An Open-Label Multicenter Phase 1b Study of H3B-6545 in Combination With Palbociclib in Women With Advanced or Metastatic Estrogen Receptor-Positive HER2-Negative Breast Cancer
Phase: PHASE1
Conditions: Receptors, Estrogen, Genes, Erbb-2, Breast Neoplasms
Sponsor: Eisai Inc.

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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
H3B-6545-G000-102
Study Protocol Title:
An Open-Label Multicenter Phase 1b Study of H3B-6545 in 
Combination With Palbociclib in Women With Advanced or Metastatic 
Estrogen Receptor–Positive HER2-Negative Breast Cancer
Sponsor:
Eisai Inc.
200 Metro Boulevard
Nutley, NJ 07110
USA
Sponsor’s 
Investigational 
Product Name:
H3B-6545 and palbociclib
Indication:
Advanced or metastatic estrogen receptor–positive HER2-negative 
breast cancer
Phase:
1b
Approval Date(s): 
V1.0
V2.0
V3.0
V4.0
V5.0
06 Dec 2019 (Original Protocol)
05 May 2020 (Amendment 1.0)
10 Jul 2020 (Amendment 2.0)     
15 Jun 2021 (Amendment 3.0)
29 Aug 2022 (Amendment 4.0)
IND Number:
133282
EudraCT Number:
2019-004622-17
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information that 
is not authorized in writing by the sponsor is strictly prohibited.  Such 
information may be used solely for the purpose of reviewing or 
performing this study.

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Date
Highlights of Major Changes
Section/Change
06 December 2019
Original Protocol
05 May 2020
Amendment 1
Synopsis and Section 8.3.2 Exclusion Criteria
-
Clarified that double-barrier contraception is considered 
acceptable, but not highly effective, method of contraception.
Synopsis and Section 8.3.3 Definition of Dose-Limiting Toxicities
-
Added ALT or AST > 3 × ULN, in conjunction with total 
bilirubin > 2 × ULN in absence of liver metastases at baseline and 
in absence of clinical or radiological evidence of biliary 
obstruction.
Section 8.1 Overall Study Design and Plan
-
Edited Table 4 hepatic toxicity criteria as follows: Added ALT or 
AST > 3 × ULN, in conjunction with total bilirubin > 2 × ULN in 
absence of liver metastases at baseline and in absence of clinical 
or radiological evidence of biliary obstruction. 
Section 8.6.2.1 Schedule of Procedures / Assessments
-
Edited Table 8 to include vital sign monitoring in all treatment 
visits.
Date
Highlights of Major Changes
Section/Change
10 July 2020
Amendment 2
Synopsis and Section 8.2, Secondary Objectives 
Secondary Objectives:  Global change of disease control rate (DCR), defined 
as complete response (CR), partial response (PR), or stable disease into clinical 
benefit rate (CBR), defined as CR, PR, or stable disease lasting for ≥23 weeks.
Rationale:  This was done in order to be consistent with the reporting standards 
of breast cancer trials.
-
To estimate the preliminary clinical activity of H3B-6545 plus 
palbociclib in terms of objective response rate (ORR), duration of 
response (DoR), disease control rate (DCR) clinical benefit rate 
(CBR; complete response [CR], partial response [PR], or stable 
disease ≥23 weeks), progression-free survival (PFS), and overall 
survival (OS)
Synopsis 
Clarifications on end of study design language:
End of study: The cutoff date for the main final analysis will be either 12 
approximately 6 months after enrollment of the last subject in the 
expansion phase or the end-of- treatment visit date for the last subject in 

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the study, whichever occurs first., respectively.  The cutoff date for an 
updated (final) analysis, including OS, will be approximately 24 
months after enrollment of the last subject.
Clarifications on dose-limiting toxicities language:
Dose-limiting toxicities (DLTs) will be assessed during the first 28 days 
starting from the 1st day of adding H3B-6545 to palbociclib (Cycle 1 Day 
9 to Cycle 2 Day 8).  Subjects who do not receive at least 75% of the 
scheduled therapy from Cycle 1 Day 91 to Cycle 2 Day 8, for reasons not 
considered to be a DLTother than toxicity, will not be considered 
evaluable for DLT assessment and will be replaced.  Disease progression 
and adverse events (AEs) deemed related to disease progression will not be 
considered DLTs.
Clarifications on Cohort 3b language:
Cohort 3b:  If none or only 1 subject experienced a DLT, doses used in this 
Cohort will and in Cohort 2 could be considered the RP2D.  In this case, 
the SRC will select between Cohort 2 and Cohort 3b for the expansion 
phase.  If 2 or more subjects experienced a DLT, doses used in Cohort 2 
will be considered the RP2D.
Synopsis and Section 9.1, Overall Study Design and Plan
Clarifications on definition of dose-limiting toxicity in the study design:
DLTs:  Unless considered not related to tumor progression study drugs, 
any of the following criteria will qualify as a DLT:
Hepatic
-
Grade 3 or 4 bilirubin increase
-
ALT or AST >≥08 × ULN
-
In absence of liver metastases at baseline and in 
absence of clinical or radiological evidence of biliary 
obstruction: ALT or AST >3 × ULN, in conjunction 
with total bilirubin >2 ×ULN
Biochemistry
-
Grade 4
-
Grade 3 lasting more than 7 days, unless 
considered not clinically significant as per the 
discretion of the investigator
Any other non-
hematologic AE
-
Grade 4 
-
Grade 3 (except diarrhea, rash, nausea, or 
vomiting lasting ≤72 hours)  
-
Any drug-related intolerable Grade 2 toxicity 
(other than hematological AEs) leading to 
administration of <75% of the dose during the 
DLT observation period
a.
Laboratory values that meet criteria listed in this table should be repeated and 
confirmed within 24 hours of the initial results being reported.
Synopsis, Section 9.1, Overall Study Design and Plan, and Section 9.4.3, 
Method of Assigning Subjects to Treatment Groups
Clarification on dose expansion in the study design:

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Dose expansion: An additional 12 subjects will be treated at the 
MTD/RP2D to further characterize safety, tolerability, and PK and to 
provide preliminary estimates of efficacy.  In Cycle 1, sSubjects will 
receive palbociclib PO QD on Days 1 to 21 PO QD and H3B-6545 PO QD 
on Days 9 to 28.  In all subsequent cycles, palbociclib will be administered 
on Days 1 through to 21 and H3B-6545 will be administered Days 1 
through to 28.
Synopsis and Section 9.3.1, Inclusion Criteria
Clarifications on inclusion criteria
5.
Prior therapy in the advanced or metastatic setting: 
a.
Dose escalation: 2 or more prior hormonal therapies.  Subjects may 
have received up to 1 prior chemotherapy regimen and up to 1 prior 
CDK4/6 inhibitor.
b.
Dose expansion: Up to 2 prior endocrine therapies and up to 1 
prior chemotherapy regimen but may not have received a prior 
CDK4/6 inhibitor.
Note: If the patient was enrolled within 12 months of the end of adjuvant 
therapy, the adjuvant therapy will also be counted.
Note:  Subjects must have documented progression while on or after 
the most recent therapy.
6.
Subject has an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1.
7.
Life expectancy >12 weeks, as per investigator’s best assessment, 
during the Screening phase.
Synopsis and Section 9.3.2, Exclusion Criteria
Removed criterion for intrauterine hormone releasing system and contraceptive 
implant.  
8.Females of childbearing potential who:
•
Within 28 days before study entry, did not use a highly effective 
method of contraception, which includes any of the following:
a
Double-barrier contraception (considered acceptable method but not 
highly effective)
b
Total abstinence (if it is their preferred and usual lifestyle)
c
An intrauterine device or intrauterine hormone-releasing system
d
A contraceptive implant
e.d Have a vasectomized partner with confirmed azoospermia.
Synopsis, Section 9.3.2, Exclusion Criteria, and Section 9.4.7.2, Prohibited 
Concomitant Therapies and Drugs
Removed proton pump inhibitor (PPI) criterion from exclusion criteria and 
prohibited concomitant medications
Rationale:  A drug-drug interaction (DDI) study of H3B-6545 with 
pantoprazole, a PPI, in healthy post-menopausal women demonstrated that 
H3B-6545 plasma exposure is similar in the absence or presence of 
pantoprazole, suggesting that restriction on use of PPI or other acid reducing 

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agents could be removed from the exclusion list.  The United States (US) 
Prescribing Information and Summary of Product Characteristics for 
palbociclib state that under fed conditions there is no clinically relevant effect 
of PPIs, H2-receptor antagonists, or local antacids on palbociclib exposure.
10. Subject received in the 7 days prior to the administration of study drug or is 
currently receiving any of the following medications:
a.
Known strong inducers or inhibitors of CYP3A4 or P-glycoprotein (P-
gp).
b.
Medications that have a narrow therapeutic window and are breast 
cancer resistance protein (BCRP) substrate.
c.
Medications that have a known risk to prolong the QT interval or 
induce Torsades de Pointes.
d.
Proton-pump inhibitors and histamine H2-receptor antagonists.
Note:  Use of antacids is allowed but should be administered ≥2 hours 
before or ≥4 hours after H3B-6545.  The use of palonosetron for the 
management of nausea and vomiting is also allowed.
e.d. Medications that have a narrow therapeutic window and are 
predominantly metabolized through CYP2C8, CYP2C9, CYP2C19, or 
CYP3A4.
f.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.
Synopsis and Section 9.3.2, Exclusion Criteria
Added criterion for history of interstitial lung disease and non-infectious 
pneumonitis. 
12. Active interstitial lung disease (ILD) or diagnosis of ILD within the 
last 12 months
Synopsis and Section 9.3.2, Exclusion Criteria
Added exclusion criterion for active COVID-19 infection or recent exposure to 
an individual with COVID-19
14. Exposure within the last 14 days to an individual with confirmed 
or probable COVID-19 or symptoms within the last 14 days or any 
other reason to consider the subject at potential risk for an acute 
COVID-19 infection.  
Note: Please consider testing for active COVID-19 infection prior to 
starting trial therapy according to the institution guidelines.
Synopsis 
Clarifications on duration of treatment: 
Treatment Phase: Subjects will continue to receive study treatment until 
radiological disease progression, development of unacceptable toxicity, or 
withdrawal of consent.  Treatment beyond radiological progression may 
be allowed if the subject continues to have clinical benefit as per the 
principal Investigator after discussion and written approval from the 
Sponsor.

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Synopsis and Section 9.4.7.3, Permitted Concomitant Medications
Clarifications on concomitant drug/therapy: 
Permitted Concomitant Medications:  The use of No routine prophylactic 
antiemetic is required.  However, the use of palonosetron, 
prochlorperazine, promethazine, and cyclizine for the management of 
nausea and vomiting is allowed according.  The use of ondansetron and 
granisetron is not permitted because of their potential to standard 
practice guidelines.  Use of antacids is allowed but should be administered 
≥2 hours before or ≥4 hours after H3B-6545prolong QT interval.
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:  Prophylactic use of GCSF is not allowed from 
Cycle 1 Day 9 to Cycle 2 Day 8.  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 ASCO guidelines may be implemented at the discretion of the 
treating physician.  
Synopsis and Section 9.6.1.3.1, Pharmacokinetic Assessments
Clarifications on dose escalation:
•
On Cycle 1 Day 8, PK blood samples to determine plasma concentrations 
of palbociclib will be collected at predose and 1, 2, 4, 6, 8, and 24 hours 
postdose (within 1 hour before administration of study drug) and 
1 (±10 minutes), 2 (±15 minutes), 4 (±20 minutes), 6 (±30 minutes), 8 
(±30 minutes), and 24 hours (±60 minutes, must be before 
administration of the next day’s dose of study drugs) postdose.  These 
windows apply to PK sampling on other days.
•
On Cycle 1 Day 21, PK blood samples to determine plasma concentrations 
of palbociclib and H3B-6545 will be collected at predose and 1, 2, 4, 6, 8, 
and 24 hours postdose.
•
On Cycle 1 Day 28, PK blood samples to determine plasma concentrations 
of H3B-6545 will be collected at predose and 1, 2, 4, 6, 8, and 24 hours 
postdose.
•
During the treatment phase, PK blood samples to determine plasma 
concentrations of palbociclib and H3B-6545 will be collected at predose in 
conjunction with each tumor assessment, that is, approximately every 
8 weeks until end of treatment.
Synopsis and Section 9.6.1.3.1 Pharmacokinetic Assessments
Clarifications on dose expansion:
•
On Cycle 1 Day 21, PK blood samples to determine plasma concentrations 
of palbociclib and H3B-6545 will be collected at predose (within 1 hour 
before administration of study drug) and 1 (±10 minutes), 2 (±15 
minutes), 4 (±20 minutes), 6 (±30 minutes), 8 (±30 minutes), and 24 

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hours (±60 minutes, must be before administration of the next day’s 
dose of study drugs) postdose.  These windows apply to PK sampling 
on other days.
•
During the treatment phase, PK blood samples to determine plasma 
concentrations of palbociclib and H3B-6545 will be collected at predose 
prior to in conjunction with each tumor assessment, that is, approximately 
every 8 weeks until progression.
Synopsis and Section 9.6.1.3.2, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments
Clarifications on dose escalation and dose expansion:
•
At baseline (during screening), pretreatment fresh biopsies or archival 
tumor tissue (the tumor sample must have been collected after the most 
recent progression or recurrence) will be obtained from all patients
subjects.  If subject consents to collection of fresh baseline biopsy, it may 
be acquired any time during the Screening period, before administration of 
the 1st dose of H3B-6545 and palbociclibstudy drug on Cycle 1 Day 1.
•
At baseline, Cycle 1 Day 1, Cycle 1 Day 21, Cycle 3 Day 1, and every 8 
weeks thereafter (coinciding with CT/MRI tumor assessments schedule 
until radiological progression), and at end of treatment (EOT, if different 
from date of progression), whole blood samples for mutation 
characterization from cell-free DNA (cfDNA) will be collected.
Synopsis and Section 9.8.1.1.2, Secondary Endpoints
Added secondary endpoint for CBR and removed DCR:  
•
CBR, defined as the proportion of subjects achieving a best overall 
response of confirmed partial or complete response, or durable stable 
disease (duration is at least 23 weeks)
•
DCR, defined as the proportion of subjects achieving a best response of 
CR, PR, or stable disease
Synopsis and Section 9.8.1.6.2, Secondary Efficacy Analyses
Added CBR and removed DCR:
All efficacy parameters will be summarized descriptively for the RES and 
FAS.  ORR and DCR CBR will be calculated with exact 95% confidence 
intervals using the method of Clopper and Pearson.  DoR will be calculated 
for subjects achieving a best overall response of confirmed PR+CR.  For 
DoR, PFS, and OS, medians will be calculated using Kaplan-Meier 
estimates.  DoR, PFS, and OS will be reported in both summary tables and 
plotted with Kaplan-Meier curve.  
Synopsis and Section 9.8.1.8, Safety Analyses
Clarifications for DLT assessments:
The determination of the MTD and/or RP2D will be based on Dose 
Evaluable Set that consists of all DLT evaluable subjects.  Subjects who do 
not receive study drug for at least 75% of the planned dose from Cycle 1 
Day 1 to Cycle 2 Day 8, for reasons not considered to be a DLT by both 
the investigators and the sponsor will be replaced.  Subjects who are 

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replaced will not be considered evaluable for DLT assessments.Subjects 
not evaluable for DLT assessment will be replaced.  
Section 4.1, Institutional Review Boards/Independent Ethics Committees
Updated end of study time:
The definition of the end of the study will be the cutoff date for the final 
analysis, which will be either 12 24 months after enrollment of the last 
subject in the expansion phase or the end-of-treatment visit date for the last 
subject in the study, whichever occurs first.
Section 6, Study Registration
Added new section:
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 email 
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.  A patient is enrolled once the approved enrollment packet is 
returned to the site in ePIP.  
The Sponsor or designee will also communicate to all sites via email 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 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 enrollment on the 
registration form, and will send the completed form back to the site as 
soon as possible, no later than 24 hours following the registration request.
All subject data collected in the study will be stored under this number.  
Only the investigator will be able to link the subject’s study data to the 
subject via an identification list kept at the site.  The subject’s original 
medical data that are reviewed at the site during source data verification 

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by the Monitor, audits, and Health Authority inspections will be kept 
strictly confidential.
Data protection and privacy regulations will be observed in capturing, 
forwarding, processing, and storing subject data.  Subjects will be 
informed accordingly and will be requested to give their consent on data 
handling procedures in accordance with national regulations.
Section 7.2.1, H3B-6545
Updated G4 value for serum bilirubin:
100 – 300 mg (N=29)
450 mg (N=21)
Adverse Event
G2
G3
G4
G2
G3
G4
Neutropenia
0
0
0
0
0
0
Thrombocytopenia
0
3
0
0
0
0
Anemia
14
7
0
14
5
0
ALT
0
3
0
10
0
0
AST
3
10
0
10
0
0
Serum bilirubin
0
3
13
5
0
0
Serum creatinine
3
0
0
0
0
0
Nausea
7
0
0
5
0
0
Vomiting
3
0
0
0
0
0
Diarrhea
7
0
0
5
5
0
Fatigue
14
0
0
5
0
0
ALT = alanine aminotransferase; AST = aspartate aminotransferase; G = grade.
Section 9.1, Overall Study Design and Plan and Section 9.1.3, Follow-Up 
Phase
Updated end of study time:
End of study will be based on the cutoff date for the final analysis, which 
will be either 12 24 months after enrollment of the last subject in the 
expansion phase or the end-of-treatment visit date for the last subject in the 
study, whichever occurs first.
Section 9.1.3, Follow-Up Phase
Updated follow-up :
The follow-up phase will extend from treatment discontinuation until the 
End of Study (24 months after enrollment of last subject) or death.
Section 9.5, Dose Modifications
Updated nonhematologic toxicities:
Grade 1 
(asymptomatic)
Heart rate <40 bpm
No dose adjustment is 
required
First occurrence: 
Withhold drug until heart 
rate is ≥50 bpm or ≥
baseline value; resume 

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drug at the same dose 
level
Second  occurrence: 
Withhold drug until heart 
rate is ≥50 bpm or ≥
baseline value; resume 
drug at the next lower 
dose
Grade 2 (symptomatic, 
intervention not 
indicated; change in 
medication initiated)
No dose adjustment is 
required
Withhold drug until (a) 
symptoms resolve and (b) 
heart rate is ≥50 bpm or ≥
baseline value; resume 
drug at the next lower 
dose
Grade 3 
(symptomatic, 
intervention 
indicated)
Withhold palbociclib 
until (a) symptoms 
resolve and (b) heart 
rate is ≥50 bpm or ≥
baseline value; resume 
drug at the next lower 
dose
Withhold drug until (a) 
symptoms resolve and (b) 
heart rate is ≥50 bpm or ≥
baseline value; resume 
drug at the next lower 
dose
Grade 4 (Life-
threatening 
consequences; urgent 
intervention 
indicated) 
Withhold palbociclib 
until (a) symptoms 
resolve and (b) heart 
rate is ≥50 bpm or ≥
baseline value; resume 
drug at the next lower 
dose
Discontinue drug
QTcF prolongation
Grade 3 (average:  
≥501 ms; >60 ms 
change from baseline)
Withhold drug until 
average is <480 ms 
and <60 ms change 
from baseline; resume 
at the next lower dose
Withhold drug until 
average is <480 ms and 
<60 ms change from 
baseline; resume at the 
next lower dose
Monitor subjects for pulmonary symptoms indicative of 
ILD/pneumonitis (eg, hypoxia, cough, dyspnea).  In patients who have 
new or worsening respiratory symptoms and are suspected to have 
developed ILD/ pneumonitis, interrupt palbociclib immediately and 
evaluate the subject.  Permanently discontinue palbociclib in subjects 
with severe ILD or pneumonitis.
Section 9.6.1.2.1, Tumor Assessments
Clarifications on disease progression:
Subjects who discontinue study treatment without radiological disease 
progression will continue to have tumor assessments as per the Schedule of 
Assessments until radiological disease progression, death, or initiation of 
another anticancer therapy, whichever occurs first, unless the study is 
terminated.

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Section 9.6.1.4.3, Laboratory Measurements
Clarifications on clinical laboratory tests:
Urinalysis Urine Dipstick
Bacteria, casts, crystals, epithelial cells, 
glucose, ketones, occult blood, pH, protein, 
RBCs, specific gravity, WBCs
Section 9.6.1.4.6, Electrocardiograms
Clarifications on ECG assessments:
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 pulse 
rate) and changes from baseline will be presented. 
In addition, the number (percentage) of subjects with at least 1 post-
baseline abnormal ECG result in QTc Fridericia during the treatment 
period will be summarized.  Clinically abnormal ECG results in QTc 
Fridericia will be categorized as follows:
•
Absolute QTcF interval prolongation:
-
QTcF interval >500 ms
•
Change from baseline in QTcF interval:
-
QTcF interval increases from baseline >60 ms
All ECG abnormalities will be listed on a per-subject basis.
Triplicate 12-lead ECG will be performed after the patient has been 
resting for 10 minutes prior to each timepoint indicated, and at 
Unscheduled visits as clinically required.  The ECGs should be taken 
while the patient in a semi-recumbent position.  At Screening, 
triplicate ECGs should be taken approximately 5 minutes apart.  On 
Cycle 1 Day 1, triplicated ECGs should be performed predose.  The 
combined QTcF values will be averaged to provide a single baseline 
value for each patient.  This averaged value will be documented in the 
ECG section of the CRF.  ECG measurements on Cycle 1 Day 8, Cycle 
1 Day 21, and Cycle 1 Day 28 should match the PK collection.  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 8.6.1.4.1) and the CRF Completion 
Guidelines.  In these instances, the AE corresponding to the ECG 
abnormality will be recorded on the Adverse Events CRF.

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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.
Section 9.6.1.4.7, Other Safety Assessments
Clarifications on multiple-gated acquisition (MUGA) scan language:
A MUGA scan (using technetium-99m-pertechnetate) or an ECHO to 
assess LVEF will be performed at screening, at Cycle 3 Day 1, and if 
clinically indicated thereafter.  MUGA scans should be performed locally 
in accordance with the institution’s standard practice; ECHO should be 
performed following the protocol provided by the cardiovascular core 
laboratory.  MUGA and ECHO electronic files will be sent to the central 
laboratory for analysis and archiving.  MUGA scans are the preferred 
modality; however, whichever modality is used for an individual subject at 
Baseline should be repeated for all subsequent LVEF assessments for that 
subject.  LVEFs as assessed by the institution will be entered onto the 
CRF.  Investigator assessment will be based upon institutional reports.
Section 9.6.2.1, Schedule of Procedures/Assessments
Added range for Safety Follow-up:  28 days (±7 days)
Added Survival Follow-up with footnote u
PK samples: added “X” to EOT 
Added PG whole blood, with an “X” for Screening, D-21 to D1
cfDNA:  added “X” for Cycle 1 D21
CT)/MRI scans: clarifications for disease progression:
Every 8 weeks or until radiological disease progression and as clinically 
indicated
Brain scan:  added “X” for EOT
Section 9.6.2.1, Schedule of Procedures/Assessments
a
All subjects will be followed for survival approximately every 3 
months for up to 24 months after enrollment of the last subject.  Additional 
survival data may be requested prior to theinterim or main 
analysisanalyses.  Subjects will be followed for adverse events for 28 days 
after the last treatment administration.  Subjects who discontinue 1 of the 2 
drugs and continue therapy with the other one are considered on treatment 
until they discontinue the 2nd drug.
b
With the exception of triplicate 12-lead ECG and cfDNA, other 
assessments performed during the 7 days prior to Cycle 1 Day 1 should 
need not be repeated, unless otherwise indicated.  On Cycle 1 Day 1, 
scheduled ECG, vital signs, and laboratory test should be performed 
predose.
c
Cycle 2 Day 1 laboratory values for CBC/CMP, INR/PT/aPTT, and 
urine testing dipstick, can be drawn on Cycle 1 Day 28, in conjunction with 
the PK blood draw.
d
Physical examinations will include measurements of weight and vital 
signs (resting heart rate, blood pressure, respiratory rate, oral temperature).  
Height will be recorded at the baseline visit only.

