A Phase 1-2 Multicenter, Open Label Trial of H3B-6545, a Covalent Antagonist of Estrogen Receptor Alpha, in Women With Locally Advanced or Metastatic Estrogen Receptor-positive, HER2 Negative Breast Cancer
Phase: PHASE1
Conditions: Breast Neoplasms, Breast Cancer, Estrogen-receptor Positive Breast Cancer, Cancer, Breast, Breast Cancer Female, Breast Adenocarcinoma, Estrogen Receptor Positive Tumor, ER Positive
Sponsor: Eisai Inc.

C O N FI D E N TI A L  
S T U D Y D R U G :  H 3 B -6 5 4 5  
P R O T O C O L A M E N D M E N T 9:   2 9  A U G 2 0 2 2  
Pa ge 1 of 1 6 0  
A P h ase 1- 2 m ultice nter, o pe n -l a bel tri al of H 3 B-6 5 4 5, a c o v ale nt a nt a g o nist 
of estr o ge n rece pt or al p h a, i n w o me n wit h l oc all y a d v a nce d or met ast atic 
estr o ge n rece pt or -p ositi ve, H E R 2 ne g ati ve bre ast c a ncer  
 
 
S P O N S O R  S T U D Y  P R O T O C O L  N U M B E R:   
H 3 B -6 5 4 5 -A 0 0 1 -1 0 1  
I N D N U M B E R:  
E U D R A C T  N U M B E R:  
1 3 3, 2 8 2  
2 0 1 8 -0 0 0 5 7 0 -2 9  
S T U D Y  D R U G:  
H 3 B -6 5 4 5  
 
S P O N S O R:  
Eisai I nc.  
2 0 0 Metr o  B o ule var d  
N utle y , NJ 0 7 1 1 0  
U S A  
 
 
 
S T U D Y  C H AI R:  
 
Sara h Ca n n o n Researc h I nstit ute  
1 1 0 0 C harl otte A ve n ue, S uite 8 0 0  
Nas h ville, T N 3 7 2 0 3  
U S A  
1- 8 7 7 -M Y - 1-S C RI  
 
P P D

 
C O N FI D E N TI A L  
S T U D Y D R U G :  H 3 B -6 5 4 5  
P R O T O C O L A M E N D M E N T 9:   2 9  A U G 2 0 2 2  
Pa ge 2 of 1 6 0  
 
D A T E  FI N A L:  
1 9 Ma y 2 0 1 7  
A M E N D M E N T  N U M B E R  1 
A M E N D M E N T  N U M B E R  2 
A M E N D M E N T  N U M B E R  3 
A M E N D M E N T  N U M B E R  4 
A M E N D M E N T  N U M B E R  5 
A M E N D M E N T  N U M B E R  6 
A M E N D M E N T  N U M B E R  7 
A M E N D M E N T  N U M B E R  8 
A M E N D M E N T  N U M B E R  9  
 
 
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CONFIDENTIAL 
STUDY DRUG:  H3B-6545 
PROTOCOL AMENDMENT 9:  29 AUG 2022 
Page 4 of 160 
CLINICAL STUDY PRINCIPAL INVESTIGATOR SIGNATURE FORM 
A Phase I-II multicenter, open-label trial of H3B-6545, a covalent antagonist 
of estrogen receptor alpha, in women with locally advanced or metastatic 
estrogen receptor-positive, HER2 negative breast cancer 
 
 
SPONSOR STUDY PROTOCOL NUMBER: 
H3B-6545-A001-101 
IND NUMBER:  
EUDRACT NUMBER: 
133,282 
2018-000570-29 
DATE FINAL: 
19 May 2017 
AMENDMENT NUMBER 9: 
29 Aug 2022 
By signing this protocol acceptance page, I confirm I have read, understand, and agree to conduct the 
study in accordance with the current protocol. 
 
 
 
__________________________ 
__________________________         ______________  
Principal Investigator Name 
<<Insert Site Name and ID info as 
applicable>> 
<<Insert Site Location>> 
 
Principal Investigator Signature 
 
Date 
 

 
C O N FI D E N TI A L  
S T U D Y D R U G :  H 3 B -6 5 4 5  
P R O T O C O L A M E N D M E N T 9:   2 9  A U G 2 0 2 2  
Pa ge 5 2  of 1 6 0  
P R O T O C O L S Y N O P SI S  
Title of St u d y:  
A P hase I -II m ultice nter, o pe n -la bel trial of H 3 B-6 5 4 5, a c o vale nt a nta g o nist of estr o ge n 
rece pt or al p ha, i n w o me n wit h l ocall y a d va nce d or metastatic estr o ge n rece pt or-p ositi ve, 
H E R 2 ne gati ve breast ca ncer  
S p o ns or St u d y 
N u m bers:  
H 3 B -6 5 4 5 -A 0 0 1 -1 0 1  
S p o ns or:  
Eisai,  I nc. 
St u d y D ur ati o n:  
T he t otal d urati o n of t he st u d y is pla n ne d t o be fi ve ( 5) years.  
P h ase of 
St u d y:   1 -2  
St u d y Sites:  
A p pr o xi matel y 4 sites pla n ne d f or P hase 1 a n d a p pr o xi matel y  
 sites f or P hase 2.  
N u m ber of 
S u bjects:   
U p t o a p pr o xi matel y 1 7 0 s u bjects wit h l ocall y a d va nce d or metastatic breast ca ncer are 
pla n ne d t o be e nr olle d i n t his st u d y.  
O bjecti ves:  
P h ase 1  
T he pri mar y o bjecti ve of t he P hase 1 p orti o n of t his st u d y is t o:  
● 
Deter mi ne t he ma xi m u m t olerate d d ose ( M T D) a n d/ or t he rec o m me n de d P hase 2 
d ose ( R P 2 D) of H 3 B -6 5 4 5 i n w o me n wit h l ocall y a d va nce d or metastatic estr o ge n 
rece pt or ( E R)-p ositi ve, h u ma n e pi der mal gr o wt h fact or rece pt or -2 ( H E R 2) -
ne gati ve breast ca ncer.  
T he sec o n dar y o bjecti ves of t he P hase 1 p orti o n of t his st u d y are t o:  
● 
E val uate t he safet y a n d t olera bilit y of H 3 B -6 5 4 5 as a si n gle a ge nt a d mi nistere d 
orall y o nce dail y ( Q D) o ver a 2 8 -da y c ycle i n t his s u bject p o p ulati o n  
● 
C haracterize t he plas ma p har mac o ki netics ( P K) of H 3 B -6 5 4 5.  
● 
Esti mate t he efficac y of H 3 B -6 5 4 5 i n ter ms of res p o nse rate, d urati o n of res p o nse 
( D o R), disease c o ntr ol rate ( D C R), pr o gressi o n-free s ur vi val ( P F S), a n d o verall 
s ur vi val ( O S).  
T he e x pl orat or y o bjecti ves of t he P hase 1 p orti o n of t his st u d y are t o:  
P h ase 2  
T he pri mar y o bjecti ve of t he P hase 2 p orti o n of t his st u d y is t o: 
● 
Esti mate t he efficac y of H 3 B -6 5 4 5 i n ter ms of best o verall res p o nse rate, D o R, 
D C R, cli nical be nefit rate, P F S, a n d O S i n all s u bjects wit h E R -p ositi ve H E R 2 -
ne gati ve breast ca ncer a n d i n t h ose wit h a n d wit h o ut E R α m utati o n ( E R α M U T) 
(i ncl udi n g a cl o nal estr o ge n rece pt or  1 [ E S R 1] Y 5 3 7 S m utati o n)  
T he sec o n dar y o bjecti ves of t he P hase 2 p orti o n of t his st u d y are t o:  
● 
F urt her c haracterize t he safet y of H 3 B -6 5 4 5 i n t his s u bject p o p ulati o n  
● 
F urt her c haracterize t he P K of H 3 B -6 5 4 5.  At least s parse P K sa m ples will be 
c ollecte d fr o m all s u bjects o n st u d y.  
● 
E val uate t he effect of a hi g h -fat meal o n t he relati ve bi oa vaila bilit y of H 3 B-6 5 4 5.  
● 
Assess t he effect of H 3 B -6 5 4 5 o n ser u m b o ne t ur n -o ver mar kers, na mel y b o ne -
s pecific al kali ne p h os p hatase ( B SA P; f or oste oclast meta b olis m), a mi n o -ter mi nal 
C CI
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C O N FI D E N TI A L  
S T U D Y D R U G :  H 3 B -6 5 4 5  
P R O T O C O L A M E N D M E N T 9:   2 9  A U G 2 0 2 2  
Pa ge 5 4  of 1 6 0  
deter mi ne d b y ce ntral la b orat or y assess me nt pri or t o si g ni n g t he mai n st u d y c o nse nt. 
See Secti o n 5. 2 . 
U n der A me n d me nt 8, a p pr o xi matel y   s u bjects will be e nr olle d  t o all o w f or 
a p pr o xi matel y   res p o nse e val ua ble s u bjects.  
I ncl usi o n 
Criteri a:  
S u bjects m ust meet t he f oll o wi n g criteria i n or der t o be i ncl u de d i n t he researc h st u d y:  
1.  Prescree ni n g: S u bjects m ust ha ve cl o nal E S R 1 Y 5 3 7 S m utati o n at A F ≥0. 5 %, i n t he 
a bse nce of E S R 1 D 5 3 8 G at A F ≥0. 5 %, as deter mi ne d at prescree ni n g b y a S p o ns or -
desi g nate d ce ntral la b orat or y fr o m a N ucleic Aci ds W h ole Bl o o d ( plas ma cf D N A) 
sa m ple.  
2.  S u bject has si g ne d i nf or me d c o nse nt f or m (I C F) bef ore a n y trial -relate d acti vities 
a n d acc or di n g t o l ocal g ui deli nes.  Mai n I C F ma y o nl y be si g ne d o nce p ositi ve 
m utati o n stat us is c o nfir me d b y a s p o ns or-desi g nate d  ce ntral la b orat or y, u nless pri or 
a ut h orizati o n has bee n recei ve d b y t he S p o ns or, base d o n l ocal m utati o n a nal ysis.   
3.  O nl y fe males are eli gi ble.  Me n o pa usal stat us:  
 
− 
P ost me n o pa usal defi ne d b y:  
 
a) Pri or bilateral o o p h orect o m y,  
b)  A ge ≥6 0 years, or  
c) A ge < 6 0 years a n d a me n orr hea f or 1 2 or m ore m o nt hs (i n t he a bse nce of 
c he m ot hera p y, ta m o xife n, t ore mife ne, or o varia n s u p pressi o n); or a 
f ollicle-sti m ulati n g h or m o ne val ue > 4 0 mI U/ m L a n d a n estra di ol val ue 
< 4 0  p g/ m L ( 1 4 0  p m ol/ L) or i n p ost me n o pa usal ra n ges per  l ocal refere nce 
ra n ges 
Or  
− 
Pre me n o pa usal or peri me n o pa usal c o nc urre ntl y gi ve n a l utei nizi n g  h or m o ne -
releasi n g h or m o ne ( L H R H) a g o nist starti n g at least 4 wee ks bef ore t he start of 
trial t hera p y a n d is pla n ne d t o c o nti n ue L H R H d uri n g t he st u d y.    
4.  S u bject has a hist ol o gicall y a n d/ or c yt ol o gicall y c o nfir me d dia g n osis of E R -p ositi ve 
breast ca ncer b y l ocal la b orat or y.  
5.  S u bject has H E R 2 -ne gati ve breast ca ncer as defi ne d b y A merica n S ociet y f or 
Cli nical O nc ol o g y C olle ge of A merica n Pat h ol o gists g ui deli nes ( W olff et al. 2 0 1 3 ). 
6.  S u bject m ust ha ve pr o gresse d o n t he m ost rece nt t hera p y.   
7.  Pri or t hera p y f or breast ca ncer i n t he a d va nce d/ metastatic setti n g m ust ha ve i ncl u de d 
a mi ni m u m of : 
a) t w o pri or h or m o nal t hera pies, or 
b)  o ne pri or h or m o nal t hera p y a n d o ne pri or c he m ot hera p y re gi me n, or  
c) o ne pri or h or m o nal t hera p y a n d a C D K 4/ 6 i n hi bit or.   
N ote: S u bjects ma y ha ve recei ve d treat me nt f or brai n metastases, b ut m ust be 
ne ur ol o gicall y sta ble, c o m plete d ra di ot hera p y a n d off c orti c oster oi ds f or at least o ne 
m o nt h pri or t o starti n g trial t hera p y.  
N ote:  S u bjects e nr olle d u n der A me n d me nt 6 (or s u bse q ue nt a me n d me nts) m ust 
ha ve recei ve d pri or t hera p y, i ncl u di n g at least o ne pri or h or m o nal t hera p y a n d a 
C D K 4/ 6 i n hi bit or.  U p t o o ne pri o r c he m ot hera p y i n t he metastatic setti n g is all o we d. 
8.  S u bject m ust ha ve at least o ne bi o psia ble lesi o n i n t he P hase 1 p orti o n.  I n t he P hase 
2 part of t he trial, s u bjects m ust ha ve eit her  
C
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CONFIDENTIAL 
STUDY DRUG:  H3B-6545 
PROTOCOL AMENDMENT 9:  29 AUG 2022 
Page 55 of 160 
a) at least one measurable lesion as per Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1, or  
b) at least one predominantly lytic bone lesion.   
Note:  Subjects enrolled under Amendment 6 (or subsequent amendments) must 
have at least one measurable lesion as per RECIST 1.1. 
9. Subject must be willing to undergo tumor biopsies prior to treatment and on Cycle 2  
Day 1.  In the Phase 2 part of the trial, subjects with bone-only disease, or those for 
whom a biopsy is contra-indicated, may opt out of providing tumor biopsies 
following investigator concern and direct discussion and approval from the Sponsor.   
Note: A subset of subjects in Phase 2 will be required to provide tumor tissue until 
tumor pairs have been collected from at least 15 subjects with ERαWT and 15 
subjects with ERαmut (determined retrospectively by Sponsor-designated central 
laboratory test).   
Note:  For subjects enrolled under Amendment 6 (or subsequent amendments), a 
recent archival tumor tissue obtained within 6 months prior to enrollment or a fresh 
tumor biopsy must be provided. A second biopsy after initiating trial therapy is not 
required. 
10. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 
0 or 1. 
11. Subject has adequate bone marrow and organ function, as defined by the following 
laboratory values: 
● 
Absolute neutrophil count ≥1.5 × 109/L 
● 
Platelets ≥100 × 109/L 
● 
Hemoglobin ≥9.0 g/dL (may have been transfused). 
● 
Potassium, sodium, calcium (corrected for serum albumin) and magnesium 
<CTCAE Grade 2 
● 
Cockcroft-Gault based creatinine clearance ≥35 mL/min 
● 
Serum albumin ≥3.0 g/dL (≥30 g/L) 
● 
In the absence of liver metastases, alanine aminotransferase (AST) and aspartate 
aminotransferase (ALT) should be below 3.0 × ULN.  If the subject has liver 
metastases, ALT and AST should be below 5.0 × ULN.  
● 
Total serum bilirubin <ULN. For subjects with documented Gilbert’s syndrome, 
total serum bilirubin <2.5 × ULN 
12. Age ≥18 years 
13. Willingness and ability to comply with study and follow-up procedures 
14. Ability to understand the nature of this study and give written informed consent 
Exclusion 
Criteria: 
Subjects who meet any of the following criteria will be excluded from study entry: 
1. Subject with bone-only disease (Phase 1 only).   
2. Phase 2 subjects may have predominantly lytic bone-only disease.   
Note:  Subjects enrolled under Amendment 6 (or subsequent amendments) must 
have at least one measurable lesion as per RECIST 1.1. 
3. Subject with inflammatory breast cancer. 
4. Subject has received more than one prior chemotherapy regimen for metastatic 
disease (Phase 2 only). 

 
CONFIDENTIAL 
STUDY DRUG:  H3B-6545 
PROTOCOL AMENDMENT 9:  29 AUG 2022 
Page 56 of 160 
5. Subject has had prior antineoplastic therapy within 14 days prior to starting study 
drug.   
6. Subject is currently receiving or has received systemic corticosteroids ≤2 weeks 
prior to starting study drug, or has not fully recovered from side effects of such 
treatment.  
Note: The following uses of corticosteroids are permitted: single doses, topical 
applications (eg, for rash), inhaled sprays (eg, for obstructive airways diseases), eye 
drops or local injections (eg, intra-articular). 
7. Subject has received radiotherapy ≤4 weeks or limited field radiation for palliation 
≤2 weeks prior to starting study drug, and who has not recovered to Grade 1 or 
better from related side effects of such therapy (with the exception of alopecia) 
and/or for whom ≥30% of the bone marrow was irradiated. 
8. Major surgical procedures ≤14 days of beginning study drug, or minor surgical 
procedures ≤7 days, or has not recovered from major side effects. No waiting 
required following port-a-cath placement.   
9. Subject has active cardiac disease or a history of cardiac dysfunction, including any 
of the following: 
● 
History of angina pectoris, symptomatic pericarditis, or myocardial infarction 
within 12 months prior to study entry 
● 
History of documented congestive heart failure (New York Heart Association 
functional classification III or IV) 
● 
Documented cardiomyopathy 
● 
Subject has a left ventricular ejection fraction <50% as determined by multiple- 
gated acquisition (MUGA) scan or echocardiogram. 
● 
History of any cardiac arrhythmias, eg, ventricular, supraventricular, nodal 
arrhythmias, or conduction abnormality, in the previous 12 months  
● 
A prolonged QTcF interval >450 msec as demonstrated by a repeated ECG; a 
history of risk factors for Torsade de pointes (eg, heart failure, hypokalemia, and 
family history of long QT syndrome); or the use of concomitant medications that 
prolonged the QTcF interval 
● 
Subject has a resting pulse rate <60 bpm 
10. Subject has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of H3B-6545 (eg, ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).  
11. Subject has a known hypersensitivity to any of the excipients of H3B-6545. 
12. Subject has a known history of human immunodeficiency virus infection or hepatitis 
C virus, or requires treatment with protease inhibitors (testing not mandatory). 
13. Subject has any other concurrent severe and/or uncontrolled medical condition that 
would, in the investigator’s judgment, contraindicate subject participation in the 
clinical study (eg, chronic pancreatitis, active hepatitis, etc). 
14. Subject received in the 7 days prior to the administration of study drug or is 
currently receiving any of the following medications (see Appendix H and 
Appendix I for details): 
a. 
Known strong inducers or inhibitors of cytochrome P450 (CYP) 3A4 or P-
glycoprotein 
b. Medications that have a known risk to prolong the QT interval or induce 
Torsades de Pointes. 
c. Medications that have a narrow therapeutic window and are predominantly 
metabolized through CYP2C8, CYP2C9, CYP2C19, or CYP3A4 

 
CONFIDENTIAL 
STUDY DRUG:  H3B-6545 
PROTOCOL AMENDMENT 9:  29 AUG 2022 
Page 57 of 160 
d. Medications that have a narrow therapeutic window and are breast cancer 
resistance protein substrates 
e. 
Herbal preparations/medications; these herbal medications include, but are not 
limited to, St. John’s wort, kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng 
15. Any adverse event related to previous therapies for breast cancer that has not resolved 
to ≤Grade 1.  
16. Females who are breastfeeding or pregnant at Screening or Baseline (as documented 
by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic 
gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units 
of ß-hCG [or hCG]).  A separate baseline assessment is required if a negative 
screening pregnancy test was obtained more than 72 hours before the first dose of 
study drug. 
17. Females of childbearing potential who: 
● 
Had unprotected sexual intercourse within 30 days before study entry and who do 
not agree to use a highly effective method of contraception (eg, total abstinence, 
an intrauterine device, a double-barrier method [such as condom plus diaphragm 
with spermicide], a contraceptive implant, an oral contraceptive, or have a 
vasectomized partner with confirmed azoospermia) throughout the entire study 
period or for 28 days after study drug discontinuation. 
● 
Are currently abstinent, and do not agree to use a double-barrier method (as 
described above) or refrain from sexual activity during the study period or for 28 
days after study drug discontinuation. 
● 
Are using hormonal contraceptives but are not on a stable dose of the same 
hormonal contraceptive product for at least 4 weeks before dosing and who do not 
agree to use the same contraceptive during the study or for 28 days after study 
drug discontinuation 
All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause] or have been sterilized 
surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, 
all with surgery at least 1 month before dosing]). 
18. Alcohol dependency within 6 months before study entry.  
19. Subject has a concurrent malignancy or malignancy within 3 years of enrollment, 
with the exception of adequately treated basal or squamous cell carcinoma, non-
melanomatous skin cancer, or curatively resected cervical cancer. 
20. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol.  
21. Subjects with advanced, symptomatic visceral spread, that are at risk of life-
threatening complications in the short term. 
22. Subjects with abnormal coagulation profiles, or any history of coagulopathy within 
6 months prior to the first dose of study drug, including history of deep vein 
thrombosis (DVT) or pulmonary embolism.  
Note: subjects (except pre/perimenopausal women) with adequately treated 
catheter-related venous thrombosis occurring more than one month prior to the first 
dose of study drug will be allowed to participate. 
23. Prothrombin time/international normalized ratio (INR) >1.5 times the upper limit 
of normal (ULN) or outside therapeutic range if receiving anticoagulation that 
would affect the prothrombin time/INR.  

