Clinical trial NCT02834780
Conditions: Advanced Hepatocellular Carcinoma Hepatocellular Carcinoma Liver Cancer Liver Neoplasms Hepatic Cancer Hepatic Carcinoma
Keywords: Advanced Hepatocellular Carcinoma H3B-6527 Fibroblast growth factor receptor 4 (FGFR4) Fibroblast growth factor 19 (FGF19)
Sponsor: H3 Biomedicine Inc.
Start date: 2016-12-28; Completion date: 2022-02-23
Enrollment: 128 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of H3B-6527, and to assess the safety, tolerability and pharmacokinetics of H3B-6527.

Detailed description:

Arms: arm 1: Hepatocellular Carcinoma
Interventions: intervention 1: H3B-6527
Intervention descriptions: intervention 1: H3B-6527 by mouth once or twice daily at specified doses.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol  
H3B-6527-G000-101 
 
 
H3 Biomedicine, Inc. 
Amendment 09:  30 Sep 2020 
Confidential 
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1 
TITLE PAGE 
  
 
 
 
 
CLINICAL STUDY PROTOCOL 
Study Protocol 
Number: 
H3B-6527-G000-101 
Study Protocol 
Title: 
An Open-Label Multicenter Phase 1 Study to Evaluate the Safety, 
Pharmacokinetics and Pharmacodynamics of H3B-6527 in Subjects 
With Advanced Hepatocellular Carcinoma 
Sponsors:  
H3 Biomedicine Inc. 
(United States Research Subsidiary of Eisai Co., Ltd.) 
300 Technology Square 
Fifth Floor 
Cambridge, MA 02139 
 
 
Eisai Inc. 
155 Tice Boulevard 
Woodcliff Lake,  
New Jersey 07677 
USA 
 
Eisai Co., Ltd.  
4-6-10 Koishikawa 
Bunkyo-Ku,  
Tokyo 112 8088 
Japan 
Investigational 
Product Name: 
H3B-6527 
Indication: 
Advanced Hepatocellular Carcinoma 
Phase: 
1 
 
 


Clinical Study Protocol  
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Amendment 09:  30 Sep 2020 
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Approval Date:  
Original Protocol   
15 Mar 2016 
Amendment 01 
 
29 Apr 2016 
Amendment 01.1  
12 May 2016 
Amendment 02 
 
06 Oct 2016 
Amendment 03 
 
15 Dec 2016 
Amendment 04           31 May 2017 
Amendment 04.1        14 Jun 2017 
Amendment 05           06 Jul 2017 
Amendment 06           22 Feb 2018 
Amendment 07           14 Nov 2018 
Amendment 08           28 Aug 2019 
Amendment 09           30 Sep 2020 
IND Number: 
128686 
EudraCT Number: 2016-001915-19 
GCP Statement: 
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Registration of 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 H3 Biomedicine, Inc and Eisai (the Sponsors).  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. 


Clinical Study Protocol  
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H3 Biomedicine, Inc. 
Amendment 09:  30 Sep 2020 
Confidential 
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DATE 
Highlights of Major Changes 
Section/Change 
15 Mar 2016 
Original Protocol 
29 Apr 2016 
Amendment 01 
 
Title Page: 
- 
Added Amendment 01 and the EudraCT number 
- 
Changed address of the location of the Oncology Business Group 
 
Corrected typographical errors in the following sections: 
- 
Section 2 - changed OTC to OTV 
- 
Section 7.1 – deleted extra () 
- 
Section 2 (Clinical Study Synopsis) and Section 9.3.1 – added missing 
parenthesis to Inclusion Criteria 13. 
- 
Section 9.4.4.1, Table 3 – deleted duplicate word (“in”) 
- 
Section 9.4.8 - added missing parenthesis after the word “consent” 
- 
Section 9.5.1.4.1 – added missing parenthesis before the word 
“whichever” 
 
In Section 2 (Clinical Study Synopsis) and Section 9.3.2 - deleted Exclusion 
criterion 1 with renumbering of remaining exclusion criteria 
 
Edited text in Section 5.1: 
- 
to include the option for electronic study approval by the IRB/IEC 
chairman. 
- 
to allow the Sponsor’s designee to notify the IRB/IEC at the end of the 
study if required. 
 
Added text to Section 9.1.1.1 and Section 9.4.4.1 to clarify that if ≥2 subjects 
within a cohort experience a DLT and the previous dose level did not enroll 
6 subjects, enrollment will move down to the previous dose level and continue 
until 6 subjects are enrolled; the same guidelines for determining the MTD will 
be followed. 
 
Edited text for consistency throughout the protocol (Section 2 [Clinical Study 
Synopsis]; Section 9.1.2.3, Section 9.1.2.4, and Section 9.5.5) to clarify that a 
subject can continue to receive study treatment after disease progression if they 
demonstrate clinical benefit as determined by the investigator after discussion 
with the Sponsor. 
 
Edited text in Section 2 and Section 9.5.1.2.1 to clarify when brain scans are 
required to be performed. 
 
Edited text in the Section 2 and Section 9.5.1.3.3 to indicate that paired-skin 
biopsies are optional. 
 
Edited Table 6 as follows: 
- 
Table format changed to ensure that table heading rows do not appear 
on footnote pages. 
- 
Deleted requirement for ECGs on Cycle 1 Day 8 and Cycle 1 Day 15 
- 
Edited Footnote “i” to clarify timing of ECGs during Dose Escalation 


Clinical Study Protocol  
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Amendment 09:  30 Sep 2020 
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DATE 
Highlights of Major Changes 
Section/Change 
- 
Deleted row containing Bile Acids 
- 
Edited Footnote “k” to clarify that measurement of total bile salts is 
done as part of the safety blood chemistry panel. 
- 
Added row to clarify timing of brain scans.  Edited table footnotes as 
required. 
- 
Edited footnote “t” to indicate that paired-skin biopsies are optional. 
 
Edited Table 7 as follows: 
- 
Deleted requirement for ECGs to be performed on Cycle 1 Day 8 and 
Cycle 1 Day 15 
- 
Edited Footnote “j” to clarify timing of ECGs in the Food Effect and 
Expansion Cohorts. 
- 
Deleted row containing Bile Acids. 
- 
Edited Footnote “k” to clarify that measurement of total bile salts is 
done as part of the safety blood chemistry panel. 
- 
Added row to clarify timing of brain scans.  Edited table footnotes as 
required. 
- 
Edited Footnote “t” to indicate that paired-skin biopsies are optional. 
12 May 2016 
Exclusion criteria numbers 9 and 10 were added to the Synopsis and Section to 
specify that: 
- 
Subjects taking a strong inhibitor or inducer of CYP3A4 enzyme within 
at least 2 weeks before the start of the study drug and during the 
conduct of the study unless there was an emergent or life threatening 
medical condition that required it (exclusion criterion number 9), and 
- 
Subjects taking any drug known to prolong QTc interval within at least 
2 weeks before the start of the study drug and during the conduct of the 
study (exclusion criterion number 10) 
Are excluded from enrollment into the study.  
 
Subjects were instructed to follow the storage requirements listed on the study 
drug label (Section 9.4.3.4)  
 
Tables 6 and 7, Schedule of Assessments 
- 
Edited Footnote “o” of Table 6 and Footnote “n” of Table 7 to clarify 
PK the 24 h sampling time will be collected prior to the next dose. 
 
Table 7, Schedule of Assessments 
- 
Added an ‘X’ for collection of a hematology laboratory sample to 
ensure collection of hematology laboratory sample at the Screening 
Visit. 
 
Appendix 5, item number 2 of Urine Samples for Metabolism Profiling, was 
updated to remove the requirement of a preweighted stainless steel container for 
collection of urine samples.  


Clinical Study Protocol  
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Amendment 09:  30 Sep 2020 
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DATE 
Highlights of Major Changes 
Section/Change 
06 Oct 2016 
Amendment 02 
 
Global:  Revised protocol to remove enrollment of subjects with intrahepatic 
cholangiocarcinoma (IHCC) and all corresponding text. 
 
Global:  Removed reference to subjects with/without cirrhosis 
 
Global:  Changed “Part 2, 3-arm Cohort Expansion,” to “Part 2, Expansion 
phase” 
 
List of Abbreviations:  Updated to reflect changes to protocol 
 
Section 6:  Revised to clarify Eisai’s role in the conduct of the study 
 
Section 6 and Synopsis:  Revised to reflect increase in the number of anticipated 
participating sites from 20 to 25 
 
Section 7.1.1.1:  Included statement that data from ongoing preclinical studies 
show tumor regression has been observed in xenograft mouse models having 
undetectable levels of FGF19. 
 
Sections 7.2, 9.1, 9.1.1.3, 9.2, and 9.4.4.3, Table 8, and Synopsis:  Revised 
protocol to clarify that the first 12 subjects enrolled in the Expansion phase will 
participate in the Food Effect part of the study 
 
Section 7.2 and Synopsis:  Revised protocol so that subjects with or without 
elevated baseline levels of FGF19 could be enrolled in the Expansion phase. 
 
Section 8.2, Table 8 in Section 9.5.2, and Synopsis:  Clarified that subjects with 
or without elevated levels of FGF19 could be enrolled in the study. 
 
Sections 8.2, 9.1.1.2, and Synopsis:  Clarified that FGF19 concentration would 
be determined by a Sponsor-designated laboratory. 
 
Sections 8.3, 9.5.1.3.3, 9.7.1.1, Table 7 and Table 8, and Synopsis: Removed 
the requirement to perform skin biopsies and the measurement of FGF19 levels 
in skin as an exploratory endpoint. 
 
Sections 9.1, 9.1.1.2, and Synopsis:  Increased enrollment in the Expansion 
phase to 60 subjects (including a minimum of 20 subjects with tumors 
expressing elevated levels of FGF19). 
 
Table 1 in Section 9.1.1.1 and Synopsis:  Removed reference to determination 
of the MTD by subpopulation and added a footnote to show that 300 mg QD is 
the planned starting dose level 
 
Table 2 in Section 9.1.1.1.1, Section 9.7.1.8, and Synopsis:  Added language for 
drug-related Grade 2 nonhematologic toxicities that required dose modification; 
changed subject eligibility requirement for determination of DLTs from 
completion of 17 days to 14 days of treatment; deleted all footnotes in Table 2 
and made minor grammatical changes for consistency throughout table 
 
Section 9.1.1.3:  Added new Figure 1, Dosing Schema for Food Effect Cohort 
 


Clinical Study Protocol  
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Amendment 09:  30 Sep 2020 
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06 Oct 2016 
(continued) 
Sections 9.1.2.4, 9.5.1.2.2, 9.5.5, and Synopsis:  Text revised to reflect that 
subjects will be followed for survival every 6 weeks; clarified that termination 
of the study will occur 18 months after enrollment of the last subject. 
 
Sections 9.3, 9.7.2, and Synopsis:  Total sample size changed from 60-90 
subjects to 78 to 90 subjects, including 60 subjects in the Expansion phase 
 
Section 9.3.1 and Synopsis:  Revised inclusion criteria nos. 2, 3, 4, 7, and 8 per 
changes to included population and mRECIST; minor grammatical changes for 
consistency 
 
Section 9.3.2 and Synopsis:  Removed exclusion criterion no. 19 (pregnancy 
and lactation) and renumbered subsequent criteria; minor grammatical changes 
made to criteria nos. 6, 8, 9, and 22. 
 
Sections 9.4.4.1, 9.5.5, 9.7.1.8 and Synopsis:  Revised text to clarify subjects 
eligible for determination of DLTs 
 
Section 9.4.8.1 and Synopsis:  Added strong inducers/inhibitors of CYP3A4 as 
prohibited concomitant medication; changed text to prohibit the use of any long-
acting proton pump inhibitors; added new Table 5, Inducers and Strong 
Inhibitors of CYP3A4 
 
Section 9.5.1.2.1 and Synopsis:  Clarified procedure for retention of tumor scans 
 
Section 9.5.1.3.1:  Clarified that a nonvalidated assay such as matrix-assisted 
laser desorption/ionization will be used to measure H3B-6527 concentration in 
tumor tissue 
 
Sections 9.5.1.3.3 and Synopsis:  Revised the procedure for tumor biopsies. 
Clarified that all subjects with elevated baseline levels of FGF19 in the 
Expansion phase will undergo paired tumor biopsies, with one taken predose 
(any time during Screening before the first dose of H3B-6527 on C1 Day 1) and 
one taken approximately 3 hours (±2 h) postdose on C2 Day 1. 
 
Sections 9.5.1.3.3, 9.7.1.1, Table 7 and Table 8, and Synopsis: Removed the 
requirement to perform skin biopsies and the measurement of FGF19 levels in 
skin as an exploratory endpoint. 
 
Section 9.5.2, Schedules of Assessments:  Added visit windows; clarified PK, 
PD and urine collection times, posttreatment procedures, and time points for 
survival follow-up; revised the footnotes pertaining to the timing for paired 
tumor biopsies.  Tables 6 and 7 were renumbered Tables 7 and 8. 
 