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e
A standard 12-lead ECG will be performed after the patient has been 
resting for 10 minutes prior to each timepoint indicated.  The ECGs should 
be taken while the patient in a semi-recumbent position.  At Screening, 
triplicate ECGs should be taken approximately 5 minutes apart.  On Cycle 
1 Day 1, triplicated ECGs should be performed predose.  The 
combined QTcF values will be averaged to provide a single baseline 
value for each patient.  This averaged value will be documented in the 
ECG section of the CRF.  ECG measurements on Cycle 1 Day 8, Cycle 
1 Day 21, and Cycle 1 Day 28 should match the PK collection.
ef
The combined QTcF values will be averaged to provide a single 
baseline value for each patient.  This averaged value will be documented in 
the ECG section of the CRF.  At screening, at Cycle 3 Day 1, and if 
clinically indicated thereafter.
fg
Pregnancy test during the screening period should be serum (no need 
to repeat on Cycle 1 Day 1 if within 72 hours).  During the study, urine 
testing should be performed at Day 1 of each cycle or serum testing should 
be performed to confirm a positive urine testing.
gh CBC count consisting of hematocrit, hemoglobin, total WBC with 5-
part differential, and platelet count plus RBC count.
hi
CMP panel includes the following: glucose, calcium, albumin, total 
protein, electrolytes (sodium, potassium, carbon dioxide, and chloride), 
renal function tests (blood urea/blood urea nitrogen, and creatinine), and 
liver function tests (ALP, ALT, AST, and bilirubin).
ij
Other includes the following: albumin, CRP, fasting lipase, fasting 
amylase, lactate dehydrogenase, magnesium, phosphorus, gamma-glutamyl 
transpeptidase, and thyroid function tests (TSH and free T4).
jk INR, PT, aPTT will be assessed by standard methods at a local 
laboratory.
l
See Appendix 3 for HBV/HCV testing criteria.
km If abnormalities are present, microscopic testing should be done.
ln H3B-6545: daily starting Cycle 1 Day 9; palbociclib: daily from Day 1 
to Day 21 every 28-day cycle.
mo Plasma samples for pharmacokinetics:
a.
During the escalation part of the study: On Cycle 1 Day 8, PK blood 
samples to determine plasma concentrations of palbociclib will be 
collected at predose and 1, 2, 4, 6, 8, and 24 hours postdose. (within 
1 hour before administration of study drug) and 1 (±10 minutes), 
2 (±15 minutes), 4 (±20 minutes), 6 (±30 minutes), 8 (±30 minutes), and 
24 hours (±60 minutes, must be before administration of the next day’s 
dose of study drugs) postdose.  These windows apply to PK sampling 
on other days.  On Cycle 1 Day 21, PK blood samples to determine 
plasma concentrations of palbociclib and H3B-6545 will be collected at 
predose and 1, 2, 4, 6, 8, and 24 hours postdose.  On Cycle 1 Day 28, PK 
blood samples to determine plasma concentrations of H3B-6545 will be 
collected at predose and 1, 2, 4, 6, 8, and 24 hours postdose.  
b.
During the expansion phase: On Cycle 1 Day 21, PK blood samples to 
determine plasma concentrations of palbociclib and H3B-6545 will be 

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collected predose (within 1 hour before administration of study drug) and 1 
(±10 minutes), 2 (±15 minutes), 4 (±20 minutes), 6 (±30 minutes), 8 
(±30 minutes), and 24 hours (±60 minutes, must be before administration 
of the next day’s dose of study drugs) postdose.  These windows apply to 
PK sampling on other days.
c.
During both phases of the trial: additional PK blood samples will be 
collected in conjunction with tumor assessments until disease 
progressionEOT.
d.
Samples should be collected via peripheral vein when possible.
np New biopsy (preferred) or archival tumor block or slides (15 slides 
minimum from a surgical specimen, 20 slides minimum from a biopsy) 
must be provided. If archival tissue is provided, the tumor sample must 
have been collected after the most recent progression or recurrence.
oq Whole blood for cfDNA (8 mL) will be collected during the screening 
period, Cycle 1 Day 1, Cycle 1 Day 21, Cycle 3 Day 1, every 8 weeks 
thereafter (in conjunction with tumor assessments), and EOT.  Two tubes 
(2x8 mL) will be collected at Screening and EOT.
pr A bone scan using whole-body bone MRI, 99m-technetium-based bone 
scans, or 18F-sodium fluoride positron emission tomography will be 
performed during Screening to establish a baseline (a historical bone scan 
performed within 6 weeks before Cycle 1 Day 1 is acceptable), 
approximately every 24 weeks (in conjunction with a scheduled tumor 
assessment visit), and as clinically indicated.  Lesions identified on bone 
scans should be followed with cross-sectional imaging.
qs Tumor assessments (CT of the chest with and without IV contrast and 
CT [oral and IV contrast] or MRI [IV contrast] of the abdomen, pelvis, and 
other known or suspected sites of disease) will be performed during 
Screening (Day -21 to Cycle 1 Day 1) and every 8 weeks (±7 days) after 
Cycle 1 Day 1 (ie, 8, 16, 24 weeks) or as indicated if disease progression is 
suspected clinically.
rt
A brain scan (CT with contrast or MRI [pre- and postgadolinium]) will 
be performed at Screening and as clinically indicated to assess potential for 
central nervous system disease and/or metastases.  For subjects with a 
history of protocol-eligible treated brain metastases, a brain scan will be 
required at all tumor assessment timepoints, including EOT.  For all 
subjects, a follow-up brain scan must be performed to confirm CR within 1 
week following response confirmation or if clinically indicated.
u
Following progression, all subjects will be followed for survival 
every 12 weeks or more often if requested prior to interim or final 
analysis.  The follow-up can be done by telephone call at the 
investigator’s discretion.
Section 9.6.4.6, Regulatory Reporting of Adverse Events
Clarifications on palbociclib Reference Safety Information:
For this study, the Reference Safety Information for palbociclib, which the 
sponsor will use to assess expectedness, is the approved palbociclib 
(Ibrance) EMA SmPC and palbociclib (Ibrance USPI, 2019).

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Section 9.8.1.8.1, Extent of Exposure
Clarifications on extent of exposure language:
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.  
Details will be provided in the SAP.
Section 9.8.1.8.3, Laboratory Values
Clarifications on laboratory values language:
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, ANC, 
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 overallpost baseline.  Details will be provided in the SAP.
Section 9.8.1.8.5, Electrocardiograms
Clarifications on electrocardiograms language:
ECG assessments will be performed at each visit throughout the study 
according to the schedule of assessments.  Descriptive statistics for ECG 
parameters and changes from baseline will be presented by visit and 
treatment group.
Shift tables will present changes from baseline in ECG interpretation 
(categorized as normal; abnormal, not clinically significant; and abnormal, 
clinically significant) to end of treatment.  In addition, summarySummary 
tables and listings for the various intervals (eg, QT and pulse rate) and 
changes from baseline will be presented.  Additional analysis will be 
detailed in the SAP.
Appendix 3, HBV/HCV Testing Criteria
Added new appendix:
Eligibility Based on Serologic Markers for Hepatitis B and Hepatitis C
Test
Result
HBsAg
+
-
-
-
-
HBcAb
Any
+
-
+
-
HBsAb
Any
-
+
+
-
HCV Ab
Any
Any
-
-
-
Eligibility
Not 
Eligible
Not 
Eligible
Eligible
Eligible
Eligible
If indeterminate results are obtained, viral DNA (hepatitis B) or RNA 
(hepatitis C) should be measured to confirm negative viral status.

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HCV Ab positive: Indicates active infection and risk for reactivation.  
These patients are not eligible for this trial.
 HBsAg positive: Indicates active infection and risk for reactivation 
with fulminant hepatitis.  These patients are not eligible for this trial.
 HBcAb positive and HBsAb negative: indicate active infection and 
risk for reactivation.  These patients are not eligible for this trial.
HBsAb positive: As a standalone marker, it indicates successful 
vaccination or previous infection that has been successfully resolved if 
it is the only positive finding.  These patients are eligible for this trial.
HBsAg negative, HBcAb positive, HBsAb positive: Resolved or latent 
infection.  These patients are eligible for this trial.
All markers negative: No prior exposure or vaccination to hepatitis B 
and no prior exposure to Hepatitis C.  Patients are eligible for this trial
Date
Highlights of Major Changes
15 June 2021
Amendment 03
Deletions are shown as strikethrough; new content is shown in bold.
Section Affected, Description of Change
Rationale
Synopsis; 
Section 9.1, Overall Study Design and Plan
Updated description of a cohort:  
Each cohort will consist of 6 DLT-evaluable
subjects to ensure sufficient safety and PK data are 
obtained prior to dose escalation.
Synopsis table;
Section 9.1, Overall Study Design and Plan Table 3
Updated table column header: 
Number of DLT-Evaluable Subjects
Synopsis
Updated description of SRC review: 
After 6 DLT-evaluable all subjects in a cohort 
have completed the DLT observation period, all 
available safety data will be reviewed by the Safety 
Review Committee (SRC) consisting of sponsor 
personnel and investigators.
To clarify the number of 
evaluable subjects 
required to complete 
evaluation of a treatment 
cohort.
Synopsis; 
Section 9.6.1.2.1, Tumor assessments; 
Section 9.6.2.1, Schedule of 
Procedures/Assessments Table 8 footnote s
To clarify the description 
of tumor assessment 
requirements.

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Updated description of tumor assessments:
Tumor assessments (computed tomography [CT] of 
the chest with and without intravenous [IV] contrast 
and CT [(oral and IV contrast)] or magnetic 
resonance imaging [MRI] (IV contrast)  of the 
abdomen, pelvis, and other known or suspected 
sites of disease) will be performed during the 
Screening/Baseline period (Day -21 to Cycle 1 
Day 1). If imaging with contrast, as requested in 
above, is contraindicated, imaging without 
contrast should be performed and reason for 
contraindication should be captured in the 
source documents.
Synopsis; 
Section 9.6.1.3.1, Pharmacokinetic Assessments; 
Section 9.6.2.1, Schedule of 
Procedures/Assessments Table 8 footnotes (o)
Amended Pharmacokinetic Assessments:  
In dose escalation: 
On Cycle 1 Day 8, PK (palbociclib) blood samples 
to determine plasma concentrations of palbociclib 
will be collected at predose (within 1 hour before 
administration of study drug) and 1 (±10 minutes), 
2 (±15 minutes), 4 (±20 minutes), 6 (±30 minutes), 
8 (±30 minutes), and 24 hours (±60 minutes, must 
be before administration of the next day’s dose of 
study drugs) postdose.  These windows apply to PK 
sampling on other days.
On Cycle 1 Day 21, PK (palbociclib and H3B 
6545) blood samples to determine plasma 
concentrations of palbociclib and H3B-6545 will be 
collected at predose and 1, 2, 4, 6, 8, and 24 hours 
postdose.
On Cycle 1 Day 28, PK (H3B 6545) blood samples 
to determine plasma concentrations of H3B-6545 
will be collected at predose and 1, 2, 4, 6, 8, and 24 
hours postdose.
During the treatment phase, PK (palbociclib and 
H3B 6545) blood samples to determine plasma 
concentrations of palbociclib and H3B-6545 will be 
collected at predose in conjunction with each tumor 
assessment, that is, approximately every 8 weeks 
until end of treatment (EOT).
In dose expansion:
On Cycle 1 Day 21, PK (palbociclib and H3B 
6545) blood samples to determine plasma 
concentrations of palbociclib and H3B-6545 will be 
collected at predose (within 1 hour before 
To clarify samples to be 
taken for PK assessment.

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administration of study drug) and 1 (±10 minutes), 
2 (±15 minutes), 4 (±20 minutes), 6 (±30 minutes), 
8 (±30 minutes), and 24 hours (±60 minutes, must 
be before administration of the next day’s dose of 
study drugs) postdose.  These windows apply to PK 
sampling on other days.
During the treatment phase, PK (palbociclib and 
H3B 6545) blood samples to determine plasma 
concentrations of palbociclib and H3B-6545 will be 
collected at predose in conjunction with each tumor 
assessment, that is, approximately every 8 weeks 
until progression.
Synopsis
Amended Pharmacodynamic, Pharmacogenomic, 
and Other Biomarker Assessments:  

At baseline (during screening), pretreatment 
fresh biopsies or archival tumor tissue (the 
tumor sample must have been collected after 
the most recent progression or recurrence) will 
be obtained from all subjects.  If a subject 
consents to collection of fresh baseline biopsy, 
it may be acquired any time during the 
Screening period, before administration of the 
1st dose of study drug on Cycle 1 Day 1. If 
collection of a biopsy during the screening 
period poses disproportionate risk to 
subject’s safety, the reason for the 
contraindication must be documented in 
source at site. Once documentation detailing 
risk is captured in the site records, subject
may continue screening and if all I/E criteria 
are met, subject may be enrolled and 
treated.
Section 9.6.1.1, Screening Assessments

Collection of pretreatment fresh biopsies or 
archival tumor tissue (the tumor sample must 
have been collected after the most recent 
progression or recurrence). If collection of a 
biopsy during the screening period poses 
disproportionate risk to subject’s safety, the 
reason for the contraindication must be 
documented in source at site. Once 
documentation detailing risk is captured in 
the site records, subject may continue 
screening and if all I/E criteria are met, 
subject may be enrolled and treated.
To describe the 
procedure to be followed 
if collection of a biopsy 
poses disproportionate 
risk to subject.

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Section 9.1, Overall Study Design and Plan
Amended description of allocation of subjects to 
treatment cohorts:
The dose escalation part of the study will determine 
the MTD and/or the RP2D of H3B-6545 in 
combination with palbociclib.  Each cohort will 
consist of 6 subjects to ensure sufficient safety and 
PK data are obtained prior to dose escalation.  A 
cycle of treatment will be 28 days. 
Due to the potential for screen failures and/or a 
subject discontinuing treatment before 
completion of the cohort DLT assessment 
window (non-evaluable for DLT assessment), up 
to 8 slots will be opened for screening in order to 
obtain 6 DLT-evaluable subjects (see Section 
9.1). In addition, subjects considered screen 
failures or unevaluable for DLT will be replaced.
Once 6 subjects have been dosed at the current 
cohort dose level, any additional subjects in 
screening will be allocated to one of the following 
cohorts for enrollment:

The current cohort so that the total number 
of DLT-evaluable subjects is maintained at 
6, if any of the 6 already dosed subjects 
becomes non-evaluable for DLT;

A lower dose cohort which has already been 
deemed safe per dose escalation meeting, if 
none of the 6 already dosed subjects becomes 
non-evaluable for DLT in the cohort 
currently under evaluation; the additional 
subject(s) will not contribute to DLT 
evaluation of the lower dose cohort, but will 
contribute to the overall safety evaluation.

The next cohort to be opened to enrollment 
including the expansion cohort if the RP2D 
has been reached and the expansion phase is 
open to enrollment
Sponsor approval of any enrollment scenario not 
described above must take place prior to 
screened subject enrollment.
In the 1st cycle, palbociclib will be administered 
PO QD on Days 1 to 21 and H3B 6545 will be 
administered PO QD on Days 9 to 28.  In all 
subsequent cycles, palbociclib will be administered 
on Days 1 to 21 and H3B-6545 will be administered 
Days 1 to 28.
To describe in more 
detail the process for 
allocation of subjects to 
treatment cohorts on 
completion of screening.

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Section 9.1, Overall Study Design and Plan Table 4
Hepatic: ALT or AST criterion for defining Dose-
Limiting Toxicity changed from ≥8 × ULN to >8 × 
ULN
To correct an 
inconsistency.
Section 9.1.3 Follow-Up Phase
Added language for Extension Phase 
To clarify safety 
assessments for subjects 
who will remain on study 
treatment after the data 
cutoff date for the 
planned final PFS 
analysis (24 months after 
the last patient receives 
their first dose).  All 
subjects who are still on 
study treatment at that 
time will enter the 
Extension Phase
Section 9.5, Dose Modifications
Added further detail of dose reductions:
Recommendations for dose reduction, interruption 
or discontinuation of either drug in the management 
of adverse reactions are summarized in Table 5 
(hematologic toxicities) and Table 6 (non-
hematologic toxicities).  Clinical judgment of the 
treating physician should guide the management 
plan of each patient based on individual benefit/risk 
assessment.
Two dose reductions of H3B-6545 (450 mg to 300 
mg, then to 150 mg QD) for toxicity will be 
allowed as per the guidance summarized in 
Table 5 and Table 6.  If persistent toxicity occurs 
despite two dose reductions, the subject will 
discontinue study treatment
Two dose reductions for palbociclib (125 mg to 
100 mg, then to 75 mg QD) for toxicity will be 
allowed (Table 5 and Table 6). If persistent 
toxicity occurs despite two dose reductions, the 
subject will discontinue study treatment.
To provide further detail 
of H3B-6545 dose 
reductions and to
simplify the dose 
reduction guidance to 
multiples of 150 mg.
Section 9.5, Dose Modifications
Table 5 Dose Modifications and Management 
Recommendation – Hematologic Toxicities
CTCAE 
Grade
Palbociclib
H3B-6545
Anemia
Grade 4
Withhold dose until 
recovery to Grade ≤2;
Withhold 
dose until 
Hematologic toxicities 
are not predicted to be 
associated with H3B-
6545 treatment.  
Dose modification of 
H3B-6545 is not 
predicted to be of benefit 
in the management of 
hematologic toxicities.

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resume drug at next 
lower dose
recovery to 
Grade ≤2; 
resume drug 
at next lower 
dose 
Withhold 
dose until 
recovery to 
Grade ≤2; 
resume at the 
same dose
Grade 3
Day 1 of cycle: 
Withhold drug, repeat 
complete blood cell 
count monitoring 
within 1 week.  When 
recovered to Grade 
≤2, start the next cycle 
at the same dose. 
Day 15 of first 2 
cycles: Continue 
palbociclib at current 
dose to complete 
cycle and repeat 
complete blood cell 
count on Day 22.
Withhold 
dose until 
recovery to 
Grade ≤2; 
resume drug 
at next lower 
dose 
Withhold 
dose until 
recovery to 
Grade ≤2; 
resume at the 
same dose
Grade 1 or 2
No dose adjustment is 
required
No dose 
adjustment is 
required
All Other Hematological Toxicity 
Grade 4
Withhold dose until 
recovery to Grade ≤2; 
resume drug at next 
lower dose
No dose 
adjustment 
is required. 
Grade 3

Day 1 of cycle: 
Withhold drug, 
repeat complete 
blood cell count 
monitoring within 
1 week.  When 
recovered to 
Grade ≤2, start 
the next cycle at 
the same dose.

Day 15 of first 2 
cycles: Continue 
palbociclib at 
current dose to 
complete cycle 
and repeat 
complete blood 
cell count on Day 
22.
No dose 
adjustment 
is required.  
Grade 1 or 2
No dose adjustment is 
required
No dose 
adjustment 
is required

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Grade 3 
neutropenia 
with fever 
≥38.5 °C 
and/or 
infection
Withhold palbociclib 
until recovery to Grade 
≤2; resume at the next 
lower dose
Withhold 
dose until 
fever 
subsides
recovery to 
Grade ≤2; 
resume at the 
same dose
Section 9.5, Dose Modifications
Dose modifications for use with strong CYP3A 
inhibitors

Reduce the H3B-6545 dose to 150200 mg QD
To simplify the dose 
reduction guidance for 
use with strong CYP3A 
inhibitors to multiples of 
150 mg
Section 9.6.1.4.3, laboratory measurements Table 7
Table 8 footnote i
In the Comprehensive Metabolic Panel, Glucose
updated to Fasting glucose.
To reduce the potential 
variability of glucose test 
results.
Section 9.6.1.4.6, Electrocardiograms
ECG assessments will be performed throughout the 
study in triplicate for all study visits where ECGs 
are required and ECGs should be collected 
predose on days where PK samples are not 
collected (Table 8 Schedule of 
Procedures/Assessments in Study H3B-6545-
G000-102).
To clarify the 
requirements for ECG 
assessments.
Section 9.6.1.4.7, Other Safety Assessments
A MUGA scan or an ECHO to assess LVEF will be 
performed at screening, at Cycle 3 Day 1, and if 
clinically indicated thereafter.  MUGA scans should 
be performed locally in accordance with the 
institution’s standard practice; ECHO should be 
performed following the protocol provided by the 
cardiovascular core laboratory.  MUGA and ECHO 
electronic files will be sent to the central laboratory 
for analysis and archiving.  MUGA scans are the 
preferred modality; however, whichever modality is 
used for an individual subject at Baseline should be 
repeated for all subsequent LVEF assessments for 
that subject.  LVEFs as assessed by the institution 
will be entered onto the CRF.  Investigator 
assessment will be based upon institutional reports.
Central laboratory 
analysis and archiving of 
MUGA and ECHO 
electronic files are not 
required.
Section 9.6.2.1, Schedule of 
Procedures/Assessments Table 8 footnotes
e
A standard 12-lead ECG will be performed 
after the patient has been resting for 10 minutes 
prior to each timepoint indicated.  The ECGs should 
be taken while the patient in a semi-recumbent 
To clarify procedures.
(Other footnote changes 
are described above)

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position.  At Screening, triplicate ECGs should be 
taken approximately 5 minutes apart.  On Cycle 1 
Day 1, triplicated ECGs should be performed 
predose.  The combined QTcF values will be 
averaged to provide a single baseline value for each 
patient.  This averaged value will be documented in 
the ECG section of the CRF.  ECG measurements 
on Cycle 1 Day 8, Cycle 1 Day 21, and Cycle 1 
Day 28 should match the PK collection. Triplicate 
ECGs are to be performed at all visits indicated
and should be collected predose on C3D1 and D1 
of all subsequent cycles.  C1D28 24-hour ECG 
can also meet the requirement for C2D1 ECG.
p
New biopsy (preferred) or archival tumor block 
or slides (15 slides minimum from a surgical 
specimen, 20 slides minimum from a biopsy) must 
be provided.  If archival tumor tissue is provided, 
the tumor sample must have been collected after the 
most recent progression or recurrence. Not 
required for subjects with bone only disease
v
Any protocol assessment, including labs, 
performed within 3 days prior to D1 of the next 
cycle do not need to be repeated on D1 of the 
new cycle.
New Section added
9.6.4.1 REPORTING OF ABNORMAL 
HEPATIC TESTS OF CLINICAL INTEREST
The following combination of abnormal 
laboratory tests*, as determined by way of 
protocol-specified laboratory testing or 
unscheduled laboratory testing and whether 
nonserious or serious, should be entered on the 
Adverse Event CRF and reported using the 
procedures detailed in Reporting of Serious 
Adverse Events (Section 9.6.4.2).  If the event 
does not meet serious criteria, the seriousness 
criteria on the SAE form should be indicated as 
“nonserious.”  
1.
Elevated AST or ALT laboratory value that 
is greater than or equal to 3× the ULN or if 
elevated greater than the ULN at baseline, then 
3× the baseline for the subject
AND
2.
Elevated total bilirubin laboratory value that 
is greater than or equal to 2× the ULN or if 
elevated greater than the ULN at baseline, then 
1.5× the baseline for the subject
To provide detail of the 
procedure for identifying 
and reporting abnormal 
hepatic tests of clinical 
interest.