 
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STUDY DRUG:  H3B-6545 
PROTOCOL AMENDMENT 9:  29 AUG 2022 
Page 60 of 160 
LIST OF ABBREVIATIONS  
AE 
Adverse event 
AESI 
Adverse event of special interest 
AF 
Allelic frequency 
ALP 
Alkaline phosphatase 
ALT  
Alanine aminotransferase 
AR 
Adverse reaction 
AST  
Aspartate aminotransferase 
AUC 
Area under the curve 
ß-hCG 
beta-human chorionic gonadotropin 
BCRP 
Breast cancer resistance protein 
BP 
Blood pressure 
BSAP 
Bone-specific alkaline phosphatase 
CBC 
Complete blood count 
cfDNA 
Cell-free DNA 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL/F 
Apparent total body clearance following oral administration 
Cmax 
Maximum observed plasma concentration 
CMP 
Comprehensive metabolic profile 
CR 
Complete response 
CRF 
Case report form 
CRO 
Contract research organization 
CT 
Computed tomography 
CTA 
Clinical trial agreement 
CTX 
C-terminal cross-linking telopeptide of type 1 collagen 
CYP 
cytochrome P450 
DCR 
Disease control rate 
DDI 
Drug-drug interaction 
DHEA 
Dehydroepiandrosterone 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
EC 
Ethics Committee 
EC50 
Half-maximal exhibitory concentration 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EOT 
End-of-Treatment 
ER 
Estrogen receptor 
ERα 
Estrogen receptor alpha 
ERαWT  
Estrogen receptor alpha wild-type 
ERαmut 
Estrogen receptor alpha mutant 
ESR1 
Estrogen receptor 1 gene 
FAS 
Full Analysis Set 

 
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STUDY DRUG:  H3B-6545 
PROTOCOL AMENDMENT 9:  29 AUG 2022 
Page 61 of 160 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
HED 
Human equivalent dose 
HER2 
Human epidermal growth factor receptor-2 
HNSTD 
Highest non-severely toxic dose 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISF 
Investigatory study file 
LHRH 
Luteinizing hormone-releasing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MRSD 
Maximum recommended starting dose 
MTD 
Maximum tolerated dose 
MUGA 
Multiple-gated acquisition  
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Pharmacodynamic(s) 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PG 
Pharmacogenetic(s) 
PHI 
Protected health information 
PI 
Principal Investigator 
PINP 
Amino-terminal propeptide of type 1 collagen 
PK 
Pharmacokinetic(s) 
PO 
Orally/by mouth 
PS 
Performance status 
PT/PTT 
Prothrombin time/partial thromboplastin time 
QD 
Once daily 
QRS interval 
Q, R, and S heart waves shown on electrocardiogram 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
Racc 
Accumulation ratio 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RES 
Response-Evaluable Set 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
RR 
Respiratory rate 
SAE 
Serious adverse event 

 
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PROTOCOL AMENDMENT 9:  29 AUG 2022 
Page 62 of 160 
SAR 
Suspected adverse reaction 
SD 
Stable disease 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
STD10 
Severely toxic dose in 10% of animals 
t½  
Terminal elimination half-life 
TEAE 
Treatment-emergent adverse event 
tmax 
Time of maximum observed plasma concentration 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
Vz/F 
Apparent volume of distribution during terminal phase 
WBC 
White blood count 
WHO DD 
World Health Organization Drug Dictionary 

 
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Page 63 of 160 
TABLE OF CONTENTS 
H3B-6545-A001-101 PROTOCOL SUMMARY OF CHANGES ......................................... 5 
PROTOCOL SYNOPSIS....................................................................................................... 52 
1. 
INTRODUCTION ................................................................................................. 69 
1.1 
Background ........................................................................................................... 69 
1.2 
Role of the Estrogen Pathway in Breast Cancer .................................................... 69 
1.3 
Role of H3B-6545 in Breast Cancer ...................................................................... 70 
1.3.1 
Nonclinical Pharmacokinetics ............................................................................... 70 
1.3.2 
Nonclinical Safety ................................................................................................. 70 
1.4 
Rationale for the Study .......................................................................................... 72 
1.5 
Rationale for the Starting Dose ............................................................................. 72 
1.5.1 
Rationale for Recommended Phase 2 Dose .......................................................... 73 
1.6 
Risk Assessment and Summary ............................................................................ 73 
2. 
STUDY OBJECTIVES ......................................................................................... 73 
2.1 
Phase 1 Primary Objective .................................................................................... 73 
2.2 
Phase 1 Secondary Objectives ............................................................................... 73 
2.3 
Phase 1 Exploratory Objectives ............................................................................ 73 
2.4 
Phase 2 Primary Objective .................................................................................... 74 
2.5 
Phase 2 Secondary Objectives ............................................................................... 74 
2.6 
Phase 2 Exploratory Objectives ............................................................................ 74 
3. 
STUDY SUBJECT POPULATION AND DISCONTINUATION ...................... 74 
3.1 
Inclusion Criteria ................................................................................................... 75 
3.2 
Exclusion Criteria .................................................................................................. 77 
3.3 
Discontinuation from Study Treatment ................................................................. 79 
4. 
STUDY REGISTRATION.................................................................................... 80 
5. 
STUDY DESIGN .................................................................................................. 81 
5.1 
Phase 1 ................................................................................................................... 82 
5.1.1 
Starting Dose and Cohort Management ................................................................ 82 
5.1.2 
Definition of Dose-Limiting Toxicities ................................................................. 84 
5.1.3 
Maximum Tolerated Dose ..................................................................................... 86 
5.1.4 
Recommended Phase 2 Dose ................................................................................ 86 
5.2 
Phase 2 ................................................................................................................... 86 

 
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5.2.1 
Food-Effect Evaluation ......................................................................................... 87 
5.2.2 
Endometrium Evaluation in Subjects .................................................................... 88 
5.3 
Treatment Plan ...................................................................................................... 89 
5.4 
Concomitant Medications...................................................................................... 89 
5.4.1 
Permitted Concomitant Medications ..................................................................... 89 
5.4.2 
Prohibited Concomitant Medications .................................................................... 90 
6. 
DOSE MODIFICATIONS .................................................................................... 91 
6.1 
Dose Modifications Due to Toxicity ..................................................................... 91 
7. 
STUDY ASSESSMENTS AND EVALUATIONS .............................................. 95 
7.1 
Overview ............................................................................................................... 95 
7.2 
Baseline Study Assessments (Visit 2) ................................................................... 96 
7.3 
Study Treatment Assessments ............................................................................... 97 
7.3.1 
Cycle 1 Days 1 (Visit 3), 8 (Visit 4), 15 (Visit 5), and 22 (Visit 6) ...................... 97 
7.3.2 
Cycle 2 Days 1 (Visit 7) and 15 (Visit 8) .............................................................. 98 
7.3.3 
Cycle 3 Days 1 (Visit 9) and 15 (Visit 10) ............................................................ 99 
7.3.4 
Cycle 4 and Beyond - Days 1 (Visits 11, 13, 15, and beyond) and 15 (Visit 
12) ........................................................................................................................ 100 
7.4 
Response Assessment Every 8 Weeks ................................................................ 101 
7.5 
End-of-Treatment Visit ....................................................................................... 101 
7.6 
Follow-up after End-of-Treatment Visit ............................................................. 102 
7.7 
Pharmacokinetics ................................................................................................. 102 
7.8 
Biomarkers .......................................................................................................... 103 
7.8.1 
Prescreening Phase .............................................................................................. 104 
7.8.2 
Screening Phase Biomarkers ............................................................................... 104 
7.8.3 
Baseline and Treatment Phase Biomarkers ......................................................... 105 
7.8.4 
Pharmacogenetics Assessment ............................................................................ 105 
7.9 
Biomarkers of Bone Resorption and Formation .................................................. 106 
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION ............................................................................. 106 
8.1 
H3B-6545 ............................................................................................................ 106 
8.1.1 
Labeling, Packaging, and Supply ........................................................................ 106 
8.1.2 
Administration of H3B-6545............................................................................... 107 
8.1.3 
Precautions and Risks Associated with H3B-6545 ............................................. 107 

 
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8.2 
Storage Conditions .............................................................................................. 108 
8.3 
Accountability for All Study Drugs .................................................................... 108 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS ................................ 109 
10. 
STATISTICAL CONSIDERATIONS ................................................................ 109 
10.1 
Statistical Design ................................................................................................. 109 
10.2 
Phase 1 Primary Objective .................................................................................. 110 
10.3 
Phase 1 Secondary Objectives ............................................................................. 110 
10.4 
Phase 1 Exploratory Objectives .......................................................................... 110 
10.5 
Phase 2 Primary Objective .................................................................................. 110 
10.6 
Phase 2 Secondary Objectives ............................................................................. 110 
10.7 
Phase 2 Exploratory Objectives .......................................................................... 110 
10.8 
Study Endpoints .................................................................................................. 111 
10.8.1.1 Phase 1 ................................................................................................................. 111 
10.8.1.2 Phase 2 ................................................................................................................. 112 
10.9 
Sample Size Considerations ................................................................................ 112 
10.9.1 
Sample Size Calculation for Phase 1 ................................................................... 112 
10.9.2 
Sample Size Calculation for Phase 2 ................................................................... 112 
10.9.2.1 Sample Size Calculation for the Phase 2 Food-Effect Sub-Study ....................... 113 
10.9.2.2 Sample Size Calculation for the Phase 2 Endometrium Sub-Study .................... 113 
10.10 
Analysis Populations ........................................................................................... 114 
10.11 
Data Analysis ...................................................................................................... 114 
10.11.1 
Subject Disposition ............................................................................................. 115 
10.11.2 
Demographic and Other Baseline Characteristics ............................................... 115 
10.11.3 
Prior and Concomitant Therapy .......................................................................... 115 
10.11.4 
Efficacy Analysis ................................................................................................ 115 
10.11.5 
Safety Analysis .................................................................................................... 116 
10.11.5.1 Extent of Exposure .............................................................................................. 117 
10.11.5.2 Adverse Events .................................................................................................... 117 
10.11.5.3 Laboratory Values ............................................................................................... 118 
10.11.5.4 Vital Signs ........................................................................................................... 119 
10.11.5.5 Electrocardiograms .............................................................................................. 119 
10.11.6 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other  
Biomarker Analyses ............................................................................................ 119 

 
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10.11.6.1 Pharmacokinetic Analyses .................................................................................. 119 
10.11.6.2 Pharmacodynamic, Pharmacogenetic, and Other Biomarker Analyses .............. 120 
10.12 
Analysis Time Points .......................................................................................... 120 
10.12.1 
Primary Analysis ................................................................................................. 120 
10.12.2 
Planned Interim Analysis .................................................................................... 120 
10.12.3 
Safety Review Committee ................................................................................... 120 
11. 
SAFETY REPORTING ...................................................................................... 121 
11.1 
Definitions ........................................................................................................... 121 
11.1.1 
Adverse Events .................................................................................................... 121 
11.1.2 
Serious Adverse Event ........................................................................................ 123 
11.1.3 
Adverse Reaction ................................................................................................ 124 
11.1.4 
Suspected Adverse Reaction ............................................................................... 124 
11.1.5 
Recording and Reporting of Adverse Events ...................................................... 124 
11.1.5.1 Regulatory Reporting of Adverse Events ............................................................ 125 
11.2 
Serious Adverse Event Reporting by Investigators ............................................. 125 
11.2.1 
Investigator Reporting After Study Discontinuation ........................................... 126 
11.3 
Recording of Adverse Events and Serious Adverse Events ................................ 126 
11.3.1 
Diagnosis Versus Signs and Symptoms .............................................................. 126 
11.3.2 
Persistent or Recurrent Adverse Events .............................................................. 126 
11.3.3 
Abnormal Laboratory Values .............................................................................. 126 
11.3.4 
Deaths .................................................................................................................. 127 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery ...................................... 127 
11.3.6 
Pre-Existing Medical Conditions ........................................................................ 127 
11.3.7 
New Cancers........................................................................................................ 128 
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies ............................... 128 
11.3.9 
H3B-6545 Overdose ............................................................................................ 128 
11.4 
Cardiovascular ..................................................................................................... 129 
11.5 
Sponsor Serious Adverse Event Reporting Requirements .................................. 129 
11.5.1.1 Expedited Reporting ............................................................................................ 130 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .................................. 130 
12.1 
Monitoring ........................................................................................................... 130 
12.2 
Audits and Inspections ........................................................................................ 130 
13. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS .......... 130 

 
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13.1 
Institutional Review Board Approval.................................................................. 130 
13.2 
Regulatory Approval ........................................................................................... 131 
13.3 
Informed Consent ................................................................................................ 131 
13.3.1 
Confidentiality ..................................................................................................... 131 
13.3.1.1 Subject Confidentiality ........................................................................................ 131 
13.3.1.2 Investigator and Staff Information ...................................................................... 132 
13.4 
Financial Information .......................................................................................... 132 
14. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY ...... 133 
14.1 
Amendments to the Protocol ............................................................................... 133 
14.2 
Documentation Required to Initiate the Study .................................................... 133 
14.3 
Study Documentation and Storage ...................................................................... 134 
14.4 
Data Collection .................................................................................................... 135 
14.5 
Discontinuation of Study ..................................................................................... 136 
14.6 
Disclosure and Publication Policy ....................................................................... 136 
15. 
REFERENCES .................................................................................................... 137 
16. 
APPENDICES ..................................................................................................... 142 
 
 
 

 
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LIST OF TABLES 
Table 1 
Dose Cohorts in H3B-6545 Dose Escalation Phase ............................. 83 
Table 2 
Definition of Dose-Limiting Toxicity (Cycle 1 Phase 1 Only) or 
Dose-Modifying Event (Cycle 2 or Beyond and Any Cycle in 
Phase 2) ................................................................................................... 85 
Table 3 
Dose Modifications Due to Hematologic Toxicities ............................. 92 
Table 4 
Dose Modification for Grade 3, Grade 4, or Intolerable Grade 2 
Non-Hematologic Toxicities .................................................................. 93 
Table 5  
Time Points and Minimum Blood Volume for Biomarker 
Specimensg ............................................................................................ 104 
 
LIST OF FIGURES 
Figure 1: 
Study Design ........................................................................................... 81 
 
LIST OF APPENDICES 
APPENDIX A: 
ECOG Performance Status Criteria ....................................................... 143 
APPENDIX B: 
New York Heart Association (NYHA) Classification of Cardiac 
Disease ................................................................................................... 144 
APPENDIX C: 
Guidelines for Women of Childbearing Potential ................................. 145 
APPENDIX D: 
Prescreening for ESR1 Mutations (Amendment 6 and subsequent 
amendments) .......................................................................................... 147 
APPENDIX E: 
Schedule of Assessments ....................................................................... 148 
APPENDIX F: 
Extension Phase ..................................................................................... 153 
APPENDIX G: 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 . 155 
APPENDIX H: 
Concomitant Medications ...................................................................... 156 
APPENDIX I: 
Drugs That Prolong Qt Interval And/Or Induce Torsades De Pointes .. 158 
APPENDIX J: 
Security of the Samples, Use of the Samples, and Retention of the 
Samples .................................................................................................. 160 
 
 

 
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1. 
INTRODUCTION 
1.1 
Background 
In 2015, an estimated 231,840 new cases of invasive breast cancer were diagnosed in women in 
the United States (US), as well as an estimated 60,290 additional cases of in situ breast cancer.  It 
was estimated that over 3 million women in the US are living with breast cancer (NCI SEER, 
2016).  The estimated number of deaths from breast cancer in the same year in the US was 
40,290 (American Cancer Society, 2015).  In the European Union, the predicted number of 
deaths from breast cancer among women for 2016 was 92,300 (Malvezzi et al., 2016).   
The age-standardized incidence rate of breast cancer is 92.9 cases per 100,000  person-years in 
the US 95.0 cases per 100,000 person-years in the United Kingdom [UK] and 51.5 cases per 
100,000 person-years in Japan and the incidence is increasing with time (Ferlay et al., 2013).   
1.2 
Role of the Estrogen Pathway in Breast Cancer 
Approximately 70% of breast cancers express estrogen receptor alpha (ERα), a hormone-
regulated transcription factor (Lumachi et al., 2013).  Nonclinical and clinical epidemiological 
studies highlight an important oncogenic role for estrogen and ERα, through genomic- and non-
genomic-mediated activation of proliferation and survival pathways, in the genesis and 
progression of breast cancer (Spicer and Pike, 1993).  Mouse models genetically engineered to 
express ERα induce mammary adenocarcinoma formation (Tilli et al., 2003), whereas small 
inhibitor ribonucleic acid-mediated knockdown of ERα results in reduced proliferation and 
enhanced apoptosis in vitro and in vivo (Fu et al., 2006), confirming the critical role for this 
pathway in breast cancer.   
Several estrogen receptor (ER)-directed therapies have been developed to antagonize the 
oncogenic ERα function in pre- and post-menopausal women with locally advanced, recurrent, 
or metastatic cancer, including selective ER modulators such as tamoxifen, selective ER 
downregulators such as fulvestrant, selective nonsteroidal aromatase inhibitors such as 
anastrozole and letrozole, and steroidal aromatase inhibitors such as exemestane (Beslija et al., 
2009).  Although these therapies have demonstrated efficacy in the nonclinical and clinical 
settings, innate and acquired resistance remains a major challenge.   
Several mechanisms of resistance to ERα antagonists have been identified including: 
ERα/human epidermal growth factor receptor-2 (HER2) “crosstalk” (Shou et al., 2004), aberrant 
expression of ERα coactivators/corepressors (Osborne et al., 2003) and most recently, recurrent 
mutations in ERα (Li et al., 2013; Robinson et al., 2013; Toy et al., 2013).  The recurrent 
mutations in ERα, which are enriched in nearly 30% of endocrine-therapy resistant metastases, 
confer ligand-independent activation of the ERα pathway (Li et al., 2013; Robinson et al., 2013; 
Toy et al., 2013; Merenbakh-Lamin et al., 2013; Yu et al., 2014; Segal and Dowsett, 2014; 
Jeselsohn et al., 2014; Chandarlapaty et al., 2016), and are associated with more aggressive 
disease biology with shorter overall survival (OS) relative to WT ERα (Chandarlapaty et al., 
2016).  Furthermore, ERα mutations (ERαmut) confer partial resistance to existing classes of 
endocrine therapies, likely through promoting constitutive activity.   
The fact that current endocrine therapies are only partially effective in the ERαmut setting and 
that a significant proportion of endocrine-therapy resistant metastases continue to remain 