Section 9.5.5:  Revised criteria for subjects who are and are not evaluable for 
DLT assessments 
 
Section 9.7.1.1 and Synopsis:  Revised criteria for determining objective 
response rate (ORR) 
 
Sections 9.7.1.2 and Synopsis:  Redefined the Full Analysis Set 
 
Section 9.7.1.6:  Removed definition for the calculation of ORR 


Clinical Study Protocol  
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Amendment 09:  30 Sep 2020 
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List of References;  Updated citation for Nexavar prescribing information; 
added new reference: Hagel, et al., 2015.; deleted references Sia D, et al., 2013 
and Churi CR, et al., 2014 
06 Oct 2016 
(continued) 
Removed Appendix 2, Response Evaluation Criteria in Solid Tumors (Subjects 
with IHCC); renumbered subsequent appendices accordingly 
15 Dec 2016 
Amendment 03 
 
Revised the criteria for Grade 4 GI dose-limiting toxicities (ie, diarrhea and 
vomiting) in Table 2 (Section 9.1.1.1.1) and Synopsis per the FDA’s 
recommendation 
14 Jun 2017 
Amendment 04.1 (country-specific to South Korea) 
 
Section 9.3.2 and Synopsis: Added exclusion criteria # 22 to exclude subjects 
with inorganic phosphorus > upper limit of normal for the institution, per South 
Korea health authority request.  
Section 9.3.2 and Synopsis: Added exclusion criteria # 23 to exclude subjects 
with total or ionized serum calcium > upper limit of normal for the institution, 
per South Korea health authority request. 
Section 9.3.2 and Synopsis: Added exclusion criteria # 24 to exclude subjects 
with endocrine changes that may result in increases in calcium or phosphate, 
including but not limited to hyperparathyroidism and tumoral calcinosis, per 
South Korea health authority request. 
Section 9.3.2 and Synopsis: Added exclusion criteria # 25 to exclude subjects 
with past medical history and/or current evidence of tumoral calcinosis, per 
South Korea health authority request. 
Section 9.3.2 and Synopsis: Added exclusion criteria # 26 to exclude subjects 
who take calcium, vitamin D or systemic corticosteroids, per South Korea 
health authority request. 
Section 9.4.8.1 to include drugs that raise serum calcium and phosphorus levels 
(eg, vitamin D supplements, calcium dietary supplements, calcium antacids, 
etc.) and systemic corticosteroids as prohibited medications, per South Korea 
health authority request. 
Section 9.4.8.2 and Synopsis: Added language to clarify management of 
hyperphosphatemia or hypercalcemia, per South Korea health authority request. 
06 Jul 2017 
Amendment 05 
 
Global:  Revised protocol to include enrollment of subjects with intrahepatic 
cholangiocarcinoma (ICC).  Rationale:  new article by Yoo et. al. (2017) shows 
that ICC has genomic alterations in FGF19 that are very similar to HCC and 
FGF19/FGFR4 could also potentially play a critical role in ICC. 
 
List of Abbreviations:  Updated to reflect changes to protocol (addition of ICC). 
 
Section 5.3:  Removed sentence “Subjects will be required to provide separate 
informed consent for the collection of samples for pharmacogenomics (PG); see 
Section 9.5.1.3.4.”; in Section 9.5.1.3.4:  Removed portion of sentence stating 
that PG samples are collected “from all subjects who provide consent to have 


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such samples collected.”  Rationale:  subjects are consented for PG sample 
collection in the main ICF (no separate ICF required). 
 
Sections 7.2, 9.1, 9.1.1.3, 9.2, 9.4.4.3, Table 8, and Synopsis:  clarified that the 
food effect cohort will be comprised of the first 12 HCC subjects enrolled in 
dose expansion.  Rationale:  food effect may be different for ICC subjects 
compared with HCC subjects. 
 
Section 9.1.1.1 and Synopsis:  revised protocol to allow for intrapatient dose 
escalation during dose escalation.  Rationale:  The possibility of intrapatient 
dose escalation theoretically reduces the number of subjects who are treated at 
sub-therapeutic doses.  Permitting intrapatient dose escalation gives some 
subjects the opportunity to be treated at higher and presumably more effective 
doses. 
 
Section 9.1.1.1 and Synopsis:  revised protocol to clarify that once the 
MTD/RP2D is reached, at least 6 HCC subjects must be enrolled at the RP2D 
(regardless of the total number of subjects enrolled at that dose level) in order to 
proceed with dose expansion. As subjects with ICC may have a better 
tolerability than subjects with HCC, the SRC may decide to continue dose 
escalation for ICC subjects after the RP2D has been established for HCC 
subjects. 
 
Table 2 and Synopsis:  Revised DLT definition to include subjects with CTCAE 
Grade 3 anemia if transfused or if lasting for more than 7 days, or CTCAE 
Grade 4 anemia of any duration, per Taiwan health authority request. 
 
Table 2 and Synopsis:  Revised DLT definition to clarify that for subjects with a 
starting ALT within the normal range for the local laboratory, an elevation ALT 
≥ 5 × ULN for the local laboratory will be considered a DLT; for subjects with 
an abnormal value ≥ ULN at baseline based on the local laboratory ranges, an 
ALT elevation ≥ 10 × ULN for the local laboratory will be considered a DLT, 
per Taiwan health authority request. 
 
Section 9.3.1 and Synopsis:  Revised inclusion criteria # 3, 4, and 8 per changes 
to included population and RECIST 1.1. 
 
Section 9.3.2 and Synopsis:  Added clarifications to exclusion criteria # 22, 23, 
24, 25, and 26. 
 
Section 9.4.3.4:  Updated study drug storage conditions to clarify that study 
drug should be stored refrigerated at 2-8°C at the study center due to availability 
of stability data for refrigerated conditions. 
 
Section 9.4.8.1:  added systemic corticosteroids to prohibited medications and 
clarification of systemic corticosteroid washout period. 
 
Section 9.4.8.2 and Synopsis:  Added minor language clarifications to 
management of hyperphosphatemia or hypercalcemia section. 
 
Section 9.5.1.3.3, Synopsis, Table 7, and Table 8:  Clarified that tumor biopsy 
samples should not be formalin fixed paraffin embedded, for consistency with 
collection instructions in the lab manual. 


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Table 7 and Table 8:  updated footnotes to clarify that the ±3 day-window for 
C1D8 does not apply to the PK sampling (administrative change). 
 
List of References:  added new references:  Sia, et al, 2013, Churi, et al., 2014, 
and Yoo, et al., 2017 to support inclusion of ICC subjects. 
 
Added Appendix 2, Response Evaluation Criteria in Solid Tumors (Subjects 
with ICC); renumbered subsequent appendices accordingly 
22 Feb 2018 
Amendment 06 
Global edits applied to conform with Eisai Writing Style Guideline (eg, parallel 
structure of bulleted lists, P value, capitalization and spacing). 
Section 7.2:  Edited to remove reference to the food-effect portion of the study, 
which will no longer be included in the current study.  The effect of food on the 
bioavailability of H3B-6527 will be assessed in a separate, concurrent clinical 
study, H3B-6527-A001-001:  A Randomized Phase 1 Food-Effect Study of 
H3B-6527 in Healthy Subjects.  Conditional language has been added to 
indicate that subjects may be asked to take study drug in conjunction with a 
meal depending on study results from this Healthy Volunteer Food Effect 
(HVFE) study. 
 
Section 8.2:  Removed the objective to determine whether a high-fat meal had 
any effect on bioavailability since sufficient data will be obtained from HVFE 
study to support administration with or without food in the current study. 
 
Section 9.1:  Edits to clarify the dose schedules and sample size for the dose 
escalation and expansion portions of the study and to allow simultaneous 
exploration of QD and BID dosing schedules. 
 
Figure 1:  Add this study diagram to clarify the overall study design between 
Parts 1 and 2 of the study, including the number of subjects planned for 
enrollment. 
 
Section 9.1.1.1:  Added a statement to further clarify that the selection of the 
RP2D will be based on an integrated evaluation of safety and tolerability, as 
well as PD and PK data to allow flexibility in study design and dosing schedule. 
Added a statement to clarify that subjects who experience a dose-limiting 
toxicity (DLT) or dose-modifying event (an adverse event that meet the criteria 
for a DLT but occurring after Cycle 1) have the option for resuming treatment at 
a reduced dose following resolution of the event and joint consultation between 
the investigator and the Sponsor as to what is in the best clinical interest of the 
subject as previously outlined in Section 9.4.2.  
 
Table 1:  Revised the table footnote to include potential for a BID dose schedule 
and to allow greater flexibility with BID dose schedule or alternate dosing 
options.  Revised the table to reflect the total daily dose amounts so as to 
include the BID dose schedule. 
 
Table 2:  Updated table caption (this was Table 2). Minor correction to the CTC 
AE Grade 3 bilirubin to specify that it must be >3 × ULN (not ≥3 × ULN) to 
align with CTCAE v4.03. 


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Section 9.1.1.2:  Expanded this section to include additional study design details 
regarding the QD and BID dose schedules and to discuss the overall number of 
subjects to be recruited for this part of the study. 
 
Section 9.1.1.3:  Deleted this section since the food effect cohort will no longer 
be applicable for this study.  
 
Section 9.2:  Added additional information about food recommendations for the 
study.  If study drug plasma exposure is found to be increased with food (based 
on the HVFE study), this section included a few details about how study drug 
would be administered with food, including details about fasting for PK/PD 
testing prior to study drug administration.  This text helps to clarify important 
criteria if study drug administration is to occur in conjunction with a meal.   
 
Section 9.3:  Revised the total number of subjects to be enrolled in the study 
based upon changes to the study design for Parts 1 and 2. 
 
Sections 9.3.1 and 9.3.2 General:  Edits to reflect parallel construction to adhere 
to the Eisai Writing Style Guide. 
 
Section 9.3.1 #3:  Revised this bullet to allow for noninvasive diagnosis of HCC 
and to further clarify criteria to be used.   
Also added a sub-bullet to clarify that eligible subjects must have had at least 
one prior standard-of-care therapy or declined such therapy given the changing 
treatment landscape in this subject population.  
 
Section 9.3.1 #5:  New criterion to indicate that all subjects must be FGF19-
positive, as determined by Sponsor-designated laboratory prior to enrollment in 
the Dose Expansion phase of the study.  
 
Section 9.3.1 #6:  Added a window for the receipt of prior chemotherapy or 
immunotherapy to include 4 weeks or 5 half-lives (whichever is shorter). 
 
Section 9.3.1 #7:  Edit to clarify the washout period for radiopharmaceuticals 
from “within 8 weeks” to “8 weeks before study drug administration.” 
 
Section 9.3.2 #1:  Revised this criterion to indicate that subjects with stage 1 
prostate cancer are eligible for study participation. 
 
Section 9.3.2 #11:  Revised this criterion to remove specific reference to “long-
acting” PPIs.  Additionally, added a statement to allow antacid use during the 
study with the exception of calcium carbonate antacids, which could interfere 
with calcium levels. 
 
Section 9.3.2 #13:  Removed selective pan-FGFR inhibitor as an exclusionary 
previous treatment. 
 
Section 9.3.2 #14:  Clarified that only live vaccines are prohibited. 
 
Section 9.4.2:  Added a statement to discuss DLTs and to specify when a 
subject may continue on treatment at a reduced dose following a DLT. 
 
Section 9.4.4.1:  Clarified the threshold for subjects to be evaluable as 17 of 
21 days (80%) to accommodate the potential for a BID dose schedule. 
 
 


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Section 9.4.4.3:  Removed this food effect cohort, which will no longer be 
included in the current study.  The effect of food on the bioavailability of H3B-
6527 will be assessed in a separate, concurrent clinical study, H3B-6527-A001-
001:  A Randomized Phase 1 Food-Effect Study of H3B-6527 in Healthy 
Subjects.  Conditional language has been added to indicate that subjects may be 
asked to take study drug in conjunction with a meal depending on study results 
from this HVFE study as needed.  
 
Section 9.4.6:  Added a sentence to clarify guidance on missed doses, 
particularly for the BID schedule. 
 
Section 9.4.8:  Added language to specify that study drug must be withheld if a 
subject requires a short course of steroids while on-treatment. 
 
Section 9.4.9:  Removed some of the restrictions that were included in this 
section for the food effect cohort since that is no longer being included for 
reasons stated above.  Subjects are still required to limit physical activity 
immediately before and after blood draws. 
 
Section 9.5.1.1.1:  Added this section to discuss prescreening requirements for 
subjects and to include that an optional separate consent may be used to screen 
subjects and collect tumor tissue samples. 
 
Section 9.5.1.1.3:  Revised the medical history to specifically state the 
collection of disease history of portal vein invasion or thrombosis. 
 
Section 9.5.1.3.3:  Revised this section to state that a separate consent may be 
used to allow screening of tumor tissue samples prior to enrollment and to 
include a visit window for the collection of the second tumor biopsy sample. 
 
Section 9.5.1.4.3:  Revised this section to remove specific reference to the 
requirement to review bile salts/acids prior to study drug administration since 
turnaround time for results precludes real-time review.  However, results will be 
reviewed by the site team when available, and in aggregate to look for any 
potential safety trends as outlined in the existing safety review plan. 
 
Section 9.5.1.4.5:  Added language to the OCT examination to clarify that any 
abnormalities would be recorded as AEs and to provide a window for the 
completion of the examination prior to Day 1 of each specified cycle. 
 
Section 9.5.1.4.6:  Revised this section to include appropriate windows/timing 
for Holter monitoring to be consistent with the ECG manual. 
 