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AND AT THE SAME TIME
3.
Alkaline phosphatase laboratory value that 
is less than 2× the ULN
*Note: These criteria are based upon available 
regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal 
hepatic tests that may require additional 
evaluation for an underlying etiology.  In 
addition to reporting the abnormal hepatic 
laboratory tests on a SAE form, the site should 
also consult the medical monitor for guidance on
assessment and follow-up.  At a minimum, 
laboratory testing should be repeated at least 
once weekly until improvement or identification 
of a cause unrelated to study drug use that is 
unlikely to improve.
Table 9 Extension Phase Assessment table added
Section 9.6.5 Completion/Discontinuation of 
Subjects 
Qualification added to list of reasons for treatment 
discontinuation:
*Subjects may continue to receive treatment after 
progression only if, after discussion with the 
medical monitor, it is determined that the subject 
continues to derive clinical benefit.
To clarify that subjects 
with disease progression 
may continue to receive 
treatment if the subject 
continues to derive 
clinical benefit.
Section 12, Appendices
Appendix 1, Concomitant Medications:
Use of antacids is allowed but should be 
administered ≥2 hours before or ≥4 hours after 
H3B-6545.  The use of palonosetron for the 
management of nausea and vomiting is also allowed
For consistency with
changes introduced in 
Amendment 2.0.
Date
Highlights of Major Changes
29 August
2022
Amendment 04
Sections Affected, Description of Changes
Rationale
The primary analysis data cutoff will occur 6 months 
after the last subject receives their first dose. Changed 
the “main analysis” wording to “primary analysis”.
-
Protocol Synopsis, Overall Study Design
-
Protocol Synopsis, Efficacy Assessments
-
Section 9.1 Overall Study Design and Plan
-
Section 9.1.3 Follow-up Phase
To clarify the primary 
analysis data cutoff will 
occur 6 months after the 
last subject receives their 
first dose, and to no longer 
perform the previously 
planned final overall 

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-
Section 9.6.2.1 Schedule of 
Procedures/Assessments, Table 9
survival analysis at 
24 months. Further 
development of H3B-6545 
is not planned at this time.
Survival follow-up will end at the primary analysis data 
cutoff and clarified the survival follow-up will not be 
done in the Extension Phase. The first anti-cancer 
therapy following treatment discontinuation will be 
recorded up until the data cutoff for the primary analysis
-
Protocol Synopsis, Overall Study Design
-
Section 9.1.3 Follow-up Phase
-
Section 9.3.3 Removal of Subjects From Therapy or 
Assessment
-
Section 9.6.2.1 Schedule of Procedure/Assessments, 
Table 8 footnotes a and u
Pharmacokinetic and biomarker sample collection will 
no longer be performed and the data cutoff date for the 
primary analysis.
-
Protocol Synopsis, Pharmacokinetic Assessments, 
Biomarker Assessments
-
Section 9.6.1.3.1 Pharmacokinetic Assessments
-
Section 9.6.1.3.2 Pharmacodynamic, 
Pharmacogenomic, and Other Biomarker 
Assessments
-
Section 9.6.2.1 Schedule of 
Procedures/Assessments, Table 8, footnotes o (c.) 
and q
To align with the primary 
analysis cutoff date.
The end of study definition is clarified.
-
Section 4.1 Institutional Review Boards/Independent 
Ethics Committees; removed end of study definition 
here because this is not required to be defined in this 
section
-
Section 9.1 Overall Study Design and Plan
For clarification and 
consistency.
Specified the visit (Cycle X Day 1) in the Extension 
Phase schedule of assessments.
-
Section 9.6.2.1 Schedule of 
Procedures/Assessments, Table 9, footnote a.
For clarification.
H3 Biomedicine Inc. is removed from the protocol. 
Eisai, Inc. remains as the Sponsor.
-
Title page
-
Section 5 Investigators and Study Personnel
Revised to clarify the 
current Sponsor since this 
Eisai subsidiary is being 
closed.
Minor editorial changes (grammar, formatting), 
throughout
To enhance clarity and 
consistency

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2
CLINICAL PROTOCOL SYNOPSIS
Compound No. H3B-6545
Name of Active Ingredient:  H3B-6545 and palbociclib
Study Protocol Title
An open-label multicenter Phase 1b study of H3B-6545 in combination with palbociclib in 
women with advanced or metastatic estrogen receptor–positive HER2-negative breast cancer
Investigator(s)
Global Principal Investigator: Stephen R. D. Johnston, MA, FRCP, PhD 
The Royal Marsden NHS Foundation Trust, 203 Fulham Road, Chelsea, London, SW3 6JJ, 
UK
Sites
Global, approximately 7 centers
Study Period and Phase of Development
Approximately 24 months,
Phase 1b dose escalation with dose expansion
Objectives
Primary Objective
The primary objective of the study is to evaluate the safety and tolerability of H3B-6545 and 
palbociclib when administered in combination in order to determine the maximum tolerated 
dose (MTD) and/or the recommended Phase 2 dose (RP2D) of this combination in women 
with advanced or metastatic estrogen receptor–positive (ER+) human epidermal growth 
factor receptor-2–negative (HER2–) breast cancer.
Secondary Objectives
The secondary objectives of the study are as follows:
•
To evaluate the pharmacokinetic (PK) profile of H3B-6545 and palbociclib when 
administered in combination 
•
To estimate the preliminary clinical activity of H3B-6545 plus palbociclib in terms of 
objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR; 
complete response [CR], partial response [PR], or stable disease ≥23 weeks), 
progression-free survival (PFS), and overall survival (OS)
Exploratory Objective
•
To explore the relationship of blood and tumor biomarkers with clinical endpoints 
including safety, clinical activity, and PK
Study Design
Overall Design:

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This is a multicenter, open-label, dose escalation and dose expansion study of H3B-6545 in 
combination with palbociclib for women with advanced or metastatic ER+ HER2– breast 
cancer. 
End of study: The cutoff date for the primary analysis will be approximately 6 months after 
the last subject receives their first dose of study treatment.  The end of study will be the last 
assessment for the last subject (eg, the last assessment in the Extension Phase)
Subjects in dose escalation must have progressed after 2 prior endocrine therapies and may 
have received up to 1 prior chemotherapy regimen and up to 1 prior CDK4/6 inhibitor.  
Subjects in dose expansion may have received up to 2 prior endocrine therapies and up to 1 
prior chemotherapy regimen but may not have received a prior CDK4/6 inhibitor in the 
advanced or metastatic setting.  
Subjects who are tolerating therapy and are without progressive disease may receive 
treatment until progression.
Dose escalation will determine the MTD and/or the RP2D of H3B-6545 in combination with 
palbociclib. Due to the potential for screen failures and/or a subject discontinuing treatment 
before completion of the cohort DLT assessment window (non-evaluable for DLT 
assessment), up to 8 slots will be opened for screening in order to obtain 6 DLT-evaluable 
subjects (See Section 9.1). In addition, subjects considered screen failures or unevaluable for 
DLT will be replaced. Each cohort will consist of 6 DLT-evaluable subjects to ensure 
sufficient safety and PK data are obtained prior to dose escalation.  A cycle of treatment will 
be 28 days. 
In the 1st cycle, palbociclib will be administered orally (PO) once daily (QD) on Days 1 to 
21 and H3B-6545 will be administered PO QD on Days 9 to 28.  In all subsequent cycles, 
palbociclib will be administered on Days 1 to 21 and H3B-6545 will be administered Days 1 
to 28. 
A maximum of 4 dose levels are planned, with palbociclib escalated no higher than 125 mg 
QD and H3B-6545 escalated no higher than 450 mg QD (RP2D).
Dose Escalation Table
Dose Level
(Cohort)
Palbociclib Dose 
(mg QD)
H3B-6545 Dose 
(mg QD)
Number of DLT-
Evaluable Subjects
-1
75
300
6
1 (starting dose)
100
300
6
2
125
300
6
3
125
450
6
3b
100
450
6
DLT= dose-limiting toxicity; QD = once daily.
Subjects will be assigned to a dose level in the order of study entry.  
Dose-limiting toxicities (DLTs) will be assessed during the first 28 days starting from the 1st 
day of adding H3B-6545 to palbociclib (Cycle 1 Day 9 to Cycle 2 Day 8).  Subjects who do 
not receive at least 75% of the scheduled therapy from Cycle 1 Day 9 to Cycle 2 Day 8, for 

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reasons other than toxicity, will not be considered evaluable for DLT assessment and will be 
replaced.  Disease progression and adverse events (AEs) deemed related to disease 
progression will not be considered DLTs.
After 6 DLT-evaluable subjects in a cohort have completed the DLT observation period, all 
available safety data will be reviewed by the Safety Review Committee (SRC) consisting of 
sponsor personnel and investigators.
•
Cohort 1:  If none or only 1 subject experienced a DLT, initiate enrollment in Cohort 2.  
If 2 or more subjects experienced a DLT, initiate enrollment in Cohort -1.
•
Cohort -1:  If none or only 1 subject experienced a DLT, the doses used in Cohort –1 
will be considered the RP2D.  If 2 or more subjects experienced a DLT, the combination 
of H3B-6545 and palbociclib at clinically meaningful doses will be considered 
unfeasible.
•
Cohort 2:  If none or only 1 subject experienced a DLT, initiate enrollment in Cohort 3.  
If 2 or more subjects experienced a DLT, the doses used in Cohort 1 will be considered 
the MTD and the RP2D.
•
Cohort 3:  If none or only 1 subject experienced a DLT, doses used in this Cohort will 
be considered the RP2D.  If 2 or more subjects experienced a DLT, consideration will be 
given to opening cohort 3b depending upon observed toxicity profile.
•
Cohort 3b:  If none or only 1 subject experienced a DLT, doses used in this Cohort and 
in Cohort 2 could be considered the RP2D.  In this case, the SRC will select between 
Cohort 2 and Cohort 3b for the expansion phase.  If 2 or more subjects experienced a 
DLT, doses used in Cohort 2 will be considered the RP2D.
The MTD is defined as the highest dose at which no more than 1 of 6 subjects experiences a 
DLT in the dose cohort.  The RP2D may not exceed the MTD and will be agreed upon by the 
SRC based on an integrated evaluation of available safety, clinical benefit, PK, and 
pharmacodynamics data, for all dose levels tested.  
DLTs:  Unless considered not related to study drugs, any of the following criteria will 
qualify as a DLT:
Toxicity
Criteriaa
Hematology
-
Febrile neutropenia (ANC <1×109/L and fever ≥38.5 °C)
-
Grade 4 neutropenia that does not resolve to Grade ≤2 (ANC ≥1×109/L) 
within 7 days; use of GM-CSF is allowed
-
Grade 4 thrombocytopenia (<25.0×109/L)
-
Grade 3 thrombocytopenia (25.0 – 50.0×109/L) lasting more than 7 days or 
associated with clinically significant bleeding
Vomiting
-
CTCAE Grade 4 vomiting
-
Grade 3 vomiting lasting >72 hours despite optimal antiemetic treatment
Diarrhea
-
CTCAE Grade 4 diarrhea
-
Grade 3 diarrhea lasting >72 hours despite optimal antidiarrheal treatment

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Electrolytes 
abnormality
-
Grade 4
-
Grade 3 lasting for more than 24 hours
Note: Grade 3 that lasts <24 hours and resolves spontaneously or responds 
to conventional medical interventions is not considered a DLT.
Renal
-
Grade 3 or 4 serum creatinine
Hepatic
-
Grade 3 or 4 bilirubin increase
-
ALT or AST >8 × ULN
-
In absence of liver metastases at baseline and in absence of clinical or 
radiological evidence of biliary obstruction: ALT or AST >3 × ULN, in 
conjunction with total bilirubin >2 ×ULN
Biochemistry
-
Grade 4
-
Grade 3 lasting more than 7 days, unless considered not clinically significant 
as per the discretion of the investigator
Any other non-
hematologic AE
Grade 4 
Grade 3 (except diarrhea, rash, nausea, or vomiting lasting ≤72 hours)  
Any drug-related intolerable Grade 2 toxicity (other than hematological AEs) 
leading to administration of <75% of the dose during the DLT observation 
period
AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
CTCAE = Common Terminology Criteria for Adverse Events; DLT = dose-limiting toxicity; GM-CSF = granulocyte–
macrophage colony-stimulating factor; ULN = upper limit of normal.
a. Laboratory values that meet criteria listed in this table should be repeated and confirmed within 24 hours of the initial 
results being reported.
Intrasubject dose escalation: Once a subject has completed Cycle 3 at her assigned dose 
level of drug, intrasubject dose escalation will be allowed.  No more than 2 dose escalations 
are allowed for any subject.  Only subjects who have not progressed on treatment and did not 
have a dose reduction of either palbociclib or H3B-6545 because of AEs can escalate to the 
highest dose level that has completed DLT assessment and has been shown to be safe (no 
more than 1 DLT in 6 subjects).  Subjects on the intra-subject dose escalation will not be 
included in the DLT analysis at the higher dose level.  
Dose expansion: An additional 12 subjects will be treated at the MTD/RP2D to further 
characterize safety, tolerability, and PK and to provide preliminary estimates of efficacy.  In 
Cycle 1, subjects will receive palbociclib PO QD on Days 1 to 21 and H3B-6545 PO QD on 
Days 9 to 28.  In all subsequent cycles, palbociclib will be administered on Days 1 through to 
21 and H3B-6545 will be administered Days 1 through to 28.
AEs will be managed by treatment interruption, dose reduction, and/or treatment 
discontinuation in accordance with the dose modification instructions outlined in the 
protocol.  Treatment will continue until disease progression, development of unacceptable 
toxicity, or withdrawal of consent.

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Number of Subjects
Dose escalation – Total sample size will be determined based upon the number of DLTs 
observed and the number of dose levels (cohorts) studied.  Dose escalation may accrue 
approximately 12 to 24 subjects.
Dose expansion will enroll 12 additional subjects at the RP2D.  Therefore, the study is 
expected to enroll approximately 24 to 36 subjects.  
Inclusion Criteria
1. Subject has signed informed consent form before any study-related activities and 
according to local guidelines. 
2. Female, aged ≥18 years, at the time of informed consent
3. Subject has histopathologically or cytologically confirmed ER+ HER2– locally 
advanced, recurrent, or metastatic breast cancer, as per local laboratory
4. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.  
Subjects enrolling to the study who do not have measurable disease at baseline per 
RECIST 1.1 guidelines may be enrolled if they have at least 1 mainly lytic bone lesion, 
provided that the lesion has not been irradiated, or exhibits demonstrable progression 
since irradiation.
5. Prior therapy in the advanced or metastatic setting: 
a.
Dose escalation: 2 or more prior hormonal therapies.  Subjects may have received up 
to 1 prior chemotherapy regimen and up to 1 prior CDK4/6 inhibitor.
b. Dose expansion: Up to 2 prior endocrine therapies and up to 1 prior chemotherapy 
regimen but may not have received a prior CDK4/6 inhibitor.
Note: If the patient was enrolled within 12 months of the end of adjuvant therapy, the 
adjuvant therapy will also be counted.
Note:  Subjects must have documented progression while on or after the most recent 
therapy. 
6. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 
1.
7. Life expectancy >12 weeks, as per investigator’s best assessment, during the Screening 
phase.
8. Subject has adequate bone marrow and organ function, as defined by the following 
laboratory values:
a.
Absolute neutrophil count (ANC) ≥1.5×109/L
b. Platelets ≥100×109/L
c.
Hemoglobin ≥9.0 g/dL (may have been transfused)
d. Potassium, sodium, calcium (corrected for serum albumin), and magnesium Common 
Terminology Criteria for Adverse Events (CTCAE) ≤Grade 1
e.
International normalized ratio ≤1.5
f.
Serum creatinine ≤1.5× upper limit of normal (ULN)
g. Serum albumin ≥3.0 g/dL (≥30 g/L)

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h. In absence of liver metastases, alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) ≤3.0×ULN.  If the patient has liver metastases, ALT and 
AST ≤5×ULN
i.
Total serum bilirubin <1.5×ULN except for patients with Gilbert’s syndrome who 
may be included if the total serum bilirubin is ≤3.0×ULN or direct bilirubin ≤ 
1.5×ULN
9. Willingness and ability to comply with study and follow-up procedures.
10. No concurrent antineoplastic therapy.  Use of bone-modifying agents, including 
bisphosphonate and receptor activator of nuclear factor kappa-B ligand (RANKL) 
inhibitors is permitted.  
Exclusion Criteria
1. Known central nervous system (CNS) metastases, including meningeal carcinomatosis.  
Brain or subdural metastases are not allowable, unless the patient has completed local 
therapy and has discontinued the use of corticosteroids for at least 4 weeks before 
starting treatment in this study.  Any signs (eg, radiologic) or symptoms of brain 
metastases must be stable for at least 4 weeks before starting study treatment.
2. Subject has a concurrent malignancy or malignancy within 3 years of enrollment, with 
the exception for basal or squamous cell skin cancer, superficial bladder cancer, or 
carcinoma in situ of the cervix or breast that has completed curative therapy), or known 
human immunodeficiency virus infection.
3. Uncontrolled significant active infections.  Note: subjects with hepatitis B virus and/or 
hepatitis C virus infection must have undetectable viral load during screening.     
4. Major surgery or other locoregional treatment within 4 weeks before the 1st dose of 
study drug.
5. Inability to take oral medication, or presence of malabsorption syndrome or any other
uncontrolled gastrointestinal condition (eg, nausea, diarrhea, or vomiting) that might 
impair the bioavailability of H3B-6545.  Palbociclib contains lactose.  Patients with rare 
hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-
galactose malabsorption should not take this medicine.
6. Currently participating in another clinical study or has received other investigational 
drugs within 28 days.
7. Active cardiac disease or a history of cardiac dysfunction, including any of the following:
a.
History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 
12 months prior to study entry.
b. History of documented congestive heart failure (New York Heart Association 
functional classification III or IV).
c.
Documented cardiomyopathy.
d. Subject has a left ventricular ejection fraction <50% as determined by multiple-gated 
acquisition (MUGA) scan or echocardiogram (ECHO).
e.
History of any cardiac arrhythmias in the previous 12 months.
f.
A prolonged QT interval corrected for heart rate using Fridericia’s formula (QTcF) 
>450 ms as demonstrated by a repeated ECG; a history of risk factors for Torsade de 

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pointes (eg, heart failure, hypokalemia, family history of long QT syndrome) or the 
use of concomitant medications that prolonged the QTcF interval.
g. Subject has resting pulse rate <60 bpm 
8. Females of childbearing potential who:
•
Within 28 days before study entry, did not use a highly effective method of 
contraception, which includes any of the following:
a.
Double-barrier contraception (considered acceptable method but not highly effective)
b. Total abstinence (if it is their preferred and usual lifestyle)
c.
An intrauterine device 
d. Have a vasectomized partner with confirmed azoospermia.
•
Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days (or 5 times the half-life of the study 
drug, whichever is longer) after study drug discontinuation.
Note: All females will be considered to be of childbearing potential unless they are 
postmenopausal (has amenorrhea 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).
9. Known intolerance to either study drug or any of the excipients.
10. Subject received in the 7 days prior to the administration of study drug or is currently 
receiving any of the following medications:
a.
Known strong inducers or inhibitors of cytochrome P450 (CYP) 3A4 or P-
glycoprotein (P-gp).
b. Medications that have a narrow therapeutic window and are breast cancer resistance 
protein (BCRP) substrate.
c.
Medications that have a known risk to prolong the QT interval or induce Torsades de 
Pointes.
d. Medications that have a narrow therapeutic window and are predominantly 
metabolized through CYP2C8, CYP2C9, CYP2C19, or CYP3A4.
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.
11. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [β-hCG] (or hCG) test with a minimum 
sensitivity of 25 IU/L or equivalent units of β-hCG [or hCG]).  A separate baseline 
assessment is required if a negative screening pregnancy test was obtained more than 
72 hours before the 1st dose of the study drug.
12. Active interstitial lung disease (ILD) or diagnosis of ILD within the last 12 months.
13. Any medical or other condition that in the opinion of the investigator(s) would preclude 
the subject’s participation in a clinical study.

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14. Exposure within the last 14 days to an individual with confirmed or probable COVID-19 
or symptoms within the last 14 days or any other reason to consider the subject at 
potential risk for an acute COVID-19 infection.  
Note: Please consider testing for active COVID-19 infection prior to starting trial therapy 
according to the institution guidelines.
15. Evidence of ongoing alcohol or drug abuse. 
Study Treatments
Test drug: H3B-6545 will be supplied as opaque, hypromellose shell capsules, size 4 
containing 50 mg or size 1 containing 150 mg of H3B-6545 drug substance.  The 
composition ratio of the capsule content is the same for both strengths. 
H3B-6545 is administered orally.  All subjects will take H3B-6545 at their assigned dose 
(PO, QD), in an open-label fashion, for 28-day cycles.  On days that H3B-6545 will be taken 
with palbociclib, subjects should take H3B-6545 at the same time as palbociclib.
Palbociclib will be supplied as 125, 100, and 75 mg capsules or tablets.  Palbociclib is taken 
PO QD for 21 consecutive days followed by 7 days off treatment to comprise a complete 
cycle of 28 days. 
H3B-6545 and palbociclib should be taken with food.  Subjects should be encouraged to take 
their dose at approximately the same time each day and within 30 minutes of completing a 
meal.  H3B-6545 capsules and palbociclib capsules or tablets should be swallowed whole.  
Capsules or tablets should not be ingested if they are broken, cracked, or otherwise not 
intact.  Dosing should not be repeated if a subject vomits.  A dose missed by more than 12 
hours should be skipped.  The next prescribed dose should be taken at the usual time.
Duration of Treatment
Study duration for each subject is estimated to be:
•
Screening/Baseline Phase: Up to 21 days.
•
Treatment Phase: Subjects will continue to receive study treatment until radiological 
disease progression, development of unacceptable toxicity, or withdrawal of consent.  
Treatment beyond radiological progression may be allowed if the subject continues to 
have clinical benefit as per the principal Investigator after discussion and written 
approval from the Sponsor.
•
Follow-Up Phase: All subjects will be followed for survival approximately every 3 
months for up to 6 months after the last subject receives their first dose of study 
treatment [ie, primary analysis data cutoff date]).
Subjects will be followed for AEs for 28 days after the last treatment administration.  
Subjects who discontinue 1 of the 2 drugs and continue therapy with the other one are 
considered on treatment until they discontinue the 2nd drug.