 
C O N FI D E N TI A L  
S T U D Y D R U G :  H 3 B -6 5 4 5  
P R O T O C O L A M E N D M E N T 9:   2 9  A U G 2 0 2 2  
Pa ge 7 0  of 1 6 0  
de pe n de nt o n E R α si g nali n g f or gr o wt h a n d s ur vi val i n dicates a c o nti n ui n g nee d t o de vel o p t he 
ne xt ge nerati o n of E R α a nta g o nists t hat ca n o verc o me a berra nt acti vities of b ot h wil d -t y pe 
( E Rα W T ) a n d m uta nt E Rα.  T o t his e n d, we i ntr o d uce herei n a n orall y bi oa vaila ble s mall 
m olec ule i n hi bit or t hat p ote ntl y i n hi bits b ot h E R α W T  a n d E R αm ut  f u ncti o n b y a n o vel m o de of 
acti o n.  
1. 3  
R ole of H 3 B - 6 5 4 5 i n Bre ast C a ncer 
H 3 B - 6 5 4 5 is a n oral, selecti ve, a n d c o vale nt s mall-m olec ule i n hi bit or of E R.  H 3 B - 6 5 4 5 bi n ds 
p ote ntl y t o E R α ( half- ma xi mal e x hi bit or y c o nce ntrati o n [ E C5 0], 
 a n d E R β ( E C5 0, 
 a n d is a p ote nt i n hi bit or of E R α c oacti vator recr uit me nt ( half-ma xi mal i n hi bit or y 
c o nce ntrati o n [I C 5 0], 
 de m o nstrati n g  
-f ol d selecti vit y o ver ot her n uclear 
h or m o ne rece pt ors teste d.  A d diti o n of H 3 B- 6 5 4 5 t o E R α W T  a n d E R αm ut  breast ca ncer cell li nes 
lea ds t o d ose- de pe n de nt i n hi biti o n of E R α- de pe n de nt tra nscri pti o n a n d c o nc o mita nt re d ucti o n i n 
cell pr oliferati o n.  Oral d osi n g of H 3 B - 6 5 4 5 i n mice lea ds t o i n hi biti o n of E R α- de pe n de nt 
tra nscri pti o n i n t he E Rα m ut  e x pressi n g s u bject- deri ve d xe n o graft m o del.  H 3 B- 6 5 4 5 als o lea ds t o 
d ose- de pe n de nt t u m or gr o wt h i n hi biti o n a n d/ or stasis i n b ot h E R α W T  a n d E R α m ut  xe n o graft 
m o dels at well -t olerate d d oses.  
T hese n o ncli nical fi n di n gs s u p p ort t he cli nical i n vesti gati o n of H 3 B- 6 5 4 5 i n s u bjects wit h E R-
p ositi ve ( E R α W T  a n d E R αm ut ) H E R 2-ne gati ve breast ca ncer.   
1. 3. 1  
N o ncli nic al P h ar m ac o ki netics  
T he p har mac o ki netics ( P K ) of H 3 B- 6 5 4 5 ha ve bee n c haracterize d i n S pra g ue Da wle y rats a n d 
c y n o m ol g us m o n ke ys, s pecies use d i n t he n o ncli nical safet y e val uati o n of H 3 B- 6 5 4 5.  T he P K of 
H 3 B -6 5 4 5 were c haracterize d b y a l o w cleara nce i n rats a n d a m o derate cleara nce i n m o n ke ys 
after i ntra ve n o us a d mi nistrati o n, wit h ter mi nal eli mi nati o n half -life (t½ ) of  
 h o urs i n rats a n d 
 h o urs i n m o n ke ys.  Re nal cleara nce was n ot a si g nifica nt c o ntri b ut or t o t he eli mi nati o n of 
H 3 B - 6 5 4 5 i n rats.   
I n b ot h s pecies, H 3 B- 6 5 4 5 a p pears t o be distri bute d well i nt o tiss ues wit h a v ol u me of 
distri b uti o n at stea d y state t hat e xcee ds t otal b o d y water.  I n b ot h s pecies, after oral d osi n g, t ma x  
was t y picall y bei n g ac hie ve d at   h o urs p ost d ose a n d H 3 B- 6 5 4 5 oral bi oa vaila bilit y was 
m o derate.  I n vitr o, H 3 B- 6 5 4 5 s h o we d si milar hi g h plas ma pr otei n bi n di n g i n rats, m o n ke ys, a n d 
h u ma ns 
 a n d was pre d o mi na ntl y meta b olize d b y h u ma n c yt oc hr o me P 4 5 0 
( C Y P) 3 A 4, f oll o we d b y C Y P 3 A 5 a n d C Y P 2 C 8. H 3 B- 6 5 4 5 is a s u bstrate of P- gl yc o pr otei n ( P-
g p), b ut n ot t he breast ca ncer resista nce pr otei n ( B C R P).  
1. 3. 2  
N o ncli nic al S afet y  
T he t o xic ol o g y pr o gra m f or H 3 B- 6 5 4 5 was desi g ne d t o s u p p ort t he oral ( P O) a d mi nistrati o n of 
H 3 B - 6 5 4 5 as a si n gle a ge nt gi ve n o nce dail y ( Q D) f or at least 2 8 da ys t o w o me n wit h metastatic 
breast ca ncer.  T he h y dr oc hl ori de salt f or m of H 3 B- 6 5 4 5 was use d i n all pi v otal safet y st u dies 
a n d is i nte n de d f or cli nical use i n P hase  1/ 2 trials.   
Rats a n d c y n o m ol g us m o n ke ys were c h ose n as a p pr o priate s pecies f or t o xic ol o g y st u dies base d 
o n meta b olic pr ofiles si milar t o t hat of h u ma ns, a n d o nl y fe male a ni mals were use d i n t o xic ol o g y 
st u dies base d o n t he i nte n de d s u bject p o p ulati o n.   
T he n o ncli nical t o xicit y fi n di n gs i n t he t o xic ol o g y st u dies i ncl u de d a ntici pate d p har mac ol o gical 
effects of E R i n hi biti o n, l y m p h o c yte de pleti o n i n peri p heral l y m p h oi d or ga ns, gastr oi ntesti nal 
C CI
C CI
C CI
C CI
C CI
C CI
C
C
C CI

 
C O N FI D E N TI A L  
S T U D Y D R U G :  H 3 B -6 5 4 5  
P R O T O C O L A M E N D M E N T 9:   2 9  A U G 2 0 2 2  
Pa ge 7 4  of 1 6 0  
2. 4  
P h ase 2 P ri m ar y O bjecti ve 
T he pri mar y o bjecti ve of t he P hase 2 p orti o n of t his st u d y is t o: 
● Esti mate t he efficac y of H 3 B - 6 5 4 5 i n ter ms of best o verall res p o nse rate, D o R, D C R, 
cli nical be nefit rate ( C B R), P F S, a n d O S i n all s u bjects wit h ( E R) - p ositi ve, H E R 2-
ne gati ve breast ca ncer a n d t h ose wit h a n d wit h o ut E R α m utati o n (i ncl u di n g a cl o nal E S R 1 
Y 5 3 7 S m utati o n). 
2. 5  
P h ase 2 Sec o n d ar y O bjecti ves  
T he sec o n dar y o bjecti ves of t he P hase 2 p orti o n of t his st u d y are t o: 
● F urt her c haracterize t he safet y of H 3 B - 6 5 4 5 i n t his s u bject p o p ulati o n. 
● F urt her c haracterize t he P K of H 3 B -6 5 4 5. At least s parse P K sa m ples will be c ollecte d 
fr o m all s u bjects o n st u d y. 
● E val uate t he effect of a hi g h -fat meal o n t he relati ve bi oa vaila bilit y of H 3 B- 6 5 4 5. 
● Assess t he effect of H 3 B - 6 5 4 5 o n ser u m b o ne t ur n- o ver mar kers, na mel y b o ne-s pecific 
al kali ne p h os p hatase ( B S A P, f or oste oclast meta b olis m), a mi n o- ter mi nal pr o pe pti de of 
t y pe 1 c olla ge n ( PI N P, f or b o ne f or mati o n), a n d C-ter mi nal cr oss-li n ki n g tel o pe pti de of 
t y pe 1 c olla ge n ( C T X, f or b o ne res or pti o n). 
● Assess t he effect of H 3 B - 6 5 4 5 o n e n d o metrial t hic k ness a n d uteri ne v ol u me.  T his 
o bjecti ve will be assesse d i n a s u b gr o u p of w o me n wit h i ntact uteri.  
2. 6  
P h ase 2 E x pl or at or y O b jecti ves 
T he e x pl orat or y o bjecti ves of t he P hase 2 p orti o n of t his st u d y are t o: 
3.  
S T U D Y S U B J E C T P O P U L A TI O N A N D DI S C O N TI N U A TI O N  
T he st u d y will i ncl u de w o me n wit h E R- p ositi ve, H E R 2 -ne gati ve, l ocall y a d va nce d or metastatic 
breast ca ncer.  I n A me n d me nt 6 ( a n d s u bse q ue nt a me n d me nts), p ote ntial s u bjects will si g n a 
prescree ni n g c o nse nt t o pr o vi de a w h ole bl o o d sa m ple t o perf or m E S R 1  m utati o n a nal ysis. 
Eli gi ble s u bjects m ust ha ve E S R 1 Y 5 3 7 S m utati o n at allelic fre q ue nc y ( A F) ≥0. 5 %, i n t he 
C CI
C CI

 
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absence of D538G mutation at the same AF value.  This will be determined by central laboratory 
assessment prior to signing the main study consent, unless prior authorization has been received 
by the Sponsor, based on local mutation analysis. 
Eligible subjects must have progressed on their most recent therapy.  The investigator or 
designee must ensure that only subjects who meet all the following inclusion criteria and none of 
the exclusion criteria are enrolled in the study. 
3.1 
Inclusion Criteria 
Subjects must meet the following criteria in order to be included in the research study: 
1. Prescreening:  Subjects must have clonal ESR1 Y537S mutation at AF ≥0.5%, in the absence 
of ESR1 D538G at AF ≥0.5%, as determined at prescreening by a Sponsor-designated central 
laboratory from a Nucleic Acids Whole Blood (plasma cfDNA) sample.  
2. Subject has signed informed consent form (ICF) before any trial-related activities and 
according to local guidelines.  Main ICF may only be signed once positive mutation status is 
confirmed by a sponsor-designated central laboratory, unless prior authorization has been 
received by the Sponsor, based on local mutation analysis.   
3. Only females are eligible.  Menopausal status: 
 
− Postmenopausal defined by: 
 
a) Prior bilateral oophorectomy, 
 
b) Age ≥60 years, or 
 
c) Age <60 years and amenorrhea for 12 or more months (in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression); or a follicle-
stimulating hormone value >40 mIU/mL and an estradiol value <40 pg/mL 
(140 pmol/L) or in postmenopausal ranges per local reference ranges 
Or  
− Premenopausal or perimenopausal concurrently given a luteinizing hormone-releasing 
hormone (LHRH) agonist starting at least 4 weeks before the start of trial therapy and is 
planned to continue LHRH during the study.    
4. Subject has a histologically and/or cytologically confirmed diagnosis of ER-positive breast 
cancer by local laboratory.  
5. Subject has HER2-negative breast cancer as defined by American Society for Clinical 
Oncology-College of American Pathologists guidelines (Wolff et al., 2013).   
6. Subject must have progressed on the most recent therapy.   
7. Prior therapy for breast cancer in the advanced/metastatic setting must have included a 
minimum of: 
a) two prior hormonal therapies, or  
b) one prior hormonal therapy and one prior chemotherapy regimen, or  
c) one prior hormonal therapy and a CDK4/6 inhibitor.   

 
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Note: Subjects may have received treatment for brain metastases, but must be neurologically 
stable, completed radiotherapy and off corticosteroids for at least one month prior to starting 
trial therapy.  
Note:  Subjects enrolled under Amendment 6 (and subsequent amendments) must have 
received prior therapy including at least one prior hormonal therapy and a CDK4/6 inhibitor. 
Up to one prior chemotherapy in the metastatic setting is allowed. 
8. Subject must have at least one biopsiable lesion in the Phase 1 portion. In the Phase 2 part of 
the trial subjects must also have either:  
a) at least one measurable lesion as per Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1, or  
b) at least one predominantly lytic bone lesion.   
Note:  Subjects enrolled under Amendment 6 (and subsequent amendments) must have at 
least one measurable lesion as per RECIST 1.1. 
9. Subject must be willing to undergo tumor biopsies prior to treatment and on Cycle 2 Day 1.  
In the Phase 2 part of the trial, subjects with bone-only disease, or subjects for whom a 
biopsy is contra-indicated, may opt out of providing tumor biopsies following investigator 
concern and direct discussion and approval from the Sponsor.   
Note: A subset of subjects in Phase 2 will be required to provide tumor tissue until tumor 
pairs have been collected from at least 15 subjects with ERαWT and 15 subjects with ERαmut 
(determined retrospectively by Sponsor-designated central laboratory test).  
Note:  For subjects enrolled under Amendment 6 (and subsequent amendments), a recent 
archival tumor tissue obtained within the 6 months prior to enrollment or a fresh tumor 
biopsy must be provided. A second biopsy after initiating trial therapy is not required. 
10. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 
or 1. 
11. Subject has adequate bone marrow and organ function, as defined by the following 
laboratory values: 
− Absolute neutrophil count ≥1.5 × 109/L 
− Platelets ≥100 × 109/L 
− Hemoglobin ≥9.0 g/dL (may have been transfused). 
− Potassium, sodium, calcium (corrected for serum albumin) and magnesium <National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Grade 2 
−  Cockcroft-Gault based creatinine clearance ≥35 mL/min 
− Serum albumin ≥3.0 g/dL (≥30 g/L) 
− In the absence of liver metastases, AST, and ALT should be below 3.0 × upper limit of 
normal (ULN).  If the subject has liver metastases, ALT and AST should be below 5.0 × 
ULN.  
− Total serum bilirubin <ULN. For subjects with documented Gilbert’s syndrome, total 
serum bilirubin <2.5 × ULN 

 
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Page 77 of 160 
12. Age ≥18 years 
13. Willingness and ability to comply with study and follow-up procedures 
14. Ability to understand the nature of this study and give written informed consent 
3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from study entry: 
1. Subject with bone-only disease (Phase 1 only).   
2. Phase 2 subjects may have predominantly lytic bone only disease.  
Note:  Subjects enrolled under Amendment 6 (and subsequent amendments) must have at 
least one measurable lesion as per RECIST 1.1. 
3. Subject with inflammatory breast cancer. 
4. Subject has received more than one prior chemotherapy regimen for metastatic disease 
(Phase 2 only). 
5. Subject has had prior antineoplastic therapy within 14 days prior to starting study drug.   
6. Subject is currently receiving or has received systemic corticosteroids ≤2 weeks prior to 
starting study drug, or has not fully recovered from side effects of such treatment.  
Note: The following uses of corticosteroids are permitted: single doses, topical applications 
(eg, for rash), inhaled sprays (eg, for obstructive airways diseases), eye drops or local 
injections (eg, intra-articular). 
7. Subject has received radiotherapy ≤4 weeks or limited field radiation for palliation ≤2 
weeks prior to starting study drug, and who has not recovered to Grade 1 or better from 
related side effects of such therapy (with the exception of alopecia) and/or for whom ≥30% 
of the bone marrow was irradiated. 
8. Major surgical procedures ≤14 days of beginning study drug, or minor surgical procedures 
≤7 days, or has not recovered from major side effects.  No waiting required following port-
a-cath placement.   
9. Subject has active cardiac disease or a history of cardiac dysfunction, including any of the 
following: 
− History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 
12 months prior to study entry 
− History of documented congestive heart failure (New York Heart Association functional 
classification III or IV) 
− Documented cardiomyopathy 
− Subject has a left ventricular ejection fraction <50% as determined by multiple-gated 
acquisition (MUGA) scan or echocardiogram 
− History of any cardiac arrhythmias, eg, ventricular, supraventricular, nodal arrhythmias, 
or conduction abnormality in the previous 12 months 
− A prolonged QT interval corrected for HR using Fridericia’s formula (QTcF) >450 msec 
as demonstrated by a repeated ECG; a history of risk factors for Torsade de pointes (eg, 

 
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STUDY DRUG:  H3B-6545 
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Page 78 of 160 
heart failure, hypokalemia, and family history of long QT syndrome); or the use of 
concomitant medications that prolonged the QTcF interval 
− Subject has a resting pulse rate <60 bpm. 
10. Subject has impairment of GI function or GI disease that may significantly alter the 
absorption of H3B-6545 (eg, ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, or small bowel resection).  
11. Subject has a known hypersensitivity to any of the excipients of H3B-6545. 
12. Subject has a known history of human immunodeficiency virus infection or hepatitis C 
virus, or requires treatment with protease inhibitors (testing not mandatory). 
13. Subject has any other concurrent severe and/or uncontrolled medical condition that would, 
in the investigator’s judgment, contraindicate subject participation in the clinical study (eg, 
chronic pancreatitis, active hepatitis, etc). 
14. Subject that received in the 7 days prior to the administration of study drug or is currently 
receiving any of the following medications (see Appendix H and Appendix I for details): 
a. Known strong inducers or inhibitors of CYP3A4 or P-gp  
b. Medications that have a known risk to prolong the QT interval or induce Torsades de 
Pointes  
c. Medications that have a narrow therapeutic window and are predominantly metabolized 
through CYP2C8, CYP2C9, CYP2C19, or CYP3A4.  
d. Medications that have a narrow therapeutic window and are BCRP substrates. 
e. Herbal preparations/medications.  These herbal medications include, but are not limited 
to, St. John’s wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone 
(DHEA), yohimbe, saw palmetto, and ginseng.   
15. Any adverse event related to previous therapies for breast cancer that has not resolved to 
≤Grade 1.  
16. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin 
[hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]).  
A separate baseline assessment is required if a negative screening pregnancy test was 
obtained more than 72 hours before the first dose of study drug. 
17. Females of childbearing potential who: 
● Had unprotected sexual intercourse within 30 days before study entry and who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study period or for 28 days 
after study drug discontinuation. 
● Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexual activity during the study period or for 28 days after study 
drug discontinuation. 

 
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● Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use the 
same contraceptive during the study or for 28 days after study drug discontinuation. 
All females will be considered to be of childbearing potential unless they are postmenopausal 
[amenorrheic for at least 12 consecutive months, in the appropriate age group, and without 
other known or suspected cause] or have been sterilized surgically [ie, bilateral tubal ligation, 
total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before 
dosing]). 
18. Alcohol dependency within 6 months before study entry.  
19. Subject has a concurrent malignancy or malignancy within 3 years of enrollment, with the 
exception of adequately treated basal or squamous cell carcinoma, non-melanomatous skin 
cancer, or curatively resected cervical cancer. 
20. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol.  
21. Subjects with advanced, symptomatic visceral spread, that are at risk of life-threatening 
complications in the short term. 
22. Subjects with abnormal coagulation profiles, or any history of coagulopathy within 6 
months prior to the first dose of study drug, including history of deep vein thrombosis 
(DVT) or pulmonary embolism.  
Note: subjects (except pre/perimenopausal women) with adequately treated catheter-related 
venous thrombosis occurring more than one month prior to the first dose of study drug will 
be allowed to participate. 
23. Prothrombin time/international normalized ratio (INR) >1.5 times the upper limit of 
normal (ULN) or outside therapeutic range if receiving anticoagulation that would affect 
the prothrombin time/INR.  
Note: subjects (except pre/perimenopausal women) treated with an anticoagulant, that 
affects prothrombin time/INR, for a stable and allowed medical condition (eg, well 
controlled atrial fibrillation), will be allowed to participate, provided dose and coagulation 
parameters (as defined by local standard of care) are stable for at least one month prior to 
the first dose of study drug (hospital data prior to date of signature of the ICF will be used if 
necessary). 
3.3 
Discontinuation from Study Treatment 
Subjects will be discontinued from study treatment for any of the following reasons: 
● Disease progression 
● Irreversible or intolerable toxicity or abnormal laboratory values thought to be related to 
drug toxicity 
● Cycle 1 DLT 
● Conditions requiring therapeutic intervention not permitted by the protocol 
● Intercurrent illness (at the investigator’s discretion 

 
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PROTOCOL AMENDMENT 9:  29 AUG 2022 
Page 80 of 160 
● Inability of the subject to comply with study requirements, or subject is lost to follow-up 
● Subject requests to discontinue treatment 
● Subject withdraws consent from the study 
● Pregnancy 
After discontinuation from protocol treatment, subjects must be followed for adverse events 
(AEs) for 28 days after their last dose of study drug.  All new AEs, including serious AEs 
(SAEs), occurring during this period must be reported and all SAEs must be followed until 
resolution, unless, in the opinion of the investigator, these events are not likely to improve 
because of the underlying disease.  In this case, the investigator must record his or her reasoning 
for this decision in the subject’s medical records and indicate on the AE pages that the outcome 
is not resolved on the Electronic Case Report Form (eCRF). 
All subjects who have Grade 3 or 4 laboratory abnormalities (per NCI CTCAE v4.03) at the time 
of discontinuation must be followed until the laboratory values have returned to Grade 1,2 or 
baseline for the subject, unless it is, in the opinion of the investigator, not likely that these values 
are to improve.  In this case, the investigator must record his or her reasoning for making this 
decision in the subject’s medical records and indicate on the AE pages that the outcome is not 
resolved on the eCRF. 
4. 
STUDY REGISTRATION 
The subject must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, and the potential benefits, alternatives, side effects, risks, 
and discomforts.  Human protection committee (Institutional Review Board [IRB]/Ethics 
Committee [EC]) approval of this protocol and consent form is required.  Eligible subjects who 
wish to participate in the study will be enrolled into the study. 
In Phase 1 of the study, the Sponsor or designee will notify sites via e-mail when a new Dose 
Level/Cohort is opened and enrollment slot(s) becomes available.  As soon as a potential subject 
has been identified following the slot availability announcement, sites will notify the Sponsor or 
designee via email.  Sponsor or designee will reply to verify an available slot, and reserve the 
slot for the subject.  Upon receipt of confirmation, sites will have 5 business days to consent the 
identified subject.  If a subject is not consented within 5 business days, the slot will open to all 
sites for enrollment.   
Sponsor or designee will also communicate to all sites via e-mail when a cohort has been fully 
reserved and screening is closed.  This communication may also include language that describes 
any opportunity for additional screening should a subject screen-fail and/or meet replacement 
criteria. 
Once a site receives confirmation of successful slot reservation, the subject may be consented 
and screening procedures may begin.  All screening procedures must be completed as outlined in 
the protocol, and the Principal Investigator (PI) must assess and confirm eligibility of the subject 
prior to requesting enrollment. Once eligibility is confirmed by the PI and Sponsor or designee, 
subject registration and dose level assignment will be performed by the Sponsor or designee.  
The Sponsor or designee will document the subject identification number, dose level, and date of 