Section 9.5.1.4.9:  Revised the sentence on pregnancy testing to include 
flexibility for urine or serum pregnancy testing before the first dose and at OTV. 
 
Tables 6 and 7:  Additional edits were made to the schedule of events to adhere 
to edits made in the protocol text. 
 
Section 9.7.1.1:  Updated the study endpoints to clarify that ORR is determined 
by a best overall confirmed response of CR or PR.  Clarified that confirmed 
progression is not required for DOR and PFS. 
 
 


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Section 9.7.2:  Revisions here to encompass decisions made regarding overall 
study design in the Dose Expansion Phase, including the removal of the food 
effect cohort, the inclusion of 2 separate treatment arms and fixed sample sizes 
for both arms in expansion. 
 
Tables 8 and 9:  Added two tables to depict the dose schedules in the Dose 
Expansion arm and the precision estimates for ORR of 30% in 40 subjects. 
 
Section 9.7.3:  Added a statement that database locks are not required for 
interim analysis and clarified that PK summaries may also be periodically 
provided. 
 
Section 10:  
European Medicine Agency (2012) reference on drug interactions and Food and 
Drug Administration (2002) reference on food interactions was removed since 
the food effect portion of the study was removed. 
Hagel (2015) was removed from this list following the edits applied to the 
statistical sample size section. 
 
Section 12:  Added Appendix 7, Child-Pugh scoring as it is part of the eligibility 
requirements for subjects in the study. 
14 Nov 2018 
Amendment 07 
Section 9.3.1 #3:  Revised sub-bullet to clarify that eligible subjects must have 
had at least one prior standard-of-care therapy, unless contraindicated. 
28 Aug 2019 
Amendment 08 
Global:  Revised protocol to remove enrollment of subjects with intrahepatic 
cholangiocarcinoma (ICC) and all corresponding text.  Data indicates that 
fibroblast growth factor 19 (FGF19) is not a driver in ICC, and that fibroblast 
growth factor receptor 4 (FGFR4) dependence is likewise not observed in ICC. 
List of Abbreviations:  Updated to reflect changes to protocol. 
Section 5.3:  Revised to indicate that subjects will be asked to sign an informed 
consent form (ICF) up to 8 weeks before the first dose of study drug. 
Section 5.3:  Removed the mention of the separate consent form for the 
collection of tumor tissue for screening purposes prior to enrollment as the 
collection of tumor tissue will be conducted with the ICF signing up to 8 weeks 
before the first dose of study drug. 
Section 8.3:  Revised the exploratory biomarkers to remove the assessment of 
the pharmacodynamic effects of phospho-extracellular-signal-regulated kinases 
(pERK) and cytochrome P450 (CYP) 7A1 and other FGFR4-related biomarkers 
in tumor samples, as the in-treatment biopsy will not be collected. 


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Synopsis, Section 9.1, and Section 9.2:  Updated the study design to indicate 
that subjects will be administered the study drug with food based on the Healthy 
Volunteers Food-Effect study (Study H3B-6527-A001-001:  A Randomized 
Phase 1 Food-Effect Study of H3B-6527 in Healthy Subjects).  Also, the 
starting dose of study drug when given with food was agreed upon with the 
Safety Review Committee to meet the criteria that it be no more than one-half 
of the previously determined safe total daily dose level and that any additional 
dose escalation will follow the procedures outlined in Section 9.1.1. 
Section 9.1.1.1:  Added a statement that information about DLTs or safety 
concerns to all sites will be communicated by the Sponsor as per the separate 
Dose Escalation Plan. 
Synopsis and Section 9.1.1.1.1:  Included the definition of dose-modifying 
events to the section and Table 2 as any event that occurs in Cycle 2 or beyond 
(including any cycle in Phase 2). 
Section 9.1.1.1.1 and Table 2:  Added aspartate aminotransferase (AST) to the 
criteria for hepatic toxicity. 
Synopsis and Section 9.1.2.1:  Removed “to obtain informed consent” from the 
28-day Screening Period as the ICF signing will be up to 8 weeks before the 
first dose of study drug. 
Section 9.2:  Clarified that subjects will be required to fast 2 hours prior to 
pharmacodynamic assessments. 
Synopsis and Section 9.3.1:  Revised inclusion criteria number 4 to reflect that 
the tumor sample is collected up to 8 weeks before administration of study drug. 
Synopsis and Section 9.3.1:  Revised inclusion criteria number 7, Part 2, Dose 
Expansion, to indicate that the fresh tumor tissue must be available and 
collected up to 8 weeks before administration of H3B-6527 on Cycle 1 Day 1. 
Synopsis and Section 9.3.1:  Revised inclusion criteria number 14 to define 
sexual abstinence in accordance with the Clinical Trial Facilitation Group 
guidance. 
Synopsis and Section 9.3.2:  Revised exclusion criteria number 9 to include the 
mention of the P-glycoprotein transporter. 
Synopsis and Section 9.3.2:  Revised exclusion criteria number 16 to replace 
corrected QT (QTc) >500 ms with QTc >450 ms, as >500 ms is considered a 
Grade 3 QTc prolongation as per Common Terminology Criteria for Adverse 
Events (CTCAE). 
Synopsis and Section 9.3.2:  Added exclusion criteria number 27, “Hereditary 
problems of galactose intolerance, the Lapp lactase deficiency, or glucose 
galactose malabsorption.” 
Section 9.4.6:  Revised to indicate that subjects will be instructed to take the 
dose in conjunction with a meal. 
Synopsis and Section 9.4.8.1:  Revised the list of prohibited concomitant 
therapy and procedures to include P-glycoprotein transporter 


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Section 9.5.1:  Revised to indicate that all subjects must provide written 
informed consent up to 8 weeks before the first dose of study drug. 
Section 9.5.1.1.1:  Revised to indicate that a fresh tumor biopsy, the signing of 
the ICF, and the collection of blood samples for pharmacodynamic analysis 
(same day as fresh tumor biopsy) will be required up to 8 weeks before 
administration of H3B-6527 on Cycle 1 (C1) Day 1, in order to enroll in the 
Dose Expansion Phase of the study.  The 28-day Screening Period will begin 
when any of the remaining screening assessments are performed.  The entire 
Pretreatment Phase must be completed within 8 weeks of study drug 
administration on C1 Day 1. 
Synopsis and Section 9.5.1.2.1:  Revised to indicate that a brain scan should be 
performed for all subjects as clinically indicated. 
Section 9.5.1.3.3:  Removed the mention of a separate consent form for 
screening purposes, as a fresh tumor biopsy, the signing of the ICF, and the 
collection of blood samples for pharmacodynamic analysis (same day as fresh 
tumor biopsy) will be required up to 8 weeks before study drug administration. 
Synopsis and Section 9.5.1.3.3:  Revised to indicate that the signing of the ICF, 
the collection of blood samples for pharmacodynamic analysis (same day as 
fresh tumor biopsy), and a fresh tumor tissue sample is required to be collected 
up to 8 weeks before administration of the first dose of H3B-6527 on C1 Day 1.  
The 28-day Screening Period will begin when any of the remaining screening 
assessments are performed. 
Synopsis and Section 9.5.1.3.3:  Removed the requirement of paired tumor 
biopsies for the Dose Expansion phase. 
Section 9.5.1.4.1:  Corrected the adverse event and serious adverse event 
collection timeframe to be within 30 days after the last study drug dose. 
Section 9.5.1.4.5:  Added a statement to indicate that ophthalmic examinations 
performed within 8 weeks of C1 Day 1 can be used in the event of a rescreen. 
Section 9.5.1.4.6:  Revised to indicate that all subjects in the dose expansion 
phase of the study will have a single 12-lead safety electrocardiogram (ECG) 
performed at Screening or Baseline (single unless abnormalities are observed or 
otherwise clinically indicated, in which case ECGs will be performed in 
triplicate at 2-minute intervals), Day 1 of each cycle (pre- and post-dose), and at 
the Off-treatment Visit (OTV). 
Section 9.5.1.4.8:  Added a statement to indicate that multiple-gate acquisition 
(MUGA) scans or echocardiograms performed within 8 weeks of C1 Day 1 can 
be used in the event of a rescreen. 
Section 9.5.2, Table 6:  Added footnote “a” to the screening column of informed 
consent, as it indicates that the signing of the ICF may be up to 8 weeks before 
the first dose of study drug. 
Section 9.5.2, Table 6:  Added “if clinically indicated” to the Treatment and 
Extension columns of Echocardiogram/MUGA to reflect the corresponding 
footnote. 


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Section 9.5.2, Table 6:  Removed the statement, “Subjects will be fasted 2 hours 
before and 2 hours after dose,” from the Treatment and Extension columns of 
H3B-6527 administration to reflect the corresponding revised footnote “y” that 
H3B-6527 should be taken in conjunction with a meal. 
Section 9.5.2, Table 6:  For footnote “f,” added a statement to indicate that 
ophthalmic examinations performed within 8 weeks of C1 Day 1 can be used in 
the event of a rescreen. 
Section 9.5.2, Table 6:  For footnote “g,” added a statement to indicate that 
MUGA scans or echocardiograms performed within 8 weeks of C1 Day 1 can 
be used in the event of a rescreen. 
Section 9.5.2, Table 6:  For footnote “j,” revised to indicate that 12-lead ECGs 
will be collected at the following time points:  Screening (single) or Baseline 
(single unless abnormalities are observed or if clinically indicated, then in 
triplicate at 2-minute intervals); Day 1 of all cycles (before and after study drug 
administration); and at the OTV. 
Section 9.5.2, Table 6:  For footnotes “q” and “r,” clarified that all subjects will 
be required to fast 2 hours prior to those assessments. 
Section 9.5.2, Table 6:  For footnote “s,” removed the mention of the separate 
consent form for screening of sample tumor tissue. 
Section 9.5.2, Table 6:  For footnote “u,” revised to state that the screening 
computed tomography (CT)/magnetic resonance imaging (MRI) of the brain 
should be performed as clinically indicated. 
Section 9.5.2, Table 6:  For footnote “y,” revised to state that H3B-6527 should 
be taken daily at the assigned schedule and dose in conjunction with a meal. 
Section 9.5.2, Table 7:  For the Extension phase, corrected the Visit column for 
Day 8 to reflect odd numbered visits. 
Section 9.5.2, Table 7:  Added footnote “a” to the screening column of informed 
consent, pharmacodynamic blood samples, and fresh tumor tissue biopsy, as the 
footnote indicates that those procedures/assessments may be up to 8 weeks 
before the first dose of study drug. 
Section 9.5.2, Table 7:  Added “if clinically indicated” to the Treatment and 
Extension columns of Echocardiogram/MUGA to reflect the corresponding 
footnote. 
Section 9.5.2, Table 7:  Removed the row for in-treatment tumor tissue biopsy 
and the corresponding footnote “r.” 
Section 9.5.2, Table 7:  For footnote “a,” revised to state that the Screening 
Period extends from Day -28 to Day -1, except for signing of the ICF, the fresh 
tumor tissue biopsy, and the blood samples for pharmacodynamic analysis, 
which may be up to 8 weeks before the first dose of study drug.  The 28-day 
Screening Period will begin when any of the remaining screening assessments 
are performed. 


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Section 9.5.2, Table 7:  For footnote “e,” added a statement to indicate that 
ophthalmic examinations performed within 8 weeks of C1 Day 1 can be used in 
the event of a rescreen. 
Section 9.5.2, Table 7:  For footnote “f,” added a statement to indicate that 
MUGA scans or echocardiograms performed within 8 weeks of C1 Day 1 can 
be used in the event of a rescreen. 
Section 9.5.2, Table 7:  For footnote “i,” revised to indicate that 12-lead ECGs 
will be collected at the following time points:  Screening (single) or Baseline 
(single unless abnormalities are observed or if clinically indicated, then in 
triplicate at 2-minute intervals); Day 1 of all cycles (before and after study drug 
administration); and at the OTV. 
Section 9.5.2, Table 7:  For footnotes “n” and “o,” clarified that all subjects will 
be required to fast 2 hours prior to those assessments. 
Section 9.5.2, Table 7:  For footnote “p,” removed the mention of the separate 
consent form for screening of tumor tissue. 
Section 9.5.2, Table 7:  For footnote “q,” revised to state that a fresh tumor 
tissue sample is required to be collected up to 8 weeks before administration of 
H3B-6527 on C1 Day 1. 
Section 9.5.2, Table 7:  For footnote “r,” revised to state that the screening 
CT/MRI of the brain should be performed as clinically indicated. 
Section 9.5.2, Table 7:  For footnote “v,” revised to state that all subjects in the 
Expansion phase will take H3B-6527 daily in conjunction with a meal. 
Section 9.5.5:  Corrected the number of days that would allow for subject 
replacement to at least 17 of 21 days. 
Section 10, Reference List:  Updated to reflect changes to protocol 
Removed Appendix 2 Response Evaluation Criteria in Solid Tumors (Subjects 
with ICC). 
Appendix 4:  For urine samples for metabolite profiling, removed the recording 
of mass of urine from the case report form, as the total volume is recorded. 
30 Sep 2020 
Amendment 09           
 
Synopsis, Section 9.1.2.4, Section 9.5.1.2.2, Section 9.5.2 (Table 6 [footnote z] 
and Table 7 [footnote w]), and Section 9.5.5:  Updated survival follow-up 
language.  
 
Synopsis and Section 9.1.2.4:  Specified when data cutoff for the primary 
analysis will occur.   
 