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Concomitant Drug/Therapy
Subjects will be instructed not to take any additional medications during the course of the 
study without prior consultation with the treating physician.  At each visit, the subject will be 
asked about any new medications she is taking or has taken after the start of the study drug. 
Permitted Concomitant Medications:
No routine prophylactic antiemetic is required.  However, the use of palonosetron, 
prochlorperazine, promethazine, and cyclizine for management of nausea and vomiting is 
allowed.  The use of ondansetron and granisetron is not permitted because of their potential 
to prolong QT interval.
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:  Prophylactic use of GCSF is not allowed from Cycle 1 Day 9 to Cycle 2 
Day 8.  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  
•
RANKL 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.  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 national diabetes management 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 below.
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, as well as an inhibitor of the BCRP, multidrug and toxin extrusion 
transporter (MATE)1, MATE2-K, organic anion transporting polypeptide (OATP)1B1, 
and P-gp mediated transport. Drugs with narrow therapeutic index and known to be 
metabolized by CYP2Cs or CYP3A4 are not permitted because of the inherent potential 

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risk of either reduced activity or enhanced toxicity of the respective concomitant 
medication (and/or inhibition of P-gp).  Medications that are strong inducers or inhibitors 
of CYP3A or P-gp should also be avoided since H3B-6545 is a substrate of P-gp and 
mainly metabolized by CYP3A4, followed by 3A5 and 2C8, and palbociclib is also 
mainly metabolized by CYP3A. For the most updated information, visit the following 
Web address: http://medicine.iupui.edu/clinpharm/ddis/.
•
Because of 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) 
•
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 the subject receives the concomitant medication.  Resumption of treatment with 
H3B-6545 may be considered following discontinuation and washout (at least 5 half-
lives) of the concomitant medication if the subject has not progressed and is agreed upon 
with the sponsor.  Excluded medications that may cause QTc interval prolongation are 
also listed and updated at the following Web address: http://crediblemeds.org.
•
Herbal preparations/medications are not allowed throughout the study.  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.  Subjects 
should stop using these herbal medications 7 days prior to the first dose of the study drug. 
•
Nutritional supplements, juice, other foods, or beverages that may affect the various 
drug-metabolizing enzymes and transporters (eg, alcohol, grapefruit, grapefruit juice, 
grapefruit-containing beverages) are not allowed for 1 week before and throughout the 
study.
•
Systemic corticosteroids are not allowed during the study.  Note: The following uses of 
corticosteroids are permitted: single doses, topical applications (eg, for rash), inhaled 
sprays (eg, for obstructive airway diseases), eye drops, or local injections (eg, intra-
articular).  Short courses of systemic corticosteroids may be considered in consultation 
with the medical monitor.
•
Use of short course palliative radiotherapy for symptomatic isolated bone metastases may 
be allowed following discussion with sponsor. 
Assessments
Efficacy Assessments
Tumor assessments will be performed according to RECIST 1.1.  Investigator-determined 
response assessments will be performed at each assessment timepoint and entered onto the 
case report form.  Tumor assessments (computed tomography [CT] chest with IV contrast,
and CT (oral and IV contrast) or MRI (IV contrast) of the abdomen, pelvis, and other known 
or suspected sites of disease) will be performed during the Screening/Baseline period (Day -
21 to Cycle 1 Day 1).  If imaging with contrast, as requested in above, is contraindicated, 
imaging without contrast should be performed and reason for contraindication should be
captured in the source documents.

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Tumor assessments will be performed at post-baseline timepoints (every 8 weeks (±7 days) 
after Cycle 1 Day 1, or as indicated if disease progression is suspected clinically) using the 
same imaging modality (eg, contrast-enhanced CT, MRI scan) and under the same operating 
conditions as the Screening/Baseline scans.  
A brain scan (CT with contrast or MRI [pre- and post-gadolinium]) will be performed at 
Screening, and as clinically indicated to assess potential for CNS disease and/or metastases.  
For subjects with a history of protocol-eligible treated brain metastases, a brain scan will be 
required at all tumor assessment timepoints.  For all subjects, a follow-up brain scan must be 
performed to confirm CR within 1 week following response confirmation, or if clinically 
indicated.
A bone scan using whole body bone MRI, 99m-technetium based bone scans, or 18F-sodium 
fluoride positron emission tomography will be performed during screening to establish a 
baseline (a historical bone scan performed within 6 weeks before Cycle 1 Day 1 is 
acceptable), approximately every 24 weeks (in conjunction with a scheduled tumor 
assessment visit), and as clinically indicated.  Lesions identified on bone scans should be 
followed with cross-sectional imaging.
Tumor assessments will be performed at Screening and every 8 weeks (±7 days) after 
Cycle 1 Day 1 (ie, 8, 16, 24 weeks) or as indicated if disease progression is suspected 
clinically.  
All responses must be confirmed no less than 28 days following the initial assessment of 
response.  In order for stable disease to be considered the best overall response, it must occur 
≥7 weeks following the first dose of study drug.
Subjects who discontinue study treatment without disease progression will continue to have 
tumor assessments (recorded up to the data cutoff date for the primary analysis) as per the 
Schedule of Assessments until disease progression, death, or initiation of another anticancer 
therapy, whichever occurs first, unless the study is terminated.
Pharmacokinetic Assessments
In dose escalation: 
•
On Cycle 1 Day 8, PK (palbociclib) blood samples to determine plasma concentrations of 
palbociclib will be collected at predose (within 1 hour before administration of study 
drug) and 1 (±10 minutes), 2 (±15 minutes), 4 (±20 minutes), 6 (±30 minutes), 8 (±30 
minutes), and 24 hours (±60 minutes, must be before administration of the next day’s 
dose of study drugs) postdose.  These windows apply to PK sampling on other days.
•
On Cycle 1 Day 21, PK (palbociclib and H3B-6545) blood samples to determine plasma 
concentrations of palbociclib and H3B-6545 will be collected at predose and 1, 2, 4, 6, 8, 
and 24 hours postdose.
•
On Cycle 1 Day 28, PK (H3B-6545) blood samples to determine plasma concentrations 
of H3B-6545 will be collected at predose and 1, 2, 4, 6, 8, and 24 hours postdose.
•
During the treatment phase, PK (palbociclib and H3B-6545) blood samples to determine 
plasma concentrations of palbociclib and H3B-6545 will be collected at predose in 
conjunction with each tumor assessment, that is, approximately every 8 weeks until end 
of treatment (EOT) or data cutoff date for the primary analysis, whichever is earlier.

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In dose expansion:
•
On Cycle 1 Day 21, PK (palbociclib and H3B-6545) blood samples to determine plasma 
concentrations of palbociclib and H3B-6545 will be collected at predose (within 1 hour 
before administration of study drug) and 1 (±10 minutes), 2 (±15 minutes), 4 (±20 
minutes), 6 (±30 minutes), 8 (±30 minutes), and 24 hours (±60 minutes, must be before 
administration of the next day’s dose of study drugs) postdose.  These windows apply to 
PK sampling on other days.
•
During the treatment phase, PK (palbociclib and H3B-6545) blood samples to determine 
plasma concentrations of palbociclib and H3B-6545 will be collected at predose in 
conjunction with each tumor assessment, that is, approximately every 8 weeks until 
progression.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
In dose escalation and expansion:
•
At baseline (during screening), pretreatment fresh biopsies or archival tumor tissue (the 
tumor sample must have been collected after the most recent progression or recurrence) 
will be obtained from all subjects.  If a subject consents to collection of fresh baseline 
biopsy, it may be acquired any time during the Screening period, before administration of 
the 1st dose of study drug on Cycle 1 Day 1. If collection of a biopsy during the 
screening period poses disproportionate risk to subject’s safety, the reason for the 
contraindication must be documented in source at site. Once documentation detailing risk 
is captured in the site records, subject may continue screening and if all I/E criteria are 
met, subject may be enrolled and treated.
•
At baseline, Cycle 1 Day 1, Cycle 1 Day 21, Cycle 3 Day 1, and every 8 weeks thereafter 
(coinciding with CT/MRI tumor assessments schedule until radiological progression), 
and at EOT (if different from date of progression), whole blood samples for mutation 
characterization from cell-free DNA (cfDNA) will be collected. Biomarker sample 
collection will end at the time of the primary analysis data cutoff date.
Safety Assessments
Safety assessments will consist of monitoring and recording the following:
-
Physical examination
-
ECOG performance status 
-
Height, weight, and vital signs 
-
12-lead ECGs 
-
ECHO, MUGA scan 
-
Laboratory assessments including but not limited to hematology, biochemistry, and 
lipid panel 

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Bioanalytical Methods
Plasma concentrations of H3B-6545 and palbociclib will be determined using validated high-
performance liquid chromatography/tandem mass spectrometry (LC-MS/MS) methods.  If 
appropriate, assessment of plasma concentration for any metabolites of H3B-6545 may be 
explored.  
Statistical Methods
Primary Endpoint
The primary study endpoint is to determine the MTD and/or RP2D.
Secondary Endpoints
•
AEs and serious adverse events (SAEs) as well as changes in clinical laboratory values, 
vital sign measurements and ECG parameters.
•
Standard primary PK parameters including, but not limited to, the area under the plasma 
concentration-time curve from timepoint 0 through the last measurable point (AUC0-t), 
Cmax, time of the maximum observed plasma concentration (Tmax), C24, and ratio of the 
DDI effect
•
ORR, defined as the proportion of subjects achieving a best overall response of 
confirmed partial or CR (PR+CR)
•
DoR, defined as the time from the date of the 1st documented CR/PR until the 1st 
documentation of disease progression or death, whichever comes first
•
CBR, defined as the proportion of subjects achieving a best overall response of 
confirmed partial or CR, or durable stable disease (duration is at least 23 weeks)
•
PFS, defined as the time from the 1st dose date to the date of the 1st documentation of 
disease progression or death (whichever occurs 1st)
•
OS, defined as the time from 1st dose date to the date of death from any cause
Analysis Sets
•
Safety Analysis Set: which will consist of all subjects who receive at least 1 dose of study 
drug.  This will be the analysis set for all safety evaluations except DLT results.
•
Full Analysis Set: which will consist of all subjects who receive at least 1 dose of study 
drug.
•
Dose Evaluable Set: which will consist of all subjects who were evaluable for DLT in 
Phase 1b.  This will be the analysis set for DLT results.
•
Response-Evaluable Set: which will consist of those subjects who receive at least 1 dose 
of study drug and have measurable disease at baseline and at least 1 postbaseline tumor 
assessment.  This will be the primary analysis set for efficacy evaluations.
•
Pharmacokinetic Analysis Set: which will consist of subjects who received at least 1 dose 
of study drug and all valid plasma concentrations (at least 3 valid concentrations for 
noncompartmental analysis).

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Efficacy Analyses
All efficacy parameters will be summarized descriptively for the Response-Evaluable Set
and Full Analysis Set.  ORR and CBR will be calculated with exact 95% confidence 
intervals using the method of Clopper and Pearson.  DoR will be calculated for subjects 
achieving a best overall response of confirmed PR+CR.  For DoR, PFS, and OS, medians 
will be calculated using Kaplan-Meier estimates.  DoR, PFS, and OS will be reported in both 
summary tables and plotted with Kaplan-Meier curve.  
Pharmacokinetic Analyses
The plasma concentrations of palbociclib and H3B-6545 will be presented by dose level and 
day, as the number of subjects with data, geometric mean, mean, standard deviation (SD), 
median, minimum, and maximum values by nominal sampling timepoint.  The PK 
parameters will include, as applicable, Cmax (Tmax), AUC0-24 (AUC from zero time to 24 
hours), AUC0-t (AUC from zero time to last measurable concentration), AUC0-inf (AUC from 
zero time to infinity), percentage of AUC that is due to extrapolation from the last 
measurable concentration to infinity (%AUCExtrap), apparent terminal disposition rate 
constant (λz), apparent plasma terminal elimination half-life, apparent total plasma clearance 
(CL/F), and apparent volume of distribution (V/F).
The palbociclib and H3B-6545 PK parameters will be tabulated per dose level and day, with 
the number of measurements, number of non-missing data, mean, SD, median, minimum, 
maximum, geometric mean, and coefficient of variation (CV%; based on untransformed 
data).
The DDI effect on each other at steady state will be calculated as summarized appropriately 
(refer to Section 9.4.7.1).
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
The baseline tissue biopsies collected will be used to examine potential baseline markers of 
response.  These markers may include but are not limited to ER, PR, RB, Ki67, HER2, gene 
expression and DNA mutations (using standard technologies like quantitative polymerase 
chain reaction, immunohistochemistry, and other appropriate technology) along with global 
transcription levels (RNA sequencing).
The whole blood samples will be analyzed for evaluation of cfDNA as a source of circulating 
biomarker (DNA mutations).  The samples might be used for exploratory analysis for 
evaluation of response-related and/or safety-related outcomes as well as for potential use in 
companion diagnostic and drug development, and would be reported separately if conducted.
Exposure-response with biomarkers and/or other efficacy endpoints might be explored as 
appropriate with a population PK model-predicted exposure values and will be reported 
separately.
Safety Analyses
The determination of the MTD and/or RP2D will be based on Dose Evaluable Set that 
consists of all DLT-evaluable subjects.  Subjects not evaluable for DLT assessment will be 
replaced.  
All other safety analyses will be performed on the Safety Analysis Set.  Safety data will be 
summarized using descriptive statistics (eg, n, mean, standard deviation, median, minimum, 
maximum for continuous variables; n [%] for categorical variables).  Safety variables include 

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treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, and 
12-lead ECG results.
Safety will be assessed through the analysis of the reported incidence of TEAEs.  The AEs 
will be coded using the Medical Dictionary for Regulatory Activities, and summarized using 
system organ class and preferred term.  In addition, summaries of SAEs, AEs leading to 
treatment discontinuation, AEs by maximum National Cancer Institute CTCAE v5.0 grade, 
and AEs related to study treatment will also be presented by dose level.
Other safety endpoints, including laboratory results, vital signs, and ECG findings, will be 
summarized for all subjects in the Safety Analysis Set.
Interim Analyses
No formal interim analyses are planned.  However, the cumulated safety and efficacy data by 
dose level will be reviewed periodically by the sponsors and investigators.  The continuation 
of study enrollment will depend on the totality of the efficacy and safety data. 
Sample Size Rationale
Depending on the dose levels to be studied in the dose escalation part, approximately 
12 to 24 subjects may be treated.  Dose expansion will enroll 12 additional subjects at the 
RP2D.  Therefore, the study is expected to enroll approximately 24 to 36 subjects.  No 
formal sample size calculation is performed.

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3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS..........................................................................26
3
TABLE OF CONTENTS.............................................................................................41
4
ETHICS.......................................................................................................................48
4.1
Institutional Review Boards/Independent Ethics Committees.............................48
4.2
Ethical Conduct of the Study..............................................................................48
4.3
Subject Information and Informed Consent ........................................................49
5
INVESTIGATORS AND STUDY PERSONNEL .......................................................50
6
STUDY REGISTRATION ..........................................................................................50
7
INTRODUCTION.......................................................................................................51
7.1
Compound Overview .........................................................................................51
7.2
Clinical Experience............................................................................................52
7.2.1
H3B-6545.................................................................................................52
7.2.2
Palbociclib ...............................................................................................53
7.3
Study Rationale..................................................................................................53
8
STUDY OBJECTIVES................................................................................................53
8.1
Primary Objective ..............................................................................................53
8.2
Secondary Objectives.........................................................................................54
8.3
Exploratory Objective ........................................................................................54
9
INVESTIGATIONAL PLAN ......................................................................................54
9.1
Overall Study Design and Plan...........................................................................54
9.1.1
Pretreatment Phase ...................................................................................58
9.1.2
Treatment Phase.......................................................................................58
9.1.3
Follow-Up Phase......................................................................................59
9.2
Discussion of Study Design, Including Choice of Control Groups......................60
9.3
Selection of Study Population ............................................................................60
9.3.1
Inclusion Criteria......................................................................................60
9.3.2
Exclusion Criteria.....................................................................................61
9.3.3
Removal of Subjects From Therapy or Assessment ..................................63
9.4
Treatments.........................................................................................................64
9.4.1
Treatments Administered..........................................................................64
9.4.2
Identity of Investigational Products ..........................................................65
9.4.2.1
Chemical Name of H3B-6545.........................................................65
9.4.2.2
Chemical Name of Palbociclib........................................................65
9.4.2.3
Labeling for Study Drug .................................................................65
9.4.2.4
Storage Conditions..........................................................................66
9.4.3
Method of Assigning Subjects to Treatment Groups.................................66

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9.4.4
Selection of Doses in the Study ................................................................66
9.4.5
Selection and Timing of Dose for Each Subject........................................67
9.4.6
Blinding ...................................................................................................67
9.4.7
Prior and Concomitant Therapy................................................................67
9.4.7.1
Drug-Drug Interactions...................................................................68
9.4.7.2
Prohibited Concomitant Therapies and Drugs .................................68
9.4.7.3
Permitted Concomitant Medications ...............................................69
9.4.8
Treatment Compliance .............................................................................70
9.4.9
Drug Supplies and Accountability ............................................................70
9.5
Dose Modifications............................................................................................71
9.6
Study Assessments.............................................................................................75
9.6.1
Assessments .............................................................................................75
9.6.1.1
Screening Assessments ...................................................................75
9.6.1.2
Efficacy Assessments......................................................................75
9.6.1.2.1
Tumor Assessments........................................................................75
9.6.1.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments ........................................................76
9.6.1.3.1
Pharmacokinetic Assessments.........................................................76
9.6.1.3.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments.....................................................................................................77
9.6.1.4
Safety Assessments.........................................................................78
9.6.1.4.1
Adverse Events...............................................................................79
9.6.1.4.2
Serious Adverse Events and Events Associated With Special 
Situations 81
9.6.1.4.3
Laboratory Measurements...............................................................82
9.6.1.4.4
Vital Signs and Weight Measurements............................................83
9.6.1.4.5
Physical Examinations....................................................................83
9.6.1.4.6
Electrocardiograms.........................................................................83
9.6.1.4.7
Other Safety Assessments...............................................................84
9.6.2
Schedule of Procedures/Assessments........................................................84
9.6.2.1
Schedule of Procedures/Assessments..............................................84
9.6.2.2
Description of Procedures/Assessments Schedule ...........................91
9.6.3
Appropriateness of Measurements............................................................91
9.6.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated With Special Situations...........................................................91
9.6.4.1
Reporting of Abnormal Hepatic Tests of Clinical Interest.........................91
9.6.4.2
Reporting of Serious Adverse Events..............................................92
9.6.4.3
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding..................................................................................92
9.6.4.4
Reporting of Events Associated With Special Situations.................93

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9.6.4.4.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ................................................93
9.6.4.5
Expedited Reporting .......................................................................93
9.6.4.6
Breaking the Blind..........................................................................94
9.6.4.7
Regulatory Reporting of Adverse Events ........................................94
9.6.5
Completion/Discontinuation of Subjects...................................................94
9.6.6
Confirmation of Medical Care by Another Physician................................95
9.7
Data Quality Assurance......................................................................................95
9.7.1
Data Collection.........................................................................................95
9.7.2
Clinical Data Management .......................................................................96
9.8
Statistical Methods.............................................................................................96
9.8.1
Statistical and Analytical Plans.................................................................96
9.8.1.1
Study Endpoints..............................................................................96
9.8.1.1.1
Primary Endpoint............................................................................96
9.8.1.1.2
Secondary Endpoints ......................................................................96
9.8.1.2
Definitions of Analysis Sets............................................................97
9.8.1.3
Subject Disposition.........................................................................97
9.8.1.4
Demographic and Other Baseline Characteristics............................97
9.8.1.5
Prior and Concomitant Therapy ......................................................97
9.8.1.6
Efficacy Analyses...........................................................................98
9.8.1.6.1
Primary Efficacy Analysis ..............................................................98
9.8.1.6.2
Secondary Efficacy Analyses..........................................................98
9.8.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses..............................................................98
9.8.1.7.1
Pharmacokinetic Analyses ..............................................................98
9.8.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses
98
9.8.1.8
Safety Analyses ..............................................................................99
9.8.1.8.1
Extent of Exposure .........................................................................99
9.8.1.8.2
Adverse Events...............................................................................99
9.8.1.8.3
Laboratory Values ........................................................................101
9.8.1.8.4
Vital Signs....................................................................................101
9.8.1.8.5
Electrocardiograms.......................................................................101
9.8.2
Determination of Sample Size ................................................................102
9.8.3
Interim Analysis.....................................................................................102
9.8.4
Other Statistical/Analytical Issues ..........................................................102
9.8.5
Procedure for Revising the Statistical Analysis Plan...............................102
10
REFERENCE LIST...................................................................................................103
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....105
11.1
Changes to the Protocol....................................................................................105

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11.2
Adherence to the Protocol................................................................................105
11.3
Monitoring Procedures.....................................................................................105
11.4
Recording of Data............................................................................................106
11.5
Identification of Source Data............................................................................106
11.6
Retention of Records........................................................................................107
11.7
Auditing Procedures and Inspection .................................................................107
11.8
Handling of Study Drug ...................................................................................107
11.9
Publication of Results ......................................................................................108
11.10 Disclosure and Confidentiality .........................................................................108
11.11 Discontinuation of Study..................................................................................108
11.12 Subject Insurance and Indemnity......................................................................109
12
APPENDICES...........................................................................................................110

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ALT 
alanine aminotransferase
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
β-hCG
beta-human chorionic gonadotropin
BCRP
breast cancer resistance protein
BP
blood pressure
CBC
complete blood cell (count)
CBR
clinical benefit rate
cfDNA
cell-free DNA
CL/F
apparent total body clearance following oral administration
Cmax
maximum observed plasma concentration
CNS
central nervous system
CR
complete response
CRA
clinical research associates
CRF
case report form
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DDI
drug-drug interaction
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DoR
duration of response
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
EOT
end of treatment

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ER
estrogen receptor
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HER2
human epidermal growth factor receptor-2
ICF
informed consent form
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
institutional review board
IV
intravenous
LVEF
left ventricular ejection fraction
MATE
multidrug and toxin extrusion transporter
MedDRA
Medical Dictionary for Regulatory Activities
MUGA
multiple-gated acquisition 
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute 
ORR
objective response rate
OS
overall survival
PD
pharmacodynamic(s)
PFS
progression-free survival
P-gp
P-glycoprotein
PI
principal investigator
PK
pharmacokinetic(s)
PO
orally
PR
partial response
PT
preferred term
QD
once daily
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RANKL
receptor activator of nuclear factor kappa-B ligand
RECIST
Response Evaluation Criteria in Solid Tumors

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RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOC
system organ class
SOP
standard operating procedure
SRC
Safety Review Committee
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
Tmax
time of maximum observed plasma concentration
ULN
upper limit of normal
WHO DD
World Health Organization Drug Dictionary

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4
ETHICS
4.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with ICH E6 (Good Clinical 
Practice [GCP]), Section 3, and any local regulations.  Any protocol amendment or revision 
to the ICF will be resubmitted to the IRB/IEC for review and approval, except for changes 
involving only logistical or administrative aspects of the study (eg, change in clinical 
research associates [CRA(s)], change of telephone number[s]).  Documentation of IRB/IEC 
compliance with the ICH E6 and any local regulations regarding constitution and review 
conduct will be provided to the sponsor.
Documented study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required.
Where appropriate, at the end of the study, the sponsor should notify the IRB/IEC and 
Competent Authority within 90 days. 
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.
4.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures (SOPs) of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:
•
Principles of the World Medical Association Declaration of Helsinki 2013
•
ICH E6 (R2) Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 

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International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
•
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312
•
European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any EU country.  All suspected unexpected 
serious adverse reactions (SUSARs) will be reported, as required, to the Competent 
Authorities of all involved EU member states. 
4.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject or guardian, in accordance with applicable professional standards and local 
laws/regulations or legally acceptable representative, the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits involved, any 
potential discomfort, potential alternative procedure(s) or course(s) of treatment available to 
the subject, and the extent of maintaining confidentiality of the subject’s records.  Each 
subject must be informed that participation in the study is voluntary, that he/she may 
withdraw from the study at any time, and that withdrawal of consent will not affect her 
subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally (PO) consented to the 
subject’s participation in the study and, if capable of doing so, has signed and personally 
dated the ICF, the witness should sign and personally date the consent form.  The subject will 
be asked to sign an ICF at the screening visit before any study-specific procedures are 
performed.  No subject can enter the study before her informed consent has been obtained.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject must sign an approved ICF 
before study participation.  The form must be signed and dated by the appropriate parties.  
The original, signed ICF for each subject will be verified by the sponsor and kept on file 
according to local procedures at the site.  
The subject or the subject’s legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented.

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5
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai, Inc. at 
approximately 7 investigational site(s) globally.
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization(s) (CRO[s]) are listed in the 
Investigator Study File provided to each site.
6
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 (IRB/Independent Ethics Committee 
[IEC]) 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 email when a new Dose 
Level/Cohort is opened and an 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.  A patient is enrolled once the approved enrollment 
packet is returned to the site in ePIP.  
The Sponsor or designee will also communicate to all sites via email 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 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 enrollment on the registration form, and will send the completed form back 
to the site as soon as possible, no later than 24 hours following the registration request.
All subject data collected in the study will be stored under this number.  Only the investigator 
will be able to link the subject’s study data to the subject via an identification list kept at the 
site.  The subject’s original medical data that are reviewed at the site during source data 
verification by the Monitor, audits, and Health Authority inspections will be kept strictly 
confidential.