 
C O N FI D E N TI A L  
S T U D Y D R U G :  H 3 B -6 5 4 5  
P R O T O C O L A M E N D M E N T 9:   2 9  A U G 2 0 2 2  
Pa ge 8 9  of 1 6 0  
N o i nter ve nti o ns will be perf or me d o n a n y as y m pt o matic uteri ne a b n or malities t hat are  detecte d 
at baseli ne.  A si milar a p pr oac h was a d o pte d f or t he assess me nt of t he effect of f ul vestra nt o n t he 
e n d o metri u m ( M orales et al. , 2 0 0 9). 
5. 3  
Tre at me nt Pl a n  
H 3 B- 6 5 4 5  
Or al ( P O) c o nti n u o us d ail y d osi n g  
T he R P 2 D  was deter mi ne d t o be  
 (secti o n 1. 5. 1 Rati o nale f or Rec o m me n de d P hase 2 
D ose ). 
All s u bjects e nteri n g t his st u d y will recei ve H 3 B - 6 5 4 5 P O Q D  base d o n data e val uati o n fr o m t he 
pri or c o h ort(s).  Wit h t he e xce pti o n of t he fe d d oses of t he f o o d- effect c o h ort (eit her C ycle 1 Da y 
1 5 or C ycle 1 Da y 2 2), s u bjects will be i nstr ucte d t o ta ke t he d ose o n a n e m pt y st o mac h ( n o f o o d 
2 h o urs bef ore or 2 h o ur s after d ose) at a p pr o xi matel y t he sa me ti me eac h m or ni n g.  Ca ps ules 
s h o ul d be s wall o we d w h ole.  If t he s u bject misses a d ose of st u d y dr u g b y less t ha n 8 h o urs, t he 
s u bject s h o ul d ta ke t he d ose as s o o n as p ossi ble.  If a d ose is misse d b y greater t ha n 8 ho urs, t he 
s u bject s h o ul d s ki p t he misse d d ose a n d ta ke t he ne xt d ose as sc he d ule d. 
F or A me n d me nt 6 a n d s u bse q ue nt a me n d me nts, s u bjects ma y ta ke t heir d ose of H 3 B- 6 5 4 5 
irres pecti ve of f o o d c o n diti o ns; u n der fasti n g or after a meal. 
If v o miti n g occ urs after ta ki n g t he st u d y me dicati o n, t he s u bject s h o ul d be i nstr ucte d n ot t o 
reta ke t he d ose.  S u bjects s h o ul d ta ke t he ne xt sc he d ule d d ose of H 3 B- 6 5 4 5.  If v o miti n g 
persists, t he s u bject s h o ul d c o ntact t he i n vesti gat or.  
N o r o uti ne pr o p h ylactic a ntie metics will be  gi ve n.  H o we ver, t he use of pal o n osetr o n, 
pr oc hl or perazi ne, pr o met hazi ne, a n d c yclizi ne f or ma na ge me nt of na usea a n d v o miti n g is 
all o we d.  T he use of o n da nsetr o n a n d gra nisetr o n is n ot per mitte d beca use of t heir p ote ntial t o 
pr ol o n g Q T i nter val. 
Treat me nt  D urati o n 
T he Pri mar y C o m pleti o n Date f or t he st u d y is defi ne d as t he date of t he last visit f or assess me nt 
of t he pri mar y e n d p oi nt of t he last s u bject o n t he trial.  
S u bjects will be e val uate d f or t o xicit y at t he start of eac h c ycle ( 2 8 cale n dar da ys).  E v er y 2 
c ycles, a detaile d assess me nt will occ ur wit h i ma gi n g, la b orat or y c he mistries, a n d t u m or mar kers 
as defi ne d i n A p pe n di x E .  Su bjects will c o nti n ue o n treat me nt u ntil pr o gressi o n, as defi ne d i n 
A p pe n di x G  or int olera nce t o si de effects, or wit h dra wal of c o nse nt.  
5. 4  
C o nc o mit a nt Me dic ati o ns  
S u bjects will be i nstr ucte d n ot t o ta ke a n y a d diti o nal me dicati o ns d uri n g t he c o urse of t he st u d y 
wit h o ut pri or c o ns ultati o n wit h t he researc h tea m.  At eac h visit, t he s u bject w ill be as ke d a b o ut 
a n y ne w me dicati o ns s he is ta ki n g or has ta ke n after t he start of t he st u d y dr u g.   
5. 4. 1  
Per mitte d C o nc o mit a nt Me dic ati o ns  
T he use of pal o n osetr o n, pr oc hl or perazi ne, pr o met hazi ne, a n d c yclizi ne f or ma na ge me nt of 
na usea a n d v o miti n g is all o we d.   T he use of o n da nsetr o n a n d gra nisetr o n is n ot per mitte d 
beca use of t heir p ote ntial t o pr ol o n g Q T i nter val.  
Use of a ntaci ds is all o we d . 
C CI

 
CONFIDENTIAL 
STUDY DRUG:  H3B-6545 
PROTOCOL AMENDMENT 9:  29 AUG 2022 
Page 90 of 160 
Medications may be administered for maintenance of existing conditions prior to study 
enrollment or for a new condition that develops while on study, including but not limited to the 
following: 
● Growth Factors:  Subjects receiving recombinant erythropoietin or darbepoietin-α prior to 
study start may continue to receive pretreatment doses.  
Following initiation of study treatment, the use of erythropoietic and granulocyte growth 
factors in accordance with local practice or American Society of Clinical Oncology 
guidelines may be implemented at the discretion of the treating physician.   
● Bisphosphonate use, as recommended according to practice guidelines as long as the 
subject has been on a stable dose for >30 days prior to study enrollment   
● Receptor activator of nuclear factor kappa-B ligand inhibitor use, as recommended 
according to practice guidelines, as long as the subject has been on a stable dose >30 days 
prior to study enrollment 
● Anticoagulation with warfarin and derivatives will not be permitted.  However, a 
maximum daily dose of 1 mg of warfarin will be permitted for port line patency.  Should a 
thrombotic event occur while the subject is receiving treatment, the subject may continue, 
but low molecular weight heparin, dabigatran, or edoxaban will be the preferred treatment.   
● Subjects who develop hyperglycemia during the study should be treated as determined by 
the treating clinician, according to the American Diabetes Association guidelines.   
Other medications considered necessary for the subject’s safety and well-being may be given at 
the discretion of the investigator with the exception of those listed in Section 5.4.2 or 
Appendix H and Appendix I. 
5.4.2 
Prohibited Concomitant Medications 
The following treatments are prohibited while on this study: 
● No other investigational therapy should be given to subjects.  No anticancer agents other 
than the study medications should be given to subjects.  If such agents are required for a 
subject, then the subject must first be withdrawn from the study. 
● In vitro, H3B-6545 is a reversible and time-dependent inhibitor of CYP2C8, 2C9, 2C19, 
and CYP3A4.  Drugs with narrow therapeutic index and known to be metabolized by 
CYP2Cs or CYP3A4 are not permitted because of the inherent potential risk of either 
reduced activity or enhanced toxicity of the respective concomitant medication 
(Appendix H).   
● H3B-6545 is a substrate of CYP3A4 and P-gp, thus medications that are strong inducers 
or inhibitors of CYP3A4 or P-gp (Appendix H) should be avoided.  For the most updated 
information, visit the following Web address:  http://medicine.iupui.edu/clinpharm/ddis/. 
● Due to a potential drug-drug interaction (DDI), BCRP substrates with narrow therapeutic 
index are not permitted because H3B-6545 is an inhibitor of BCRP (but not a substrate) 
(Appendix H). 
● If, after a subject has been enrolled, she requires the concomitant use of any of the 
medications that may cause QTc interval prolongation, then H3B-6545 must be held while 

 
C O N FI D E N TI A L  
S T U D Y D R U G :  H 3 B -6 5 4 5  
P R O T O C O L A M E N D M E N T 9:   2 9  A U G 2 0 2 2  
Pa ge 9 1  of 1 6 0  
t he s u bject recei ves t he c o nc o mita nt me dicati o n (A p pe n di x I ).  Res u m pti o n of treat me nt 
wit h H 3 B - 6 5 4 5 ma y be c o nsi dere d f oll o wi n g disc o nti n uati o n a n d was h o ut (at least 5 half-
li ves) of t he c o nc o mita nt me dicati o n if t he s u bject has n ot pr o gresse d a n d is a gree d u p o n 
wit h t he S p o ns or.  E xcl u de d me dicati o ns t hat ma y ca use Q Tc i nter val pr ol o n g ati o n are 
als o liste d a n d u p date d at t he f oll o wi n g We b a d dress: htt p://cre di ble me ds. or g. 
● Her bal pre parati o ns/ me dicati o ns are n ot all o we d t hr o u g h o ut t he st u d y.  T hese her bal 
me dicati o ns i ncl u de, b ut are n ot li mite d t o St. J o h n’s w ort, ka va, e p he dra ( ma h ua n g), 
gi n g k o bil o ba, D H E A, y o hi m be, sa w pal mett o, a n d gi nse n g.  S u bjects s h o ul d st o p usi n g 
t hese her bal me dicati o ns 7 da ys pri or t o first d ose of st u d y dr u g.  
● S yste mic c ortic oster oi ds are n ot all o we d d uri n g t he st u d y.  N ote: T he f oll o wi n g uses of 
c ortic oster oi ds are per mitte d: si n gle d oses, t o pical a p plicati o ns (e g , f or ras h), i n hale d 
s pra ys (e g, f or o bstr ucti ve air wa y diseases), e ye dr o ps, or l ocal i njecti o ns (e g, i ntra-
artic ular).  S h ort c o urses of s yste mic c ortic oster oi ds ma y be c o nsi dere d i n c o ns ultati o n 
wit h t he Me dical M o nit or.  
6.  
D O S E M O DI FI C A TI O N S  
If a n y t o xicit y occ urs, it will be gra de d utilizi n g t he N CI C T C A E v 4. 0 3,  an d a p pr o priate 
s u p p orti ve care treat me nt will be a d mi nistere d t o decrease t he si g ns a n d s y m pt o ms t here of.  
D ose a dj ust me nts will be base d o n t he or ga n s yste m e x hi biti n g t he greatest de gree of t o xicit y. 
6. 1  
D ose M o dific ati o ns D ue t o T o xicit y 
D ose re d ucti o ns or h ol ds a n d i nitiati o n of s u p p orti ve care are all o we d as cli nicall y i n dicate d b y 
t he treati n g p h ysicia n.  S u bjects w h o re q uire a treat me nt i nterr u pti o n d ue t o dr u g-relate d t o xicit y 
f or m ore t ha n 4 wee ks will disc o nti n ue st u d y treat me nt.  Treat me nt wit h H 3 B- 6 5 4 5 will be hel d 
i n a n y s u bject e x perie nci n g a d ose m o dif yi n g e ve nt as descri be d i n Secti o n 5. 1. 2  at a n y ti me 
d uri n g t he st u d y.  S u bjects w h o e x pe rie nce a D L T i n P hase 1 C ycle 1 acc or di n g t o Ta ble 2  ab o ve 
will be disc o nti n ue d fr o m treat me nt u nless ot her wise s pecifie d i n writi n g fr o m t he S p o ns or.  
D ose m o dificati o ns f oll o wi n g a d ose m o dif yi n g e ve nt will be acc or di n g t o Ta ble 3  a n d Ta ble 4  
bel o w. 
T w o d ose re d ucti o ns 
 f or 
t o xicit y will be all o we d.  I n a d diti o n, d ose re d ucti o ns will als o be all o we d base d o n cli nical 
j u d g me nt of t he treati n g p h ysicia n.  If persiste nt t o xicit y occ urs des pite t w o d ose re d ucti o ns, t he 
s u bject will disc o nti n ue st u d y treat me nt.   
 
C CI

 
CONFIDENTIAL 
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Page 95 of 160 
7. 
STUDY ASSESSMENTS AND EVALUATIONS 
7.1 
Overview 
All subjects should visit the study site on the days specified within this protocol.  The complete 
Schedule of Assessments for this study is shown in Appendix D, Appendix E, and Appendix F.    
With Sponsor approval, in certain situations (eg, due to the COVID pandemic), and as per local 
regulations, certain assessments and study related activities may be performed remotely. 
Prescreening Visit - starting from Amendment 6 (or subsequent amendments):  
If all the following criteria are satisfied: 
a) An ESR1 mutation status report is already available for the subject from one of the 
sponsor-designated laboratories based on cfDNA test report 
b) The blood sample for this report was drawn within 3 months of the date of main study 
consent 
c) The report clearly shows ESR1 Y537S mutation at an AF ≥0.5% in absence of ESR1 
D538G at AF ≥0.5% (that is, clonal Y537S) 
Then the subject may proceed to sign the main consent of the study and no prescreening blood 
sample is needed for re-testing the ESR1 mutation status. 
Otherwise, potential subjects will be asked to sign a prescreening consent in order to determine if 
their tumor carries a clonal ESR1 Y537S mutation. Only after confirmation of the presence of a 
ESR1 Y537S mutation at an AF ≥0.5% and absence of ESR1 D538G at AF ≥0.5% from a 
sponsor-designated laboratory will the subject be invited to sign the main study consent.   
-During the Prescreening Visit:  
● Pre-screening consent for the collection of a whole blood sample for cfDNA testing - 
● Collection of a whole blood sample for cfDNA testing  
If a redraw is necessary due to quality concerns at the analysis laboratory (eg, not acceptable for 
analysis), an additional sample may be collected. 
-Study Informed Consent (Visit 1): 
In addition to the 2 previous scenarios, subjects may sign the main consent form if they have 
clonal ESR1 Y537S mutation, as defined above, based on a local laboratory report, but may not 
be dosed on C1D1 until their mutational status has been confirmed by a sponsor-designated 
cfDNA test from a blood sample obtained during the screening period. 
Informed consent (Visit 1) must be obtained ≤28 days prior to initiation of treatment and before 
any protocol-specific procedures are performed.  The screening physical examination, medical 
history, ECOG PS, complete blood counts (CBCs), differential and platelets, comprehensive 
metabolic profile (CMP) including liver (alkaline phosphatase [ALP], AST, and ALT) and 
thyroid function (thyroid-stimulating hormone [TSH] and Free T4) tests, urinalysis, and 
prothrombin time/partial thromboplastin time (PT/PTT) using international normalized ratio 
(INR) should be done ≤7 days prior to initiation of treatment (Study Visit 2).   
Whole blood and a pre-treatment biopsy will be collected at baseline for biomarker analysis.  
Subjects must be willing to undergo tumor biopsies prior to treatment and on Cycle 2 Day 1.  In 

 
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the Phase 2 part of the trial, subjects with bone-only disease, or subjects for whom a biopsy is 
contra-indicated, may opt out of providing tumor biopsies following investigator concern and 
discussion and approval from the Sponsor.  A urine or serum pregnancy test must be performed 
within 72 hours of Cycle 1 Day 1 for all pre-and peri-menopausal subjects.  Computed 
tomography (CT) scans (Visit 1) should be performed ≤28 days prior to initiation of treatment 
(Cycle 1 Day 1).  A bone scan (99m-technetium-based scintigraphy, whole-body bone magnetic 
resonance imaging (MRI), or 18F-sodium fluoride position emission tomography [NaF PET]) to 
establish a baseline should be performed prior to first dose of study drug (a historical bone scan 
performed within 6 weeks prior to the first dose is acceptable), and as clinically indicated.  
Lesions identified on bone scans should be followed with cross-sectional imaging. 
The prescreening and screening assessments described in Appendix D and Appendix E, 
respectively, will be collected, reviewed, and determined to be acceptable by the site PI or 
designee after obtaining informed consent prior to the initiation of treatment. 
A cycle of treatment is scheduled to last 4 weeks (28 calendar days).   
Multiple procedures may be scheduled at the same time point relative to H3B-6545 dosing.  
Priority should be given to PK collection at the time specified.  Vital signs and triplicate 
electrocardiogram (ECG) assessments should be performed prior to specimen collections. 
7.2 
Baseline Study Assessments (Visit 2) 
The following information will be collected and procedures will be performed for each subject at 
screening ≤7 days prior to initiation of treatment, unless otherwise noted: 
● Written ICF prior to any other study-related procedures (≤28 days prior to initiation of 
treatment).  
● Assessment of inclusion/exclusion criteria. 
● Medical history, including cancer history, eg, date and stage at diagnosis, hormone 
receptor status, extent of disease, and all previous anti-cancer treatments, response to such 
treatments, best overall response, and the Time to Progression (TTP) (per RECIST 1.1) for 
the most recent prior therapy. 
● A bone scan (99m-technetium-based scintigraphy, whole-body bone MRI, or NaF PET) 
will be performed to establish a baseline (a historical bone scan performed within 6 weeks 
prior to the first dose of study drug is acceptable), and as clinically indicated.  Lesions 
identified on bone scans should be followed with cross-sectional imaging. 
● Physical examination, measurements of height (first visit only), weight, and vital signs 
(resting HR, BP, respiratory rate [RR], and oral temperature). 
● ECOG PS (Appendix A). 
● 12-lead ECG in triplicate. 
● Echocardiogram/MUGA assessment (≤28 days prior to initiation of treatment). 
● Review and record concomitant medications (all concomitant medications taken within 
28 days prior to Cycle 1 Day 1 should be documented in the eCRF). 
● CBC including hemoglobin, hematocrit, white blood count (WBC) with 5-part differential, 
and platelets plus reticulocytes. 

 
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● CMP to include:  glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, 
chloride, calcium, magnesium, phosphorus, lactate dehydrogenase, carbon dioxide (CO2), 
ALP, AST, ALT, TSH, free T4, total bilirubin, total protein, and albumin.  
● PT/PTT. 
● Urine testing dipstick. 
● Serum or urine pregnancy test for all pre-and perimenopausal subjects (must be performed 
within 72 hours prior to the initiation of treatment). 
● Archived tumor tissue if available (see Section 7.8.2).  For subjects enrolled under 
Amendment 6 (or subsequent amendments), a recent archival tumor tissue obtained within 
6 months prior to enrollment or a fresh tumor biopsy must be provided. A second biopsy 
after initiating trial therapy is not required. 
● Whole blood for nucleic acids (cfDNA).  
● Tumor biopsy (unless contraindicated) 
● Transvaginal ultrasound (subjects in the Phase 2 endometrium sub-study only)  
(≤14 days prior to initiation of treatment). 
● Disease assessment:  CT scan of chest, abdomen, and pelvis (≤28 days prior to initiation 
of treatment).  All study imaging for tumor assessments will be sent to an imaging core 
laboratory designated by the Sponsor for review of quality, and archived for potential 
independent review. 
 
7.3 
Study Treatment Assessments  
7.3.1 
Cycle 1 Days 1 (Visit 3), 8 (Visit 4), 15 (Visit 5), and 22 (Visit 6)  
For all subjects and all visits, unless otherwise stated: 
● Physical examination, measurements of weight, and vital signs (resting HR, BP, RR, and 
oral temperature) (Day 1 only). No need to repeat physical exams on Cycle 1 Day 1 if the 
baseline physical exam was performed ≤72 hours. 
● ECOG PS (Day 1 only).  
● 12-lead ECG or continuous Holter monitor:  
Phase 1: continuous Holter monitoring must begin at least 1 hour prior to dose on Cycle 
1, Days 1 and 15, and continue through at least 24 hours post-dose.  For convenience, 
Holter monitoring may begin up to 12 hours prior to dosing on Cycle 1, Day 1 or Day 15.  
Phase 2:  in place of Holter monitoring, a 12-lead ECG will be performed in triplicate on 
Cycle 1, Days 1 and 15.  
o If sinus bradycardia is observed at any point during treatment (from ECG or other 
clinical assessment), it is recommended the subject undergo a stress test per 
institution policy. A stress test is recommended to be done only once for each 
subject who has under 60 beats per minute (while on treatment) and more than a 

 
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20 percent reduction from baseline in beats per minute. The stress test should be 
triggered by the previous two cardiac observations at rest. 
● Assessment and recording of AEs (from the time informed consent was signed).  
● Review and recording of concomitant medication (all concomitant medications taken 
within 28 days prior to Cycle 1 Day 1 should be documented in the eCRF) 
● CBC including hemoglobin, hematocrit, WBC with 5-part differential, and platelets plus 
reticulocytes. Do not repeat on Cycle 1 Day 1 if it is within 72 hours of baseline. 
● CMP.  Do not repeat on Cycle 1 Day 1 if it is within 72 hours of baseline. 
● PT/PTT. 
● Urine testing dipstick. 
● Phase 1 – PK samples for all subjects (Days 1 and 15: collected at time points 0 (pre-
dose), 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, and 24 hr post-dose; Days 8 and 22: 
collected pre-dose only) (See Section 7.7).   
● Phase 2 – PK samples for subjects in the food-effect sub-study: Days 15 and 22: collected 
at time points 0 (pre-dose), 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, and 24 hr post-dose) 
(See Section 7.7).   
● Phase 2 – All other subjects: Sparse PK samples will be performed on Day 15 following 
one of three schedules, assigned sequentially:  
o Schedule 1: pre-dose (0 hr), 0.5 hr, and 6 hr post-dose 
o Schedule 2: pre-dose (0 hr), 2 hr, and 8 hr post-dose 
o Schedule 3: 1 hr, 4 hr, 24 hr post-dose (See Section 7.7).  Plasma for cfDNA 
(nucleic acids) on Days 1 and 15. 
o For subjects enrolled under Amendment 6 (and subsequent amendments), PK 
samples will be collected on Days 1 and 15 at pre-dose (0 hr) and at 1, 2, 4, and 6 
hours post-dose.   
● Whole blood for pharmacogenetics (PG) on Day 1 only.  
● Blood sample for markers of bone resorption and formation markers (anytime from 
screening period up to Day 1 pre-dose).  
● H3B-6545 administration.  
● Schedule next visits for the cycle (Day 1 only). 
7.3.2 
Cycle 2 Days 1 (Visit 7) and 15 (Visit 8)  
Both visits unless otherwise stated:  
● Physical examination and vital signs (Day 1 only). 
● ECOG PS (Day 1 only). 
● 12-lead ECG in triplicate prior to dosing and 3 hours post-dose (Day 1 only). If sinus 
bradycardia is observed at any point during treatment (from ECG or other clinical 
assessment), it is recommended the subject undergo a stress test per institution policy. A 
stress test is recommended to be done only once for each subject who has under 60 beats 

 
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per minute (while on treatment) and more than a 20 percent reduction from baseline in 
beats per minute. The stress test should be triggered by the previous two cardiac 
observations at rest. 
● AE assessment. 
● Review and recording of concomitant medication.  
● CBC including hemoglobin, hematocrit, WBC with 5-part differential, and platelets plus 
reticulocytes. 
● CMP.  
● PT/PTT. 
● Urine testing dipstick. 
● Serum or urine pregnancy test for all pre- and perimenopausal subjects (Day 1 only).  
● Tumor biopsy (unless contraindicated)  
o The subject must have received at least 7 days of consecutive dosing prior to 
collection of the second biopsy.  The window for collection of the Cycle 2 biopsy 
may be extended if needed in order to ensure 7 consecutive days of dosing prior 
to collection. 
● Whole blood for nucleic acids (cfDNA) on Day 1 only.  
● Blood sample for markers of bone resorption and formation on Day 15 only. 
● H3B-6545 administration.  
● Schedule next visit (Day 1 only). 
7.3.3 
Cycle 3 Days 1 (Visit 9) and 15 (Visit 10) 
For all subjects, during both visits, unless otherwise stated: 
● Physical examination and vital signs (Day 1 only). 
● ECOG PS (Day 1 only). 
● 12-lead ECG in triplicate prior to dosing and 3 hours post-dose (Day 1 only). 
● AE assessment. 
● Review and recording of concomitant medication.  
● CBC including hemoglobin, hematocrit, WBC with 5-part differential, and platelets plus 
reticulocytes. 
● CMP (Day 1 only).  
● PT/PTT. 
● Urine testing dipstick. 
● Serum or urine pregnancy test for all pre-and perimenopausal subjects (Day 1 only).  