Synopsis and Section 9.1.2.4:  Defined end of study as when the last ongoing 
subject completes their off treatment visit.  
 
Synopsis, Section 9.1.2.4:  Clarified that the off treatment visit should occur 30 
days after final dose with a window of ± 3 days.  


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Synopsis, Section 9.5.1.4.6, and Section 9.5.2 (Table 6 [footnote j] and Table 7 
[footnote i]):  Updated language concerning ECG assessments.  
 
Section 9.5.2 (Table 6 [footnotes q, r] and Table 7 [footnotes n, o]):  Updated 
language for collection of biomarker samples.     
 
Section 9.7.1.2:  Clarified that summary of efficacy will be based on the Full 
Analysis Set for HCC subjects, and that the Response Evaluable Set will only 
include HCC subjects.   
 
Section 9.7.1.6:  Clarified that efficacy analysis will be performed at the time of 
data cutoff for primary analysis.  Clarified that all efficacy parameters will be 
summarized for the Full Analysis Set for HCC subjects.  Clarified that ORR, 
duration of response, and time to response will also be summarized for the 
Response Evaluable Set as appropriate. 


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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.  H3B-6527 
Name of Active Ingredient:  N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-
methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acrylamide 
Study Protocol Title 
An Open-Label Multicenter Phase 1 Study to Evaluate the Safety, Pharmacokinetics and 
Pharmacodynamics of H3B-6527 in Subjects With Advanced Hepatocellular Carcinoma 
Investigators 
Multiple investigators  
Sites 
Up to approximately 40 sites planned globally  
Study Period and Phase of Development 
Approximately 48 months 
Phase 1 
Objectives 
Primary objectives  
• 
Determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) 
of H3B-6527 in subjects with advanced hepatocellular carcinoma (HCC) 
• 
Assess the safety and tolerability of H3B-6527 as a single agent administered orally 
Secondary objectives 
• 
Evaluate the pharmacokinetic (PK) profile of H3B-6527 
• 
Evaluate the preliminary antitumor activity of H3B-6527 at the RP2D and schedule in subjects 
with advanced HCC who are fibroblast growth factor 19 (FGF19)-positive as determined by 
the Sponsor-designated laboratory 
Exploratory objectives 
• 
Explore biomarkers and their correlation with safety and efficacy endpoints 
• 
Assess the pharmacodynamic effects of H3B-6527 on FGF19, Ki67, bile acids, and other 
fibroblast growth factor receptor 4 (FGFR4)-related biomarkers in blood  
• 
Explore the relationship between PK and pharmacodynamics 
• 
Exposure to H3B-6527 in tumor samples may be assessed 
• 
Explore the metabolite profile of H3B-6527 in plasma and urine 


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Study Design 
This is an open-label, multicenter, Phase 1 study that will be conducted in 2 parts, a Dose Escalation 
phase (Part 1) and a Dose Expansion phase (Part 2).  Approximately 30 to 128 are planned for 
enrollment. 
Dose escalation will follow a standard 3+3 cohort design until the MTD/RP2D for each dosing 
schedule is determined in this population.  
H3B-6527 will be administered as a single-agent by oral administration in 21-day cycles without 
break to examine both once daily (QD) and twice daily (BID) dosing schedules, with flexibility to 
also examine additional alternate dosing schedules.  The study drug will be administered with food 
based on the Healthy Volunteers Food-Effect study (Study H3B-6527-A001-001:  A Randomized 
Phase 1 Food-Effect Study of H3B-6527 in Healthy Subjects).  The starting dose of study drug when 
given with food was agreed upon with the Safety Review Committee (SRC) to meet the criteria that it 
be no more than one-half of the previously determined safe total daily dose level.  Any additional 
dose escalation will follow the procedures outlined in Section 9.1.1. 
Safety, tumor response, PK, and pharmacodynamic assessments will be performed for every subject; 
details are described under Assessments. 
This study makes provision for exploring a BID schedule of H3B-6527 if evaluation of the PK, 
pharmacodynamics, or safety of H3B-6527 suggests that it may be preferable to administer H3B-
6527 BID rather than QD.  The criteria to evaluate a BID schedule will be based on an integrated 
evaluation of safety, tolerability, clinical benefit, PK, and pharmacodynamic data, for all dose levels 
tested.  In this case, a new cohort of 3 subjects will be enrolled and treated with a BID dose.  The 
initial total daily dose given BID will be equal to a total daily dose that has been well tolerated as a 
QD dose (dose-limiting toxicity [DLT] rate < 33% in a cohort of 3-6 subjects).  If BID dosing of 
H3B-6527 is well tolerated in this initial cohort then dose escalation may continue with BID dosing, 
following the same dose escalation rules applied to QD dosing.   
Furthermore, additional cohorts of subjects may be enrolled to evaluate a less frequent dosing 
schedule (eg, daily for 2 consecutive weeks every 3 weeks [dosing on Days 1-14 of a 21-day cycle]). 
Dose Escalation (Part 1) 
The objective of Part 1, the Dose Escalation phase is to determine the MTD and/or RP2D of 
H3B-6527 in subjects with HCC.  The total number of subjects to be enrolled will depend on the 
observed safety profile, which will determine the number of subjects per dose cohort, as well as the 
number of dose escalations required to achieve the MTD and/or RP2D of H3B-6527.  Assuming 5 
dose levels will be studied for the QD dose schedule and 3 dose levels for the BID dose schedule and 
a maximum of 6 subjects will be enrolled per dose level, approximately 30 to 48 subjects may be 
accrued during dose escalation.  
The criteria to evaluate the BID dose schedule will be based on an integrated evaluation of safety, 
tolerability, clinical benefit, PK, and pharmacodynamic data, for all QD dose levels tested.  In this 
case, a new cohort of 3 subjects will be enrolled and treated with a BID dose.  The initial total daily 
dose given BID will be equal to a total daily dose that has been well tolerated as a QD dose (DLT 
<33% in a cohort of 3-6 subjects).   
Due to the potential for dropouts during the first cycle of treatment (eg, because of early disease 
progression), a cohort may initially be expanded to include up to 2 additional subjects.  However, if 
these additional subjects are to be enrolled, they must start treatment within 14 days after the third 
subject enrolled in the cohort was first dosed with H3B-6527.  The decision to dose escalate may still 


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be made after the third subject enrolled to the dose level in question has completed the first cycle (C) 
of treatment.  However, if under these circumstances the decision is made to enroll subjects to a 
higher dose level, and one of the additional subjects treated at the preceding dose level experiences a 
DLT in the first cycle of treatment, then further enrollment of subjects to the higher dose level will be 
suspended until it can be determined whether the preceding dose level exceeds the MTD.  In the 
meantime, subjects enrolled to the higher dose level may continue treatment at that dose if they are 
tolerating it well, and if continuing treatment is considered appropriate for the toxicity in question. 
For dose-escalation purposes, toxicities assigned as DLTs during the first cycle will be assessed.  
After 3-6 subjects in a cohort have completed C1, all available safety data will be reviewed by the 
SRC consisting of Sponsor personnel and investigators and the decision to proceed to the next dose 
cohort will be made jointly.  If different dose schedules are explored, decisions regarding dose 
escalation will be made based on review of data from subjects enrolled in cohorts on the same 
schedule, however, safety data from alternate schedules may be considered by the SRC.  Toxicities 
will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE), Version 4.03. 
Once a subject has completed C3 at the initially assigned dose schedule and dose level (QD or BID), 
intrapatient dose escalation will be allowed.  Only subjects who have not progressed on treatment, 
and did not have a dose reduction or interruption because of drug-related adverse events (AEs), can 
escalate to the highest dose level that has completed DLT assessment within that schedule and has 
been shown to be safe (no DLT in the first 3 subjects or no more than 1 DLT in 6 subjects).  Subjects 
on the intrapatient dose escalation will not be included in the DLT analysis at the higher dose level.  
The investigator and the medical monitor must agree that dose escalation is appropriate for the 
subject prior to escalating their H3B-6527 dose level. 
The starting dose of 300 mg (first-in-human dose) is the human equivalent dose (HED) of 1/6th of 
the highest non-severely toxic dose in the dog.   
H3B-6527 will be tested in sequential, escalating dose cohorts (n=3 to 6) at the dose levels in the 
table below.  Dose escalation will follow a modified Fibonacci design such that the magnitude of the 
escalation will decrease as the dose level nears the HED of the highest non-severely toxic dose in 
dogs (HED ≈ 2000 mg). 
Dose Cohorts in H3B-6527 Dose Escalation Phase 
Dose level 
Initial No. of Subjects 
H3B-6527 Total Daily Dose 
-1 
3 
150 mg  
1a 
3 
300 mg  
2 
3 
600 mg  
3 
3 
1000 mg  
4 
3 
1400 mg  
5 
3 
2000 mg  
These total daily dose levels may be evaluated in QD or BID dose schedules, intermediate dose levels, 
and in expansion of an existing dose level of up to 12 evaluable subjects following discussions between 
the Sponsor and the investigators, if supported by evolving safety, tolerability, PK, and 
pharmacodynamic data. 
BID = twice daily, QD = once daily 
a:  Planned starting dose level for QD schedule. 
Subjects will be assigned to a dose level in the order of study entry.  Initially, 3 subjects will be 
enrolled at the starting dose level.  If 2 of the 3 subjects experience a DLT then the dose level -1 (one 


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dose level below starting dose) will be explored.  If 1 of the 3 subjects experiences a DLT then the 
dose will be expanded to 6 subjects.  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. 
Dose escalation to the next higher dose may proceed if no DLT is observed in C1 among the first 
3 subjects accrued to a cohort.  If 1 of 3 subjects in the cohort experiences a DLT, up to a total of 
6 subjects will be enrolled.  If 2 or more (≥33%) of the 3-6 subjects in a cohort experience a DLT, 
dose-escalation will cease, and additional subjects will be treated at a lower dose level.  Dose 
escalation will continue until a dose level where ≥2 of 6 subjects experience a DLT.   
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 safety, tolerability, clinical benefit, PK, and pharmacodynamic data, for 
all dose levels tested.  Clinically significant toxicities (eg, chronic Grade 2 toxicities) or AEs that 
meet the definition of dose limiting but occurring after C1 (dose-modifying events [DME]) may be 
considered when determining the RP2D.  Once the MTD/RP2D is reached, at least 6 HCC subjects 
must be enrolled at the RP2D (regardless of the total number of subjects enrolled at that dose level) 
in order to proceed with dose expansion. 
Subjects who do not receive study drug for at least 17 of 21 days (approximately 80%; not 
necessarily consecutively) during the first cycle for reasons not considered to be a DLT by both the 
investigators and the Sponsor will be replaced.  Subjects who are replaced will not be considered 
evaluable for DLT assessments. 
Definition of Dose-Limiting Toxicities or Dose-Modifying Events 
DLTs are any of the following toxicities occurring during C1 Phase 1 only and judged by the 
investigator as related to study drug (ie, assessed as unrelated to disease, intercurrent illness, or 
concomitant medications).  Any event that occurs in C2 or beyond (including any cycle in Phase 2) 
will be considered a DME.  
 
TOXICITY 
CRITERIA 
Hematology 
Febrile neutropenia  
CTCAE Grade 4 neutropenia that does not resolve to Grade ≤2 within 7 days  
CTCAE Grade 3 thrombocytopenia requiring transfusion 
CTCAE Grade 3 thrombocytopenia and clinically significant bleeding 
CTCAE Grade 4 thrombocytopenia 
CTCAE Grade 3 anemia if transfused or if lasting for more than 7 days  
CTCAE Grade 4 anemia of any duration 
Gastrointestinal 
CTCAE Grade 3 nausea, vomiting and/or diarrhea lasting more than 72 hours 
despite the use of optimal anti-emetic/antidiarrheal treatment 
CTCAE Grade 4 diarrhea and/or vomiting irrespective of prophylaxis or appropriate 
treatment 
Renal 
CTCAE Grade ≥3 serum creatinine 
Hepatic 
CTCAE Grade >3 bilirubin and/or AST/ALT ≥10 × ULN 
For subjects with a starting AST/ALT within the normal range for the local 
laboratory, an elevation AST/ALT ≥ 5 × ULN for the local laboratory 
For subjects with an abnormal value ≥ ULN at baseline based on the local laboratory 
ranges, an AST/ALT elevation ≥ 10 × ULN for the local laboratory 
Other AEs not listed 
above 
Nonhematologic toxicities of CTCAE Grade ≥3 except for the following. 
1. CTCAE Grade 3 fatigue lasting less than 1 week,  


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2. Isolated CTCAE Grade 3 elevations in biochemistry laboratory values without 
associated clinical symptoms that last for ≤7 days.  This includes electrolyte 
abnormalities that respond to medical intervention. 
 