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Data protection and privacy regulations will be observed in capturing, forwarding, 
processing, and storing subject data.  Subjects will be informed accordingly and will be 
requested to give their consent on data handling procedures in accordance with national 
regulations.
7
INTRODUCTION
This is an open-label multicenter Phase 1b dose escalation and dose expansion study to 
evaluate the safety and tolerability of oral H3B-6545 (300 or 450 mg) in combination with 
palbociclib.  The primary objective of the study is to determine the maximum tolerated dose 
(MTD) and/or the recommended Phase 2 dose (RP2D) of H3B-6545 in combination with 
palbociclib in women with advanced or metastatic estrogen receptor–positive (ER+) human 
epidermal growth factor receptor-2–negative (HER2–) breast cancer.
7.1
Compound Overview
Current treatment for most women with advanced ER+ HER2– breast cancer is combination 
of endocrine therapy (aromatase inhibitors, or fulvestrant) and CDK4/6 inhibitor, 
eg, palbociclib.  The use of CDK inhibitors has dramatically improved clinical outcome in 
this group of patients (Finn, et al., 2016; Hortobagyi, et al., 2018; Turner, et al., 2018).  
However, nearly all patients will eventually relapse and therapy for refractory/recurrent 
disease is suboptimal.  Additional improvements in outcome will require novel agents in the 
frontline setting.  H3B-6545 is a novel selective ER covalent antagonist with promising 
activity as a monotherapy in the nonclinical setting (Smith, et al., 2017).  Combination with 
palbociclib further improves efficacy over single treatments alone in multiple patient-derived 
human breast cancer xenograft models supporting this combination strategy (data on file).
H3B-6545 is currently in Phase 1/2 clinical trial as a monotherapy in women with advanced 
metastatic ER+ HER2– breast cancer.  Based on available safety and efficacy data from the 
current Phase 1/2 study of H3B-6545 in heavily pretreated women with ER+ HER2– breast 
cancer, the drug showed a promising level of activity and a tolerable safety profile 
(Hamilton, et al., 2019).
Palbociclib, an oral inhibitor of CDK4 and CDK6, has shown activity in metastatic disease 
settings when combined with endocrine therapy (aromatase inhibitors and fulvestrant) 
leading to significant improvements in progression-free survival (PFS), suggesting that 
combination therapy delays the onset of resistance in patients receiving endocrine therapy 
(Finn, et al., 2016; Turner, et al., 2018).  Consistent with this, we show H3B-6545, a 
selective ER covalent antagonist that covalently engages with ERa, in combination with 
palbociclib significantly improves efficacy over single-agent treatments in multiple patient-
derived human breast cancer xenograft models in female mice.

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7.2
Clinical Experience
7.2.1
H3B-6545
As of 15 Sep 2019, 57 subjects were enrolled in the Phase 1/2 Study H3B-6545-A001-101; 
47 subjects in the Phase 1 part of the trial and 10 subjects in the Phase 2 part of the trial.  The 
Phase 1 part of the trial evaluated doses ranging from 100 to 600 mg once daily (QD) PO and 
the dose of 450 mg daily was selected as the RP2D.  Median age was 61 years (range: 31 to 
81 years), and the median prior therapy for metastatic disease was 3 (range: 1 to 8), with 49% 
of the subjects receiving at least 4 prior therapies.  Prior CDK4/6i, fulvestrant, and 
chemotherapy were received by 88%, 67%, and 74% of the subjects, respectively.  The most 
common non-AEs are presented in Table 1.
Table 1
Adverse Events, Irrespective of Causality
100 – 300 mg (N=29)
450 mg (N=21)
Adverse Event
G2
G3
G4
G2
G3
G4
Neutropenia
0
0
0
0
0
0
Thrombocytopenia
0
3
0
0
0
0
Anemia
14
7
0
14
5
0
ALT
0
3
0
10
0
0
AST
3
10
0
10
0
0
Serum bilirubin
0
3
1
5
0
0
Serum creatinine
3
0
0
0
0
0
Nausea
7
0
0
5
0
0
Vomiting
3
0
0
0
0
0
Diarrhea
7
0
0
5
5
0
Fatigue
14
0
0
5
0
0
ALT = alanine aminotransferase; AST = aspartate aminotransferase; G = grade.
Sinus bradycardia, defined as heart rate less than 60 beats per minute, was observed in 
approximately 29% of the subjects (Table 2).
Table 2
Sinus Bradycardia
Grade
100 – 300 mg (N=29)
n (%)
450 mg (N=21)
n (%)
1 (asymptomatic)
10 (34)
5 (24)
2 (symptomatic, no intervention required)
0
1 (5)
No Grade 3 or 4 events were observed.  Within the range of doses tested, sinus bradycardia 
did not seem to be dose related.

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Subjects were considered eligible if their QT interval corrected for heart rate using 
Fridericia’s formula (QTcF) was ≤450 ms.  Two subjects experienced a QTcF of ≥500 ms, 
with more than 60 ms of change relative to baseline.
As of the cutoff date, 50 subjects were evaluable for response.  Partial responses from 
3 subjects were reported (6%), and clinical benefit rate (CBR) (complete response [CR], 
partial response [PR], or stable disease lasting for ≥23 weeks) was observed in 16 subjects 
(32%).  Median PFS was 5.3 months. 
These safety and efficacy data are supportive of further development of H3B-6545 in ER+ 
HER2– subjects, both as monotherapy and in combination with targeted therapy.
7.2.2
Palbociclib
Palbociclib is a CDK4/6i indicated with letrozole in the primary management of patients with 
HR+ HER2– advanced breast cancer.  The starting dose of palbociclib is 125 mg PO QD on 
Days 1 to 21 of a 28-day cycle.  The most common toxicities are cytopenias, fatigue, nausea, 
alopecia, and stomatitis.  
The toxicity profiles of H3B-6545 and palbociclib suggest that a combination of these drugs 
is feasible.  The potential drug-drug interaction (DDI) between H3B-6545 and palbociclib is 
discussed in Section 9.7.
7.3
Study Rationale
The proposed study aims to identify the recommended doses of the combination of 
palbociclib and H3B-6545 and to characterize the safety and toxicity of this combination.  
Further development of such combination could provide an additional option for the first-line 
and, potentially, adjuvant treatments of women with ER+ HER2– breast cancer.
In this trial, women with ER+ HER2– advanced breast cancer will be treated with a 
combination of palbociclib and H3B-6545.  During Cycle 1, treatment will consist of 
palbociclib PO on Days 1 to 21 and H3B-6545 PO on Days 9 to 28.  This will allow for the 
PK profile of the agents to be studied at the following timepoints: Day 8 (palbociclib alone), 
Day 21 (combination), and Day 28 (H3B-6545 alone).  For all subsequent cycles, treatment 
with both agents will be on a 28-day schedule, with palbociclib being given on Days 1 to 21 
and H3B-6545 on Days 1 to 28.
8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is to evaluate the safety and tolerability of H3B-6545 and 
palbociclib when administered in combination in order to determine the MTD and/or the 
RP2D of this combination in women with advanced or metastatic ER+ HER2– breast cancer.

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8.2
Secondary Objectives
The secondary objectives of the study are as follows:
•
To evaluate the pharmacokinetic (PK) profile of H3B-6545 and palbociclib when 
administered in combination 
•
To estimate the preliminary clinical activity of H3B-6545 plus palbociclib in terms of 
objective response rate (ORR), duration of response (DoR), CBR (CR, PR, or stable 
disease ≥23 weeks) PFS, and overall survival (OS)
8.3
Exploratory Objective
•
To explore the relationship of blood and tumor biomarkers with clinical endpoints 
including safety, clinical activity, and PK
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
H3B-6545-G000-102 is a multicenter, open-label study of H3B-6545 in combination with 
palbociclib for women with advanced or metastatic ER+ HER2– breast cancer.  This study 
consists of 2 parts: dose escalation (Part 1) and dose expansion (Part 2).  H3B-6545 will be 
administered at the assigned dose (PO, QD), in an open-label fashion, for 28-day cycles.  
During each cycle, palbociclib will be administered at the assigned dose (PO, QD) for the 
first 21 days of each cycle, in an open-label fashion.
The dose escalation part of the study will accrue approximately 12 to 24 subjects.  Total 
sample size will be determined based on the number of dose-limiting toxicities (DLTs) 
observed and the number of dose levels (cohorts) studied.  The dose expansion phase of the 
study will enroll a planned 12 additional subjects at the RP2D.  Therefore, the study is 
expected to enroll approximately 24 to 36 subjects.  Assuming a 15% screen failure rate, the 
number of screened subjects is estimated to be 28 to 41.
Subjects in dose escalation must have progressed after 2 prior endocrine therapies and may 
have received up to 1 prior chemotherapy regimen and up to 1 prior CDK4/6 inhibitor.  
Subjects in dose expansion may have received up to 2 prior endocrine therapies and up to 1 
prior chemotherapy regimen but may not have received a prior CDK4/6 inhibitor in the 
advanced or metastatic setting.  
Subjects who are tolerating therapy and are without progressive disease may receive 
treatment until progression.  
The dose escalation part of the study will determine the MTD and/or the RP2D of H3B-6545 
in combination with palbociclib.  Each cohort will consist of 6 DLT-evaluable subjects to 
ensure sufficient safety and PK data are obtained prior to dose escalation.  A cycle of 
treatment will be 28 days. 

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Due to the potential for screen failures and/or a subject discontinuing treatment before 
completion of the cohort DLT assessment window (non-evaluable for DLT assessment), up 
to 8 slots will be opened for screening in order to obtain 6 DLT-evaluable subjects (See Section 
9.1). In addition, subjects considered screen failures or unevaluable for DLT will be replaced.
Once 6 subjects have been dosed at the current cohort dose level, any additional subjects in 
screening will be allocated to one of the following cohorts for enrollment:

The current cohort so that the total number of DLT-evaluable subjects is maintained 
at 6, if any of the 6 already dosed subjects becomes non-evaluable for DLT;

A lower dose cohort which has already been deemed safe per dose escalation 
meeting, if none of the 6 already dosed subjects becomes non-evaluable for DLT in 
the cohort currently under evaluation; the additional subject(s) will not contribute to 
DLT evaluation of the lower dose cohort, but will contribute to the overall safety 
evaluation.

The next cohort to be opened to enrollment including the expansion cohort if the 
RP2D has been reached and the expansion phase is open to enrollment.
Sponsor approval of any enrollment scenario not described above must take place prior to 
screened subject enrollment.
In the 1st cycle, palbociclib will be administered PO QD on Days 1 to 21 and H3B-6545 will 
be administered PO QD on Days 9 to 28.  In all subsequent cycles, palbociclib will be 
administered on Days 1 to 21 and H3B-6545 will be administered Days 1 to 28. 
A maximum of 4 dose levels are planned, with palbociclib escalated no higher than 125 mg 
QD and H3B-6545 escalated no higher than 450 mg QD (RP2D); see dose escalation in 
Table 3.
Table 3
Dose Escalation
Dose Level
(Cohort)
Palbociclib Dose 
(mg QD)
H3B-6545 Dose 
(mg QD)
Number of DLT-
Evaluable Subjects
-1
75
300
6
1 (starting dose)
100
300
6
2
125
300
6
3
125
450
6
3b
100
450
6
DLT = dose limiting toxicity; QD = once daily.
Subjects will be assigned to a dose level in the order of study entry.  DLTs will be assessed 
during the first 28 days starting from the 1st day of adding H3B-6545 to palbociclib (Cycle 1 
Day 9 to Cycle 2 Day 8).  Subjects who do not receive at least 75% of the scheduled therapy 

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from Cycle 1 Day 9 to Cycle 2 Day 8, for reasons other than toxicity, will not be considered 
evaluable for DLT assessment and will be replaced.  Disease progression and AEs deemed 
related to disease progression will not be considered DLTs.
After all subjects in a cohort have completed the DLT observation period, all available safety 
data will be reviewed by the Safety Review Committee (SRC) consisting of sponsor 
personnel and investigators, and the decision to proceed to the next dose cohort will be made 
jointly. 
Dose escalation will proceed if <2 of 6 evaluable subjects experience a DLT and will 
continue until a dose level where ≥2 of 6 subjects experience a DLT.  If ≥2 of 6 subjects in
the starting dose cohort experience a DLT during the first cycle, then the dose level -1 will be 
explored.
The MTD is defined as the highest dose at which no more than 1 of 6 subjects experiences a 
DLT in the dose cohort.  The RP2D may not exceed the MTD and will be agreed upon by the 
SRC based on an integrated evaluation of available safety, clinical benefit, PK, and 
pharmacodynamics (PD) data, for all dose levels tested.
DLT is based on the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE).  DLT refers to toxicities experienced by subjects enrolled to the 
dose escalation portion of the trial during the first 2 cycles of treatment, which are at least 
possibly related to the study drug.  A DLT will be defined as indicated in Table 4.
Table 4
Definition of Dose-Limiting Toxicity
Toxicity
Criteriaa
Hematology
-
Febrile neutropenia (ANC <1×109/L and fever ≥38.5 °C)
-
Grade 4 neutropenia that does not resolve to Grade ≤2 (ANC ≥1×109/L) within 
7 days; use of GM-CSF is allowed
-
Grade 4 thrombocytopenia (<25.0×109/L)
-
Grade 3 thrombocytopenia (25.0 – 50.0×109/L) lasting more than 7 days or 
associated with clinically significant bleeding
Vomiting
-
CTCAE Grade 4 vomiting
-
Grade 3 vomiting lasting >72 hours despite optimal antiemetic treatment
Diarrhea
-
CTCAE Grade 4 diarrhea
-
Grade 3 diarrhea lasting >72 hours despite optimal antidiarrheal treatment
Electrolytes 
abnormality
-
Grade 4
-
Grade 3 lasting for more than 24 hours
Note: Grade 3 that lasts <24 hours and resolves spontaneously or responds to 
conventional medical interventions is not considered a DLT.
Renal
-
Grade 3 or 4 serum creatinine
Hepatic
-
Grade 3 or 4 bilirubin increase
-
ALT or AST >8 × ULN

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-
In absence of liver metastases at baseline and in absence of clinical or 
radiological evidence of biliary obstruction: ALT or AST >3 × ULN, in 
conjunction with total bilirubin >2 ×ULN
Biochemistry
-
Grade 4
-
Grade 3 lasting more than 7 days, unless considered not clinically significant as 
per the discretion of the investigator
Any other non-
hematologic AE
Grade 4 
Grade 3 (except diarrhea, rash, nausea, or vomiting lasting ≤72 hours)  
Any drug-related intolerable Grade 2 toxicity (other than hematological AEs) 
leading to administration of <75% of the dose during the DLT observation period
AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; DLT = dose-limiting toxicity; 
GM-CSF = granulocyte–macrophage colony-stimulating factor; ULN = upper limit of normal.
a.
Laboratory values that meet criteria listed in this table should be repeated and confirmed within 24 hours of the initial 
results being reported.
Intrasubject dose escalation: Once a subject has completed Cycle 3 at her assigned dose 
level of drug, intrasubject dose escalation will be allowed.  No more than 2 dose escalations 
are allowed for any subject.  Only subjects whose conditions have not progressed on 
treatment and did not have a dose reduction of either palbociclib or H3B-6545 because of 
AEs can escalate to the highest dose level that has completed DLT assessment and has been 
shown to be safe (no more than 1 DLT in 6 subjects).  Subjects on the intrasubject dose 
escalation will not be included in the DLT analysis at the higher dose level.  
Dose expansion: An additional 12 subjects will be treated at the MTD/RP2D to further 
characterize safety, tolerability, and PK and to provide preliminary estimates of efficacy.  In 
Cycle 1, subjects will receive palbociclib PO QD on Days 1 to 21 and H3B-6545 PO QD on 
Days 9 to 28.  In all subsequent cycles, palbociclib will be administered on Days 1 through to 
21 and H3B-6545 will be administered Days 1 through to 28.
AEs will be managed by treatment interruption, dose reduction, and/or treatment 
discontinuation in accordance with the dose modification instructions outlined in the 
protocol.  Treatment will continue until disease progression, development of unacceptable 
toxicity, or withdrawal of consent.
The data cutoff date for the primary analysis will be approximately 6 months after the last 
subject receives their first dose of study treatment.  The end of study will be the last 
assessment for the last subject (eg, the last assessment for the last subject in the Extension 
Phase).
An overview of the study design and the decision rules for selection of the RP2D is presented 
in Figure 1.

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Figure 1 Study Design and Selection of the Recommended Phase 2 Dose
DLT = dose-limiting toxicity; Y = yes; N = no.
9.1.1
Pretreatment Phase
The Pretreatment Phase will last for 3 weeks (from the date of consent signature to the date 
of first study drug administration) and will include a Screening Period. 
Screening will occur between Day –21 and Day 1.  The purpose of the Screening Period is to 
obtain informed consent and to establish protocol eligibility.  Informed consent will be 
obtained after the study has been fully explained to each subject and before the conduct of 
any screening procedures or assessments.  Procedures to be followed when obtaining 
informed consent are detailed in Section 4.3.
Subjects who complete the Screening Period as outlined in Table 8 and meet the criteria for 
inclusion/exclusion (Sections 9.3.1 and 9.3.2) will begin the Treatment Phase.
9.1.2
Treatment Phase
The Treatment Phase will extend from the start of the first study drug administration and 
continue until disease progression, development of unacceptable toxicity, or withdrawal of 
consent. 
Treatment cycles will begin with the first dose of palbociclib in Cycle 1 administered PO QD 
on Days 1 to 21 and H3B-6545 administered PO QD on Days 9 to 28.  In all subsequent 

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cycles, palbociclib will be administered on Days 1 to 21 and H3B-6545 will be administered 
Days 1 to 28.
9.1.3
Follow-Up Phase
The follow-up phase will extend from treatment discontinuation until the End of Study. All 
subjects will be followed for survival approximately every 3 months for up to 6 months after 
the last subject receives their first dose of study treatment). Survival follow-up will not be 
done in the Extension Phase.
Subjects will be followed for AEs for 28 days after the last treatment administration.  
Subjects who discontinue 1 of the 2 drugs and continue therapy with the other one are 
considered on treatment until they discontinue the 2nd drug.
The cutoff date for the primary analysis will be approximately 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.
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.  The Schedule of Assessments for the Extension Phase will only collect safety and 
dosing information (Table 9). The End of Treatment (EOT) Visit assessment will occur 
within 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.
If a subject becomes unavailable for follow-up (eg, misses scheduled assessment, telephone 
contact), the investigator or designee will make every attempt to contact the subject to 
determine her status.  All attempts at contact will be recorded in the subject’s medical notes.  
Subjects will only be deemed lost to follow-up:
•
After a minimum of 3 attempted contacts (eg, telephone, letter) with the subject, the 
subject’s family, or the primary care (family) physician, at least 4 weeks apart.  The last 
attempt at contact must occur no earlier than 3 months after the subject’s last successful 
contact.
•
If the last attempt at contact is unsuccessful, the site should write a letter with certified 
proof of posting or regional equivalent method to the subject, subject’s family, or the 
primary care (family) physician to request information on the subject's status.
Subjects who discontinue trial therapy for any reason other than documented radiological 
progression, entrance into the Extension Phase or withdrawal of consent must still follow all 
safety assessments until the Safety Follow-up Visit (28 days after last treatment 
administration) and efficacy assessments (every 8 weeks ± 1 week) until documented disease 
progression or starting another anticancer therapy.

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9.2
Discussion of Study Design, Including Choice of Control Groups
The goals of Phase 1 oncology studies include estimation of the initial safety and tolerability 
of a study drug, establishment of an MTD, and determination of a recommended range of 
doses for evaluation in future clinical studies, based on PK and PD effects (Dillman and 
Koziol, 1992; Gatsonis and Greenhouse, 1992; ICH E8, 1997; Ahn, 1998); the primary 
objectives of the current study are consistent with those typical of Phase 1 oncology studies.  
During the dose escalation phase of the study, 6 evaluable subjects will be enrolled at each 
cohort in order to increase confidence in the safety assessment of this combination at 
different dose levels.  An integrated evaluation of safety and tolerability will be used to select 
the RP2D schedule to be implemented before the dose expansion phase.
Preliminary assessment of activity or potential therapeutic benefit may be a secondary 
objective of Phase 1 studies (ICH E8, 1997).  Consistent with this premise, a secondary 
objective is to evaluate the potential antitumor activity of the combination of H3B-6545 and 
palbociclib.  
9.3
Selection of Study Population
Approximately 24 to 36 subjects will be enrolled at approximately 7 centers globally.  The 
dose escalation phase of the study will accrue approximately 12 to 24 subjects.  The dose 
expansion phase of the study will enroll a planned 12 additional subjects at the RP2D.  
Assuming a 15% screen failure rate, the number of screened subjects is estimated to be 28 to 
41.  The study will include women with advanced or metastatic ER+ HER2– breast cancer.
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study drug.
9.3.1
Inclusion Criteria
1. Subjects must meet all of the following criteria to be included in this study:
2. Subject has signed ICF before any study-related activities and according to local 
guidelines. 
3. Female, aged ≥18 years, at the time of informed consent
Subject has histopathologically or cytologically confirmed ER+ HER2– locally advanced, 
recurrent, or metastatic breast cancer, as per local laboratory
4. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.  
Subjects enrolling to the study who do not have measurable disease at baseline per 
RECIST 1.1 guidelines may be enrolled if they have at least 1 mainly lytic bone lesion, 
provided that the lesion has not been irradiated or exhibits demonstrable progression 
since irradiation.
5. Prior therapy in the advanced or metastatic setting: 
•
Dose escalation: 2 or more prior hormonal therapies.  Subjects may have received up to 
1 prior chemotherapy regimen and up to 1 prior CDK4/6 inhibitor.

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•
Dose expansion: Up to 2 prior endocrine therapies and up to 1 prior chemotherapy 
regimen but may not have received a prior CDK4/6 inhibitor.  
Note: If the patient was enrolled within 12 months of the end of adjuvant therapy, the 
adjuvant therapy will also be counted.
Note:  Subjects must have documented progression while on or after the most recent 
therapy.
6. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 
or 1 (Appendix 2).
7. Life expectancy >12 weeks, as per investigator’s best assessment, during the Screening 
phase.
8. Subject has adequate bone marrow and organ function, as defined by the following 
laboratory values:
a.
Absolute neutrophil count (ANC) ≥1.5×109/L
b. Platelets ≥100×109/L
c.
Hemoglobin ≥9.0 g/dL (may have been transfused)
d. Potassium, sodium, calcium (corrected for serum albumin), and magnesium CTCAE 
≤Grade 1
e.
International normalized ratio ≤1.5
f.
Serum creatinine ≤1.5× upper limit of normal (ULN)
g. Serum albumin ≥3.0 g/dL (≥30 g/L)
h. In absence of liver metastases, alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) ≤3.0×ULN.  If the patient has liver metastases, ALT and 
AST ≤5×ULN
i.
Total serum bilirubin <1.5×ULN except for patients with Gilbert’s syndrome who 
may be included if the total serum bilirubin is ≤3.0×ULN or direct bilirubin ≤1.5×
ULN
9. Willingness and ability to comply with study and follow-up procedures.
10. No concurrent antineoplastic therapy.  Use of bone-modifying agents, including 
bisphosphonate and receptor activator of nuclear factor kappa-B ligand (RANKL)
inhibitors is permitted.
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Known central nervous system (CNS) metastases, including meningeal carcinomatosis.  
Brain or subdural metastases are not allowable, unless the patient has completed local 
therapy and has discontinued the use of corticosteroids for at least 4 weeks before starting 
treatment in this study.  Any signs (eg, radiologic) or symptoms of brain metastases must 
be stable for at least 4 weeks before starting study treatment.