 
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● Disease assessment: CT scan of chest, abdomen, and pelvis.  All study imaging for tumor 
assessments will be sent to an imaging core laboratory designated by the Sponsor for 
review of quality, and archived for potential independent review. 
● Whole blood for nucleic acids (cfDNA) on Day 1 of Cycle 3 and every other cycle 
thereafter in conjunction with tumor imaging assessment. 
● H3B-6545 administration.  
● Schedule next visit (Day 1 only). 
7.3.4 
Cycle 4 and Beyond - Days 1 (Visits 11, 13, 15, and beyond) and 15 (Visit 12)  
For all subjects, during s both visits, unless otherwise stated: 
● Physical examination and vital signs (Day 1 only). 
● ECOG PS (Day 1 only). 
● 12-lead ECG in triplicate prior to dosing and 3 hours post-dose (Cycle 4 Day 1 only). If 
sinus bradycardia is observed at any point during treatment (from ECG or other clinical 
assessment), it is recommended the subject undergo a stress test per institution policy. A 
stress test is recommended to be done only once for each subject who has under 60 beats 
per minute (while on treatment) and more than a 20 percent reduction from baseline in 
beats per minute. The stress test should be triggered by the previous two cardiac 
observations at rest. 
● AE assessment. 
● Review and recording of concomitant medication.  
● CBC including hemoglobin, hematocrit, WBC with 5-part differential, and platelets plus 
reticulocytes. 
● CMP (Day 1 only). 
● PT/PTT. 
● Urine testing dipstick. 
● Serum or urine pregnancy test for all pre-and peri-menopausal subjects (Day 1 only). 
● Whole blood for nucleic acid (cfDNA) on Day 1 of Cycle 3 and every other cycle 
thereafter, in conjunction with tumor imaging assessment.  
● Blood samples for markers of bone resorption and formation (Cycle 4 Day 1 only, before 
dosing). 
● Transvaginal ultrasound (Cycle 4 Day 1 and then every 24 weeks until progression) 
(subjects in the Phase 2 endometrium sub-study only). 
● H3B-6545 administration. 
● Schedule next visit (Day 1 only) 
● Day 15 visits can be discontinued after Cycle 4 

 
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7.4 
Response Assessment Every 8 Weeks 
Subjects will be evaluated for tumor response every 8 weeks (±1 week) with a CT scan of the 
chest, abdomen, and pelvis.  Subjects with a partial response or CR will have a second 
confirmatory scan ≥ 4 weeks following the initial scan showing response. 
Subjects with progressive disease or unacceptable toxicity should discontinue trial therapy; 
subjects with stable disease (SD) or response to therapy will continue treatment. 
If a subject discontinues therapy for a reason other than radiological disease progression or 
withdrawal of consent, tumor assessment by CT and/or MRI scans should continue every 8 
weeks (± 1 week) until radiological disease progression or starting a new anti-cancer therapy.   
Refer to Section 7.6 and Appendix F for the tumor assessment schedule for subjects in the 
Extension Phase. 
7.5 
End-of-Treatment Visit 
Subjects are permitted to continue treatment with H3B-6545 until disease progression, 
unacceptable toxicity, or decision to discontinue treatment by the subject or the study physician.  
Follow-up evaluations required after end of treatment are specified in Appendix E. 
If treatment is discontinued because of toxicity or any other reason(s) at a treatment visit and no 
study treatment is administered, that visit may fulfill the EOT visit. 
If a subject withdraws from treatment during Cycle 1 (28 calendar days) due to any reason other 
than a DLT and does not meet the minimum requirements for inclusion in the DLT-evaluable 
population described in Section 10.10, that subject will be replaced. 
After discontinuation of trial therapy, subjects must be followed for any new AEs for 28 calendar 
days after the last dose of H3B-6545. 
The following EOT visit procedures will be performed: 
● Physical examination, weight, and vital signs (resting HR, BP, RR, and oral temperature).   
● ECOG PS (Appendix A). 
● AE assessment.   
● Review and recording of concomitant medication.  
● CBC, including WBC with 3-part differential, and platelets.   
● CMP. 
● PT/PTT. 
● Urine dipstick.  
● 12-lead ECG in triplicate for all subjects. If sinus bradycardia is observed at the EOT visit, 
follow up ECGs should be performed weekly until HR returns 60 or more beats per 
minute or to pre-study baseline.   
● Disease assessment: CT scan of chest, abdomen, and pelvis.  All study imaging for tumor 
assessments will be sent to an imaging core laboratory designated by the Sponsor for 
review of quality, and archived for potential independent review. 

 
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● Whole blood sample for nucleic acids (cfDNA). 
● Blood sample for markers of bone resorption and formation. 
7.6 
Follow-up after End-of-Treatment Visit 
Subjects who discontinue treatment will be followed for safety for 28 days after the subject’s last 
dose.  Subjects must complete a safety follow-up visit on the 28th day (with up to + 7-day 
window).  During the safety follow-up visit the following should be obtained: vital signs, 
hematological and CMP laboratory parameters, and triplicate ECGs on ERT provided study 
equipment.  All AEs that occur during the safety follow-up period will be recorded.  
If sinus bradycardia is observed at EOT visit, follow up ECGs should be performed weekly until 
HR returns 60 or more beats per minute or to pre-study baseline. 
If a subject discontinues therapy for any reason other than radiological disease progression or 
withdrawal of consent, tumor assessments by CT and/or MRI scans should continue every 8 
weeks (± 1 week) until radiological disease progression or until they start a new anti-cancer 
therapy.   
There will be a data cutoff for the primary analysis at 6 months after the last subject receives 
their first dose of study treatment.  All subjects who are still on study treatment at that time will 
enter the Extension Phase. 
Following disease progression, all subjects will be followed for survival at least every 12 weeks 
and until the data cutoff for the primary analysis, when survival follow-up will end for all 
subjects.  No survival follow-up will be done in the Extension Phase.  Survival follow-up can be 
done by telephone call at the investigator’s discretion.  The first anti-cancer therapy following 
treatment discontinuation will be recorded up until the data cutoff for the primary analysis.  
Subjects may continue to receive treatment after progression only if, after a discussion with the 
medical monitor, it is determined that the subject continues to derive clinical benefit. 
In the Extension Phase, subjects still on study treatment will continue to receive study drug in 
28-day cycles until disease progression, development of unacceptable toxicity, subject request, 
withdrawal of consent, or discontinuation of study by the Sponsor.  Tumor assessments will be 
performed according to the local standard of care, but no less than every 12 weeks.  As per the 
Schedule of Assessments for the Extension Phase, only safety and dosing information will be 
collected (Appendix F). The End of Treatment Visit assessment will occur 28 (+ 7 days) days 
after the final dose of study treatment.  All AEs/SAEs will be captured up to 28 days (+ 7 days) 
after the last dose of study drug.  
The end of study is the last subject’s last assessment (eg, the last assessment for the last subject 
in the Extension Phase). 
7.7 
Pharmacokinetics 
During the Phase 1 part of the trial, plasma samples will be collected during Cycle 1 on Day 1 
and Day 15 (pre-dose [0 hr], 0.5, 1, 2, 4, 6, 8, 10, and 24 hr post dose), for analysis of plasma 
concentration levels of H3B-6545 and potentially selected metabolite(s), at the specified time 
points.  Additional pre-dose trough samples will be collected during Cycle 1 on Day 8 and 
Day 22.   

 
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For the subjects enrolled in the food effect cohort of Phase 2 of the trial, plasma samples will be 
collected during Cycle 1 on Day 15 and Day 22 (pre-dose [0 hr], 0.5, 1, 2, 4, 6, 8, 10, and 24 hr 
post dose prior to the next dose).   
For all other Phase 2 subjects not enrolled in the food effect cohort, sparse PK samples will be 
collected on Day 15 following one of three schedules, assigned sequentially:  
● Schedule 1: pre-dose (0 hr), 0.5 hr, and 6 hr post-dose.  
● Schedule 2: pre-dose (0 hr), 2 hr, and 8 hr post-dose.  
● Schedule 3: 1 hr, 4 hr, and 24 hr post-dose.  
For subjects enrolled under Amendment 6 (or subsequent amendments), PK samples will be 
collected on Cycle 1 Days 1 and 15 at pre-dose (0 hr: -60 ~ 0 min) and at 1 (±10 min), 2 (±15 
min), 4 (±20 min), and 6 (±30 min) hours post-dose. 
Pharmacokinetic sample collection will end at the time of the data cutoff for the primary analysis 
(per Amendment 09). 
In Phase 1 and Phase 2, a protocol deviation will be reported only when a PK time point is not 
collected (missing) or blood is drawn on the wrong study day. 
Plasma concentrations of H3B-6545 will be tabulated and summarized by dose level, day, and 
time.  Standard PK parameters including, but not limited to, the area under the plasma 
concentration-time curve from time point 0 through the last measurable point (AUC0−t), Cmax, 
time of maximum observed plasma concentration (tmax), and accumulation ratio (Racc) will be 
determined.  If data permit, area under the plasma concentration-time curve extrapolated to 
infinity (AUC0-inf), t½, and apparent total body clearance following oral administration (CL/F) 
will be calculated.  Assessment of the effect of dose on Cmax and AUC will also be performed.  
The primary assessment of PK will be done using non-compartmental methods; additional 
compartmental analysis may also be performed.  
The effect of a high-fat meal on AUC, Cmax and tmax of H3B-6545 will be evaluated using a 
mixed linear model of logarithmically transformed values of the primary PK parameters.  Ratios 
of geometric means (fed/fasted comparison) and associated 2-sided 90% confidence intervals 
(CIs) will be presented. 
Plasma samples collected for PK analysis may also be used for an exploratory assessment of the 
H3B-6545 metabolite profile.  A report for metabolite identification will be provided in a 
separate document, and results for metabolites will be not included in the clinical study report.  
Instructions for the processing, storage, and shipment of PK and metabolite identification 
samples will be provided in the Laboratory Manual.  For PK, plasma concentrations of analyte(s) 
will be quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) 
methodology using a validated assay. 
7.8 
Biomarkers 
Instructions for the collection, processing, storage, and shipping of samples will be provided in 
the Laboratory Manual.  Time points and minimum blood volume for biomarker specimens are 
presented in Table 5 . Biomarker sample collection will end at the time of the data cutoff for the 
primary analysis. 

 
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8.2 
Storage Conditions 
All study drugs must be kept in a secure place under appropriate storage conditions.  Storage 
conditions for H3B-6545 are included on the investigational product label. 
The Sponsor or its representatives must be granted access on reasonable request to check drug 
storage, dispensing procedures, and accountability records. 
Study drug will be stored in accordance with the labeled storage conditions.  Continuous 
temperature monitoring and recording is required at the storage location to ensure that the study 
drug is maintained within an established temperature range.  The investigator or designee is 
responsible for ensuring that the temperature is recorded while the drug is at the clinic and that 
records are maintained; the temperature should be monitored continuously by using either an in-
house validated data acquisition system, a mechanical recording device, such as a calibrated 
chart recorder, or by manual means, such that minimum and maximum thermometric values over 
a specific time period can be recorded and retrieved as required.  When the H3B-6545 is 
dispensed to the subject, they will be asked to store the drug in the refrigerator.  
8.3 
Accountability for All Study Drugs 
The PI (or designee) is responsible for accountability of all used and unused study drug supplies 
at the site.  Under no circumstances will the investigator allow the study drug to be used other 
than as directed by this protocol.  Study drug will not be dispensed to any individual who is not 
enrolled in the study. 
All study drug inventories must be made available for inspection by the Sponsor or its 
representatives and regulatory agency inspectors upon request. 
The site must maintain an accurate and timely record of the following: receipt of all study drug, 
dispensing of study drug to the subject, collection and reconciliation of unused study drug that 
are either returned by the subjects or shipped to site but not dispensed to subjects, and return of 
reconciled study drug to the Sponsor or (where applicable) destruction of reconciled study drug 
at the site.   
This includes but may not be limited to: (a) documentation of receipt of study drug, (b) study 
drug dispensing/return reconciliation log, (c) study drug accountability log, (d) all shipping 
service receipts, (e) documentation of returns to the Sponsor, and (f) certificates of destruction 
for any destruction of study drugs/study supplies that occurs at the site.  All forms will be 
provided by the Sponsor. 
Any comparable forms that the site wishes to use must be approved by the Sponsor. 
The study drug and inventory records must be made available, upon request, for inspection by a 
designated representative of the Sponsor or a representative of a health authority (eg, FDA, 
Medicines & Healthcare products Regulatory Agency).  As applicable, all unused study drug and 
empty and partially empty containers from used study drug are to be returned to the investigator 
or designee by the subject and together with unused study drug that were shipped to the site but 
not dispensed to subjects are to be returned to the Sponsor’s designated central or local depot(s) 
during the study or at the conclusion of the study, unless provision is made by the Sponsor for 
destruction of study drug and containers at the site.   

 
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Approval for destruction to occur at the site must be provided by the Sponsor in advance.  Upon 
completion of drug accountability and reconciliation procedures by the site’s personnel and 
documentation procedures by the Sponsor’s personnel, study drug that are to be returned to the 
Sponsor’s designated central or local depot(s) must be boxed and sealed and shipped back to the 
central or local depot(s) following all local regulatory requirements.  In some regions, study drug 
may be removed from the site and hand delivered to the central or local depot by Sponsor 
representatives.  Where study drugs are approved for destruction at the site, destruction will 
occur following the site’s standard procedures and certificates of destruction will be provided to 
the Sponsor. 
Drug accountability will be reviewed during site visits and at the completion of the study. 
At the end of the study, all Drug Accountability Record Form(s) will be completed by the site 
and sent to the Sponsor CRA or designee.  Please contact the Sponsor or CRA regarding disposal 
of any study drug. 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS 
Tumor assessments will be performed at baseline (within 28 days of starting trial therapy) and 
every 8 weeks after starting trial therapy until progression.   
Response and progression will be evaluated in this study using the RECIST version 1.1 (see 
Appendix G).  Lesions are either measurable or non-measurable according to the criteria.  The 
term “evaluable” in reference to measurability will not be used, as it does not provide additional 
meaning or accuracy. 
The data cutoff for the primary analysis will occur at 6 months after the last subject receives their 
first dose (see Section 7.6).  All subjects who are still on study treatment at that time will enter 
the Extension Phase. Tumor assessments will be performed according to the local standard of 
care, but no less than every 12 weeks.  The Schedule of Assessments for the Extension Phase is 
found in Appendix F. 
Following progression, all subjects will be followed for survival at least every 12 weeks, and 
survival follow-up will end 6 months after the last subject receives their first dose of study 
treatment (at the time of data cutoff for the primary analysis) (as of Amendment 9), and no 
survival follow-up will be done in the Extension Phase.  Survival updates may be obtained via 
phone call to the subject or her family and the information should be documented in the subject’s 
file.  
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Statistical Design 
This is a multi-center, open-label, dose-escalation followed by dose expansion Phase 1/2 study of 
H3B-6545.  
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the Statistical Analysis Plan (SAP), which will be finalized 
before database lock. 

 
C O N FI D E N TI A L  
S T U D Y D R U G :  H 3 B -6 5 4 5  
P R O T O C O L A M E N D M E N T 9:   2 9  A U G 2 0 2 2  
Pa ge 1 1 0  of 1 6 0  
1 0. 2  
P h ase 1 Pri m ar y O bjecti ve 
T he pri mar y o bjecti ve of t he P hase 1 p orti o n of t his st u d y i s t o: 
● Deter mi ne t he M T D a n d/ or t he R P 2 D of H 3 B- 6 5 4 5 i n w o me n wit h l ocall y a d va nce d or 
metastatic E R - p ositi ve, H E R 2 ne gati ve breast ca ncer.  
1 0. 3  
P h ase 1 Sec o n d ar y O bjecti ves  
T he sec o n dar y o bjecti ves of t he P hase 1 p orti o n of t his st u d y are t o: 
● E val uate t he safe t y a n d t olera bilit y of H 3 B- 6 5 4 5 i n w o me n wit h l ocall y a d va nce d or 
metastatic ( E R) - p ositi ve, H E R 2-ne gati ve breast ca ncer   
● C haracterize t he plas ma P K of H 3 B - 6 5 4 5. 
● Esti mate t he efficac y of H 3 B - 6 5 4 5 i n ter ms of res p o nse rate, D o R, D C R, P F S, a n d O S.  
1 0. 4  
P h ase 1 E x pl or at or y O bjecti ves 
1 0. 5  
P h ase  2 Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve of t he P hase 2 p orti o n of t his st u d y is t o: 
● Esti mate t he efficac y of H 3 B - 6 5 4 5 i n ter ms of best o verall res p o nse rate, D o R, D C R, 
C B R, P F S, a n d O S i n s u bjects wit h ( E R)- p ositi ve, H E R 2- ne gati ve breast ca ncer a n d i n 
th ose wit h a n d wit h o ut E R α m ut  (i ncl u di n g a cl o nal E S R 1  Y 5 3 7 S m utati o n). 
1 0. 6  
P h ase 2 Sec o n d ar y O bjecti ves  
T he sec o n dar y o bjecti ves of t he P hase 2 p orti o n of t his st u d y are t o: 
● F urt her c haracterize t he safet y of H 3 B - 6 5 4 5 i n t his s u bject p o p ulati o n. 
● F urt her c haracterize t he P K of H 3 B -6 5 4 5.  At least s parse P K sa m ples will be c ollecte d 
fr o m all s u bjects o n st u d y. 
● E val uate t he effect of a hi g h -fat meal o n t he relati ve bi oa vaila bilit y of H 3 B- 6 5 4 5. 
● Assess t he effect of H 3 B - 6 5 4 5 o n ser u m b o ne t ur n- o ver mar kers, namel y B S A P (f or 
oste oclast meta b olis m), PI N P (f or b o ne f or mati o n), a n d C T X (f or b o ne res or pti o n). 
● Assess t he effect of H 3 B - 6 5 4 5 o n e n d o metrial t hic k ness a n d uteri ne v ol u me.  T his 
o bjecti ve will be assesse d i n a s u b gr o u p of w o me n wit h i ntact uteri.  
1 0. 7  
P h ase 2 E x pl or at or y O bjecti ves  
T he e x pl orat or y o bjecti ves of t he P hase 2 p orti o n of t his st u d y are t o: 
C CI