H3B-6527-related, CTCAE Grade 2 nonhematologic toxicities that, in the opinion 
of the treating investigator, require a dose reduction or discontinuation of study 
drug, or lead to the subject’s failure to complete at least 17 days of study drug 
administration in C1, may be deemed to be dose-limiting if agreed upon by 
participating investigators and the Sponsor. 
AE = adverse event, ALT = alanine aminotransferase, AST = aspartate aminotransferase, C = Cycle, CTCAE 
= Common Terminology Criteria for Adverse Events, ULN = Upper limit of normal. 
Expansion (Part 2) 
Prior to starting the Dose Expansion phase, the investigators and the Sponsor will use safety, 
efficacy, PK, and pharmacodynamic data obtained during the Dose Escalation Phase, as well as 
clinical judgement, to jointly determine the dose schedules (e.g., QD and/or BID) to be studied.  
During Part 2, the Dose Expansion phase, a sample size of 40 evaluable subjects per dose schedule 
will be enrolled to examine QD and/or BID dosing of H3B-6527 based on the recommended dose 
determined from Part 1.  For a reference of the precision of ORR estimates, the associated 2-sided 
95% CIs for ORR up to 30% for 40 subjects are provided.  Subjects enrolled into Part 2, Dose 
Expansion phase, must be FGF19-positive as defined by Sponsor-designated laboratory. 
When both dose schedules are accruing subjects, an alternating enrollment schema into QD and BID 
dose schedule will be followed.  
Study Phases 
The study will be conducted in the following 4 phases:  Pretreatment Phase, Treatment Phase, 
Extension Phase, and Follow-up Phase. 
Pretreatment Phase 
This Pretreatment Phase will last no longer than 28 days and includes: 
• 
A Screening Period to establish protocol eligibility. 
• 
A Baseline Period to establish disease characteristics before treatment. 
Treatment Phase 
The Treatment Phase will last for 1 treatment cycle of 21 days. 
Subjects who are receiving study drug at the end of the Treatment Phase will continue to receive 
study drug in the Extension Phase. 
Extension Phase  
In the Extension Phase, subjects will continue to receive the same treatment and dose they received 
during the Treatment Phase, provided termination criteria are not met.   
Treatment and Extension Phases 
Subjects will discontinue study drug at the time of disease progression, development of unacceptable 
toxicity, withdrawal of consent, or termination of the study by the Sponsor.  However, subjects may 
continue to receive study treatment as long as they demonstrate clinical benefit as judged by the 
investigator after discussion with the Sponsor or until the end of the study.  Disease progression will 
be determined by the investigator following relevant modified Response Evaluation Criteria in Solid 


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Tumors (mRECIST) guidelines.  The mRECIST for this protocol harmonizes the original mRECIST 
criteria (Lencioni and Llovet, 2010) using triphasic liver computed tomography (CT)/magnetic 
resonance imaging (MRI; optimized for precontrast, arterial phase, and portal venous phase) and 
elements of Response Evaluation Criteria in Solid Tumors, Version 1.1 (Eisenhauer, et al., 2009).   
Follow-up Phase 
After the Off-treatment Visit, all subjects who discontinue study treatment, regardless of their reasons 
for doing so, will be followed for survival approximately every 12 weeks for up to 12 months or until 
6 cycles after last patient in, death, loss to follow-up, or withdrawal of consent, whichever occurs 
first.  Subjects who discontinue study drug without progressive disease (PD) will continue to undergo 
tumor assessments every 6 weeks until documented PD or initiation of another anticancer therapy.   
The data cutoff for the primary analysis will occur once the last subject completes 6 cycles of 
investigational therapy.  Subjects will be allowed to continue treatment until progression or the end 
of therapeutic benefit from the study drug as determined by Sponsor discussion with investigator.   
The end of study is defined as when the last ongoing subject completes their off treatment visit.  The 
off treatment visit should occur 30 days after final dose with a window of ± 3 days.  The maximum 
estimated period for each subject on treatment is anticipated to be approximately 4 months.  
However, subjects may continue to receive study treatment, as long as they demonstrate clinical 
benefit as judged by the investigator after discussion with the Sponsor or until the end of the study. 
Number of Subjects 
Approximately 30 to 128 subjects are planned to be enrolled in this study:  30 to 48 during the Dose 
Escalation phase and 40 to 80 subjects in the Dose Expansion phase.  The total number of subjects to 
be enrolled in the Dose Escalation phase is dependent upon the observed safety profile, which will 
determine the number of subjects per dose cohort, as well as the number of dose escalations required 
to achieve the MTD and/or RP2D of H3B-6527. 
Inclusion Criteria 
In order to be eligible for participation in this study, subjects must: 
1. Be ≥18 years of age. 
2. Have an Eastern Cooperative Oncology Group Performance Status of 0 or 1. 
3. Have an HCC diagnosis with the following criteria: 
• 
Confirmed by available pathology records or current biopsy (confirmed diagnosis may be 
made by histological examination or by noninvasive criteria according to the European 
Association for the Study of the Liver or the American Association for the Study of Liver 
Disease Guidelines) 
• 
Advanced, unresectable, or recurrent 
• 
Progressing since the last antitumor therapy 
• 
Child-Pugh A classification 
• 
No clinically significant ascites 
• 
Must have received at least one prior standard-of-care therapy, unless contraindicated. 
4. Must be FGF19-positive, as determined by a Sponsor-designated laboratory from a fresh tumor 
sample prior to enrollment in the Dose Expansion phase. 
5. Have completed any prior chemotherapy, monoclonal antibody or immunotherapy (eg, tumor 
vaccine, cytokine, or growth factor given to control the cancer) at least 4 weeks or 5 half-lives 
(whichever is shorter) before study drug administration, and all AEs must have either returned to 
baseline or resolved to Grade 0 or 1. 


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6. Have completed any prior definitive radiation therapy at least 3 weeks before study drug 
administration; any prior focal radiotherapy at least 2 weeks before study drug administration; 
irradiated lesions should show evidence of size increase as defined in inclusion criterion #7 if 
they are intended to be followed as target lesions.  Radiopharmaceutical therapy (strontium, 
samarium, and yttrium) must have been completed 8 weeks before study drug administration. 
7. Have tumor tissue available as follows: 
a. Part 1, Dose Escalation:  Tumor tissue (screening acquisition or archival tissue if 
obtained) is requested but not mandated. 
b. Part 2, Dose Expansion:  Fresh tumor tissue must be available (collected up to 8 weeks 
before administration of H3B-6527 on C1 Day 1).  Archival tissue if available is 
requested but not mandated. 
8. Have measurable disease as follows:  
a. Part 1, Dose Escalation:  Subjects may have measurable or nonmeasurable disease as 
defined by mRECIST.   
b. Part 2, Expansion:  Subjects must have measurable disease meeting the following 
criteria:  
i. Subjects with HCC:  At least 1 measurable target lesion according to mRECIST 
that meets the following criteria:  
• 
Hepatic lesion 
- The lesion can be accurately measured in at least one dimension as ≥1.0 cm 
- The lesion is suitable for repeat measurement 
- The lesion shows intratumoral arterial phase enhancement on contrast-
enhanced CT or MRI 
• 
Nonhepatic lesion 
- Lymph node lesion that measures at least one dimension as ≥1.5 cm in the 
short axis, except for porta hepatis lymph node that measures ≥2.0 cm in the 
short axis 
- Non-nodal lesion that measures ≥1.0 cm in the longest diameter 
Lesions previously treated with radiotherapy or locoregional therapy must show 
radiographic evidence of disease progression by mRECIST to be deemed a target 
lesion. 
9. Have left ventricular ejection fraction >50% on echocardiography or multiple-gate acquisition 
(MUGA) scan. 
10. Have adequate renal function defined as serum creatinine <1.5 × upper limit of normal (ULN; or 
calculated creatinine clearance ≥50 mL/min per the Cockcroft and Gault formula). 
11. Have adequate bone marrow function as follows: 
a. Absolute neutrophil count ≥1500/mm3 (≥1.5 × 109/L) 
b. Platelet counts ≥75,000/mm3 (≥75 × 109/L) 
c. Hemoglobin ≥9.0 g/dL (may have been transfused). 
12. Have adequate liver function as follows:  
a. Adequate blood coagulation as evidenced by an International Normalized Ratio ≤1.5. 


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b. Total bilirubin ≤1.5 × ULN. 
c. Alanine aminotransferase and aspartate aminotransferase ≤5 × ULN. 
d. No evidence of biliary duct obstruction unless obstruction controlled by local treatment 
or, the biliary tree can be decompressed by endoscopic or percutaneous stenting with 
subsequent reduction in bilirubin to ≤1.5 × ULN. 
13. Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative 
beta-human chorionic gonadotropin [ß-hCG] test with a minimum sensitivity of 25 IU/L or 
equivalent units of ß-hCG).  A separate baseline assessment is required if a negative screening 
pregnancy test was obtained more than 72 hours before the first dose of study drug. 
NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group 
and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal 
ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least 1 month before 
dosing). 
14. Females of childbearing potential should avoid becoming pregnant and use highly effective 
contraception while on treatment and for at least 1 month after finishing treatment.  Females of 
childbearing potential must not have had unprotected sexual intercourse within 30 days before 
study entry and must agree to use a highly effective method of contraception (eg, sexual 
abstinence, an intrauterine device, a contraceptive implant, an oral contraceptive, or have a 
vasectomized partner with confirmed azoospermia) throughout the entire study period and for 
30 days after study drug discontinuation.  Sexual abstinence is considered a highly effective 
method only if defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatment.  The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical study and the preferred and usual lifestyle of the subject.  
Periodic abstinence (calendar, symptothermal, and post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of 
contraception.  Female condom and male condom should not be used together.  Females who are 
using hormonal contraceptives must have been on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and must continue to use the same 
contraceptive during the study and for 30 days after study drug discontinuation.  Women using 
oral hormonal contraceptives should add a barrier method. 
15. Be willing and able to comply with all aspects of the protocol. 
16. Provide written informed consent prior to any study-specific screening procedures. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Other malignancy active within the previous 2 years except for basal or squamous cell skin 
cancer, stage 1 prostate cancer, superficial bladder cancer or carcinoma in situ of the cervix or 
breast that has completed curative therapy. 
2. Current evidence of corneal disorder/keratopathy including but not limited to corneal epithelial 
thinning, bullous/band keratopathy, corneal abrasion, inflammation/ulceration, or 
keratoconjunctivitis (to be confirmed by ophthalmological examination).  Pre-existing cataract is 
not a reason for exclusion. 
3. Brain or subdural metastases are not eligible, unless they have completed local therapy and have 
discontinued the use of corticosteroids for this indication for at least 4 weeks before starting 


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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. 
4. Genetic diseases of the liver that may complicate review of safety data. 
5. Known human immunodeficiency virus infection. 
6. Uncontrolled significant active infections, except hepatitis B virus (HBV) or hepatitis C virus 
(HCV).  Subjects with HBV are eligible but should be taking an appropriate antiviral medication 
if indicated.  Subjects with HCV are eligible but must not be taking concomitant treatment for 
HCV while receiving H3B-6527. 
7. Major surgery or other locoregional treatment within 4 weeks before the first dose of study drug 
or radionuclide treatment (eg, 90Yttrium intra-arterial treatment) 8 weeks before study drug 
administration. 
8. Inability to take oral medication, or presence of a malabsorption syndrome or any other 
uncontrolled gastrointestinal condition (eg, nausea, diarrhea, or vomiting) that might impair the 
bioavailability of H3B-6527.  Subjects with prior gastric resection are eligible. 
9. Use of any drug that is a strong inhibitor or inducer of the cytochrome P450 (CYP) CYP3A4 
enzyme or the P-glycoprotein transporter within at least 2 weeks before the start of study drug 
and during the conduct of the study unless there is an emergent or life-threatening medical 
condition that requires it. 
10. Use of any drug known to prolong corrected QT (QTc) interval within at least 2 weeks before the 
start of the study drug and during the conduct of the study. 
11. Treatment with proton pump inhibitors that cannot be discontinued 3 days prior to the start of 
study drug and during the course of the study; antacids are permitted except for calcium 
carbonate antacids (eg, Tums®). 
12. Use of other investigational drugs within 28 days or at least 5 half-lives (whichever is shorter) 
before study drug administration. 
13. Previous treatment with a selective FGF19-FGFR4 targeted therapy. 
14. Use of any live vaccines against infectious diseases (eg, influenza, varicella) within 4 weeks 
(28 days) of initiation of study therapy. 
15. Presence of gastric or esophageal varices requiring active treatment.   
16. A clinically significant electrocardiogram (ECG) abnormality, including a marked baseline 
prolonged QTc interval (eg, a repeated demonstration of a QTc interval >450 ms). 
17. Significant cardiovascular impairment:  history of congestive heart failure greater than New York 
Heart Association Class II, uncontrolled arterial hypertension, unstable angina, myocardial 
infarction, or stroke within 6 months of the first dose of study drug; or cardiac arrhythmia 
requiring medical treatment (including oral anticoagulation). 
18. Any other major illness, medical condition or concomitant medication that, in the investigator’s 
judgment, will substantially increase the risk associated with the subject’s participation in this 
study or would compromise the subject’s ability to safely complete the study. 
19. Males who have not had a successful vasectomy (confirmed azoospermia) or they and their 
female partners do not meet the criteria above (ie, not of childbearing potential or practicing 
highly effective contraception throughout the study period or for 90 days after study drug 