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2. Subject has a concurrent malignancy or malignancy within 3 years of enrollment, with 
the exception for basal or squamous cell skin cancer, superficial bladder cancer, or 
carcinoma in situ of the cervix or breast that has completed curative therapy.  Known 
human immunodeficiency virus infection.
3. Uncontrolled significant active infections.  Note: subjects with diagnosis of hepatitis B 
virus and/or hepatitis C virus infection must have undetectable viral load during 
screening (Appendix 3).
4. Major surgery or other locoregional treatment within 4 weeks before the 1st dose of study 
drug.
5. Inability to take oral medication or presence of malabsorption syndrome or any other 
uncontrolled gastrointestinal condition (eg, nausea, diarrhea, or vomiting) that might 
impair the bioavailability of H3B-6545.  Palbociclib contains lactose.  Patients with rare 
hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-
galactose malabsorption should not take this medicine.
6. Currently participating in another clinical study or has received other investigational 
drugs within 28 days.
7. Active cardiac disease or a history of cardiac dysfunction, including any of the following:
a.
History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 
12 months prior to study entry
b. History of documented congestive heart failure (New York Heart Association 
functional classification III or IV)
c.
Documented cardiomyopathy
d. Subject has a left ventricular ejection fraction (LVEF) <50% as determined by 
multiple-gated acquisition (MUGA) scan or echocardiogram (ECHO)
e.
History of any cardiac arrhythmias in the previous 12 months
f.
A prolonged QTcF >450 ms as demonstrated by a repeated electrocardiogram (ECG); 
a history of risk factors for Torsade de pointes (eg, heart failure, hypokalemia, family 
history of long QT syndrome) or the use of concomitant medications that prolonged 
the QTcF interval
g. Subject has resting pulse rate <60 bpm 
8. Females of childbearing potential who:
Within 28 days before study entry, did not use a highly effective method of 
contraception, which includes any of the following:
a.
Double-barrier contraception (considered acceptable method but not highly effective)
b. Total abstinence (if it is their preferred and usual lifestyle)
c.
An intrauterine device 
d. Have a vasectomized partner with confirmed azoospermia.
Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days (or 5 times the half-life of the study 
drug, whichever is longer) after study drug discontinuation.

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Note: All females will be considered to be of childbearing potential unless they are 
postmenopausal (has amenorrhea 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).
9. Known intolerance to either study drug or any of the excipients.
10. Subject received in the 7 days prior to the administration of study drug or is currently 
receiving any of the following medications:
a.
Known strong inducers or inhibitors of cytochrome P450 (CYP) 3A4 or P-
glycoprotein (P-gp)
b. Medications that have a narrow therapeutic window and are breast cancer resistance 
protein (BCRP) substrate
c.
Medications that have a known risk to prolong the QT interval or induce Torsades de 
Pointes
d. Medications that have a narrow therapeutic window and are predominantly 
metabolized through CYP2C8, CYP2C9, CYP2C19, or CYP3A4
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.
11. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [β-hCG] (or hCG) test with a minimum 
sensitivity of 25 IU/L or equivalent units of β-hCG [or hCG]).  A separate baseline 
assessment is required if a negative screening pregnancy test was obtained more than 
72 hours before the 1st dose of the study drug.
12. Active interstitial lung disease (ILD) or diagnosis of ILD within the last 12 months
13. Any medical or other condition that, in the opinion of the investigator(s), would preclude 
the subject’s participation in a clinical study.
14. Exposure within the last 14 days to an individual with confirmed or probable COVID-19 
or symptoms within the last 14 days or any other reason to consider the subject at 
potential risk for an acute COVID-19 infection.  
Note: Please consider testing for active COVID-19 infection prior to starting trial therapy 
according to the institution guidelines.
15. Evidence of ongoing Alcohol or Drug Abuse
9.3.3
Removal of Subjects From Therapy or Assessment
Subjects will continue to receive study treatment until any of the following occur:  
•
Disease progression

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•
Development of unacceptable toxicity.  In absence of liver metastases at baseline and in 
absence of clinical or radiological evidence of biliary obstruction: ALT or AST >3 × 
ULN, in conjunction with total bilirubin >2 ×ULN
•
Withdrawal of consent
•
Subject request
•
Inability to comply with protocol requirements
The reason for treatment discontinuation will be documented.  If a subject discontinues study 
treatment, the subject will enter the Follow-Up Period and complete protocol-specified off-
treatment visits, procedures, and survival follow-up unless the subject withdraws consent.  
The investigator should confirm whether a subject will discontinue trial therapy but agree to 
continue protocol-specified, off-treatment study visits, procedures, and survival follow-up, or 
whether the subject will withdraw consent.  If a subject withdraws consent, the date will be 
documented in the source documents.
During the Follow-Up Period, subjects who have discontinued study treatment without 
progression will be followed for disease assessments every 8 weeks from the date of the last 
assessment until the data cutoff date for the primary analysis, or until disease progression is 
documented or another anticancer therapy is initiated.  Subjects will be followed for AEs for 
28 days after the last treatment administration.  Subjects who discontinue 1 of the 2 drugs 
and continue therapy with the other one are considered on treatment until they discontinue 
the 2nd drug.
All subjects will be followed for survival until death approximately every 3 months for up to 
6 months after the last subject receives their first dose of study treatment (ie, primary analysis 
data cutoff date), except where a subject withdraws consent or the sponsor chooses to halt 
survival follow-up.
9.4
Treatments
9.4.1
Treatments Administered
H3B-6545 is administered PO.  All subjects will take H3B-6545 at their assigned dose (PO, 
QD), in an open-label fashion, for 28-day cycles.  On days that H3B-6545 will be taken with 
palbociclib, subjects should take H3B-6545 at the same time as palbociclib.
Palbociclib is taken PO QD for 21 consecutive days followed by 7 days off treatment to 
comprise a complete cycle of 28 days.
H3B-6545 and palbociclib should be taken with food.  Subjects should be encouraged to take 
their dose at approximately the same time each day and within 30 minutes of completing a 
meal.  H3B-6545 capsules and palbociclib capsules or tablets should be swallowed whole.  
Capsules or tablets should not be ingested if they are broken, cracked, or otherwise not intact.  
Dosing should not be repeated if a subject vomits.  A dose missed by more than 12 hours 
should be skipped.  The next prescribed dose should be taken at the usual time.

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A study-specific pharmacy manual will be provided to each participating institution and will 
include information for receipt, storage, administration, accountability, and destruction of 
study supplies and/or investigational products including H3B-6545 and palbociclib.
9.4.2
Identity of Investigational Products
H3B-6545 will be supplied as opaque, hypromellose shell capsules, size 4 containing 50 mg 
or size 1 containing 150 mg of H3B-6545 drug substance.  The composition ratio of the 
capsule content is the same for both strengths.
Palbociclib will be supplied as 125, 100, and 75 mg capsules or tablets.  
9.4.2.1
Chemical Name of H3B-6545
•
Test drug code:  H3B-6545
•
Chemical name:  
Chemical Abstracts Services (CAS):  2-Butenamide, N,N-dimethyl-4-[[2-[[5-[(1Z)-4,4,4-
trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenyl-1-buten-1-yl]-2-
pyridinyl]oxy]ethyl]amino]-,hydrochloride (1:1), (2E)-
CAS registry number: 2052132-51-9
International Union of Pure and Applied Chemistry: (2E)-N,N-Dimethyl-4-{[2-({5-[(1Z)-
4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl]pyridin-2-
yl}oxy)ethyl]amino}but-2-enamide hydrochloride
•
Molecular formula:  C30H29F4N5O2·HCl
•
Molecular weight:  604.05 (567.59, free base)
9.4.2.2
Chemical Name of Palbociclib
•
Generic name:  palbociclib
•
Chemical name:  6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-
yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one
•
Molecular formula:  C24H29N7O2
•
Molecular weight:  447.54
•
Refer to the latest palbociclib (Ibrance®) package insert (Ibrance USPI, 2019)
9.4.2.3
Labeling for Study Drug
H3B-6545 and palbociclib will be labeled in accordance with text that is in full regulatory 
compliance with each participating country and is translated into the required language(s) for 
each of those countries.

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9.4.2.4
Storage Conditions
All study drugs must be kept in a secure place under appropriately labeled storage conditions. 
Study drugs will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring 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 monitored throughout the total duration of the study 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.  
The sponsor or its representatives must be granted access on reasonable request to check drug 
storage, dispensing procedures, and accountability records.
9.4.3
Method of Assigning Subjects to Treatment Groups
This is an open-label, single-arm study.  All subjects who provide signed informed consent to 
participate in this study and satisfy all eligibility requirements (see Section 9.3) will be 
assigned to receive H3B-6545 in combination with palbociclib.  There is no randomization in 
this study.
The dose escalation phase of the study will determine the MTD and/or the RP2D of H3B-
6545 in combination with palbociclib.  Each cohort will consist of 6 evaluable subjects to 
ensure sufficient safety and PK data are obtained prior to dose escalation.  A cycle of 
treatment will be 28 days. 
During the 1st cycle, palbociclib will be administered PO QD on Days 1 to 21, and H3B-
6545 will be administered PO QD on Days 9 to 28.  In all subsequent cycles, palbociclib will 
be administered on Days 1 to 21, and H3B-6545 will be administered Days 1 to 28. 
The dose expansion phase of the study will treat an additional 12 subjects at the MTD/RP2D 
to further characterize safety, tolerability, and PK and to provide preliminary estimates of 
efficacy.  In Cycle 1, subjects will receive palbociclib PO QD on Days 1 to 21 and H3B-6545 
PO QD on Days 9 to 28.  In all subsequent cycles, palbociclib will be administered on Days 1 
through to 21 and H3B-6545 will be administered Days 1 through to 28.
9.4.4
Selection of Doses in the Study
A maximum of 4 dose levels are planned with palbociclib escalated no higher than 125 mg 
QD and H3B-6545 escalated no higher than 450 mg QD (RP2D); see dose escalation in 
Table 3.

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9.4.5
Selection and Timing of Dose for Each Subject
All subjects will take H3B-6545 at their assigned dose (PO, QD), in an open-label fashion, 
for 28-day cycles.  On days that H3B-6545 will be taken with palbociclib, subjects should 
take H3B-6545 at the same time as palbociclib.
Palbociclib is taken PO QD for 21 consecutive days followed by 7 days off treatment to 
comprise a complete cycle of 28 days. 
H3B-6545 and palbociclib should be taken with food, and subjects should be encouraged to 
take their dose at approximately the same time each day and within 30 minutes of completing 
a meal.
9.4.6
Blinding
This study will not be blinded.
9.4.7
Prior and Concomitant Therapy
Subjects will be instructed not to take any additional medications during the course of the 
study without prior consultation with the treating physician.  At each visit, the subject will be 
asked about any new medications she is taking or has taken after the start of the study drug.
All prior medications (including over-the-counter medications) administered 30 days before 
the first dose of study drug and any concomitant therapy administered to the subject during 
the course of the study (starting at the date of informed consent) until 28 days after the final 
dose of study drug will be recorded.  Additionally, all diagnostic, therapeutic, or surgical 
procedures relating to malignancy should be recorded.  Any medication that is considered 
necessary for the subject’s health and that is not expected to interfere with the evaluation of 
or interact with H3B-6545 and/or palbociclib may be continued during the study.
Treatment of complications or AEs or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs) may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) H3B-6545 and/or palbociclib.
Aspirin, nonsteroidal anti-inflammatory drugs, and low-molecular-weight heparin are 
permissible but should be used with caution.  Granulocyte colony-stimulating factor or 
equivalent may be used in accordance with American Society of Clinical Oncology (ASCO), 
institutional, or national guidelines.  Erythropoietin may be used according to ASCO, 
institutional, or national guidelines, but the subject should be carefully monitored for 
increases in red blood cell counts.

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9.4.7.1
Drug-Drug Interactions
Palbociclib is primarily metabolized by CYP3A and sulfotransferase enzyme SULT2A1.  
In vivo, palbociclib is a time-dependent inhibitor of CYP3A.  Please refer to the latest 
palbociclib (Ibrance) package insert (Ibrance USPI, 2019).
In vitro metabolism studies suggest that H3B-6545 is metabolized mainly by CYP3A4, 
followed by CYP3A5 and CYP2C8; it is a reversible and time-dependent inhibitor of 
CYP2C8, 2C9, 2C19, and CYP3A4, and a potential inducer of CYP3A4 at high 
concentrations potentially achievable at a therapeutic dose.
A DDI between H3B-6545 and palbociclib is mechanistically potential, but the magnitude is 
not expected to be high due to multiple metabolic pathways for both drugs.
9.4.7.2
Prohibited Concomitant Therapies and Drugs
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, as well as an inhibitor of the BCRP, multidrug and toxin extrusion 
transporter (MATE)1, MATE2-K, organic anion transporting polypeptide (OATP)1B1, 
and P-gp mediated transport. 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 (and/or inhibition of P-gp).  Medications that are strong inducers or inhibitors 
of CYP3A or P-gp should also be avoided since H3B-6545 is a substrate of P-gp and 
mainly metabolized by CYP3A4, followed by 3A5 and 2C8, and palbociclib is also 
mainly metabolized CYP3A. For the most updated information, visit the following Web 
address: http://medicine.iupui.edu/clinpharm/ddis/.  Histamine H2-receptor antagonists.
•
Because of a potential DDI, BCRP substrates with narrow therapeutic index are not 
permitted because H3B-6545 is an inhibitor of BCRP (but not a substrate) (Appendix 1)
•
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 the subject receives the concomitant medication.  Resumption of treatment with 
H3B-6545 may be considered following discontinuation and washout (at least 5 half-
lives) of the concomitant medication if the subject has not progressed and is agreed upon 
with the sponsor.  Excluded medications that may cause QTc interval prolongation are
also listed and updated at the following Web address: http://crediblemeds.org.
•
Herbal preparations/medications are not allowed throughout the study.  These herbal 
medications include, but are not limited to, St. John’s wort, kava, ephedra (ma huang), 

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gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng.  Subjects 
should stop using these herbal medications 7 days prior to the first dose of the study drug. 
•
Nutritional supplements, juice, other foods, or beverages that may affect the various 
drug-metabolizing enzymes and transporters (eg, alcohol, grapefruit, grapefruit juice, 
grapefruit-containing beverages) are not allowed for 1 week before and throughout the 
study.
•
Systemic corticosteroids are not allowed during the study.  Note: The following uses of 
corticosteroids are permitted: single doses, topical applications (eg, for rash), inhaled 
sprays (eg, for obstructive airway diseases), eye drops, or local injections (eg, intra-
articular).  Short courses of systemic corticosteroids may be considered in consultation 
with the medical monitor.
•
Use of short course palliative radiotherapy for symptomatic isolated bone metastases may 
be allowed following discussion with sponsor.
9.4.7.3
Permitted Concomitant Medications
No routine prophylactic antiemetic is required.  However, the use of palonosetron, 
prochlorperazine, promethazine, and cyclizine for management of nausea and vomiting is 
allowed.  The use of ondansetron and granisetron is not permitted because of their potential 
to prolong QT interval.
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:  Prophylactic use of GCSF is not allowed from Cycle 1 Day 9 to Cycle 2 
Day 8.  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 ASCO 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  
•
RANKL 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.  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 national diabetes management 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 9.4.7.2.

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9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  A diary will 
be provided to subjects on Cycle 1 Day 1 to document the date and time of each study drug 
dose for all treatment cycles as well as the incidence of vomiting following administration.  
The investigator will review and document treatment compliance for each subject at each
visit.  CRAs will review treatment compliance during site visits and at the completion of the 
study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, the initial drug supply will not be sent to 
the investigator until local regulatory and IRB/IEC approvals are available, and all required 
forms and documentation have been reviewed by the sponsor:
•
A signed and dated confidentiality agreement
•
A copy of the final protocol signature page, signed and dated by both the sponsor and
investigator
•
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted
•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
An investigator-signed and dated Food and Drug Administration (FDA) Form FDA 1572, 
or a completed Investigator and Site Information Form
•
Financial disclosure form(s) for the PI and all subinvestigators listed on Form FDA 1572 
or Investigator and Site Information Form
•
A signed and dated curriculum vitae of the PI including a copy of the PI’s current 
medical license or medical registration number on the curriculum vitae
•
A signed and dated clinical studies agreement
The investigator and the study staff will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.  
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
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and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  (a) 
documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation log, 
(c) study drugs 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 drugs 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.  As 
applicable, all unused study drugs and empty and partially empty containers from used study 
drugs are to be returned to the investigator by the subject and, together with unused study 
drugs 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 drugs and containers 
at the site.  Destruction at the site will only occur under circumstances where regulation or 
supply type prohibits the return of study drugs to the central or local depot(s).  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 drugs that are to be returned to 
the sponsor’s designated central or local depot(s) must be boxed, sealed, and shipped back to 
the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs 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.
9.5
Dose Modifications
Neutropenia was the most frequently reported adverse reaction in palbociclib clinical trials, 
with an incidence of 80% to 83%.  A Grade ≥3 decrease in neutrophil counts was reported in 
66% of patients receiving palbociclib plus letrozole or fulvestrant.  The median time to first 
episode of any grade neutropenia was 15 days and the median duration of Grade ≥3 
neutropenia was 7 days.
Febrile neutropenia has been reported in 1.8% of patients exposed to palbociclib across 
studies.  Physicians should inform patients to promptly report any episodes of fever.
Management of severe or intolerable adverse reactions may require temporary dose reduction 
and/or interruption of palbociclib and/or H3B-6545.
Recommendations for dose reduction, interruption or discontinuation of either drug in the 
management of adverse reactions are summarized in Table 5 (hematologic toxicities) and 

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Table 6 (non-hematologic toxicities).  Clinical judgment of the treating physician should 
guide the management plan of each patient based on individual benefit/risk assessment.
Two dose reductions of H3B-6545 (450 mg to 300 mg, and then to 150 mg QD) for toxicity 
will be allowed as per the guidance summarized in Table 5 and Table 6.  If persistent toxicity 
occurs despite 2 dose reductions, the subject will discontinue study treatment.
Two dose reductions for palbociclib (125 mg to 100 mg, and then to 75 mg QD) for toxicity 
will be allowed (Table 5 and Table 6). If persistent toxicity occurs despite 2 dose reductions, 
the subject will discontinue study treatment.
Hematologic toxicities
Monitor complete blood cell (CBC) counts prior to the start of palbociclib therapy and at the 
beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated.  
For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, 
monitor CBC counts for subsequent cycles every 3 months, prior to the beginning of a cycle 
and as clinically indicated.
Table 5
Dose Modifications and Management Recommendation –
Hematologic Toxicities
CTCAE Grade
Palbociclib
H3B-6545
Anemia
Grade 4
Withhold dose until recovery to Grade 
≤2; resume drug at next lower dose
Withhold dose until recovery to 
Grade ≤2; resume drug at next 
lower dose
Grade 3
•
Day 1 of cycle: Withhold drug, 
repeat complete blood cell count 
monitoring within 1 week.  When 
recovered to Grade ≤2, start the next 
cycle at the same dose. 
•
Day 15 of first 2 cycles: Continue 
palbociclib at current dose to 
complete cycle and repeat complete 
blood cell count on Day 22.
Withhold dose until recovery to 
Grade ≤2; resume drug at next 
lower dose
Grade 1 or 2
No dose adjustment is required
No dose adjustment is required
All other hematological toxicity
Grade 4
Withhold dose until recovery to Grade 
≤2; resume drug at next lower dose
No dose adjustment is required. 
Grade 3
•
Day 1 of cycle: Withhold drug, 
repeat complete blood cell count 
monitoring within 1 week.  When 
recovered to Grade ≤2, start the next 
cycle at the same dose. 
No dose adjustment is required.  

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•
Day 15 of first 2 cycles: Continue 
palbociclib at current dose to 
complete cycle and repeat complete 
blood cell count on Day 22.
Grade 1 or 2
No dose adjustment is required
No dose adjustment is required
Grade 3 neutropenia with 
fever ≥38.5 °C and/or 
infection
Withhold palbociclib until recovery to 
Grade ≤2; resume at the next lower dose
Withhold dose until fever subsides; 
resume at the same dose
CTCAE = Common Terminology Criteria for Adverse Events.
a.
Laboratory values that meet criteria listed in this table should be repeated and confirmed within 24 hours of 
the initial results being reported.
b.
Subjects who do not receive at least 75% of the dose for reasons other than toxicity (eg, withdrawal of 
consent, physician decision, lost to follow-up, etc.) will not be considered evaluable for DLT
Nonhematologic Toxicities
Table 6
Dose Modifications and Management Recommendation –
Nonhematologic Toxicities
CTCAE Grade
Palbociclib
H3B-6545
Sinus bradycardia
Grade 1 (asymptomatic)
Heart rate ≥40 bpm
No dose adjustment is required
No dose adjustment is required
Grade 1 (asymptomatic)
Heart rate <40 bpm
No dose adjustment is required
First occurrence: Withhold drug until 
heart rate is ≥50 bpm; resume drug at 
the same dose level
Second  occurrence: Withhold drug 
until heart rate is ≥50 bpm; resume 
drug at the next lower dose
Grade 2 (symptomatic, 
intervention not indicated; 
change in medication 
initiated)
No dose adjustment is required
Withhold drug until (a) symptoms 
resolve and (b) heart rate is ≥50 bpm; 
resume drug at the next lower dose
Grade 3 (symptomatic, 
intervention indicated)
Withhold palbociclib until (a) 
symptoms resolve and (b) heart rate 
is ≥50 bpm; resume drug at the next 
lower dose
Withhold drug until (a) symptoms 
resolve and (b) heart rate is ≥50 bpm; 
resume drug at the next lower dose
Grade 4 (Life-threatening 
consequences; urgent 
intervention indicated) 
Withhold palbociclib until (a) 
symptoms resolve and (b) heart rate 
is ≥50 bpm; resume drug at the next 
lower dose
Discontinue drug
QTcF prolongation
Grade 1 (average: 
450 – 480 ms)
No dose adjustment is required
No dose adjustment is required

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Grade 2
(average: 481 – 500 ms)
No dose adjustment is required
No dose adjustment is required
Repeat assessment after 1 week; if the 
average is still between 481 and 
500 mg, decrease to the next lower 
dose
Grade 3 (average:  ≥501 
ms; >60 ms change from 
baseline)
Withhold drug until average is 
<480 ms and <60 ms change from 
baseline; resume at the next lower 
dose
Withhold drug until average is 
<480 ms and <60 ms change from 
baseline; resume at the next lower 
dose
Grade 4
(Torsade de pointes; 
polymorphic ventricular 
tachycardia; 
signs/symptoms of serious 
arrhythmia)
Discontinue drug
Discontinue drug
Other
Grade 1 or 2
No dose adjustment is required
No dose adjustment is required
Grade 3 or 4 
(if persisting despite 
optimal medical care)
Withhold palbociclib until symptoms 
resolve to Grade ≤2; resume drug at 
the next lower dose
Withhold drug until symptoms resolve 
to Grade ≤2; resume drug at the next 
lower dose
CTCAE = Common Terminology Criteria for Adverse Events; QTcF = QT interval corrected for heart rate 
using Fridericia’s formula.
Monitor subjects for pulmonary symptoms indicative of ILD/pneumonitis (eg, hypoxia, 
cough, dyspnea).  In patients who have new or worsening respiratory symptoms and are 
suspected to have developed ILD/pneumonitis, interrupt palbociclib immediately and 
evaluate the subject.  Permanently discontinue palbociclib in subjects with severe ILD or 
pneumonitis.
Dose modifications for use with strong CYP3A inhibitors 
Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant 
medication with no or minimal CYP3A inhibition.  If patients must be co-administered a 
strong CYP3A inhibitor: 
•
Reduce the palbociclib dose to 75 mg QD
•
Reduce the H3B-6545 dose to 150 mg QD
If the strong inhibitor is discontinued, increase the palbociclib and H3B-6545 doses (after 3 
to 5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A 
inhibitor.