 
C O N FI D E N TI A L  
S T U D Y D R U G :  H 3 B -6 5 4 5  
P R O T O C O L A M E N D M E N T 9:   2 9  A U G 2 0 2 2  
Pa ge 1 1 1  of 1 6 0  
1 0. 8  
St u d y E n d p o i nts 
1 0. 8. 1. 1  
P h ase 1  
T he pri mar y st u d y e n d p oi nt f or P hase 1 is t he occ urre nce of D L Ts as a f u ncti o n of t he d ose of 
H 3 B - 6 5 4 5 f or deter mi nati o n of t he M T D a n d/ or R P 2 D. 
Sec o n dar y st u d y e n d p oi nts f or P hase 1 are: 
● Safet y/t olera bilit y:  t he t y pe a n d fre q ue nc y of A Es a n d S A Es usi n g N CI C T C A E v 4. 0 3, as 
well as c ha n ges i n cli nical la b orat or y val ues, vital si g n meas ure me nts a n d E C G 
para meters.  
● P K: sta n dar d pri mar y P K para meters i ncl u di n g, b ut n ot li mite d t o, t he area u n der t he 
plas ma c o nce ntr ati o n-ti me c ur ve fr o m ti me p oi nt 0 t hr o u g h t he last meas ura ble p oi nt 
( A U C0 −t), Cma x , tma x  a n d Racc.   
● Preli mi nar y efficac y:  Res p o nse will be deter mi ne d b y t he i n vesti gat or assess me nts.  T he 
f oll o wi n g e n d p oi nts will be deter mi ne d: 
-  O R R , defi ne d as t he pr o p orti o n of s u bjects ac hie vi n g a best o verall res p o nse of 
c o nfir me d partial or c o m plete res p o nse ( partial res p o nse + C R)   
-  D o R , defi ne d as t he ti me fr o m t he date of first d oc u me nte d C R/partial res p o nse  u ntil 
t he first d oc u me ntati o n of c o nfir me d disease pr o gressi o n or deat h, w hic he ver c o mes 
first.   
-  D C R , defi ne d as t he pr o p orti o n of s u bjects ac hie vi n g a best res p o nse of C R or partial 
res p o nse, or S D 
-  P F S , defi ne d as t he ti me fr o m first d ose date t o t he date of t he first d oc u me ntati o n of 
c o nfir me d disease pr o gressi o n or deat h ( w hic he ver occ urs first).  
-  O S , defi ne d as t he ti me fr o m first d ose date t o t he date of deat h (e ve nt) or date last 
k n o w n ali ve (ce ns ore d).   
E x pl orat or y st u d y e n d p oi nts f or P hase 1 a n d P hase 2 (e xce pt w here n ote d) i ncl u de: 
C CI
C CI

 
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Safety data to be evaluated include AEs, clinical laboratory results, vital sign measurements, and 
ECG parameters. 
Safety parameters will be summarized using descriptive statistics (mean, standard deviation, 
median, Q1, Q3, and range for continuous variables; numbers and percentages for categorical 
measures). 
The effects of H3B-6545 on cardiovascular re-polarization will be evaluated via a 12-lead 
continuous Holter.  On Cycle 1, Day 1 and Day 15, monitoring via Holter will begin at least 1 
hour prior to dose and continue through at least 24 hours postdose for Phase 1 subjects only.   
For convenience, Holter monitoring may begin up to 12 hours prior to dosing on Cycle 1, Day 1 
or Day 15.  Individual ECGs will be extracted in triplicate from the Holter recordings at 
specified time points and will be evaluated by a central laboratory.  QT intervals will be 
measured from Lead II and will be corrected for HR (QTc) using Fridericia's (QTcF) correction 
factors.  The primary QTc parameter will be QTcF.  Secondary parameters (QTc interval using 
Bazett’s correction factor (QTcB), QT, QRS interval, and HR) and waveforms (T waves) will be 
evaluated. 
In addition, the effects of H3B-6545 on the cardiovascular system will be evaluated via 12-lead 
ECG at screening and on Day 1 and Day 15 of Cycle 1, and Day 1 of Cycle 2, 3 and 4 as well as 
at the End of Treatment visit for all subjects (Phase 1 and Phase 2 subjects).  If sinus bradycardia 
is observed at EOT visit, follow up ECGs should be performed weekly until HR has returned 60 
or more beats per minute or pre-study baseline. QT intervals will be measured from Lead II and 
will be corrected for HR (QTc) using Fridericia's (QTcF) correction factor.  The primary QTc 
parameter will be QTcF; secondary parameters (QTc corrected using Bazett’s formula, QT, QRS 
interval, and HR) and waveforms (T waves) will be evaluated. 
10.11.5.1 
Extent of Exposure 
Descriptive statistics for subjects treated, including the duration of treatment, the number of 
cycles received, and the number of subjects requiring dose changes, will be presented.  A by-
subject listing of the date of study drug administration and the dose administered will be 
presented. 
10.11.5.2 
Adverse Events 
AEs will be collected for each subject until 28 days after last trial therapy administration.  The 
NCI CTCAE v4.03 will be used for AE reporting.  
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using MedDRA.  Adverse events will be coded to the 
MedDRA (Version 19.1 or higher) lower level term closest to the verbatim term.  The linked 
MedDRA preferred term and primary SOC are also captured in the database. 
A TEAE is defined as:  
- An AE that emerges during treatment, having been absent at pretreatment (baseline), or  
- Re-emerges during treatment, having been present at pretreatment (baseline) but stopped 
before treatment, or  

 
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- Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only those AEs that were treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.  The TEAEs will be 
summarized for each study phase.  The incidence of TEAEs will be reported as the number 
(percentage) of subjects with TEAEs by SOC and preferred term.  
A subject will be counted only once within a SOC and preferred term, even if the subject 
experienced more than 1 TEAE within a specific SOC and preferred term.  The number 
(percentage) of subjects with TEAEs will also be summarized by maximum CTCAE grade and 
by relationship to study drug (Yes [related] and No [not related]). 
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and preferred term for each study phase.  A subject data listing of all AEs leading 
to death will be provided.  The number (percentage) of subjects with treatment-emergent SAEs 
will be summarized by MedDRA SOC and preferred term for each study phase.  A subject data 
listing of all SAEs will be provided.  The number (percentage) of subjects with TEAEs leading 
to discontinuation from study drug will be summarized by MedDRA SOC and preferred term for 
each study phase.  A subject data listing of all AEs leading to discontinuation from study drug 
will be provided. 
In the Dose-Evaluable Set, the number (percentage) of subjects with DLTs will be presented by 
dose level for Phase 1 of the study.  A listing of subjects with DLTs will be provided. 
AEs will be summarized using the Safety Analysis Set.  The number of AEs and number and 
incidence (%) of subjects with AEs will be summarized by cohort/dose level and overall.  To 
obtain the incidence (%), the number of subjects with at least 1 event and the percentage of 
subjects with AEs by SOC and by preferred term will be calculated.  Incidence (%) by causal 
relationship with study drug and by severity (CTCAE v 4.03) will also be calculated.  For 
clinically significant events, time of onset, and recovery will be reported.    
10.11.5.3 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units, as appropriate.   
For all quantitative parameters listed, the actual value and the change from baseline to each post-
baseline visit and to the end of treatment (defined as the last on-treatment value) will be 
summarized by visit using descriptive statistics.  Qualitative parameters listed will be 
summarized using frequencies (number and percentage of subjects), and changes from baseline 
to each post-baseline visit and to end of treatment will be reported using shift tables.  
Percentages will be based on the number of subjects with both non-missing baseline and relevant 
post-baseline results. 
Furthermore, the frequency of laboratory abnormalities by maximum post-baseline CTCAE 
grade will be tabulated by cycle and overall for selected laboratory parameters to include at least,  
hemoglobin, WBC, absolute neutrophil count, lymphocytes, platelet count,  ALP, AST, ALT,  
bilirubin, creatinine, and electrolytes.  Shift tables will also be produced for these parameters 
based on the baseline CTCAE grade and the maximum CTCAE grade by cycle and overall. 

 
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10.11.5.4 
Vital Signs 
Changes in vital sign parameters (including systolic and diastolic BP, HR, RR, and temperature) 
and body weight will be summarized over time, and any abnormal values will be tabulated.   
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, RR, 
temperature, and weight) and changes from baseline will be presented by visit. 
10.11.5.5 
Electrocardiograms 
ECG assessments will be performed throughout the study.  Descriptive statistics for ECG 
parameters and changes from baseline will be presented by visit.   
For all subjects, shift tables will present changes in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) from baseline to end of 
treatment.  In addition, summary tables and listings for the various intervals (eg, QT and PR) and 
changes from baseline will be presented.  
In addition, the number (percentage) of subjects with at least 1 post-baseline abnormal ECG 
result in QTcF during the treatment period will be summarized.  Clinically abnormal ECG results 
in QTcF will be categorized as follows: 
Absolute QTc interval prolongation: 
- QTc interval >450 msec 
- QTc interval >480 msec 
- QTc interval >500 msec 
Change from baseline in QTc interval: 
- QTc interval increases from baseline >30 msec 
- QTc interval increases from baseline >60 msec 
All ECG abnormalities will be listed on a per-subject basis.  
10.11.6 Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other  
Biomarker Analyses 
10.11.6.1 
Pharmacokinetic Analyses 
Plasma concentrations of H3B-6545 will be tabulated and summarized by dose level, day, and 
time.   
H3B-6545 PK parameters will be derived from plasma concentrations by noncompartmental 
analysis using actual times.  Minimally, the following PK parameters will be calculated: Cmax, 
tmax, AUC0-t, Racc, and if data permit, area under the plasma concentration-time curve 
extrapolated to infinity (AUC0-inf), t½, CL/F, and Vz/F. 
The effect of a high-fat meal on AUC and Cmax of H3B-6545 will be evaluated using a mixed 
linear model of logarithmically transformed values of the primary PK parameters.  Ratios of 
geometric means (fed/fasted comparison) and associated 2-sided 90% CIs will be presented.   

 
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declare an MTD and/or RP2D, escalate or de-escalate the dose, and/or recruit additional subjects 
at the current or previous dose levels. The SRC may be convened earlier at the discretion of the 
Sponsor if important safety issues arise requiring the attention of the committee. 
During the Phase 2 part of the trial, the SRC will receive all available safety data approximately 
every 6 months.  
11. 
SAFETY REPORTING 
Safety assessments will consist of monitoring and recording all AEs, including all Common 
Terminology Criteria for Adverse Events (CTCAE) v 4.03 grades (for both increasing and 
decreasing severity), and SAEs; regular monitoring of hematology, blood chemistry, and urine 
values; periodic measurement of vital signs and ECGs; and performance of physical 
examinations as detailed in Appendix D, Appendix E, and Appendix F. 
The PI is responsible for recognizing and reporting AEs to the Sponsor or designee.  It is the 
Sponsor’s responsibility to report relevant SAEs to the applicable local, national, or international 
regulatory bodies.  In addition, investigators must report SAEs and follow-up information to 
their responsible IRB/EC according to the policies of that IRB/EC.  
The PI is also responsible for ensuring that every staff member involved in the study is familiar 
with the content of this section. 
11.1 
Definitions 
11.1.1 
Adverse Events 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal relationship 
with the medicinal product.  For this study, the study drug is H3B-6545. 
The criteria for identifying AEs in this study are: 
● Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE). 
● Any new disease or exacerbation of an existing disease.  However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE, unless the event meets criteria for a serious AE as outlined in 
Section 11.1.2.  In such cases, the event should be reported as an SAE. 
● Any deterioration in non-protocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug. 
● Recurrence of an intermittent medical condition (eg, headache) not present pre-treatment 
(Baseline) 

 
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● An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not. 
All AEs, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through 28 days after the last dose of drug. 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be part 
of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute an 
AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality considered to 
constitute an AE should be reported on the Adverse Event CRF.  
Abnormal ECG (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 450 msec 
and there is an increase of more than 60 msec from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.  Note: If sinus bradycardia is 
observed at EOT visit, follow up ECGs should be performed weekly until HR has returned 60 or 
more beats per minute or pre-study baseline. 
All AEs must be followed for 28 days after the subject’s last dose.  All SAEs must be followed 
to resolution or, if resolution is unlikely, to stabilization.  
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment. 
Assessing Severity of Adverse Events 
Adverse events will be graded on a 5-point scale according to CTCAE v 4.03.  Investigators will 
report CTCAE grades for all AEs (for both increasing and decreasing severity). 
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
● Temporal relationship of the onset of the event to the initiation of the study treatment  
● The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable  
● Whether the event is known to be associated with the study treatment or with other 
similar treatments 
● The presence of risk factors in the study subject known to increase the occurrence of the 
event 
● The presence of non-study treatment-related factors that are known to be associated with 
the occurrence of the event. 
Classification of Causality 
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question: 

 
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Is there a reasonable possibility that the study drug caused the AE? 
Yes (related) 
A causal relationship between the study drug and the AE is a reasonable 
possibility. 
No (not related) A causal relationship between the study drug and the AE is not a reasonable 
possibility. 
Adverse Events of Special Interest 
Hy’s Law is the only reportable AESI for this protocol and events of Hy’s Law should be 
reported as outlined in Section 11.2. 
11.1.2 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
● Results in death. 
● Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death). 
● Requires inpatient hospitalization or prolongation of existing hospitalization. 
● Results in persistent or significant disability/incapacity. 
● Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug). 
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization but, when based on appropriate medical judgment, may jeopardize the subject or 
may require intervention to prevent one of the outcomes in the definition of SAE listed above 
should also be considered SAEs.   
For example, an isolated laboratory abnormality could be considered to meet the criteria for 
serious (eg, if the event results in hospitalization or is considered medically significant).  
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in such situations.  
In addition to the above, events associated with special situations include pregnancy or exposure 
to study drug through breastfeeding; AEs associated with study drug overdose, misuse, abuse, or 
medication error.  These events associated with special situations are to be captured using the 
SAE procedures but are to be considered as SAEs only if they meet one of the above criteria.  All 
AEs associated with special situations are to be reported on the CRF whether or not they meet 
the criteria for SAEs.   
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. 
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(ie, there is no untoward medical occurrence) associated with the hospitalization: 
● Hospitalizations for respite care.  
● Planned hospitalizations required by the protocol. 

 
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● Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration). 
● Hospitalization for administration of study drug or insertion of access for administration 
of study drug. 
● Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry 
It is important to distinguish between “serious” and “severe” AEs, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  Seriousness serves as the guide for defining regulatory 
reporting obligations.  It is based on subject/event outcome or action usually associated with 
events that pose a threat to a subject’s life or vital functions.   
For example, nausea, which persists for several hours, may be considered severe nausea, but may 
not be considered an SAE.  On the other hand, a stroke, which results in only a limited degree of 
disability, may be considered only a mild stroke, but it would be considered an SAE.  Severity 
and seriousness should be independently assessed when recording AEs on the eCRF screen and 
SAEs on the SAE Report Form. 
11.1.3 
Adverse Reaction  
An adverse reaction (AR) means any AE caused by a drug.  Adverse reactions are a subset of all 
SARs where there is a reason to conclude that the drug caused the event. 
11.1.4 
Suspected Adverse Reaction 
Suspected adverse reaction (SAR) means any AE for which there is a reasonable possibility that 
the drug caused the AE.  Reasonable possibility means that there is evidence to suggest a causal 
relationship between the drug and the AE.  An SAR implies a lesser degree of certainty about 
causality than an AR, which means any AE caused by a drug. 
11.1.5 
Recording and Reporting of Adverse Events 
Recording of Adverse Events 
All AEs of any subject during the course of the research study will be recorded in the eCRF, and 
the investigator will give his or her opinion as to the relationship of the AE to the study drug 
treatment (ie, whether the event is related or unrelated to study drug administration). 
All AEs should be documented.  A description of the event, including its date of onset and 
resolution, whether it constitutes an SAE or not, any action taken (eg, changes to study 
treatment), and outcome, should be provided, along with the investigator’s assessment of 
causality (ie, the relationship to the study treatment[s]).  For an AE to be a suspected treatment-
related event, there should be at least a reasonable possibility of a causal relationship between the 
protocol treatment and the AE.  Adverse events will be graded according to the NCI CTCAE 
v4.03, and changes will be documented. 
If the AE is serious or of special interest (eg, a case of Hy’s Law), it should be reported 
immediately to the Sponsor or designee. Other untoward events occurring in the framework of a 
clinical study are to be recorded as AEs (ie, AEs that occur prior to assignment of study 
treatment that are related to a protocol-mandated intervention, including invasive procedures 
such as biopsies, medication washout, or no treatment run-in). 

 
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Any clinically significant signs and symptoms, abnormal test findings, changes in physical 
examination, hypersensitivity, and other measurements that occur will be reported as AEs and 
recorded on the relevant eCRF screen. 
Test findings will be reported as an AE if the test results require an adjustment in the study 
drug(s) or discontinuation of treatment, test findings require additional testing or surgical 
intervention; a test result or finding is associated with accompanying symptoms; and/or a test 
result is considered to be an AE by the investigator. 
Reporting Period for Adverse Events 
All AEs, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through 28 days after the last dose of drug.  SAEs 
will be collected for 28 days after the last dose.   
All AEs resulting in discontinuation from the study should be followed until resolution or 
stabilization.  All new AEs occurring during this period must be reported and followed until 
resolution unless, in the opinion of the investigator, the AE or laboratory abnormality(ies) are not 
likely to improve because of the underlying disease.  In this case, the investigators must record 
his or her reasoning for this decision in the subject’s medical record and as a comment on the 
eCRF screen.   
After 28 days of completion of protocol-specific treatment or discontinuation, only AEs, SAEs, 
or deaths assessed by the investigator as treatment related are to be reported. 
11.1.5.1 
Regulatory Reporting of Adverse Events 
Adverse events will be reported by the Sponsor or a third party acting on behalf of the Sponsor to 
regulatory authorities in compliance with local and regional law and established guidance.  The 
format of these reports will be dictated by the local and regional requirements. 
11.2 
Serious Adverse Event Reporting by Investigators 
All SERIOUS ADVERSE EVENTS and adverse events of special interest (AESI), 
regardless of their relationship to study treatment, must be reported on a completed SAE 
form by email or fax as soon as possible but not later than 24 hours from when the investigator 
becomes aware of the event.   
SAEs, regardless of causality assessment, must be collected through the last visit.  SAEs will be 
collected for 28 days after the last dose.  All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be related to the 
study treatment or any protocol-required procedure should be reported to the Sponsor regardless 
of the length of time that has passed since study completion. 
The detailed contact information for reporting of SAEs is provided in the Investigator Study File. 
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File. 
It is very important that the SAE report form be filled out as completely as possible at the time of 
the initial report.  This includes the investigator’s assessment of causality. 

 
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Any follow-up information received on SAEs should be forwarded within 24 hours of its receipt.  
If the follow-up information changes the investigator’s assessment of causality, this should also 
be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by the 
Sponsor. 
Transmission of the SAE report should be confirmed by the site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported as soon as it is available; these reports should be submitted using the SAE 
Report Form.  The detailed SAE reporting process will be provided to the sites in the SAE 
reporting guidelines contained in the study reference manual. 
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of the responsible IRB. 
11.2.1 
Investigator Reporting After Study Discontinuation 
Twenty-eight days after completing protocol-specific treatment or study discontinuation, 
treatment-related AEs, SAEs, or deaths determined by the investigator as treatment-related are to 
be reported to the Sponsor or designee. 
11.3 
Recording of Adverse Events and Serious Adverse Events 
11.3.1 
Diagnosis Versus Signs and Symptoms 
All AEs should be recorded individually in the subject’s own words (verbatim) unless, in the 
opinion of the PI or designated physician, the AEs constitute components of a recognized 
condition, disease, or syndrome.  In the latter case, the condition, disease, or syndrome should be 
named rather than each individual sign or symptom.  If a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded as an AE or SAE as appropriate on the relevant form(s) 
(SAE Report Form and/or AE eCRF screen).  
If a diagnosis is subsequently established, it should be reported as follow-up information is 
available.  If a diagnosis is determined subsequent to the reporting of the constellation of 
symptoms, the signs/symptoms should be updated to reflect the diagnosis. 
11.3.2 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between subject evaluation 
time points.  Such events should only be recorded once on the SAE Report Form and/or the AE 
eCRF screen.  If a persistent AE becomes more severe or lessens in severity, it should be 
recorded on a separate SAE Report Form and/or AE eCRF screen. 
A recurrent AE is one that occurs and resolves between subject evaluation time points, and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form and/or AE 
eCRF screen. 
11.3.3 
Abnormal Laboratory Values 
If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, 
the sign or symptom should be reported as an AE or SAE, and the associated laboratory value or 

 
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vital sign should be considered additional information that must be collected on the relevant 
eCRF screen.  If the laboratory abnormality is a sign of a disease or syndrome, only the diagnosis 
needs to be recorded on the SAE Report Form or AE eCRF screen. 
Abnormal laboratory values will be reported as an AE if the laboratory result requires an 
adjustment in the study drug(s) or discontinuation of treatment; laboratory findings require 
additional testing or surgical intervention; a laboratory result or finding is associated with 
accompanying symptoms; and/or a laboratory result is considered to be an AE by the 
investigator. 
11.3.4 
Deaths 
All on-study treatment deaths, regardless of attribution during the AE reporting period, will be 
recorded on an SAE Report Form and expeditiously reported. 
When recording an SAE with an outcome of death, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the SAE 
Report Form and Adverse Event screen of the eCRF.  If the cause of death is unknown and 
cannot be ascertained at the time of reporting, record “Death NOS” on the eCRF Adverse Event 
screen.   
During post-study treatment survival follow-up (after the 28-day post-dose AE reporting period), 
deaths attributed to progression of disease will be recorded only on the “After Progressive 
Disease Follow-Up” eCRF screen. 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of >24 hours or prolongation of pre-existing 
hospitalization should be documented and reported as an SAE unless specifically instructed 
otherwise in this protocol.  There are some hospitalizations that do not require reporting as an 
SAE. 
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“inpatient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
● Emergency department or emergency room. 
● Outpatient or same-day surgery units. 
● Observation or short-stay unit. 
● Rehabilitation facility. 
● Hospice or skilled nursing facility. 
● Nursing homes, custodial care or respite care facility. 
Hospitalization during the study for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the study), does not require reporting as a SAE. 
11.3.6 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  Such conditions 
should be recorded on the General Medical History of the eCRF screen.  A pre-existing medical 
condition should be recorded as an AE or SAE only if the frequency, severity, or character of the 

