m  m ar y  of   Cli ni c al  L a b or at or y   V al u es 
L a b   T est   
5 0 0   m g  
1 0 0 0   m g  
1 5 0 0   m g  
P- v al u e  
M e a n     Mi n     M a x     M e a n     Mi n     M a x     M e a n     Mi n     M a x   
H  G  B ( g/ d L)   
   
   
   
   
   
   
   
   
 
 
H  C T ( v ol   %)   
   
   
   
   
   
   
   
   
 
 
R  B  C (  M/ u L)   
   
   
   
   
   
   
   
   
 
 
W  B  C   (  K/ u L) 
   
   
   
   
   
   
   
   
 
 
N E # (  K/ u L)   
   
   
   
   
   
   
   
   
 
 
L  Y # (  K/ u L)  
   
   
   
   
   
   
   
   
 
 
M  O # (  K/ u L)   
   
   
   
   
   
   
   
   
 
 
E  O # (  K/ u L)  
   
   
   
   
   
   
   
   
 
 
B  A # (  K/ u L)   
   
   
   
   
   
   
   
   
 
 
P L T (  K/ u L)  
   
   
   
   
   
   
   
   
 
 
Pr ot ei n,  T ot al ( g/ d L)  
   
   
   
   
   
   
   
   
 
 
Al b u  mi n ( g/ d L)   
   
   
   
   
   
   
   
   
 
 
C  A 2 + (  m g/ d L) 
   
   
   
   
   
   
   
   
 
 
P  O 4 (  m g/ d L) 
   
   
   
   
   
   
   
   
 
 
C h ol est er ol (  m g/ d L)   
   
   
   
   
   
   
   
   
 
 
T  G (  m g/ d L)  
   
   
   
   
   
   
   
   
 
 
Gl u c os e (  m g/ d L)   
   
   
   
   
   
   
   
   
 
 
U  A (  m g/ d L)   
   
   
   
   
   
   
   
   
 
 
B  U  N (  m g/ d L)   
   
   
   
   
   
   
   
   
 
 
Cr e ati ni n e (  m g/ d L)   
   
   
   
   
   
   
   
   
 
 
Bilir u bi n, t ot al (  m g/ d L)   
   
   
   
   
   
   
   
   
 
 
Al k ali n e  p h os p h at as e (I  U/ L)      
   
   
   
   
   
   
   
 
 
N a +  (  m  m ol/ L) 
   
   
   
   
   
   
   
   
 
 
K +  (  m  m ol/ L) 
   
   
   
   
   
   
   
   
 
 
Cl - (  m  m ol/ L) 
   
   
   
   
   
   
   
   
 
 
C  O 2 (  m  m ol/ L) 
   
   
   
   
   
   
   
   
 
 
A S T (I  U/ L)   
   
   
   
   
   
   
   
   
 
 
A L T (I  U/ L)   
   
   
   
   
   
   
   
   
 
 
A  m yl as e (I  U/ L)   
   
   
   
   
   
   
   
   
 
 
Li p as e (I  U/ L)  
   
   
   
   
   
   
   
   
 
 
 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  4 2  of  4 3 
T a bl e  1 4. 3. 4. 2  S u  m  m ar y  of   A b n or  m al (  Gr a d e  3  or   w ors e)   Cli ni c al  L a b or at or y   V al u es 
S u bj e ct  
I  D 
C  T  C  A  E  v 4  S  O  C     A  E   T e r  m     D os e (  m g)      S e v e rit y  
   
 
 
 
 
   
 
 
 
 
   
 
 
 
 
   
 
 
 
 
 
T a bl e  1 4. 3. 4. 3  S u  m  m ar y  of   Uri n al ysis/ Pr e g n a n c y   R es ults 
T est   
5 0 0   m g  
1 0 0 0   m g  
1 5 0 0   m g  
P- v al u e  
M e a n     Mi n     M a x     M e a n     Mi n     M a x     M e a n     Mi n     M a x   
S p e cifi c   Gr a vit y     
   
   
   
   
   
   
   
 
 
p  H  
   
   
   
   
   
   
   
   
 
 
Pr ot ei n (  m g/ d L)  
   
   
   
   
   
   
   
   
 
 
Gl u c os e 
(  m g/ d L)   
   
   
   
   
   
   
   
   
 
 
K e nt o n es 
(  m g/ d L)   
   
   
   
   
   
   
   
   
 
 
Bl o o d (  m g/ d L)   
   
   
   
   
   
   
   
   
 
 
H  C  G (  mI  U/  m L)   
   
   
   
   
   
   
   
   
 
 
 
 
 


Pr ot o c ol   C L 0 1 0 1- 0 1 
St atisti c al   A n al ysis  Pl a n 
C o nfi d e nti al 
 
 
 
 
BI  O  3 0 0  P h as e I/II   N S  C L  C  S  A P 
 
P a g e  4 3  of  4 3 
T a bl e  1 4. 3. 5. 1  S u  m  m ar y  of  El e ctr o c ar di o gr a  m   Q T c   R es ults 
 
5 0 0   m g    
1 0 0 0   m g    
1 5 0 0   m g    
p- v al u e  
B as eli n e   
 
 
 
 
n      
 
 
 
M e a n      
 
 
 
S T  D     
 
 
 
R a n g e      
 
 
 
1  h o ur  p ost   BI  O  3 0 0  
 
 
 
 
n      
 
 
 
M e a n      
 
 
 
S T  D     
 
 
 
R a n g e      
 
 
 
BI  O  3 0 0   st e a d y st at e 
 
 
 
 
n      
 
 
 
M e a n      
 
 
 
S T  D     
 
 
 
R a n g e      
 
 
 
C h a n g e fr o  m   B as eli n e t o  1  h o ur 
p ost   BI  O  3 0 0  
 
 
 
 
n      
 
 
 
M e a n      
 
 
 
S E     
 
 
 
9 5  %   CI     
 
 
 
C h a n g e fr o  m   B as eli n e t o   BI  O  3 0 0 
st e a d y st at e 
 
 
 
 
n      
 
 
 
M e a n      
 
 
 
S E     
 
 
 
9 5  %   CI     
 
 
 
 
T a bl e  1 4. 3. 5. 2  S u  m  m ar y  of   Vit al  Si g ns 
M e as u r e  m e nt   
5 0 0   m g  
1 0 0 0   m g  
1 5 0 0   m g  
M e a n     M a x     Mi n     M e a n     M a x     Mi n     M e a n     M a x     Mi n   
T e  m p er at ur e ( F)    
   
   
   
   
   
   
   
   
 
R es pir at or y   R at e     
   
   
   
   
   
   
   
   
 
H e art   R at e   
   
   
   
   
   
   
   
   
 
S yst oli c   B P  
   
   
   
   
   
   
   
   
 
Di ast oli c   B P   
   
   
   
   
   
   
   
   
 
H ei g ht   
   
   
   
   
   
   
   
   
 
W ei g ht (l bs)