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9.6
Study Assessments
9.6.1
Assessments
9.6.1.1
Screening Assessments
The following information will be collected, and procedures will be performed for each 
subject at screening up to 21 days prior to initiation of treatment:
•
Written ICF prior to any other study-related procedures
•
Assessment of inclusion/exclusion criteria
•
Medical history, including cancer history
•
Collection of pretreatment fresh biopsies or archival tumor tissue (the tumor sample must 
have been collected after the most recent progression or recurrence). If collection of a 
biopsy during the screening period poses disproportionate risk to subject’s safety, the 
reason for the contraindication must be documented in source at site. Once 
documentation detailing risk is captured in the site records, subject may continue 
screening and if all I/E criteria are met, subject may be enrolled and treated.
•
Demography 
-
Data to be tabulated will include at least demographic features such as sex, age, and 
race, as well as weight- and disease-specific status and medical history.
•
Medical History
-
Medical and surgical history and current medical conditions will be recorded at the 
Screening Visit.  This will include all cancer and cardiac history.  All other medical 
and surgical history within 5 years must be noted in the Medical History and Current 
Medical Conditions case report form (CRF).
Physical examinations will include measurements of weight and vital signs (resting heart 
rate, blood pressure [BP], respiratory rate, oral temperature).  Height will be recorded at the 
baseline visit only (Table 8).
9.6.1.2
Efficacy Assessments
9.6.1.2.1 Tumor Assessments
Tumor assessments will be performed according to RECIST 1.1. Investigator-determined 
response assessments will be performed at each assessment timepoint and entered onto the 
CRF.  Tumor assessments (computed tomography [CT] chest with IV contrast, and CT (oral 
and IV contrast) or magnetic resonance imaging (MRI) (IV contrast) of the abdomen, pelvis, 
and other known or suspected sites of disease) will be performed during Screening/Baseline 
period (Day -21 to Cycle 1 Day 1). If imaging with contrast, as requested in above, is 
contraindicated, imaging without contrast should be performed and reason for 
contraindication should be captured in the source documents.

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Tumor assessments will be performed at postbaseline timepoints (every 8 weeks (±7 days) 
after Cycle 1 Day 1, or as indicated if disease progression is suspected clinically) using the 
same imaging modality (eg, contrast-enhanced CT, MRI scan) and under the same operating 
conditions as the Screening/Baseline scans.  
A brain scan (CT with contrast or MRI [pre- and postgadolinium]) will be performed at 
Screening and as clinically indicated to assess potential for CNS disease and/or metastases.  
For subjects with a history of protocol-eligible treated brain metastases, a brain scan will be 
required at all tumor assessment timepoints.  For all subjects, a follow-up brain scan must be 
performed to confirm CR within 1 week following response confirmation or if clinically 
indicated.
A bone scan using whole body bone MRI, 99m-technetium based bone scans, or 18F-sodium 
fluoride positron emission tomography will be performed during screening to establish a 
baseline (a historical bone scan performed within 6 weeks before Cycle 1 Day 1 is 
acceptable), approximately every 24 weeks (in conjunction with a scheduled tumor 
assessment visit), and as clinically indicated.  Lesions identified on bone scans should be 
followed with cross-sectional imaging.
Tumor assessments will be performed at Screening and every 8 weeks (±7 days) after 
Cycle 1 Day 1 (ie, 8, 16, 24 weeks) or as indicated if disease progression is suspected 
clinically. 
All responses must be confirmed no less than 28 days following the initial assessment of 
response.  In order for stable disease to be considered the best overall response, it must occur 
≥7 weeks following the first dose of study drug.
Subjects who discontinue study treatment without radiological disease progression will 
continue to have tumor assessments as per the Schedule of Assessments until radiological 
disease progression, death, or initiation of another anticancer therapy, whichever occurs first, 
unless the study is terminated.
Refer to Section 9.1.3 and Table 9 for the schedule of tumor assessments in the Extension 
Phase. Survival follow-up will end 6 months after the last subject completes the first dose of 
study treatment.
9.6.1.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments
9.6.1.3.1 PHARMACOKINETIC ASSESSMENTS
In dose escalation: 
•
On Cycle 1 Day 8, PK (palbociclib) blood samples to determine plasma concentrations of 
palbociclib will be collected at predose (within 1 hour before administration of study 
drug) and 1 (±10 minutes), 2 (±15 minutes), 4 (±20 minutes), 6 (±30 minutes), 8 (±30 

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minutes), and 24 hours (±60 minutes, must be before administration of the next day’s 
dose of study drugs) postdose.  These windows apply to PK sampling on other days.
•
On Cycle 1 Day 21, PK (palbociclib and H3B-6545) blood samples to determine plasma 
concentrations of palbociclib and H3B-6545 will be collected at predose and 1, 2, 4, 6, 8, 
and 24 hours postdose.
•
On Cycle 1 Day 28, PK (H3B-6545) blood samples to determine plasma concentrations 
of H3B-6545 will be collected at predose and 1, 2, 4, 6, 8, and 24 hours postdose.
•
During the treatment phase, PK (palbociclib and H3B-6545) blood samples to determine 
plasma concentrations of palbociclib and H3B-6545 will be collected at predose in 
conjunction with each tumor assessment, that is, approximately every 8 weeks until EOT
or data cutoff date for the primary analysis, whichever is earlier.
In dose expansion:
On Cycle 1 Day 21, PK (palbociclib and H3B-6545) blood samples to determine plasma 
concentrations of palbociclib and H3B-6545 will be collected at predose (within 1 hour 
before administration of study drug) and 1 (±10 minutes), 2 (±15 minutes), 4 (±20 minutes), 
6 (±30 minutes), 8 (±30 minutes), and 24 hours (±60 minutes, must be before administration 
of the next day’s dose of study drugs) postdose.  These windows apply to PK sampling on 
other days.
During the treatment phase, PK (palbociclib and H3B-6545) blood samples to determine 
plasma concentrations of palbociclib and H3B-6545 will be collected at predose in 
conjunction with each tumor assessment, that is, approximately every 8 weeks until 
progression.
Blood samples (4 mL for H3B-6545 and 4 mL for palbociclib) will be collected as specified 
in Table 8.  See PK or Laboratory Manual for a description of the collection, handling, and 
shipping procedures of PK samples.
Blood will also be drawn where possible at the first report of a serious adverse event (SAE) 
or severe unexpected AE and at its resolution.
9.6.1.3.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS
In dose escalation and expansion:
•
At baseline (during screening), pretreatment fresh biopsies or archival tumor tissue (the 
tumor sample must have been collected after the most recent progression or recurrence) 
will be obtained from all subjects.  If a subject consents to collection of fresh baseline 
biopsy, it may be acquired any time during the Screening period, before administration of 
the 1st dose of study drug on Cycle 1 Day 1. If collection of a biopsy during the 
screening period poses disproportionate risk to subject’s safety, the reason for the 
contraindication must be documented in source at site. Once documentation detailing risk 
is captured in the site records, subject may continue screening and if all I/E criteria are 
met, subject may be enrolled and treated.

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•
At baseline, Cycle 1 Day 1, Cycle 1 Day 21, Cycle 3 Day 1, and every 8 weeks thereafter 
(coinciding with CT/MRI tumor assessment schedule until radiological progression), and 
at EOT (if different from date of progression), whole blood samples for mutation 
characterization from cell-free DNA (cfDNA) will be collected. No further sample 
collection will be done after the data cutoff date for the primary analysis.
Tumor tissue samples and blood samples for PD, PGx, and other biomarker assessments will 
be collected from all consented study subjects, except where prohibited by regional or local 
laws.  Samples will be collected at designated timepoints as specified in the Schedule of 
Procedures/Assessments (Table 8).  Instructions for the processing, storage, and shipping of 
samples will be provided in the Laboratory Manual.
Samples may be used for biomarker discovery and/or validation to identify blood or tumor 
biomarkers that may be useful to predict treatment response (efficacy, PD), PK, and/or 
safety-related outcomes.  Samples may also be used for potential diagnostic development.  In 
addition, biomarkers identified in other clinical studies may also be assessed in samples 
collected from subjects enrolled in this study.  The decision to perform exploratory 
biomarker analysis may be based on the clinical outcome of the study and/or the signals 
observed in other clinical studies.
Pretreatment fresh biopsies or archival tumor tissue will be collected (if available) from all 
subjects for the assessment of RNA, mutations, and other genetic alterations or proteins that 
may be important in the development and progression of cancer.
Whole blood samples will be collected for cfDNA analysis from all subjects.  cfDNA 
isolated from blood plasma samples may be used to explore tumor genetic alterations, 
including mutations observed in archival tumor samples and mutations that may emerge with 
drug treatment. 
9.6.1.4
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all 
CTCAE v5.0 grades (for both increasing and decreasing severity); regular monitoring of 
hematology, blood chemistry, and urine values; periodic measurement of vital signs and 
ECGs; and performance of physical examinations as detailed in Table 8.
The following will be monitored and recorded:
•
Physical examination
•
ECOG performance status 
•
Height, weight, and vital signs 
•
12-lead ECGs 
•
ECHO, MUGA scan 
•
Laboratory assessments (refer to Table 7 and Table 8)

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9.6.1.4.1 ADVERSE EVENTS
An AE is any untoward medical occurrence in a patient 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(s) is(are) H3B-6545 
and palbociclib. 
The criteria for identifying AEs in this study are as follows:
•
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 9.6.1.4.2.  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 before 
treatment (Baseline)
•
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 last treatment 
administration. Refer to Section 9.6.4.2 for the time period after the EOT for SAE collection.  
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 ms and there is an increase of more than 60 ms 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 
heart rate has returned 60 bpm or more or prestudy baseline.

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All AEs must be followed for 28 days after the subject’s last dose, or until resolution, 
whichever comes first.  Subjects who discontinue 1 of the 2 drugs and continue therapy with 
the other one are considered on treatment until they discontinue the 2nd drug.  All SAEs 
must be followed to resolution or, if resolution is unlikely, to stabilization.
Subjects with onset of an AE or deterioration of a preexisting AE during the AE collection 
period will be followed until resolution to baseline, start of a new anticancer treatment, or 
death.
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
AEs will be graded on a 5-point scale according to CTCAE v5.0.  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 as 
follows:
•
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:
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.

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9.6.1.4.2 SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An 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 AE 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
•
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 

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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.
9.6.1.4.3 LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 7.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 8) shows the visits and 
timepoints at which blood for clinical laboratory tests and urine for urinalysis will be 
collected in the study.
Table 7
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and total WBC 
count with 5-part differential
Coagulation 
INR, PT, aPTT
Comprehensive metabolic panel
Fasting glucose, calcium, albumin, total protein, electrolytes 
(sodium, potassium, carbon dioxide, chloride), renal function tests 
(blood urea/blood urea nitrogen, creatinine), liver function tests 
(ALP, ALT, AST, bilirubin)
Other
Albumin, CRP, fasting lipase, fasting amylase, lactate 
dehydrogenase, magnesium, phosphorus, gamma-glutamyl 
transpeptidase, and thyroid function tests (TSH and free T4) 
Virology
HBV, HCV, HIV 
Urine dipstick
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; CRP = C-reactive protein; HBV = hepatitis B virus; HCV = hepatitis C 
virus; HIV = human immunodeficiency virus; INR = International normalized ratio; PT = prothrombin time; 
RBC = red blood cell; T4 = thyroxine; TSH = thyroid-stimulating hormone; WBC = white blood cell.
Central laboratory will be used for PK/PD and biomarker assessments.  For all safety 
assessments (eg, liver and kidney function, blood count), the sites will use local laboratories.
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained prior to study drug administration, and results will be reviewed 
prior to administration/dispensing of study drug at the beginning of each treatment cycle.

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A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.6.1.4.1 and the CRF Completion Guidelines).  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
9.6.1.4.4 VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, resting heart rate, BP, respiratory rate, oral temperature) and 
weight (kg) will be obtained at the visits designated in the Schedule of 
Procedures/Assessments (Table 8) by a validated method.  Blood pressure and pulse will be 
measured after the subject has been resting for 10 minutes.  All BP measurements should be 
performed on the same arm, preferably by the same person.  For subjects with an elevated BP 
(≥140/90 mmHg), confirmation should be obtained by performing 3 measurements (at least 
5 minutes apart) to yield a mean value.  Systolic BP ≥160 mmHg or diastolic BP 
≥100 mmHg should be confirmed by repeat measurements after 1 hour.
9.6.1.4.5 PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 8).  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the Adverse 
Events CRF.
9.6.1.4.6 ELECTROCARDIOGRAMS
ECG assessments will be performed in triplicate for all study visits where ECGs are required 
and ECGs should be collected predose on days where PK samples are not collected (Table 8).
Triplicate 12-lead ECG will be performed after the patient has been resting for 10 minutes 
prior to each timepoint indicated and at unscheduled visits as clinically required.  The ECGs 
should be taken while the patient in a semi-recumbent position.  At Screening, triplicate 
ECGs should be taken approximately 5 minutes apart.  On Cycle 1 Day 1, triplicated ECGs 
should be performed predose.  The combined QTcF values will be averaged to provide a 
single baseline value for each patient.  This averaged value will be documented in the ECG 
section of the CRF.  ECG measurements on Cycle 1 Day 8, Cycle 1 Day 21, and Cycle 1 Day 
28 should match the PK collection.  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 9.6.1.4.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.

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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.
9.6.1.4.7 OTHER SAFETY ASSESSMENTS
A MUGA scan or an ECHO to assess LVEF will be performed at screening, at Cycle 3 
Day 1, and if clinically indicated thereafter.  MUGA scans should be performed locally in 
accordance with the institution’s standard practice; ECHO should be performed following the 
protocol provided by the cardiovascular core laboratory.  MUGA scans are the preferred 
modality; however, whichever modality is used for an individual subject at Baseline should 
be repeated for all subsequent LVEF assessments for that subject.  LVEFs as assessed by the 
institution will be entered onto the CRF.  Investigator assessment will be based upon 
institutional reports.
Pregnancy Test
A serum pregnancy test must be performed at Screening for all women of childbearing 
potential (ie, pre- and perimenopausal subjects).  There is no need to repeat the test on 
Cycle 1 Day 1 if performed within 72 hours.  Thereafter, during the study, urine testing 
should be performed at Day 1 of each cycle or serum testing should be performed to confirm 
a positive urine testing. 
9.6.2
Schedule of Procedures/Assessments
9.6.2.1
Schedule of Procedures/Assessments
Table 8 presents the schedule of procedures/assessments for the dose escalation and dose 
expansion phases of the study. Table 9 presents the procedures during the Extension Phase.

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Table 8
Schedule of Procedures/Assessments in Study H3B-6545-G000-102
Period
Screening
Cycle 1
Cycle 2
Cycle 3+
EOT
Safety
Follow-
up
28 days 
(+7 
days)
Survivala
Follow-up
Day
D-21 to 
D1
D1b
D8
D15
D21
D28±1cv
D1
D8
D15
D1
Procedure
Informed consent
X
Eligibility criteria
X
Medical history
X
Concomitant 
medication/ adverse 
events
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
examinationd
X
X
X
X
X
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
X
Triplicate 12-lead 
ECGe
X
X
X
X
X
X
X
X
X
X
ECHO or MUGA 
scanf
X
X
Pregnancy testg
X
X
X
X
Laboratory
CBCh
X
X
X
X
X
X
X
X
X
X
X
X
CMPi
X
X
X
X
X
X
X
X
Otherj
X
X
X
X
X
X
X
X
INR/PT/aPTTk
X
X
X
X
X

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Table 8
Schedule of Procedures/Assessments in Study H3B-6545-G000-102
Period
Screening
Cycle 1
Cycle 2
Cycle 3+
EOT
Safety
Follow-
up
28 days 
(+7 
days)
Survivala
Follow-up
Day
D-21 to 
D1
D1b
D8
D15
D21
D28±1cv
D1
D8
D15
D1
Virology (HCV, 
HBV)l
X
Urine testing 
dipstickm
X
X
X
X
X
Study treatments 
dispensing/returnn
X
X
X
X
PK sampleso
X
X
X
X
PG whole blood 
X
Biomarkers and 
exploratory analysis
Tumor biopsyp
X
cfDNA whole bloodq
X
X
     
X
X
Efficacy
PET scan or whole 
body bone scanr
X
Every 24 weeks in conjunction with the scheduled tumor assessment visit or as clinically 
indicated
CT/MRI scanss
X
Every 8 weeks until radiological disease progression and as clinically indicated 
X
     
Brain scant
X
As clinically indicated and to confirm CR
X
Survival follow-upu
X
aPTT = activated partial thromboplastin time; CBC = complete blood cell (count); cfDNA = circulating free deoxyribonucleic acid; CMP = comprehensive 
metabolic profile; CR = complete response; CRF = case report form; CRP = C-reactive protein; CT = computed tomography; D = day; ECG = electrocardiogram; 
ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; HBV = hepatitis B virus; HCV = hepatitis C virus; 
INR = international normalized ratio; IV = intravenous; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition; PET = positron emission 

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tomography; PK = pharmacokinetics; PT = prothrombin time; QTcF = QT interval corrected for heart rate using Fridericia’s formula; T4 = thyroxine; TSH = 
thyroid-stimulating hormone.
a.
All subjects will be followed for survival approximately every 3 months for up to  6 months after the last subject receives their first dose of study treatment.  Subjects will be 
followed for adverse events for 28 days after the last treatment administration.  Subjects who discontinue 1 of the 2 drugs and continue therapy with the other one are 
considered on treatment until they discontinue the 2nd drug.
b.
With the exception of triplicate 12-lead ECG and cfDNA, other assessments performed during the 7 days prior to Cycle 1 Day 1 should need not be repeated, unless otherwise 
indicated.  On Cycle 1 Day 1, scheduled ECG, vital signs, and laboratory tests should be performed predose.
c.
Cycle 2 Day 1 laboratory values for CBC/CMP, INR/PT/aPTT, and urine testing dipstick, can be drawn on Cycle 1 Day 28, in conjunction with the PK blood draw.
d.
Physical examinations will include measurements of weight and vital signs (resting heart rate, blood pressure, respiratory rate, oral temperature).  Height will be recorded at 
the baseline visit only.
e.
A standard 12-lead ECG will be performed after the patient has been resting for 10 minutes prior to each timepoint indicated.  The ECGs should be taken while the patient in a 
semi-recumbent position.  At Screening, triplicate ECGs should be taken approximately 5 minutes apart.  On Cycle 1 Day 1, triplicated ECGs should be performed predose.  
The combined QTcF values will be averaged to provide a single baseline value for each patient.  This averaged value will be documented in the ECG section of the CRF.  
ECG measurements on Cycle 1 Day 8, Cycle 1 Day 21, and Cycle 1 Day 28 should match the PK collection. Triplicate ECGs are to be performed at all visits indicated and 
should be collected predose on C3D1 and D1 of all subsequent cycles. C1D28 24 hour ECG can also meet the requirement for C2D1 ECG. 
f.
At screening, at Cycle 3 Day 1, and if clinically indicated thereafter.
g.
Pregnancy test during the screening period should be serum (no need to repeat on Cycle 1 Day 1 if within 72 hours).  During the study, urine testing should be performed at 
Day 1 of each cycle or serum testing should be performed to confirm a positive urine testing.
h.
CBC count consisting of hematocrit, hemoglobin, total WBC with 5-part differential, and platelet count plus RBC count.
i.
CMP panel includes the following: fasting glucose, calcium, albumin, total protein, electrolytes (sodium, potassium, carbon dioxide, and chloride), renal function tests (blood 
urea/blood urea nitrogen, and creatinine), and liver function tests (ALP, ALT, AST, and bilirubin).
j.
Other includes the following: albumin, CRP, fasting lipase, fasting amylase, lactate dehydrogenase, magnesium, phosphorus, gamma-glutamyl transpeptidase, and thyroid 
function tests (TSH and free T4).
k.
INR, PT, aPTT will be assessed by standard methods at a local laboratory.
l.
See Appendix 3 for HBV/HCV testing criteria.
m. If abnormalities are present, microscopic testing should be done.
n.
H3B-6545: daily starting Cycle 1 Day 9; palbociclib: daily from Day 1 to Day 21 every 28-day cycle.
o.
Plasma samples for PK:
a. During the escalation part of the study: On Cycle 1 Day 8, PK (palbociclib) blood samples to determine plasma concentrations of palbociclib will be collected at predose 
(within 1 hour before administration of study drug) and 1 (±10 minutes), 2 (±15 minutes), 4 (±20 minutes), 6 (±30 minutes), 8 (±30 minutes), and 24 hours (±60 minutes, must 
be before administration of the next day’s dose of study drugs) postdose.  These windows apply to PK sampling on other days.  On Cycle 1 Day 21, PK (palbociclib and H3B-

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6545) blood samples to determine plasma concentrations of palbociclib and H3B-6545 will be collected at predose and 1, 2, 4, 6, 8, and 24 hours postdose.  On Cycle 1 Day 
28, PK (H3B-6545) blood samples to determine plasma concentrations of H3B-6545 will be collected at predose and 1, 2, 4, 6, 8, and 24 hours postdose.
b. During the expansion phase: On Cycle 1 Day 21, PK (palbociclib and H3B-6545) blood samples to determine plasma concentrations of palbociclib and H3B-6545 will be 
collected predose (within 1 hour before administration of study drug) and 1 (±10 minutes), 2 (±15 minutes), 4 (±20 minutes), 6 (±30 minutes), 8 (±30 minutes), and 24 hours 
(±60 minutes, must be before administration of the next day’s dose of study drugs) postdose.  These windows apply to PK sampling on other days.
c. During both phases of the trial: additional PK blood samples will be collected in conjunction with tumor assessments until EOT or until data cutoff date for the primary 
analysis, whichever is earlier.
d. Samples should be collected via peripheral vein when possible.
p.
New biopsy (preferred) or archival tumor block or slides (15 slides minimum from a surgical specimen, 20 slides minimum from a biopsy) must be provided.  If archival 
tumor tissue is provided, the tumor sample must have been collected after the most recent progression or recurrence. Not required for subjects with bone only disease
q.
Whole blood for cfDNA (8 mL) will be collected during the screening period, Cycle 1 Day 1, Cycle 1 Day 21, Cycle 3 Day 1, every 8 weeks thereafter (in conjunction with 
tumor assessments), and EOT, or until data cutoff date for the primary analysis, whichever is earlier.  Two tubes (2×8 mL) will be collected at Screening and EOT.
r.
A bone scan using whole-body bone MRI, 99m-technetium-based bone scans, or 18F-sodium fluoride positron emission tomography will be performed during Screening to 
establish a baseline (a historical bone scan performed within 6 weeks before Cycle 1 Day 1 is acceptable), approximately every 24 weeks (in conjunction with a scheduled 
tumor assessment visit), and as clinically indicated.  Lesions identified on bone scans should be followed with cross-sectional imaging.
s.
Tumor assessments (CT chest with IV contrast, and CT [oral and IV contrast] or MRI [IV contrast] of the abdomen, pelvis, and other known or suspected sites of disease) will 
be performed during Screening (Day -21 to Cycle 1 Day 1) and every 8 weeks (±7 days) starting from Cycle 1 Day 1 (ie, 8, 16, 24 weeks) or as indicated if disease 
progression is suspected clinically. If imaging with contrast, as requested in above, is contraindicated, imaging without contrast should be performed and reason for 
contraindication should be captured in the source documents.
t.
A brain scan (CT with contrast or MRI [pre- and postgadolinium]) will be performed at Screening and as clinically indicated to assess potential for central nervous system 
disease and/or metastases.  For subjects with a history of protocol-eligible treated brain metastases, a brain scan will be required at all tumor assessment timepoints, including 
EOT.  For all subjects, a follow-up brain scan must be performed to confirm CR within 1 week following response confirmation or if clinically indicated.
u.
Following progression, all subjects will be followed for survival every 3 months for up to 6 months after the last subject receives their first dose of study treatment.  The 
follow-up can be done by telephone call at the investigator’s discretion. 
v.
Any protocol assessment, including labs, performed within 3 days prior to D1 of the next cycle do not need to be repeated on D1 of the new cycle.