 
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condition worsens during the study.  When recording such events on an SAE Report Form and/or 
AE eCRF screen, it is important to convey the concept that the pre-existing condition has 
changed by including applicable descriptors. 
11.3.7 
New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the seriousness criteria.  New primary cancers are those that are not the primary 
reason for the administration of the study treatment and have developed after the inclusion of the 
subject into the study.  They do not include metastases of the original cancer.   
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
Any pregnancy in a female subject in which the estimated date of conception is either before the 
last visit or within 28 days of last study treatment, or any exposure to study drug through 
breastfeeding during study treatment or within 28 days of last study treatment, must be reported. 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in the 
same format as all other SAEs (see Reporting of Serious Adverse Events in Section 11.2). 
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or email as 
soon as possible but no later than 1 business day from the date the investigator becomes aware of 
the pregnancy.  The contact information for the reporting of pregnancies and exposure to study 
drug through breastfeeding is provided in the Investigator Study File.  The Pregnancy Report 
Form must be used for reporting.  All pregnancies must be followed to outcome.  The outcome 
of the pregnancy must be reported as soon as possible but no later than 1 business day from the 
date the investigator becomes aware of the outcome. 
A subject who becomes pregnant must be withdrawn from the study. 
The detailed contact information for reporting of pregnancies is provided in the Investigator 
Study File. If a subject becomes pregnant while enrolled in the study, a Pregnancy Form should 
be completed and submitted expeditiously, irrespective of whether or not it meets the criteria for 
expedited reporting.  Abortions (spontaneous, accidental, or therapeutic) must also be reported. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting.  A 
Pregnancy Form should also have been previously completed and will need to be updated to 
reflect the outcome of the pregnancy. 
11.3.9 
H3B-6545 Overdose 
Adverse events associated with study drug overdose, misuse, abuse, and medication error refer to 
AEs associated with uses of the study drug outside of that specified by the protocol.  Overdose, 
misuse, abuse, and medication error are defined as follows:  
Overdose 
Accidental or intentional use of the study drug in an amount higher than 
the protocol-defined dose 

 
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Misuse 
Intentional and inappropriate use of study drug not in accordance with the 
protocol.  
Abuse 
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects. 
Medication error 
Any unintentional event that causes or leads to inappropriate study drug 
use or subject harm while the study drug is in the control of site personnel 
or the subject.   
All AEs associated with overdose, misuse, abuse, or medication error should be captured on the 
Adverse Event CRF and also reported using the procedures detailed in Reporting of Serious 
Adverse Events even if the AEs do not meet serious criteria.  Abuse is always to be captured as 
an AE.  If the AE associated with an overdose, misuse, abuse, or medication error does not meet 
serious criteria, it must still be reported using the SAE form and in an expedited manner but 
should be noted as nonserious on the SAE form and the Adverse Event CRF. 
Symptomatic and non-symptomatic overdose must be reported in the eCRF system.  Any 
accidental or intentional overdose with the study treatment that is symptomatic, even if not 
fulfilling a seriousness criterion, is to be reported no greater than 24 hours from first knowledge 
of the event using the corresponding screens in the eCRF and following the same process 
described for SAE reporting (see Section 11.2) if the overdose is symptomatic. 
For information on how to manage an overdose of H3B-6545, refer to the IB. 
11.4 
Cardiovascular 
Triplicate 12-lead ECGs will be collected approximately 5 minutes apart at the screening visit, 
and prior to dosing and 3-hour post dose on Day 1 and Day 15 of Cycle 1, and Day 1 of Cycle 2, 
Cycle 3, and Cycle 4, as well as at the end of treatment for all subjects (Phase 1 and Phase 2 
subjects).  12-lead safety ECGs will be performed locally from Day 1 of each cycle starting 
Cycle 5 till the last cycle prior to the EOT visit, and at Unscheduled visits as clinically required.  
A single 12-lead safety ECG is required at a minimum.  Data from local safety ECGs should be 
entered into the clinical database.  
In addition, in the event of any alteration or if clinically indicated, additional ECGs and/or 
cardiac enzyme evaluations should be performed. If sinus bradycardia is observed at EOT visit, 
follow up ECGs should be performed weekly until heart rate has returned to 60 or more beats per 
minute or pre-study baseline. 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 11.1.1) and the CRF Completion Guidelines.  In these instances, the AE corresponding 
to the ECG abnormality will be recorded on the Adverse Events CRF. 
For ECG abnormalities meeting the criteria of an SAE, the site must fax or email the SAE report 
including the ECG report to the Sponsor using the SAE form. 
11.5 
Sponsor Serious Adverse Event Reporting Requirements 
Adverse events will be reported by the Sponsor or a third party acting on behalf of the Sponsor to 
regulatory authorities in compliance with local and regional law and established guidance.  The 
format of these reports will be dictated by the local and regional requirements. 

 
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All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All suspected 
unexpected serious adverse reactions (SUSARs) will be reported, as required, to the competent 
authorities of all involved European member states. 
11.5.1.1 
Expedited Reporting 
The Sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within specific 
time frames).  For this reason, it is imperative that sites provide complete SAE information in the 
manner described above. 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
12.1 
Monitoring 
Site monitoring shall be conducted to ensure that subject protection, study procedures, 
laboratory, study intervention administration, and data collection processes are of high quality 
and meet Sponsor, Good Clinical Practice (GCP)/International Conference on Harmonisation 
(ICH) and, when appropriate, regulatory guidelines. 
12.2 
Audits and Inspections 
The investigator will permit study-related quality audits and inspections by the Sponsor or its 
representative(s), government regulatory authorities, and the IRB/EC of all study-related 
documents (eg, source documents, regulatory documents, data collection instruments, CRFs).  
The investigator will ensure the capability for review of applicable study-related facilities.  The 
investigator will ensure that the auditor or inspector or any other compliance or quality assurance 
reviewer is given access to all study-related documents and study-related facilities. 
Participation as an investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities, the IRB/EC, and the Sponsor or its representative(s). 
13. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This research study will be conducted according to the standards of GCP outlined in the ICH E6 
Tripartite Guideline and Code of Federal Regulations (CFR) Title 21 Part 312, applicable 
government regulations, institutional research policies and procedures and any other local 
applicable regulatory requirement(s). 
13.1 
Institutional Review Board Approval 
The clinical study protocol, ICF, IB, available safety information, subject documents (eg, study 
diary), subject recruitment procedures (eg, advertisements), information about payments (ie, PI 
payments) and compensation available to the subjects and documentation evidencing the PI’s 
qualifications should be submitted to the IRB for ethical review and approval if required by local 
regulations, prior to the study start. 
The PI/Sponsor and/or designee will follow all necessary regulations to ensure appropriate, 
initial, and on-going IRB study review.  The PI/Sponsor (as appropriate) must submit and, where 

 
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necessary, obtain approval from the IRB for all subsequent protocol amendments and changes to 
the ICF.  Investigators will be advised by the Sponsor or designee whether an amendment is 
considered substantial or non-substantial and whether it requires submission for approval or 
notification only to an IRB. 
Safety updates for H3B-6545 will be prepared by the Sponsor or its representative as required for 
distribution to the investigator(s) and submission to the relevant IRB. 
13.2 
Regulatory Approval 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, prior to study initiation.  If required, the 
Sponsor will also ensure that the implementation of substantial amendments to the protocol and 
other relevant study documents happens only after approval by the relevant regulatory 
authorities. 
13.3 
Informed Consent 
Informed consent is a process by which a subject voluntarily confirms his or her willingness to 
participate in a particular study after having been informed of all aspects of the study that are 
relevant to the subject's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated ICF. 
The ICF will be submitted for approval to the IRB that is responsible for review and approval of 
the study.  Each ICF must include all of the relevant elements currently required by the FDA, as 
well as local county authority or state regulations and national requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the research study.  
Once the essential information has been provided to the prospective candidate, and the 
investigator is sure that the individual candidate understands the implications of participating in 
this research study, the candidate will be asked to give consent to participate in the study by 
signing an ICF.  A notation that a written ICF has been obtained will be made in the subject’s 
medical record.  A copy of the ICF, to include the subject’s signature, will be provided by the 
investigator to the subject. 
If an amendment to the protocol substantially alters the study design or the potential risks to the 
subject, the subject’s consent to continue participation in the study should be obtained. 
13.3.1 
Confidentiality 
13.3.1.1 Subject Confidentiality 
The contents of this protocol and any amendments and results obtained during the study should 
be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and will not be 
disclosed in whole or in part to others, or used for any purpose other than reviewing or 
performing the study, without the written consent of the Sponsor.  No data collected as part of 
this study will be used in any written work, including publications, without the written consent of 
the Sponsor.  These obligations of confidentiality and non-use shall in no way diminish such 
obligations as set forth in either the Confidentiality Agreement or Clinical Trial Agreement 
(CTA) executed between the Sponsor/Contract Research Organization (CRO) and the 
institution/investigator. 

 
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All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or CTA executed 
between the institution/investigator and the Sponsor/CRO. 
Confidentiality of subject’s personal data will be protected in accordance with all applicable 
global regulations. Regulations require that, in order to participate in the study, a subject must 
sign an authorization from the study that he or she has been informed of following: 
● What protected health information (PHI) will be collected from subjects in this study. 
● Who will have access to that information and why. 
● Who will use or disclose that information. 
● That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal 
or state privacy laws. 
● The information collected about the research study will be kept separate from the 
subject’s medical records, but the subject will be able to obtain the research records after 
the conclusion of the study. 
● Whether the authorization contains an expiration date. 
● The rights of a research subject to revoke his or her authorization. 
In the event that a subject revokes authorization to collect or use his or her PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (ie, that the subject is alive) at 
the end of their scheduled study period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that 
the investigator and institution permit authorized representatives of the Sponsor, the regulatory 
authorities and the IRB/EC direct access to review the subject’s original medical records at the 
site for verification of study-related procedures and data.  
Measures to protect confidentiality include that only a unique study number and initials will 
identify subjects in the eCRF system or other documents submitted to the Sponsor.  This 
information, together with the subject’s date of birth, will be used in the database for subject 
identification.  Subject names or addresses will not be entered in the eCRF database system.  No 
material bearing a subject’s name will be kept on file by the Sponsor.  Subjects will be informed 
of their rights within the ICF/patient information sheet. 
13.3.1.2 Investigator and Staff Information 
Personal data of the investigators and sub-investigators may be included in the database and shall 
be treated in compliance with all applicable laws and regulations.  When archiving or processing 
personal data pertaining to the investigator or sub-investigator, all appropriate measures will be 
taken to safeguard and prevent access to this data by any unauthorized party. 
The name and telephone and fax numbers of the Medical Monitor and other contact personnel at 
the Sponsor and of the CRO(s) are listed in the Investigator Study File provided to each site. 
13.4 
Financial Information 

 
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The finances for this clinical study will be subject to a separate written agreement between the 
Sponsor and applicable parties.  Any investigator financial disclosures as applicable to 21CFR 
Part 54 shall be appropriately provided. 
14. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY 
14.1 
Amendments to the Protocol 
Amendments to the protocol shall be planned, documented and signature authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented 
by the Sponsor or its representative.  All amendments require review and approval of all 
pharmaceutical companies and the PI supporting the study.  The written amendment must be 
reviewed and approved by the Sponsor and submitted to the IRB at the investigator’s facility for 
the board’s approval. 
Amendments specifically involving change to study design, risk to subject, increase to dosing or 
exposure, subject number increase, or addition or removal of new tests or procedures shall be 
reviewed and approved by the IRB of record for the investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by the 
Sponsor as applicable and IRB/EC approval obtained, specifically when an increase to dosing or 
subject exposure and/or subject number has been proposed; or, when the addition or removal of 
an investigator is necessitated. 
Items requiring a protocol amendment with IRB and/or FDA or other regulatory authorities’ 
approval include, but are not limited to, the following: 
● Change to study design. 
● Risk to subject. 
● Increase to dose or subject exposure to drug. 
● Subject number increase 
● Addition or removal of tests and/or procedures 
● Addition/removal of a new investigator 
It should be further noted that, if an amendment to the protocol substantially alters the study 
design or the potential risks to the subjects, their consent to continue participation in the study 
should be obtained. 
14.2 
Documentation Required to Initiate the Study 
Before the study may begin certain documentation required by FDA regulations and ICH GCP 
must be provided by the investigator.  Documents required to begin a study in the US include at 
a minimum, but are not limited to, the following: 
● A signed and dated confidentiality agreement 
● A signature-authorized protocol and contract 

 
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● A copy of the official IRB approval of the study and the IRB/EC members list 
● Current curricula vitae for the PI and any associate investigator(s) who will be involved 
in the study 
● Indication of appropriate accreditation for any laboratories to be used in the study and a 
copy of the normal ranges for tests to be performed by that laboratory 
● Original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed 
● A copy of the IRB/EC-approved ICF (and patient information sheet, if applicable) 
containing permission for audit by representatives of the CRO, the Sponsor, the IRB, and 
the FDA and other regulatory agencies (as applicable). 
● Financial disclosure forms for all investigators listed on Form FDA 1572 (if applicable, 
ie, for covered trial). 
● Site qualification reports, where applicable. 
● Verification of PI acceptability from local and/or national debarment list(s)  
14.3 
Study Documentation and Storage 
The PI must maintain a list of appropriately qualified persons to whom he/she has delegated 
study duties and should ensure that all persons assisting in the conduct of the study are informed 
of their obligations.  All persons authorized to make entries and/or corrections on the eCRFs are 
to be included on this document.  All entries in the subject’s eCRF are to be supported by source 
documentation where appropriate. 
Source documents are the original documents, data, records, and certified copies of original 
records of clinical findings, observations, and activities from which the subject’s eCRF data are 
obtained.  These can include, but are not limited to: hospital records and clinical and office 
charts; laboratory, medico-technical department and pharmacy records; diaries, microfiches, and 
ECG traces; copies or transcriptions certified after verification as being accurate and complete; 
photographic negatives, microfilm or magnetic media; X-rays; and correspondence. 
The PI and each study staff member is responsible for maintaining a comprehensive and 
centralized filing system (eg, regulatory binder or investigator study file [ISF]) of all study-
related (essential) documentation, suitable for inspection at any time by representatives from the 
Sponsor and/or applicable regulatory authorities.  The ISF must consist of those documents that 
individually or collectively permit evaluation of the conduct of the study and the quality of the 
data produced.   
The ISF should contain as a minimum all relevant documents and correspondence as outlined in 
ICH GCP Section 8 and 21 CFR Part 312.57, including key documents such as the IB and any 
amendments, protocol and any amendments, signed ICFs, copies of completed eCRFs, IRB 
approval documents, Financial Disclosure forms, subject identification lists, enrollment logs, 
delegation of authority log, staff qualification documents, laboratory normal ranges, and records 
relating to the study drug including accountability records.   
Drug accountability records should, at a minimum, contain information regarding receipt, 
shipment, and disposition.  Each form of drug accountability record, at a minimum, should 
contain PI name, date drug shipped/received, quantity, and batch/code or lot number for identity 

 
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of each shipment.  In addition, all original source documents supporting entries in the eCRF must 
be maintained and be readily available. 
The Sponsor shall maintain adequate investigational product records and financial interest 
records as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not 
been approved by FDA, for no less than 2 years after the last shipment/delivery of the drug for 
investigational use is discontinued and the FDA has been notified of the discontinuation. 
The IRB shall maintain adequate documentation/records of IRB activities as per 21CFR Part 
56.115 for at least 3 years after completion of the research. 
The investigator shall maintain adequate records of drug disposition, case histories and any other 
study-related records as per 21 CFR Part 312.62 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not 
been approved by FDA, for no less than 2 years after the last shipment/delivery of the drug for 
investigational use is discontinued and FDA has been notified of the discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the investigator additionally agrees to keep records, including the identity of all 
participating subjects (sufficient information to link records eg, eCRFs, medical records), all 
original signed ICFs, and copies of all eCRFs, SAE Reporting forms, source documents, detailed 
records of treatment disposition, and related essential regulatory documents.  The documents 
listed above must be retained by the investigator for as long as needed to comply with national 
and international regulations (generally 2 years after discontinuing clinical development or after 
the last marketing approval).  The Sponsor or its representatives will notify the 
investigator(s)/institutions(s) when the study-related records are no longer required. 
If the investigator relocates, retires, or for any reason withdraws from the study, both the Sponsor 
and its representative should be prospectively notified.  The study records must be transferred to 
an acceptable designee, such as another investigator, another institution, or to the Sponsor.  The 
investigator must obtain the Sponsor’s written permission before disposing of any records, even 
if retention requirements have been met.  All ISFs will be maintained by the Sponsor or its 
representative throughout the study and will be transferred to the Sponsor at the conclusion of 
the study. 
14.4 
Data Collection 
The study eCRF is the primary data collection instrument for the study.  Case report forms will 
be completed using the English language and should be kept current to enable the Sponsor to 
review the subjects’ status throughout the course of the study. 
In order to maintain confidentiality, only study number, subject number, initials and date of birth 
will identify the subject in the eCRF system if applicable by governing laws.  If the subject’s 
name appears on any other document (eg, laboratory report), it must be obliterated on the copy of 
the document and replaced instead with the subject number and subject’s initials or allowable 
country specific subject identifying information.  The investigator will maintain a personal 
subject identification list (subject numbers with corresponding subject identifiers) to enable 
records to be identified and verified as authentic.  Subject data/information will be kept 
confidential and will be managed according to applicable local, state, and federal regulations. 

 
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All data requested by the eCRF system must be supported by and be consistent with the subject’s 
source documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the eCRF, 
a note should be created verifying that the field was “Not Done” or “Unknown.”  For any entry 
errors made, the error(s) must be corrected, and a note explaining the reason for change should 
be provided. 
The investigator will electronically sign and date the subject eCRF indicating that the data in the 
eCRF has been assessed.  Each completed eCRF will be signed and dated by the PI, once all data 
for that subject is final. 
14.5 
Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical reasons or any other reason at 
any time.  If a study is prematurely terminated or suspended, the Sponsor will promptly inform 
the investigators/institutions and regulatory authorities of the termination or suspension and the 
reason(s) for the termination or suspension.  The IRB/IEC will also be informed promptly and 
provided the reason(s) for the termination or suspension by the Sponsor or by the 
investigator/institution, as specified by the applicable regulatory requirement(s). 
The investigator reserves the right to discontinue the study should his/her judgment so dictate.  If 
the investigator terminates or suspends a study without prior agreement of the Sponsor, the 
investigator should inform the institution where applicable, and the investigator/institution 
should promptly inform the Sponsor and the IRB/IEC and provide the Sponsor and the IRB/IEC 
with a detailed written explanation of the termination or suspension.  Study records must be 
retained as noted above. 
14.6 
Disclosure and Publication Policy 
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by the Sponsor in advance of submission pursuant to 
the terms and conditions set forth in the executed CTA between the Sponsor/CRO and the 
institution/investigator.  The review is aimed at protecting the Sponsor's proprietary information 
existing either at the date of the commencement of the study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the Sponsor or CRO, as appropriate.

 
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α ligand-binding domain mutations in human breast cancer. Breast Cancer Res Treat. 
2020;180:611–22. https://doi.org/10.1007/s10549-020-05564-y 
Gyanchandani et al., 2016 
Gyanchandani R, Kota KJ, Jonnalagadda AR, et al. Detection of ESR1 mutations in circulating 
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16. 
APPENDICES 
 
 

 
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APPENDIX A: 
ECOG PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to carry 
on all pre-disease performance without 
restriction. 
 
100 
Normal, no complaints, no evidence of 
disease. 
 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of a 
light or sedentary nature (eg, light 
housework, office work). 
 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed < 50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities.  Up and about 
more than 50% of waking hours. 
 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed > 50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
 
40 
Disabled, requires special care and 
assistance 
 
30 
Severely disabled, hospitalization 
indicated.  Death no imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead 
0 
Dead 
ECOG = Eastern Cooperative Oncology Group. 
 

 
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APPENDIX B: 
NEW YORK HEART ASSOCIATION (NYHA) CLASSIFICATION OF CARDIAC 
DISEASE 
The following table presents the NYHA classification of cardiac disease. 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of physical 
activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results 
in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or the 
anginal syndrome may be present even at rest.  If any physical activity is 
undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 1994:253-256. 

 
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APPENDIX C: 
GUIDELINES FOR WOMEN OF CHILDBEARING POTENTIAL 
Acceptable Contraception Methods:   
Women of childbearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 28 days after 
stopping treatment.   
Highly effective contraception is defined as either: 
True Abstinence 
When this is in line with the preferred and usual lifestyle of the subject.  
Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Sterilization  
When a woman of childbearing potential has had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least 
six weeks prior to study entry.  In case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment. 
Male Partner Sterilization When the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate. 
Intrauterine Device Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
A Double-Barrier Method [such as condom plus diaphragm with spermicide] Barrier 
methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/vaginal suppository. 
Contraceptive Implant 
Oral Contraceptive  
Unacceptable Contraception Methods for women of childbearing potential include: 
● IUD progesterone T 
● Female condom 
● Natural family planning (rhythm method) or breastfeeding 
● Fertility awareness 
● Withdrawal 
● Cervical shield 
Pregnancies 
To ensure subject safety, each pregnancy in a subject on study treatment must be reported to 
within 24 hours of learning of its occurrence.   
The pregnancy should be followed up for 3 months after the termination of the pregnancy to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and 
the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 

 
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Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator.  Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study drug of any pregnancy outcome.  Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study.  Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
The detailed contact information for reporting of pregnancies is provided in the Investigator 
Study File. 
Women Not of Childbearing Potential are Defined as Follows:   
● Women are considered postmenopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(eg, age appropriate, history of vasomotor symptoms).  
● Women who are permanently sterilized (ie, bilateral tubal ligation, total hysterectomy, 
or bilateral oophorectomy, all with surgery at least 1 month before dosing).  