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discontinuation).  No sperm donation is allowed during the study period or for 90 days after 
study drug discontinuation. 
20. Hypersensitivity to the study drug or to any of the excipients.   
21. Intolerance or hypersensitivity to both CT and MRI contrast material that would preclude the 
ability to acquire the triphasic liver imaging required by the protocol. 
22. An inorganic phosphorus > ULN for the institution.  Note:  Subjects may be on treatment for 
hyperphosphatemia, but the levels must be normal at screening to participate in this study.  
Subjects with high levels on screening may subsequently be treated and rescreened and, should 
they have stable levels for 2 weeks prior to study, may enter the study. 
23. A total or ionized serum calcium > ULN for the institution.  Note:  Subjects may be on treatment 
for hypercalcemia, but the levels must be normal at screening to participate in this study.  
Subjects with high levels on screening may subsequently be treated and rescreened and, should 
they have stable levels for 2 weeks prior to study, may enter the study. 
24. Endocrine changes that may result in increases in calcium or phosphate, including but not limited 
to hyperparathyroidism and tumoral calcinosis. 
25. Past medical history and/or current evidence of tumoral calcinosis or tissue calcification. 
26. Use of calcium or vitamin D supplements or systemic corticosteroids.  The duration between the 
last systemic corticosteroid administration and the first dose of study drug should be at least 2 
weeks. 
27. Hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose 
malabsorption. 
Study Treatment 
Test drug:  H3B-6527 will be supplied as 50-, 100-, and 200-mg capsules.  The starting dose will be 
300 mg QD orally, with escalation of total daily doses in successive cohorts to a maximum planned 
dose of 2000 mg.  Additionally, a BID dosing schedule may be explored.  In this case, the initial total 
daily dose given BID will be equal to a total daily dose that has been well tolerated as a QD dose.  
The study drug will be administered with food based on the Healthy Volunteers Food-Effect study 
(Study H3B 6527-A001-001:  A Randomized Phase 1 Food-Effect Study of H3B-6527 in Healthy 
Subjects). 
Capsules should be swallowed whole.  Dosing should not be repeated if a subject vomits.  For 
subjects on a QD dose schedule, a dose missed by >8 hours should be skipped.  For subjects on a 
BID dose schedule, a dose missed by >4 hours should be skipped. 
Guidelines for Continuation of Treatment 
Study drug should continue to be administered until disease progression, development of 
unacceptable toxicity, withdrawal of consent, or termination of the study by the Sponsor.   
Subjects who experience a DLT during C1, will be discontinued from treatment.  In rare cases, an 
exemption to study discontinuation for a DLT in C1 may be considered after discussion between the 
treating physician, Sponsor and study medical monitor.   
If a subject experiences a DLT or dose-modifying event (ie, an AE meeting the criteria for a DLT but 
occurring after C1) during the study then study treatment will be interrupted and subjects may, at the 
discretion of the investigator, and after discussion with the Sponsor, be allowed to continue study 
drug at a reduced dose, if the following criteria are met: 
• 
Absolute neutrophil count ≥1.0 × 109/L (1,000/mm3) 
• 
Platelet count ≥75 × 109/L (75,000/mm3) 


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• 
All other nonhematologic treatment-related toxicities are Grade 0 or 1 (except alopecia) or 
return to baseline level 
• 
The subject is deriving clinical benefit, and  
• 
The subject has an otherwise favorable risk/benefit profile.  
The magnitude of the dose reduction cannot be specified a priori since the actual doses evaluated and 
the dose-toxicity relationship will not be known until there is clinical experience with H3B-6527; 
however, a minimum reduction of 33% must be taken.  The dose chosen will require discussion and 
agreement between the investigator and Sponsor following review of the relevant clinical data. 
Dose reductions are allowed for all subjects.  However, once the H3B-6527 dose has been reduced 
for a given subject, no re-escalation will be permitted for that subject.  
A maximum of 2 dose reductions will be allowed as needed but study treatment should not be 
resumed in the case of the following treatment-related events: 
• 
Occurrence of a DLT in C1 except upon agreement with investigator, Sponsor and medical 
monitor.  A dose reduction must be taken if treatment is resumed. 
• 
CTCAE Grade 3 or 4 cardiac event 
• 
Nonhematologic events of Grade 4 severity 
• 
Dose delay of ≥21 days for a treatment-related event in C2 and beyond. 
Comparator Drug:  None 
Duration of Treatment 
In the Dose Escalation and Dose Expansion phases of the study, each subject will receive 1 cycle of 
treatment during the Treatment Phase.  In the Extension Phase, study treatment will continue until the 
subject develops PD or unacceptable toxicity or withdraws consent, or until termination of the study 
by the Sponsor.  However, subjects may continue to receive study treatment, as long as clinical 
benefit is demonstrated, as judged by the investigator after discussion with the Sponsor or until the 
end of the study. 


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Concomitant Drug/Therapy 
The following are prohibited: 
• Other investigational drugs. 
• Other antitumor therapies such as chemotherapy, surgical resection, or antitumor 
immunotherapy. 
• Proton pump inhibitors. 
• Radiotherapy for central metastases (eg, vertebral, mediastinal) will not be allowed; the need 
for such radiotherapy while on study will be seen as an indication of disease progression and 
the subject should be withdrawn from therapy.  However, palliative radiotherapy for up to 
2 local peripheral metastases not being used as target lesions is allowed but the need for such 
therapy may be an indication of PD and should be discussed with the Sponsor prior to 
implementation.  
• Drugs that are strong inhibitors or inducers of CYP3A4 enzyme or P-glycoprotein 
transporter. 
• Drugs that raise serum calcium and phosphorus levels (eg, vitamin D supplements, calcium 
dietary supplements, calcium antacids) or systemic corticosteroids.  The duration between the 
last systemic corticosteroid administration and the first dose of study drug should be at least 
2 weeks.  If a short-term course of systemic corticosteroids is required while on treatment, 
then study drug must be held while the subject receives systemic corticosteroid treatment.  If 
the subject has not progressed in the interim, resumption of treatment with H3B-6527 may be 
considered following discontinuation of steroid treatment and a 2-week washout period. 
Growth Factors:  Subjects receiving recombinant erythropoietin or darbepoietin-α prior to study start 
may continue to receive pretreatment doses.  Following initiation of study treatment, the use of 
erythropoietic and granulocyte growth factors in accordance with local practice or guidelines.  
American Society for Clinical Oncology guidelines may be implemented at the discretion of the 
treating physician. 
Management of diarrhea:  Subjects should be instructed to take loperamide, 4 mg, at the occurrence 
of the first loose stool and then 2 mg every 2 hours until they are diarrhea-free for at least 12 hours.  
During the night, subjects may take 4 mg of loperamide every 4 hours.  Subjects should be advised to 
avoid dehydration through adequate fluid intake.  Bile acid sequestrants may be utilized in the case of 
bile acid diarrhea. 
Medications for the treatment of AEs or cancer symptoms, eg, packed red blood cells and pain 
medications, are allowed.  Additionally, medications (not addressed above) used to treat underlying 
medical conditions at study entry including anti-emetics and antidiarrheals will be allowed to 
continue. 
Guidelines for Management of Hyperphosphatemia or Hypercalcemia 
Phosphorus and calcium will be measured at screening, before the first dose, every week with safety 
labs during C1, and on Day 1 and Day 8 for C2 and beyond.  Please note that a cycle is 21 days.  
Subjects with elevated levels of phosphorus or calcium at screening, as defined as being >1 × ULN on 
local laboratory ranges, may not participate in this study and should be referred for management of 
such.  If successfully controlled, subjects may be rescreened.  During study participation, any levels 
of phosphorus above 7 mg/dL, or calcium equal to or above Grade 2 hypercalcemia as per CTCAE, 
Version 4.03, will result in the dose of H3B-6527 being held for 14 days.   


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The hyperphosphatemia and / or hypercalcemia should be managed by local practice, with 
medication, diet change, and potential referral as necessary.  After 14 days of holding the drug, if the 
phosphorus level has returned to 5.5 mg/dL or lower, and the calcium is less than or equal to a Grade 
1 elevation, the subject may begin taking H3B-6527 again at one dose level lower than their original 
dose and should continue other measures initiated during the drug holiday, such as phosphorus 
lowering agents, while on study.  If a subject should experience hyperphosphatemia above 7 mg/dL 
or hypercalcemia equal to or above Grade 2 again on study, then study therapy will be discontinued. 
Assessments 
Efficacy Assessments 
Tumor assessments will be performed following mRECIST guidance. 
All subjects are required to undergo chest, abdomen, and pelvis imaging at baseline and all follow-up 
time points.  Contrast-enhanced CT scan of the chest and contrast-enhanced CT or MRI scan of the 
abdomen, pelvis, and any other areas of disease, as clinically indicated, will be acquired at Screening 
and at all imaging time points.  A liver CT or MRI scan must be performed using triphasic scanning 
techniques optimized to capture precontrast, arterial, and portal venous phases.  Historical standard-
of-care scans conducted within 28 days prior to study drug administration may be used as 
screening/baseline imaging if scanning parameters are consistent with the requirements for this 
protocol as separately defined by the imaging core laboratory. 
MRI scans may be used instead of CT scans for imaging of the abdomen and pelvis.  However, the 
chest must be imaged using CT; and chest disease must be followed by CT scan (ie, chest x-ray for 
response assessment is not allowed).  The same method of assessment used during Screening must be 
used at all subsequent time points.  If iodinated intravenous contrast is contraindicated, chest CT scan 
should be performed without intravenous contrast. 
A brain scan should be performed for all subjects to assess potential central nervous system disease 
and/or metastases as clinically indicated.  For eligible subjects with previously treated brain 
metastases, a brain scan will be required at all tumor assessment time points (eg, every 6 weeks).  For 
all subjects, a follow-up brain scan must be performed to confirm a complete response (CR) within 1 
week following response confirmation.   
The first radiological assessment of tumor response status will be performed during Week 6, unless 
there is clinical indication warranting earlier radiologic imaging.  Response assessments will be 
repeated every 6 weeks until disease progression as determined by the investigator.  Although clinical 
progression may be determined by the investigator based upon clinical deterioration, every effort 
should be made to document progression using radiographic methods.  Signs and symptoms of 
clinical deterioration that lead to disease progression should be documented. 
Subjects discontinued from treatment without disease progression will continue to undergo tumor 
assessments every 6 weeks until documented disease progression or initiation of another anticancer 
therapy. 
Subjects who discontinue study treatment, regardless of their reasons for doing so, will be followed 
for survival approximately every 12 weeks for up to 12 months or until 6 cycles after last patient in, 
death, loss to follow-up, or withdrawal of consent, whichever occurs first.  
Pharmacokinetic Assessments 
Plasma samples for PK analyses will be collected during C1 on Day 1, Day 8, and Day 15 in Part 1, 
Dose Escalation.  Plasma samples for PK analyses will be collected during C1 on Day 8, and Day 15 
in Part 2, Expansion, according to the Schedule of Assessments.   


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Urine and plasma samples for assessment of the metabolite profile will be collected during C1 on 
Day 8 for urine and Day 1, Day 8, and Day 15 for plasma in Part 1, Dose Escalation, only. 
During the Expansion phase, H3B-6527 levels in tumor tissue may be analyzed.  During Dose 
Escalation, the investigators and Sponsor may agree that determination of H3B-6527 exposure in 
tumor tissue is required to guide decisions pertaining to drug administration.  In this scenario, 
biopsies of tumor tissue will be obtained from all consenting subjects.   
Pharmacodynamics, Pharmacogenomics, and Other Biomarker Assessments 
Pharmacodynamics biomarkers including biomarkers to show target engagement and impact of 
H3B-6527 treatment on disease will be evaluated from collected samples as outlined in the schedule 
of assessments.  Retrospective testing for potential subject stratification markers will also be 
explored.  Results from biomarker studies may be used to aid the selection of the RP2D and schedule, 
and for monitoring drug efficacy.  When new research results emerge, the parameters and methods 
for the pharmacodynamic biomarker analysis may change.      
 
Biomarker Sample Collection 
Screening Phase biomarkers: 
Subjects in the Dose Expansion phase will be evaluated for FGF19 expression.  A fresh tumor biopsy 
(for determining FGF19 expression levels by a Sponsor designated laboratory), the signing of the 
ICF, and the collection of blood samples for pharmacodynamic analysis (same day as fresh tumor 
biopsy) will be required up to 8 weeks before administration of H3B-6527 on C1 Day 1, in order to 
enroll in the Dose Expansion Phase of the study.  The 28-day Screening Period will begin when any 
of the remaining screening assessments are performed.  The entire Pretreatment Phase must be 
completed within 8 weeks of study drug administration on C1 Day 1.  Archived, fixed tumor tissue is 
also to be collected (if available) for all consenting subjects in both the Dose Escalation and 
Expansion phases.  These tissues and peripheral blood samples (for both Dose Escalation and Dose 
Expansion phase) may be used for assessment of mutations and other exploratory biomarkers.  
Baseline and Treatment Phase Biomarkers:  
Blood (serum/plasma) biomarker samples from study subjects may be analyzed for FGF19 (ligand of 
H3B-6527’s target FGFR4), bile acids, circulating tumor cells and other exploratory biomarker 
candidates (both protein and nucleic acids) using global proteomic/metabolomics/genomic methods, 
enzyme-linked immunosorbent assay, multiplex bead-based immunoassay, or other assays/methods.  
These blood biomarker samples may be used for exploratory analysis for evaluation of response-
related and/or safety-related outcomes as well as for potential use in diagnostic development. 
In the event a subject is required to have a repeat tumor biopsy for medically indicated reasons, 
freshly obtained biopsy tissue from the procedure should be collected and shipped to 
H3 Biomedicine, Inc., or a predesignated laboratory for exploratory biomarker analysis as outlined in 
the laboratory manual. 
Pharmacogenomics Assessment 
A blood sample will be collected for pharmacogenomic (PG) analysis.  The role of deoxyribonucleic 
acid (DNA) sequence variability on the absorption, distribution, metabolism, and elimination 
(ADME) of H3B-6527 may be evaluated in this study.  Variation in H3B-6527 exposure or the 
occurrence of AEs observed in the study population may be evaluated by correlation of single–
nucleotide polymorphisms with PK, safety, or pharmacodynamic data.  Genomic DNA extracted 
from blood samples may be used to confirm whether the DNA sequence variants observed in DNA 
extracted from tumor material are limited to the tumor. 
Data obtained will be used for research, to assist in developing safer and more effective treatments, 
and will not be used to change the diagnosis of the subject or alter the therapy of the subject.  The 


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DNA will not be used to determine or predict risks for diseases that an individual subject does not 
currently have.  Any sample or derivatives (DNA, ribonucleic acid, and protein) may be stored for up 
to 15 years to assist in any research scientific questions related to H3B-6527 or cancer and for 
potential diagnostic development. 
 