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Table 9 Extension Phase
Extension Phase will begin for subjects still on treatment at the time of the data cut-off 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; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; 
HR = heart rate; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition; RR = respiratory rate
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

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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). 
h.
A serum or urine pregnancy test will be performed at Day 1 of every cycle, and at the Off-Treatment 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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9.6.2.2
Description of Procedures/Assessments Schedule
The description of procedures and schedule of assessments is described in the Schedule of 
Procedures/Assessments (Table 8).
9.6.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of advanced or 
metastatic ER+ HER2– breast cancer.
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, and assessment of AEs, are standard evaluations to ensure subject 
safety.
9.6.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
With Special Situations
9.6.4.1
Reporting of Abnormal Hepatic Tests of Clinical Interest
The following combination of abnormal laboratory tests*, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing and whether nonserious or 
serious, should be entered on the Adverse Event CRF and reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.6.4.2).  If the event does not meet 
serious criteria, the seriousness criteria on the SAE form should be indicated as “nonserious.”  
1. Elevated AST or ALT laboratory value that is greater than or equal to 3× the ULN or if 
elevated greater than the ULN at baseline, then 3× the baseline for the subject
AND
2. Elevated total bilirubin laboratory value that is greater than or equal to 2× the ULN or if 
elevated greater than the ULN at baseline, then 1.5× the baseline for the subject
AND AT THE SAME TIME
3. Alkaline phosphatase laboratory value that is less than 2× the ULN
*Note: These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require additional 
evaluation for an underlying etiology.  In addition to reporting the abnormal hepatic 
laboratory tests on a SAE form, the site should also consult the medical monitor for guidance 
on assessment and follow-up.  At a minimum, laboratory testing should be repeated at least 
once weekly until improvement or identification of a cause unrelated to study drug use that is 
unlikely to improve.

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9.6.4.2
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no 
later than 24 hours from the date the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit.  SAEs will be collected for 28 days after the subject’s 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.
Any relevant follow-up information received on SAEs should be forwarded within 24 hours 
of its receipt.  If the relevant 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.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
or designee to be filed in the sponsor’s Trial Master File.
9.6.4.3
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
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, a spontaneous abortion or an induced 
abortion done due to safety concerns for either mother or fetus are considered to be an SAE 

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and should be reported in the same time frame and in the same format as all other SAEs (see 
Reporting of Serious Adverse Events [Section 9.6.4.2]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 24 hours 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 24 hours from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study. 
9.6.4.4
Reporting of Events Associated With Special Situations
9.6.4.4.1 REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
AEs 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 
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.  
Symptomatic and nonsymptomatic 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 9.6.4.2) if the overdose is symptomatic.
For information on how to manage an overdose of H3B-6545, reach out to the sponsor or 
CRO; and for palbociclib, refer to the latest palbociclib package insert (Ibrance USPI, 2019).
9.6.4.5
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.

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9.6.4.6
Breaking the Blind
Not applicable
9.6.4.7
Regulatory Reporting of Adverse Events
AEs 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.
For this study, the Reference Safety Information for palbociclib, which the sponsor will use 
to assess expectedness, is the approved palbociclib (Ibrance) EMA SmPC.  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 SUSARs will 
be reported, as required, to the competent authorities of all involved European member states.
9.6.5
Completion/Discontinuation of Subjects
The investigator may discontinue study drug for a subject at any time for safety or 
administrative reasons.  A subject may elect to discontinue trial therapy or withdraw consent 
for further participation in the study at any time for any reason.  All subjects who withdraw 
consent for further participation in the study are to complete the study’s early discontinuation 
procedures indicated in the Schedule of Procedures/Assessments (Table 8).
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
•
Conditions requiring therapeutic intervention not permitted by the protocol
•
Intercurrent illness (at the investigator’s discretion)
•
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
*Subjects may continue to receive treatment after progression only if, after discussion with the medical monitor, 
it is determined that the subject continues to derive clinical benefit.
After discontinuation from protocol treatment, subjects must be followed for AEs for 28 days 
after their last dose of study drug.  All new AEs, including 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 

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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 v5.0) 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.
9.6.6
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.7
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.  
The investigator will permit study-related quality audits and inspections by the sponsor or its 
representative(s), government regulatory authorities, and the IRB/IEC 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/IEC, and the sponsor or its representative(s).
9.7.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 

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1572 or Investigator and Site Information Form must sign the completed CRF to attest to its 
accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.7.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements. All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.8
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released and a snapshot of the database is obtained 
and released).  Statistical analyses will be performed using SAS software or other validated 
statistical software as required.  Details of the statistical analyses will be included in a 
separate statistical analysis plan (SAP).
9.8.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock.
9.8.1.1
Study Endpoints
9.8.1.1.1 PRIMARY ENDPOINT
The primary study endpoint is to determine the MTD and/or RP2D.
9.8.1.1.2 SECONDARY ENDPOINTS
•
AEs and SAEs as well as changes in clinical laboratory values, vital sign measurements 
and ECG parameters
•
Standard primary PK parameters, including, but not limited to, the area under the plasma 
concentration-time curve from timepoint 0 through the last measurable point (AUC0-t), 
Cmax, Tmax, C24, and ratio of the DDI effect
•
ORR, defined as the proportion of subjects achieving a best overall response of 
confirmed partial or complete response (PR+CR)
•
DoR, defined as the time from the date of the 1st documented CR/PR until the 1st 
documentation of disease progression or death, whichever comes first
•
CBR, defined as the proportion of subjects achieving a best overall response of confirmed 
partial or complete response, or durable stable disease (duration is at least 23 weeks)

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•
PFS, defined as the time from the 1st dose date to the date of the 1st documentation of 
disease progression or death (whichever occurs 1st)
•
OS, defined as the time from 1st dose date to the date of death from any cause.  
9.8.1.2
Definitions of Analysis Sets
•
Safety Analysis Set: which will consist of all subjects who receive at least 1 dose of study 
drug.  This will be the analysis set for all safety evaluations except DLT results.
•
Full Analysis Set: which will consist of all subjects who receive at least 1 dose of study 
drug.
•
Dose Evaluable Set: which will consist of all subjects who were evaluable for DLT in 
Phase 1b.  This will be the analysis set for DLT results.
•
Response-Evaluable Set: which will consist of those subjects who receive at least 1 dose 
of study drug and have measurable disease at baseline and at least 1 postbaseline tumor 
assessment.  This will be the primary analysis set for efficacy evaluations.
•
Pharmacokinetic Analysis Set: which will consist of subjects who received at least 1 dose 
of study drug and all valid plasma concentrations (at least 3 valid concentrations for 
noncompartmental analysis).
9.8.1.3
Subject Disposition
The number of subjects screened for participation and number enrolled overall and by study 
part will be tabulated along with the proportion included in each analysis population.  The 
proportion of subjects who discontinue the study will be tabulated, along with the primary 
reason for discontinuation.
9.8.1.4
Demographic and Other Baseline Characteristics
Demographic and baseline disease characteristic data will be summarized descriptively.  Data 
to be tabulated will include at least demographic features such as sex, age, and race, as well 
as weight and disease-specific status and medical history.
9.8.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the current version of the World Health Organization Drug Dictionary (WHO DD). 
The number (percentage) of subjects who took prior and concomitant medications will be 
summarized on the Full Analysis Set by study part, cohort and overall Anatomical 
Therapeutic Chemical class (ie, anatomical class, therapeutic class, pharmacologic class, 
chemical class), as well as WHO DD preferred term.  Prior medications will be defined as 
medications that stopped before the first dose of study drug.  Concomitant medications will 
be defined as medications that started after the date of the first dose of study drug up to 28 
days after the subject’s last dose.  All medications will be presented in subject data listings.

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9.8.1.6
Efficacy Analyses
All efficacy parameters will be summarized descriptively for the Response-Evaluable Set and 
Full Analysis Set. 
9.8.1.6.1 PRIMARY EFFICACY ANALYSIS
Not applicable.
9.8.1.6.2 SECONDARY EFFICACY ANALYSES
ORR and CBR will be calculated with exact 95% confidence intervals using the method of 
Clopper and Pearson.  
DoR will be calculated for subjects achieving a best overall response of confirmed PR+CR.
For DoR, PFS, and OS, medians will be calculated using Kaplan-Meier estimates.  DoR, 
PFS, and OS will be reported in both summary tables and plotted with Kaplan-Meier curve.
9.8.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses
9.8.1.7.1 PHARMACOKINETIC ANALYSES
The plasma concentrations of palbociclib and H3B-6545 will be presented by dose level and 
day, as the number of subjects with data, geometric mean, mean, standard deviation (SD), 
median, minimum, and maximum values by nominal sampling timepoint.  The PK 
parameters will include, as applicable, Cmax (maximum observed plasma concentration), Tmax
(time of the maximum observed plasma concentration), AUC0-24 (AUC from zero time to 
24 hours), AUC0-t (AUC from zero time to last measurable concentration), AUC0-inf (AUC 
from zero time to infinity), percentage of AUC that is due to extrapolation from the last 
measurable concentration to infinity (%AUCExtrap), apparent terminal disposition rate 
constant (λz), apparent plasma terminal elimination half-life, apparent total plasma clearance 
(CL/F), and apparent volume of distribution (V/F) and will be summarized by cohorts and 
day, with the number of measurements, number of non-missing data, the number of subjects, 
geometric mean (CV%), mean, SD, median, minimum, and maximum.
The DDI effect will be estimated as a ratio of exposure index (Cmax, AUC0-24, and C24) in the 
following way in the dose escalation cohort: ratio of palbociclib exposure on Day 
21/palbociclib exposure on Day 8 for potential effect of H3B-6545 on palbociclib and ratio 
of H3B-6545 exposure on Day 21/H3B-6545 exposure on Day 28 for potential effect of 
palbociclib on H3B-6545.  This ratio will be summarized by cohorts with the number of 
subjects, geometric mean (CV%), mean, SD, median, minimum, and maximum.
9.8.1.7.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
The baseline tissue biopsies collected will be used to examine potential baseline markers of 
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expression and DNA mutations (using standard technologies like quantitative polymerase 
chain reaction, immunohistochemistry, and other appropriate technology) along with global 
transcription levels (RNA sequencing).
The whole blood samples will be analyzed for evaluation of cfDNA as a source of circulating 
biomarker (DNA mutations).  The samples might be used for exploratory analysis for 
evaluation of response-related and/or safety-related outcomes, as well as for potential use in 
companion diagnostic and drug development, and would be reported separately if conducted.
Exposure-response with biomarkers and/or other efficacy endpoints might be explored as 
appropriate with a population PK model-predicted exposure values and will be reported 
separately.
9.8.1.8
Safety Analyses
The determination of the MTD and/or RP2D will be based on Dose Evaluable Set that 
consists of all DLT-evaluable subjects.  Subjects not evaluable for DLT assessment will be 
replaced.  
All other safety analyses will be performed on the Safety Analysis Set.  Safety data will be 
summarized using descriptive statistics (eg, n, mean, SD, median, minimum, maximum for 
continuous variables; n [%] for categorical variables).  Safety variables include treatment-
emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, and 12-lead 
ECG results.
Safety will be assessed through the analysis of the reported incidence of TEAEs.  The AEs 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and will be 
summarized using system organ class (SOC) and preferred term (PT).  In addition, 
summaries of SAEs, AEs leading to treatment discontinuation, AEs by maximum NCI 
CTCAE v5.0 grade, and AEs related to study treatment will also be presented by dose level.
Other safety endpoints, including laboratory results, vital signs, and ECG findings, will be 
summarized for all subjects in the Safety Analysis Set.
9.8.1.8.1 EXTENT OF EXPOSURE
Descriptive statistics for subjects treated, including the duration of treatment, 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.  Details will be 
provided in the SAP.
9.8.1.8.2 ADVERSE EVENTS
The AEs will be coded using MedDRA and summarized using SOC and PT.  In addition, 
summaries of SAEs, AEs leading to treatment discontinuation, AEs by maximum NCI 
CTCAE v5.0 grade, and AEs related to study treatment will also be presented by dose level.

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AEs will be collected for each subject until 28 days after last trial therapy administration.  
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using MedDRA.  AEs will be coded to the MedDRA 
(Version 22.1 or higher) lower level term closest to the verbatim term.  The linked MedDRA 
PT 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 
•
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 
•
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are 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.  The incidence of TEAEs will be reported as the number 
(percentage) of subjects with TEAEs by SOC and PT.  A subject will be counted only once 
within an SOC and PT, even if the subject experienced more than 1 TEAE within a specific 
SOC and PT.  The number (percentage) of subjects with TEAEs will also be summarized by 
maximum CTCAE grade. 
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum CTCAE grade.
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT.  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 PT.  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 PT.  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 1b of the study.  A listing of subjects with DLTs will be provided.

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9.8.1.8.3 LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.6.1.4.3, the actual value and the change 
from baseline to each postbaseline visit will be summarized by visit using descriptive 
statistics.  Qualitative parameters listed in Section 9.6.1.4.3 will be summarized using 
frequencies (number and percentage of subjects), and changes from baseline to each 
postbaseline visit will be reported using shift tables.  Percentages will be based on the 
number of subjects with both nonmissing baseline and relevant postbaseline results.
Furthermore, the frequency of laboratory abnormalities by maximum post-baseline CTCAE 
grade will be tabulated for selected laboratory parameters to include at least, hemoglobin, 
WBC, ANC, lymphocytes, platelet count, alkaline phosphatase, 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 post baseline.  Details will be 
provided in the SAP.
9.8.1.8.4 VITAL SIGNS
Changes in vital sign parameters (including systolic and diastolic BP, heart rate, respiratory 
rate, 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, 
respiratory rate, temperature, and weight) and changes from baseline will be presented by 
visit.
9.8.1.8.5 ELECTROCARDIOGRAMS
ECG assessments will be performed throughout the study according to the schedule of 
assessments.  Descriptive statistics for ECG parameters and changes from baseline will be 
presented by visit and treatment group.
Summary tables and listings for the various intervals (eg, QT and pulse rate) and changes 
from baseline will be presented.  Additional analysis will be detailed in the SAP.
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTcF during the treatment period will be summarized.  Clinically abnormal ECG 
results in QTcF will be categorized as follows:
•
Absolute QTcF interval prolongation:
QTcF interval >480 ms
QTcF interval >500 ms
•
Change from baseline in QTcF interval:

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QTcF interval increases from baseline >30 ms
QTcF interval increases from baseline >60 ms
QTcF interval >500 ms and QTcF interval increases from baseline >60 ms
All ECG abnormalities will be listed on a per-subject basis.
9.8.2
Determination of Sample Size
Depending on the dose levels to be studied in the dose escalation phase, approximately 12 to 
24 subjects may be treated.  Dose expansion will enroll 12 additional subjects at the RP2D.  
Therefore, the study is expected to enroll approximately 24 to 36 subjects.  No formal sample 
size calculation is performed.
9.8.3
Interim Analysis
No formal interim analyses are planned.  However, the cumulated safety and efficacy data by 
dose level will be reviewed periodically by the sponsors and investigators.  The continuation 
of study enrollment will depend on the totality of the efficacy and safety data.
9.8.4
Other Statistical/Analytical Issues
Not applicable.
9.8.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.

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10 REFERENCE LIST
Ahn C. An evaluation of Phase 1 cancer clinical trial designs. Stat Med. 1998;17(14):1537–
49.
Dillman RO, Koziol JA. Phase 1 cancer trials: limitations and implications. Mol Biother. 
1992;4(3):117–21.
Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K,  et al. Palbociclib and letrozole in 
advanced breast cancer. N Engl J Med. 2016;375:1925–36.
Gatsonis C, Greenhouse JB. Bayesian methods for Phase 1 clinical trials. Stat Med.
1992;11(10):1377–89.
Hamilton EP, Dees EC, Judy Wang SZ, Kim A, Korpal M, Rimkunas V, et al. Phase I dose 
escalation of H3B-6545, a first-in-class highly Selective ERα Covalent Antagonist (SERCA), 
in women with ER-positive, HER2-negative breast cancer (HR+ BC). J Clin Oncol. 
2019;37(15 Suppl):1059. Epub 20 May 2019.
Hortobagyi GN, Stemmer SM, Burris HA, Elmeliegy M, Germa C, O’Shaughnessy J, et al. 
Updated results from MONALEESA-2, a Phase III trial of first-line ribociclib plus letrozole 
versus placebo plus letrozole in hormone receptor–positive, HER2-negative advanced breast 
cancer. Ann Oncol. 2018;29(7):1541–7.
Ibrance® EMA Summary of Product Characteristics (SmPC) by Pfizer Limited   Available 
from: https://www.medicines.org.uk/emc/product/4449/smpc. Last updated on emc on 20 
Feb 2020.
Ibrance® United States Prescribing Information, Revised 9/2019. Available from: 
http://labeling.pfizer.com/ShowLabeling.aspx?id=2191. Accessed 07 Nov 2019.
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. General Considerations for Clinical Trials, E8 1997. 
Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E8/Step4/
E8_Guideline.pdf.
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0 [27 Nov 2017]. Available from: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick
_Reference_5x7.pdf.
Smith PG, Puyang X, Furman C, Zheng GZ, Banka D, Thomas M, et al. Discovery and 
development of H3B-6545: a novel, oral, Selective Estrogen Receptor Covalent Antagonist 
(SERCA) for the treatment of breast cancer. Cancer Res 2017;77(13 Suppl): Abstract 
DDT01–04. doi: 10.1158/1538-7445.AM2017-DDT01-04.

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Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, et al. Overall survival with 
palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379:1926–36.

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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor (or appropriate 
study team member) and the IRB/IEC for the site must be notified immediately.  The sponsor 
must notify the health or regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and to IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to, 
the following:  
•
Clinic, office, or hospital charts

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•
Copies or transcribed health care provider notes that have been certified for accuracy 
after production
•
Recorded data from automated instruments such as an Interactive Voice/Web Response 
System (IxRS), x-rays, and other imaging reports (eg, sonograms, CT scans, magnetic 
resonance images, radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, 
pulmonary function tests) regardless of how these images are stored, including 
microfiche and photographic negatives
•
Pain, quality of life, or medical history questionnaires completed by subjects
•
Records of telephone contacts
•
Diaries or evaluation checklists
•
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
•
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
•
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  For 
the following item(s), the data recorded directly on the CRF are to be considered source data:
•
Reasons for discontinuation of study treatment, 
•
comments and other information on AEs [eg, severity, relationship to study drug, 
outcome], 

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•
reasons for dose modification, indication for prior/concomitant medication, 
•
sampling times for drug concentrations, 
•
sampling times for clinical laboratory tests.
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator is responsible for retaining all study documents, including but not limited to the 
protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572 for US sites), Investigator and Site Information Form (for 
non-US sites), ICFs, and IRB/IEC correspondence).  In addition, the sponsor will send a list 
of treatment codes by study subject to the investigator after the clinical database for this 
study has been locked.  The site should plan to retain study documents, as directed by the 
sponsor, for at least 15 years following the completion of the study.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drugs will be supplied to the PI (or a designated pharmacist) by the sponsor.  Drug 
supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored according 
to the conditions specified on the drug labels.  The investigator (or a designated pharmacist) 
must maintain an accurate record of the shipment and dispensing of the study drug in a drug 
accountability ledger, a copy of which must be given to the sponsor at the end of the study.  
An accurate record of the date and amount of study drug dispensed to each subject must be 
available for inspection at any time.  The CRA will visit the site and review these documents 
along with all other study conduct documents at appropriate intervals once study drug has 
been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor) or, when approval is given by the sponsor, 
will destroy supplies and containers at the site.

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11.9
Publication of Results
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 Clinical Trial Agreement 
between the sponsor 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.
11.10 Disclosure and 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 executed between the sponsor/CRO and the 
institution/investigator.
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 Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 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.

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11.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.

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H3B-6545-G000-102
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12 APPENDICES

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H3B-6545-G000-102
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Appendix 1 Concomitant Medications
Combination administration of study drugs could result in DDIs 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 the first dose of H3B-6545.  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.
The list of prohibited medications is based on FDA guidance (October 
2017, https://www.fda.gov/media/82734/download) and its table of substrates, inhibitors and 
inducers (updated as of 12/03/2019, https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers)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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H3B-6545-G000-102
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Appendix 2 ECOG Performance Status Criteria
ECOG Performance Status Scale
Grade
Descriptions
0
Normal activity
Fully active, able to carry on all predisease performance without restriction
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)
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
3
In bed >50% of the time
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
4
100% bedridden
Completely disabled
Cannot carry on any self-care
Totally confined to bed or chair
5
Dead

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H3B-6545-G000-102
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Appendix 3 HBV/HCV Testing Criteria
Eligibility Based on Serologic Markers for Hepatitis B and Hepatitis C
Test
Result
HBsAg
+
-
-
-
-
HBcAb
Any
+
-
+
-
HBsAb
Any
-
+
+
-
HCV Ab
Any
Any
-
-
-
Eligibility
Not Eligible
Not Eligible
Eligible
Eligible
Eligible
If indeterminate results are obtained, viral DNA (hepatitis B) or RNA (hepatitis C) should be measured to 
confirm negative viral status.
HCV Ab positive: Indicates active infection and risk for reactivation. These patients are not 
eligible for this trial.
HBsAg positive: Indicates active infection and risk for reactivation with fulminant hepatitis. 
These patients are not eligible for this trial.
HBcAb positive and HBsAb negative: indicate active infection and risk for reactivation. 
These patients are not eligible for this trial.
HBsAb positive: As a standalone marker, it indicates successful vaccination or previous 
infection that has been successfully resolved if it is the only positive finding. These patients 
are eligible for this trial.
HBsAg negative, HBcAb positive, HBsAb positive: Resolved or latent infection. These 
patients are eligible for this trial.
All markers negative: No prior exposure or vaccination to hepatitis B and no prior exposure 
to Hepatitis C. Patients are eligible for this trial

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H3B-6545-G000-102
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
H3B-6545-G000-102
Study Protocol Title:
An Open-Label Multicenter Phase 1b Study of H3B-6545 in 
Combination With Palbociclib in Women With Advanced or 
Metastatic Estrogen Receptor–Positive HER2-Negative Breast 
Cancer
Investigational Product 
Name:
H3B-6545 and palbociclib 
IND Number:
133282
EudraCT Number:
2019-004622-17
SIGNATURES
 Eisai, Inc.
Date
 Eisai Inc.
Date
PPD
PPD
PPD
PPD

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H3B-6545-G000-102
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
H3B-6545-G000-102
Study Protocol Title:
An Open-Label Multicenter Phase 1b Study of H3B-6545 in 
Combination With Palbociclib in Women With Advanced or 
Metastatic Estrogen Receptor–Positive HER2-Negative Breast 
Cancer 
Investigational Product 
Name:
H3B-6545 and palbociclib 
IND Number:
133282
EudraCT Number:
2019-004622-17
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
<Name of institution>
Medical Institution
<Name, degree(s)>
Investigator
Signature
Date
As regionally required.
<Name, degree(s)>