 
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acquisition; PD = pharmacodynamics; PG = pharamacogenetic; PK = pharmacokinetic; PT/PTT = prothrombin time/partial thromboplastin time; RECIST = Response Evaluation Criteria in Solid 
Tumors; TSH = thyroid-stimulating hormone 
a. 
Informed consent must be obtained ≤28 days prior to the initiation of study treatment.  Informed consent must be obtained for pre-screening for ESR1 mutations, and the results from a 
sponsor-designated cfDNA test confirming subject eligibility must be obtained prior to signature of the informed consent form, unless prior authorization has been received by the Sponsor, 
based on local mutation analysis-. 
b. 
Physical examinations will include measurements of weight and vital signs (resting heart rate [HR], blood pressure [BP], respiratory rate [RR], oral temperature).  No need to repeat physical 
exams on Cycle 1 Day 1 if the baseline physical exam was performed ≤72 hours.  Height will be recorded at the baseline visit only.  Cycle 2 and beyond, physical exam will be obtained on 
Day 1 of each cycle.   
c. 
A bone scan (99m-technetium-based scintigraphy, whole-body bone magnetic resonance imaging, or 18F-sodium fluoride position emission tomography) to establish a baseline should be 
performed prior to first dose of study drug (a historical bone scan performed within 6 weeks prior to the first dose is acceptable), and as clinically indicated.  Lesions identified on bone scans 
should be followed with cross-sectional imaging. 
d. 
Triplicate 12-lead ECGs will be collected approximately 5 minutes apart at the screening visit for all subjects.  On Day 1 of Cycles 1, 2, 3, and 4, triplicate ECGs will be collected 
approximately 5 minutes apart pre-dose and 3 hours (± 1 hour) post-dose for all subjects. Mandatory collections will be taken for both Phase 1 and Phase 2 subjects on Day 1 and Day 15 of 
Cycle 1. 12-lead safety ECGs will be performed locally from Day 1 of each cycle starting Cycle 5 till the last cycle prior to the EOT visit, and at Unscheduled visits as clinically required.  A 
single 12-lead safety ECG is required at a minimum.  Data from local safety ECGs should be entered into the clinical database.  At the end-of-treatment visit, 1 set of triplicate ECGs will be 
collected approximately 5 minutes apart.  If sinus bradycardia is ongoing at the EOT visit, ECGs should be obtained at least once a week until confirmation obtained that subject has returned 
to 60 or more beats per minute or to pre-treatment baseline value. If sinus bradycardia is observed at any point during treatment (from ECG or other clinical assessment), it is recommended 
the subject undergo a stress test per institution policy and data is recorded in the clinical database. A stress test is recommended to be done only once for each subject who has under 60 beats 
per minute (while on treatment) and more than a 20 percent reduction from baseline in beats per minute. The stress test should be triggered by the previous two cardiac observations at rest. 
Baseline, Cycle 1- Cycle 4, EOT, and 28 Day Safety Follow-up visit ECGs should be collected on study specific equipment provided by ERT. Additional ECGs taken during the study 
period on local machines should also be reported in the clinical database. 
e. 
A 12-lead continuous Holter will be used in Cycle 1, Days 1 and 15 [at least 1 hour prior to the first administration of the drug and continue through at least 24 hours after] for Phase 1 
subjects only (ECG and Holter monitoring grouped together in Phase 1).  For convenience, Holter monitoring may begin up to 12 hours prior to dosing on Cycle 1, Day 1 and Day 15. Holter 
monitoring will not apply to subjects enrolled under Amendment 6 (or subsequent amendments). 
f. 
All concomitant medications taken within 28 days prior to Cycle 1 Day 1 and while on study treatment through 28 days post-last dose should be documented in the electronic case report 
form (eCRF). 
g. 
Hematological parameters include the following laboratory tests: CBC consisting of hematocrit, hemoglobin, total white blood count (WBC) with 5-part differential, and platelet count plus 
reticulocyte count.  Do not repeat on Cycle 1 Day 1 if it is within 72 hours of baseline.  CBCs are collected every visit before treatment.  
h. 
CMP panel includes the following: blood urea nitrogen (BUN), creatinine, sodium, potassium, calcium, chloride, carbon dioxide, magnesium, phosphorous, glucose, albumin, total protein, 
total bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase, and thyroid function tests (TSH and Free T4).  Do not 
repeat on Cycle 1 Day 1 if it is within 72 hours of baseline. 
i. 
PT/PTT will be assessed at screening by standard method at a local laboratory.  PT/PTT will be analyzed weekly during the first cycle and on Day 1 and Day 15 of all subsequent cycles and 
at the end-of-treatment visit. This must be obtained with a peripheral blood stick.  
j. 
Urine testing dipstick will be done at baseline and weekly during Cycle 1.  Thereafter urine dipstick will be done on Day 1 and Day 15 of each 28-day cycle.  If abnormalities are present, 
microscopic testing should be done. 
k. 
A serum or urine pregnancy test must be performed at baseline for all women of childbearing potential (ie, pre-and perimenopausal subjects) (no need to repeat on Cycle 1 Day 1 if within 72 
hours).  For women of childbearing potential, the test will be repeated on Day 1 of each additional cycle prior to administration, at end of treatment visit and safety follow up visit (28 days 
(with up to +7 day window).  A negative result must be confirmed prior to administration. 

 
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l. 
PK blood samples will be collected for all Phase 1 subjects on Cycle 1 Day 1 and Day 15 (at time points 0 (pre-dose), 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr 8 hr, 10 hr and 24 hr post-dose) and at pre-
dose on Cycle 1 Day 8 and Day 22.  The ±1 day-window does not apply to the Day 1 and Day 15 visits.  Subjects in the food-effect portion of Phase 2 will have PK blood samples collected 
on Cycle 1 Day 15 and Cycle 1 Day 22 at time points 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 10, and 24 hr post-dose.  Subjects in the food-effect cohort will be randomly assigned to receive the 
Cycle 1 Day 15 dose of H3B-6545 in a fed or fasted state.  Each subject will then receive the Cycle 1 Day 22 dose in the reverse/untried state. At least sparse sampling for PK (3 time points 
per subjects) will be performed on Day 15 for the Phase 2 subjects not enrolled in the food-effect sub-study following one of three schedules, assigned sequentially: Schedule 1:  pre-dose (0 
hr), 0.5 hr, and 6 hr, Schedule 2:  pre-dose (0 hr), 2 hr, 8 hr, or Schedule 3:  1 hr, 4 hr, 24 hr.  As this is a first-in-human clinical trial and no prior human pharmacokinetics data are available, 
it is essential that the clinical staff take the blood samples for PK analysis as close as possible to the scheduled time point.  This should help improve the accuracy of the PK modeling and 
minimize the variability around the PK estimates for H3B-6545.  The exact date and time of the trial therapy administration must be recorded.  The exact time and date of the blood draw 
must be recorded.  A protocol deviation will be reported only when a PK time point is not collected (missing) or blood is drawn on the wrong study day.  
For subjects enrolled under Amendment 6 (or subsequent amendments), PK samples will be collected on Cycle 1 Days 1 and 15 at pre-dose (0 hr) and at 1, 2, 4, and 6 hr post-dose. 
m. Archival tumor samples will be requested prior to the subject’s first dose.  Material should be provided as a tissue block or 15 unstained slides. 
n. 
Subjects will be restaged according to RECIST 1.1 at 8-week intervals (± 1 week) until radiologic disease progression or starting a new cancer therapy. All study imaging for tumor 
assessments will be sent to an imaging core laboratory designated by the Sponsor for review of quality and archived for potential independent review. 
o. 
Tumor assessments will only be done in subjects who have not previously demonstrated disease progression in the study unless completed within the previous 4 weeks.   
p. 
In addition to prescreening, screening, whole blood for cell-free DNA (nucleic acids) will be collected at Cycle 1 Day 1 and Day 15 and at the same day (or as close as possible) to each 
tumor assessment, that is, approximately every 8 weeks after Cycle 1 Day 1. Only 1 tube of 10 mL of whole blood is needed at each time point, except at prescreening, screening, Cycle 1 
Day1, and EoT, where 2 tubes of 10 mL of whole blood are required. 
q. 
Blood for CTCs in Phase 1 only. All biomarkers should optimally be collected pre-dose. 
r. 
The ±1 assessment window for Cycle 1 Day 15 does not apply to Phase 2 subjects participating in the food effect study.  
s. 
Subject must have at least one biopsiable lesion in the Phase 1 portion.  In Phase 2, subjects must also have either (a) at least 1 measurable lesion as per RECIST 1.1, or (b) at least one 
predominantly lytic bone lesion.  Subjects must be willing to undergo tumor biopsies prior to treatment and on Cycle 2 Day 1.  In the Phase 2 part of the trial, subjects with bone-only 
disease, or subjects for whom a biopsy is contra-indicated, may opt out of providing tumor biopsies following investigator concern and direct discussion and approval from Sponsor The 
second biopsy must be acquired during the first week of Cycle 2 (Cycle 2 Day 1-Cycle 2 Day 8).  The subject must have received at least 7 days of consecutive dosing prior to collection of 
the second biopsy.  The window for collection of the Cycle 2 biopsy may be extended if needed in order to ensure 7 consecutive days of dosing prior to collection. 
For subjects enrolled under Amendment 6 (or subsequent amendments), a recent archival tumor tissue obtained within 6 months prior to enrollment or a fresh tumor biopsy must be 
provided. A second biopsy after initiating trial therapy is not required. 
t. 
Biomarkers of bone turn-over will be collected at Cycle 1 Day 1 (any time during screening up to pre-dose), Cycle 2 Day 15 and Cycle 4, Day 1 and EOT.  A total of 6 mL of blood will 
be collected in a serum separating tube at each visit.  There can be an important circadian rhythm variation of these markers; samples should thus optimally be collected after fasting in the 
morning (between 8:00 and 10:00 am) and specimen collection should be consistent during study visits.  
u. 
Transvaginal ultrasound will be performed during the screening period and at Cycle 4 Day 1 (±10 days), and every 24 weeks after that, as long as the subject is on study treatment; only for 
subjects who are part of the endometrium safety sub-study.  
v. 
All subjects will undergo the end-of-treatment assessments listed within 28 days after treatment ends.   
w. Following progression, all subjects will be followed for survival at least every 12 weeks from EOT visit.  The follow-up can be done by telephone call at the investigator’s discretion.  
x. 
Subjects must be followed for AEs for 28 calendar days after the last dose and complete a safety follow-up visit on the 28th day (with up to + 7 day window). During the safety follow-up 
visit, the following should be obtained: vital signs, hematological and CMP laboratory parameters and triplicate ECGs on ERT provided study equipment.  
y. 
Missed visits:  If a scheduled protocol visit is missed or rescheduled for any reason, all clinic visits will be scheduled based on the subject’s Cycle 1 Day 1 date. Missed safety assessments 
are to be performed at the subsequent visit when patient resumes study treatment.  

 
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Dose interruption:  During or immediately following a dose interruption, the protocol requires that study visit take place in order for the completion of required safety assessments. PK/PD 
samples missed due to dose interruptions do not have to be retroactively collected. 
Unscheduled visit:  Safety assessments that are obtained outside of the routine visits are recorded in the eCRF under “Unscheduled Visit” using the actual visit date. 
z. 
Subjects may discontinue Day 15 visits for all cycles beyond cycle 4. 
 
 
 
 

 
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APPENDIX F: 
EXTENSION PHASE 
 
Extension Phase will begin for subjects still on treatment at the time of the data cutoff for primary analysis 
 
Procedure 
TreatmentA 
EoTN 
Safety Follow-Up 
Vital signs and weightB 
X 
 
 
Physical examinationC 
X 
X 
 
ECOG performance status 
X 
X 
 
12-Lead ECGD 
X 
X 
 
Echocardiogram or MUGA scanE 
As clinically indicated 
As clinically indicated 
 
Hematology and clinical chemistry (local lab)F 
X 
X 
 
Urine dipstick testingG 
X 
X 
 
Pregnancy testH 
X 
X 
 
Tumor assessments (CT/MRI)I 
As per local standard of care but not less 
frequently than every 12 weeks or earlier if 
clinically indicated 
 
 
Bone ScanJ 
As clinically indicated 
 
 
Brain scan (CT/MRI)K 
As clinically indicated 
 
 
Study Treatment  
28 Day cycle 
 
 
Concomitant medicationsL 
X 
X 
X 
AEs/SAEsM 
X 
X 
X 
AE = adverse event; BP = blood pressure; CT = computed tomography; ECG = electrocardiogram; EoT=end of treatment assessment; HR = heart rate; LVEF = left 
ventricular ejection fraction; MRI=magnetic resonance imaging; MUGA = multiple-gated acquisition; RR = respiratory rate; SAE-serious adverse event. 
 
A. Efforts should be made to conduct study visits on the day scheduled (Cycle X Day 1 ±3 days). The study visit (and safety assessments) still needs to occur regardless of a 
study medication hold per the visit schedule.   
B. Assessments will include vital signs (resting BP [including date and time of measurement], HR, RR and body temperature) and weight.  
C. A symptom-directed physical examination during the study, as clinically indicated. 
D. Single 12-lead ECG. Subjects are suggested to be in the recumbent position for a period of 5 minutes prior to obtaining ECG. 
E. An echocardiogram or MUGA scan to assess LVEF will be performed as clinically indicated 
F. Clinical laboratory assessments will be conducted at a local laboratory. Clinical chemistry and hematology results should be reviewed prior to administration of study 
drug for all cycles. Assessments may be performed within 72 hours prior to the visit. 
G. Urine dipstick testing for subjects should be performed preferably at the investigational site (but may be performed locally by the primary care physician or a local 
laboratory if the subject does not have to come for a visit to the site).  

 
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H. A serum or urine pregnancy test will be performed at Day 1 of every cycle, and at the EoT assessment in women of childbearing potential (ie, premenopausal and 
perimenopausal women who have been amenorrheic for less than 12 months). 
I. 
After the data cutoff for the primary analysis: Tumor assessments using contrast-enhanced CT of the chest and contrast-enhanced CT or MRI of the abdomen, pelvis and 
other areas of known disease at screening or newly suspected disease should be performed as per local standard of care but not less frequently than every 12 weeks or 
earlier if clinically indicated.  The same methodology (CT or MRI) and scan acquisition techniques that were used for the assessment during the Study Treatment Phase 
should be used after the data cutoff for the primary analysis.   
J. 
A bone scan to assess bone metastases should be performed as clinically indicated. 
K. Brain scans should be performed as clinically indicated. 
L. Concomitant medications will be recorded until 28 days after last dose 
M. Subjects must be followed for AEs for 28 calendar days after the last dose and complete a safety follow-up visit on the 28th day (with up to + 7 day window). 
N. Tumor assessments will only be done in subjects who have not previously demonstrated disease progression in the study unless completed within the previous 4 weeks. 
 
 

 
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APPENDIX G: 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 
VERSION 1.1 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1).  Eur J Cancer.  2009;45(2):228-47. 
 
 

 
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APPENDIX H: 
CONCOMITANT MEDICATIONS 
Combination administration of study drugs could result in DDI that could potentially lead to 
reduced activity or enhanced toxicity of the concomitant medication and/or H3B-6545.  
Use of antacids is allowed. 
The use of palonosetron, prochlorperazine, promethazine, and cyclizine for management of 
nausea and vomiting is also allowed.  The use of ondansetron and granisetron is not permitted 
because of their potential to prolong QT interval 
Herbal preparations/medications are not allowed throughout the study; thus, the subject should 
stop using herbal medications 7 days prior to first dose of H3B-6545.  These herbal medications 
include, but are not limited to:  St. John’s wort, kava, ephedra (ma huang), gingko biloba, 
DHEA, yohimbe, saw palmetto, and ginseng.   
The following list of prohibited medications is based on the Oncology Clinical Pharmacology 
Drug-Drug Interaction Database (release date: 29 Oct 2012), which was compiled from the 
Indiana University School of Medicine’s “Clinically Relevant” Table and supplemented with the 
FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
Implications for Dosing and Labeling (February 2012).  These lists are not comprehensive and 
are only meant to be used as a guide.  Please contact the medical monitor with any questions. 
 
 

 
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List of prohibited medications (including but not limited to:) 
Category 
Drug Name 
Strong CYP3A4 inhibitors 
and inducers 
Carbamazepine, clarithromycin, conivaptan, itraconazole, 
ketoconazole, nefazodone, phenobarbital, phenytoin, 
posaconazole, rifabulin, rifampin, telithromycin, 
voriconazole 
Strong CYP3A4 inhibitors 
Clarithromycin, conivaptan, itraconazole, ketoconazole, 
nefazodone, posaconazole, telithromycin, voriconazole,  
Strong CYP3A4 inducers  
Carbamazepine phenobarbital, phenytoin, rifabulin, rifampin,  
St. John’s wort 
P-gp inhibitors1 
Amiodarone, cyclosporine, dronedarone, ranolazine, 
verapamil 
CYP2C9 substrates with 
narrow therapeutic index2 
(NTI) 
Phenytoin, warfarin 
CYP2C19 substrates with 
NTI 
Diazepam, amitriptyline, phenytoin 
CYP3A substrates with NTI 
Alfentanil, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, tacrolimus 
P-gp substrate with NTI 
Digoxin 
BCRP substrate with NTI 
Sulfasalazine, methotrexate 
Medications with a known 
risk for QT prolongation 
See Appendix I  
BCRP = breast cancer resistance protein; CYP = cytochrome P450; P-gp = P-glycoprotein. 
1. P-gp inducers already listed as CYP3A4 inducers. 
2. Narrow therapeutic index drugs are drugs where small differences in dose or blood concentration may lead 
to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent 
or significant disability or incapacity. 
 
 

 
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APPENDIX I: 
DRUGS THAT PROLONG QT INTERVAL AND/OR INDUCE TORSADES DE 
POINTES 
This is not a comprehensive list.  A complete list may be found in Woosley, RL and Romero, 
KA, QTdrugs List, Accession Date, AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, 
AZ  85755 and updated at the following Web address: http://crediblemeds.org. 
 
Antiarrhythmics  
Amiodarone Disopyramide Dofetilide  
Ibutilide  
Procainamide Quinidine  
Sotalol  
 
Antibiotics 
Clarithromycin Erythromycin Gatifloxacin 
Moxifloxacin 
Sparfloxacin  
Antipsychotics 
Chlorpromazine Haloperidol Mesoridazine  
Pimozide Risperidone 
Thioridazine  
Ziprasidone 
Antidepressants 
Amitriptyline 
Desipramine 
Doxepin  
Imipramine 
Maprotiline 
Venlafaxine 
Antifungals (azoles)  
Ketoconazole 
Itraconazole 
Antimalarials 
Chloroquine  
Halofantrine  
Antiemetics 
Dolasetron 
Domperidone  
Droperidol  
Ondansetron 
Tropisetron  

 
CONFIDENTIAL 
STUDY DRUG:  H3B-6545 
PROTOCOL AMENDMENT 9:  29 AUG 2022 
Page 159 of 160 
APPENDIX I: 
DRUGS THAT PROLONG QT INTERVAL AND/OR INDUCE TORSADES DE 
POINTES 
This is not a comprehensive list.  A complete list may be found in Woosley, RL and Romero, 
KA, QTdrugs List, Accession Date, AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, 
AZ  85755 and updated at the following Web address: http://crediblemeds.org. 
 
Antihistamines 
Astemizole 
Terfenadine 
Alimemazine 
Hydroxyzine 
Diphenhydramine 
Miscellaneous  
Arsenic trioxide  
Bepridil Methadone  
Pentamidine  
Cisapride  
Tacrolimus 
 
 
 

 
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APPENDIX J: 
SECURITY OF THE SAMPLES, USE OF THE SAMPLES, AND RETENTION OF THE 
SAMPLES 
Sample processing, for example, DNA and/or RNA extraction, genotyping, sequencing, or other 
analysis, will be performed by a laboratory under the direction of the Sponsor. Processing, 
analysis, and storage will be performed at a secure laboratory facility to protect the validity of 
the data and maintain subject privacy.  Samples will only be used for the purposes described in 
this protocol.  Laboratories contracted to perform the analysis on behalf of the Sponsor will not 
retain rights to the samples beyond those necessary to perform the specified analysis and will not 
transfer or sell those samples.  The Sponsor will not sell the samples to a third party. 
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of the 
storage period, samples will be destroyed.  Samples may be stored longer if a health authority (or 
medicinal product approval agency) has active questions about the study.  In this special 
circumstance, the samples will be stored until the questions have been adequately addressed. 
It is possible that future research and technological advances may identify genomic variants of 
interest or allow alternative types of genomic analysis not foreseen at this time. Because it is not 
possible to prospectively define every avenue of future testing, all samples collected will be 
single or double coded (according to the ICH E15 guidelines) in order to maintain subject 
privacy.