General 
Archived tumor tissue samples and blood samples for pharmacodynamic, PG, 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 time points as specified in the Schedule of 
Procedures/Assessments. 
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, pharmacodynamics), 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 will be 
based on the clinical outcome of the study, the signals observed in other clinical studies and/or the 
scientific rationale of the study.   
Instructions for the processing, storage, and shipping of samples will be provided in the Laboratory 
Manual. 
Safety Assessments 
Safety assessments include monitoring and recording all AEs, including serious adverse events 
(SAEs); clinical laboratory tests (including hematology, coagulation parameters, clinical chemistry 
(including total bile acids, cholesterol, triglycerides), and urinalysis; and periodic measurement of 
vital signs, ECGs, MUGA scans/echocardiograms, ophthalmic and physical examinations.  
Additionally, QTc intervals will be evaluated during Dose-Escalation.  All AEs will be assessed 
using the National Cancer Institute CTCAE, Version 4.03. 
Bioanalytical Methods 
Plasma concentrations of H3B-6527 will be determined using a validated assay.  If appropriate, 
assessment of plasma and urine samples for any metabolites of H3B-6527 may be explored. 
The ability to determine tumor concentrations of H3B-6527 may be explored using a nonvalidated 
assay such as matrix-assisted laser desorption/ionization.  
Statistical Methods 
Primary Endpoints 
• Occurrence of DLTs as a function of the dose of H3B-6527 for determination of the MTD and 
RP2D. 
• Safety/tolerability:  the type and frequency of AEs, SAEs using CTCAE, Version 4.03, as well as 
changes in clinical laboratory values, ECG parameters and vital sign measurements. 
Secondary Endpoints 
• PK:  Standard primary PK parameters including but not limited to the area under the plasma 
concentration-time curve from time 0 through the last measurable point (AUC0-t), maximum 
observed plasma concentration (Cmax) and time of maximum observed plasma concentration 
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• Preliminary antitumor activity:  Response will be determined by the investigator using 
mRECIST.  The following endpoints will be determined: 
- 
Objective response rate (ORR), defined as the proportion of subjects achieving a best overall 
response of partial response (PR) or CR (PR + CR), from first dose date until disease 
progression/recurrence.  
- 
Duration of response, defined as the time from the date of first documented CR/PR until the 
first documentation of disease progression as determined by the investigator or death, 
whichever comes first.   
- 
Progression-free survival (PFS), defined as the time from first dose date to the date of the 
first documentation of disease progression as determined by the investigator or death 
(whichever occurs first).   
- 
Overall survival (OS), defined as the time from first dose date to the date of death. 
- 
Time to response, defined as the time from first dose date to the date of first documented 
CR/PR.   
Exploratory Endpoints 
• 
Correlation of biomarker expression levels with antitumor activity and safety 
• 
Expression levels of biomarkers in blood and tumor samples 
• 
Correlation of biomarker expression levels with H3B-6527 exposure in plasma 
• 
H3B-6527 levels in tumor tissue may be assessed 
• 
H3B-6527 metabolites in plasma and urine. 
 
Analysis Sets 
Full Analysis Set will include all subjects who received at least 1 dose of study drug.  This will be 
the primary analysis set for efficacy evaluations, as well as for demographic and baseline 
characteristics.  The summary of efficacy will be based on this set for HCC subjects. 
Safety Analysis Set will include all subjects who received at least 1 dose of the study drug.  This will 
be the analysis set for all safety evaluations except DLT results. 
PK Analysis Set will include all subjects who have received at least 1 dose of study drug and have at 
least 1 evaluable plasma concentrations.   
Pharmacodynamics Analysis Set will include all subjects who have received at least 1 dose of study 
drug and have evaluable pharmacodynamic data. 
PK/Pharmacodynamics Analysis Set will consist of all subjects in the Safety Analysis Set that also 
have evaluable plasma PK and pharmacodynamic pretreatment assessment and at least 1 post 
treatment assessment. 
Response Evaluable Set will consist of those HCC subjects who have received at least 1 dose of 
study drug and have measurable disease at baseline and at least 1 postbaseline evaluation. 
Efficacy Analyses 
ORR, response duration, time to response, PFS, and OS will be listed and descriptively summarized 
as appropriate.   
• 
Response duration and time to response:  Summary statistics (median Q1, Q3 and range) 


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will be generated on subjects achieving a best overall response of PR or CR (PR + CR).   
PFS and OS:  The PFS censoring rules will follow the Food and Drug Administration 
guidance.  PFS will be reported in both summary tables and plotted with Kaplan-Meier 
curve.  Time of death will be censored for subjects who are without death information at the 
time of OS analysis.  OS will be reported in both summary tables and plotted with Kaplan-
Meier curve. 
Pharmacokinetic Analyses 
Plasma concentrations of H3B-6527 will be tabulated and summarized by dose level, day, and time.  
H3B-6527 PK parameters will be derived from plasma concentrations by noncompartmental analysis 
using actual times.  Minimally, the following PK parameters will be calculated:  Cmax, tmax, AUC0-t, 
accumulation ratio (Racc); and if data permit, area under the plasma concentration-time curve 
extrapolated to infinity (AUC0-inf), terminal elimination half-life (t½), apparent total body clearance 
(CL/F), and apparent volume of distribution during the terminal phase (Vz/F). 
Pharmacodynamics, Pharmacogenomics, and Other Biomarker Analyses 
Pharmacodynamics, PG and other biomarker analyses may be performed and reported separately.  
Details of these analyses will be described in a separate analysis plan. 
Safety Analyses 
Evaluation of safety will be performed on the Safety Analysis Set.  Safety data to be evaluated 
include AEs, clinical laboratory results, vital signs, ECGs, and the results of ophthalmic and physical 
examinations. 
Safety parameters will be summarized using descriptive statistics (mean, standard deviation, median, 
Q1, Q3, and range for continuous variables; numbers and percentages for categorical measures). 
The effects of H3B-6527 on cardiovascular repolarization will be evaluated via 12-lead continuous 
Holter/ECG monitoring on C1 Day 1 and Day 8 in the Dose Escalation phase of the study only.  
Individual ECGs will be extracted from the Holter recordings at specified time points per ECG 
manual and will be evaluated by a central laboratory.  QT intervals will be measured from Lead II 
and will be corrected for heart rate using Fridericia's formula (QTcF) correction factor.  The primary 
QTc parameter will be QTcF.  Secondary parameters (QT corrected for heart rate using Bazett’s 
formula [QTcB], QT, PR, QRS, and heart rate) and waveforms (T waves) will be evaluated. 
Interim Analyses 
There is no formal interim analysis for efficacy.  There will be an interim analysis to define the MTD 
and/or RP2D prior to initiating the Expansion phase of the study.  Other interim analyses may be 
performed to determine if a different dose schedule (eg, BID) or frequency (eg, 2 weeks on/1-week 
off) may be preferable.  Safety and PK summaries may be provided periodically.   
Sample Size Rationale 
Dose Escalation phase (Part 1) 
It is anticipated that selection of the RP2D will be based on an integrated evaluation of 
safety, tolerability, clinical benefit, PK, and pharmacodynamic data.  The total number of 
subjects to be enrolled is dependent upon the observed safety profile, which will determine 
the number of subjects per dose cohort, as well as the number of dose escalations required to 
achieve the MTD of H3B-6527 and establish the RP2D.  For each dose schedule of QD and 
BID, assuming 5 dose levels for QD dose schedule and 3 dose levels for the BID dose 


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schedule will be studied and a maximum of 6 subjects will be enrolled per dose level, then 
between 30 to 48 subjects may be accrued during dose escalation. 
Dose Expansion phase (Part 2) 
Prior to starting the Dose Expansion phase, the investigators and the Sponsor will use safety, 
efficacy, PK, and pharmacodynamic data obtained during the Dose Escalation Phase, as well 
as clinical judgement, to jointly determine the dose schedules to be studied.  
During Part 2, the Dose Expansion phase, a sample size of 40 evaluable subjects per dose 
schedule will be enrolled to examine QD and/or BID dosing of H3B-6527 based on the 
recommended dose determined from Part 1.  For a reference of the precision of ORR 
estimates, the associated 2-sided 95% CIs for ORR up to 30% for 40 subjects are provided.  
This study makes provision for exploring a BID schedule of H3B-6527 during the Dose 
Expansion phase if evaluation of the PK, pharmacodynamics, or safety of H3B-6527 
suggests that it may be preferable to administer H3B-6527 BID rather than QD.  When both 
dose schedules are accruing subjects, an alternating enrollment schema into QD and BID 
dose schedules will be followed.  
Treatment Arms for Part 2, Dose Expansion 
Treatment Arm 
Number of Subjects 
1:  Subjects with advanced HCC who are FGF19-positive to 
receive H3B-6527 QD for 21-day cycles 
40 subjects 
2:  Subjects with advanced HCC who are FGF19-positive to 
receive H3B-6527 BID for 21-day cycles 
40 subjects 
BID = twice daily, HCC = hepatocellular carcinoma. 
 
2-sided 95% Confidence Interval for ORR Estimate Up to 30% (40 subjects) 
 
ORR (N=40) 
2-sided 95% CI 
5% (2 responders in 40 subjects) 
(0.006, 0.169) 
7.5% (3 responders in 40 subjects) 
(0.016, 0.204) 
10% (4 responders in 40 subjects) 
(0.028, 0.234) 
12.5% (5 responders in 40 subjects) 
(0.042, 0.268) 
15% (6 responders in 40 subjects) 
(0.057, 0.298) 
17.5% (7 responders in 40 subjects) 
(0.073, 0.328) 
20% (8 responders in 40 subjects) 
(0.091, 0.356) 
22.5% (9 responders in 40 subjects) 
(0.108, 0.385) 
25% (10 responders in 40 subjects) 
(0.127, 0.412) 
27.5% (11 responders in 40 subjects) 
(0.146, 0.439) 
30% (12 responders in 40 subjects) 
(0.166, 0.465) 
CI = confidence interval, ORR = objective response rate. 


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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
2 
CLINICAL PROTOCOL SYNOPSIS .............................................................................18 
3 
TABLE OF CONTENTS .................................................................................................36 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................41 
5 
ETHICS............................................................................................................................44 
5.1 
INSTITUTIONAL REVIEW BOARDS/INDEPENDENT ETHICS 
COMMITTEES......................................................................................................44 
5.2 
ETHICAL CONDUCT OF THE STUDY .............................................................44 
5.3 
SUBJECT INFORMATION AND INFORMED CONSENT ...............................45 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................46 
7 
INTRODUCTION ...........................................................................................................46 
7.1 
INDICATION ........................................................................................................46 
7.1.1 
H3B-6527 .....................................................................................................48 
7.1.1.1 
Therapeutic Pathway ............................................................................48 
7.1.1.2 
Clinical Experience with H3B-6527 ....................................................48 
7.1.1.3 
Common Serious Adverse Events Expected to Occur in the Study 
Population in the Absence of Study Drug Exposure ...........................48 
7.2 
STUDY RATIONALE ..........................................................................................48 
8 
STUDY OBJECTIVES ....................................................................................................49 
8.1 
PRIMARY OBJECTIVES .....................................................................................49 
8.2 
SECONDARY OBJECTIVES...............................................................................50 
8.3 
EXPLORATORY OBJECTIVES ..........................................................................50 
9 
INVESTIGATIONAL PLAN ..........................................................................................50 
9.1 
OVERALL STUDY DESIGN AND PLAN ..........................................................50 
9.1.1 
STUDY PARTS ...........................................................................................52 
9.1.1.1 
Dose Escalation (Part 1) .......................................................................52 
9.1.1.1.1 
Definition of Dose-Limiting Toxicities or Dose-Modifying 
Events .............................................................................................54 
9.1.1.2 
Expansion (Part 2)................................................................................55 
9.1.2 
STUDY PHASES ........................................................................................56 
9.1.2.1 
Pretreatment Phase ...............................................................................56 
9.1.2.2 
Treatment Phase ...................................................................................56 
9.1.2.3 
Extension Phase ...................................................................................56 
9.1.2.4 
Follow-Up Phase ..................................................................................56 
9.2 
DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL 
GROUPS ................................................................................................................57 
9.3 
SELECTION OF STUDY POPULATION ...........................................................58 


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9.3.1 
INCLUSION CRITERIA .............................................................................58 
9.3.2 
EXCLUSION CRITERIA ...........................................................................61 
9.4 
TREATMENTS .....................................................................................................63 
9.4.1 
TREATMENTS ADMINISTERED ............................................................63 
9.4.2 
GUIDELINES FOR CONTINUATION OF TREATMENT ......................63 
9.4.3 
IDENTITY OF INVESTIGATIONAL PRODUCT ....................................64 
9.4.3.1 
Chemical Name, Structural Formula of H3B-6527 .............................64 
9.4.3.2 
Comparator Drug .................................................................................64 
9.4.3.3 
Labeling for Study Drug ......................................................................64 
9.4.3.4 
Storage Conditions ...............................................................................65 
9.4.4 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ...65 
9.4.4.1 
Dose Escalation Scheme (Part 1) .........................................................65 
9.4.4.2 
Expansion (Part 2)................................................................................67 
9.4.5 
SELECTION OF DOSES IN THE STUDY ................................................67 
9.4.6 
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT ...............67 
9.4.7 
BLINDING ..................................................................................................67 
9.4.8 
PRIOR AND CONCOMITANT THERAPY ..............................................67 
9.4.8.1 
Prohibited Concomitant Therapy and Procedures ...............................68 
9.4.8.2 
Permitted Concomitant Therapy and Procedures ................................69 
9.4.9 
TREATMENT COMPLIANCE ..................................................................70 
9.4.10 
DRUG SUPPLIES AND ACCOUNTABILITY .........................................70 
9.5 
STUDY ASSESSMENTS .....................................................................................71 
9.5.1 
ASSESSMENTS ..........................................................................................71 
9.5.1.1 
Pretreatment Assessments ....................................................................71 
9.5.1.1.1 
Screening........................................................................................71 
9.5.1.1.2 
Demography ...................................................................................72 
9.5.1.1.3 
Medical History .............................................................................72 
9.5.1.2 
Efficacy Assessments ...........................................................................72 
9.5.1.2.1 
Tumor Imaging ..............................................................................72 
9.5.1.2.2 
Survival ..........................................................................................74 
9.5.1.3 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments .............................................................74 
9.5.1.3.1 
Pharmacokinetic Assessments .......................................................74 
9.5.1.3.2 
Pharmacodynamic and Other Biomarker Assessments in Blood ..74 
9.5.1.3.3 
Pharmacodynamics and Biomarkers in Tissue ..............................75 
9.5.1.3.4 
Pharmacogenomic Assessments ....................................................75 
9.5.1.4 
Safety Assessments ..............................................................................76 
9.5.1.4.1 
Adverse Events and Events Associated with Special Situations ...76 


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9.5.1.4.2 
Serious Adverse Events and Other Events of Interest ...................78 
9.5.1.4.3 
Laboratory Measurements .............................................................79 
9.5.1.4.4 
Vital Signs and Weight Measurements ..........................................80 
9.5.1.4.5 
Physical Examinations ...................................................................81 
9.5.1.4.6 
Electrocardiograms and Holter Monitoring ...................................81 
9.5.1.4.7 
ECOG Performance Status ............................................................82 
9.5.1.4.8 
Echocardiogram/MUGA ................................................................82 
9.5.1.4.9 
Pregnancy Test ...............................................................................82 
9.5.2 
SCHEDULE OF PROCEDURES/ASSESSMENTS ...................................83 
9.5.2.1 
Description of Procedures/Assessments Schedule ...............................93 
9.5.3 
APPROPRIATENESS OF MEASUREMENTS .........................................93 
9.5.4 
REPORTING OF SERIOUS ADVERSE EVENTS, PREGNANCY, 
AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS .............93 
9.5.4.1 
Reporting of Serious Adverse Events ..................................................93 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................94 
9.5.4.3 
Reporting of Events Associated with Special Situations .....................95 
9.5.4.3.1 
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................95 
9.5.4.4 
Expedited Reporting ............................................................................95 
9.5.4.5 
Breaking the Blind ...............................................................................95 
9.5.4.6 
Regulatory Reporting of Adverse Events ............................................95 
9.5.5 
COMPLETION/DISCONTINUATION OF SUBJECTS ............................96 
9.5.6 
ABUSE OR DIVERSION OF STUDY DRUG ...........................................97 
9.5.7 
CONFIRMATION OF MEDICAL CARE BY ANOTHER 
PHYSICIAN ................................................................................................97 
9.6 
DATA QUALITY ASSURANCE .........................................................................97 
9.6.1 
DATA COLLECTION ................................................................................97 
9.6.2 
CLINICAL DATA MANAGEMENT .........................................................98 
9.7 
STATISTICAL METHODS ..................................................................................98 
9.7.1 
STATISTICAL AND ANALYTICAL PLANS ..........................................98 
9.7.1.1 
Study Endpoints ...................................................................................98 
9.7.1.2 
Definitions of Analysis Sets.................................................................99 
9.7.1.3 
Subject Disposition ............................................................................100 
9.7.1.4 
Demographic and Other Baseline Characteristics .............................100 
9.7.1.5 
Prior and Concomitant Therapy .........................................................100 
9.7.1.6 
Efficacy Analyses ..............................................................................100 


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9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses .................................................................101 
9.7.1.7.1 
Pharmacokinetic Analyses ...........................................................101 
9.7.1.7.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .......................................................................................101 
9.7.1.8 
Safety Analyses ..................................................................................101 
9.7.1.8.1 
Extent of Exposure .......................................................................102 
9.7.1.8.2 
Adverse Events ............................................................................102 
9.7.1.8.3 
Laboratory Values ........................................................................103 
9.7.1.8.4 
Vital Signs ....................................................................................103 
9.7.1.8.5 
Electrocardiograms and Holter Monitoring .................................103 
9.7.2 
DETERMINATION OF SAMPLE SIZE ..................................................104 
9.7.3 
INTERIM ANALYSIS ..............................................................................106 
9.7.4 
OTHER STATISTICAL/ANALYTICAL ISSUES ...................................106 
10 REFERENCE LIST .......................................................................................................107 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .....109 
11.1 
CHANGES TO THE PROTOCOL .....................................................................109 
11.2 
ADHERENCE TO THE PROTOCOL ................................................................109 
11.3 
MONITORING PROCEDURES .........................................................................109 
11.4 
RECORDING OF DATA ....................................................................................110 
11.5 
IDENTIFICATION OF SOURCE DATA...........................................................110 
11.6 
RETENTION OF RECORDS..............................................................................111 
11.7 
AUDITING PROCEDURES AND INSPECTION .............................................111 
11.8 
HANDLING OF STUDY DRUG ........................................................................111 
11.9 
PUBLICATION OF RESULTS ..........................................................................112 
11.10 DISCLOSURE AND CONFIDENTIALITY ......................................................112 
11.11 DISCONTINUATION OF STUDY ....................................................................112 
11.12 SUBJECT INSURANCE AND INDEMNITY ...................................................113 
12 APPENDICES ...............................................................................................................114 
 
LIST OF IN-TEXT TABLES 
Table 1 
Dose Cohorts in H3B-6527 Dose-Escalation ............................................53 
Table 2 
Definition of Dose-Limiting Toxicity (Cycle 1 Phase 1 Only) or Dose-
Modifying Event (Cycle 2 or Beyond and Any Cycle in Phase 2) ............54 
Table 3 
Summary of Dose Escalation Procedure ....................................................66 
Table 4 
Inducers and Strong Inhibitors of CYP3A4 ...............................................68 
Table 5 
Clinical Laboratory Tests ...........................................................................80 


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Table 6 
Schedule of Assessments in H3B-6527-G000-101 – Dose Escalation 
Cohort ........................................................................................................84 
Table 7 
Schedule of Assessments in Study H3B-6527-G000-101 – Expansion 
Cohorts .......................................................................................................89 
Table 8 
Treatment Arms for Part 2, Dose Expansion ...........................................105 
Table 9 
2-sided 95% Confidence Interval for ORR estimate up to 30%  (40 
subjects) ...................................................................................................106 
Table 10 
Overall Response Assessments per mRECIST ........................................117 
 
LIST OF IN-TEXT FIGURES 
Figure 1: Overall Study Design .........................................................................................51 
 
LIST OF APPENDICES 
Appendix 1 
Modified Response Evaluation Criteria in Solid Tumors ........................115 
Appendix 2 
Common Terminology Criteria for Adverse Events (v4.03) ...................118 
Appendix 3 
Eastern Cooperative Oncology Group Performance Status and 
Karnofsky Performance Status Scale .......................................................119 
Appendix 4 
Pharmacokinetic Sample Collection, Handling, and Shipping ................120 
Appendix 5 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 121 
Appendix 6 
Child Pugh Classification Scoring ...........................................................124 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ß-hCG 
beta-human chorionic gonadotropin 
ADME 
absorption, distribution, metabolism, and elimination 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC0-inf 
area under the plasma concentration-time curve extrapolated to 
infinity 
AUC0−t 
area under the plasma concentration-time curve from time 0 through 
the last measurable point 
BID 
twice daily 
BP 
blood pressure 
C 
cycle 
CA 
Competent Authority 
CFR 
Code of Federal Regulations 
CL/F 
apparent total body clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum observed plasma concentration 
CR 
complete response 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DME 
dose-modifying events 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EU 
European Union 
FDA 
Food and Drug Administration 


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Abbreviation 
Term 
FGF19 
fibroblast growth factor 19 
FGFR 
fibroblast growth factor receptor 
FGFR4 
fibroblast growth factor receptor 4 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HED 
human equivalent dose 
HNSTD 
highest non-severely toxic dose 
HR 
heart rate 
HU 
Hounsfield units 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ID 
identification 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRECIST 
Modified Response Evaluation Criteria in Solid Tumors 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple-gate acquisition 
NE 
not evaluable 
OCT 
optical coherence tomography 
ORR 
objective response rate 
OS 
overall survival 
OTV 
off-treatment visit 
PD 
progressive disease 
PFS 
progression-free survival 
PG 
pharmacogenomics 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PO 
by mouth 


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Abbreviation 
Term 
PR 
partial response 
PT 
preferred term 
QD 
once daily 
QTc 
corrected QT 
QTcF 
QT corrected for heart rate using Fridericia’s formula 
QTcB 
QT corrected for heart rate using Bazett’s formula 
Racc 
accumulation ratio  
RP2D 
Recommended Phase 2 dose 
RR 
respiratory rate 
SAE 
serious adverse event 
SD 
stable disease 
SI 
Système International 
SOC 
system organ class 
SOD 
sum of diameters 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reactions 
t½ 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time of maximum observed plasma concentration 
ULN 
upper limit of normal 
US 
United States 
USPI 
US Prescribing Information 
Vz/F 
apparent volume of distribution during the terminal phase 
WHO 
World Health Organization 
 


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5 
ETHICS 
5.1 
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 International Council for 
Harmonisation (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 associate [CRA], 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. 
A signed letter of study approval (or an electronic 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. 
At the end of the study, the Sponsor (or designee) should notify the IRB/IEC and Competent 
Authority (CA) within 90 days if required.  The end of the study will be the date of the last 
study visit for the last subject in the study.  The Sponsor should also provide the IRB/IEC 
with a summary of the study’s outcome. 
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons 
for the termination/halt should be given. 
5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures 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 (64th WMA 
General Assembly, Fortalenza Brazil, October 2013) 


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• ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of 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 GCP Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies 
conducted within any European Union (EU) country.  All suspected unexpected serious 
adverse reactions (SUSARs) will be reported, as required, to the CAs of all involved EU 
member states. 
• Other applicable regulatory authorities’ requirements or directives. 
5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the investigator must explain to 
each subject (or guardian/legally authorized 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 his/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 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 up to 8 weeks before the first dose of study drug.  No subject can enter the 
study before his/her informed consent has been obtained. 
An unsigned copy of an IRB-approved ICF must be prepared in accordance with ICH E6, 
Section 4, and all applicable local regulations (ie, Title 21 CFR Part 50).  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.   


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6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of 
H3 Biomedicine, Inc. (H3B; the Sponsor), a wholly owned subsidiary of Eisai Co, Ltd. in the 
United States (US) and under the sponsorship of Eisai Co, Ltd. outside the US.  A total of 
approximately 40 investigational site(s) will be activated 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 Study 
Operations Manual provided to each site. 
7 
INTRODUCTION 
Liver cancer is the second leading cause of cancer-mortality and the 16th absolute cause of 
death worldwide (GBD 2013 Mortality and Causes of Death Collaborators, 2015).  The high 
incidence and poor prognosis associated with advanced hepatocellular carcinoma (HCC) 
together with the lack of effective systemic therapies warrant the development of new 
therapies for this indication (Llovet, et al., 2008).  Although there are many studies ongoing, 
sorafenib, a multi-receptor kinase inhibitor, currently is considered the standard of care for 
unresectable HCC in the US, the EU, and multiple countries in the rest of the world 
(Nexavar® US Prescribing Information [USPI], 2015). 
H3B-6527 is an oral, selective, and covalent small molecule inhibitor of fibroblast growth 
factor receptor 4 (FGFR4).  In vitro, H3B-6527 showed >250-fold selectivity towards 
FGFR4 compared to other kinases tested.  FGFR4 and its major activator fibroblast growth 
factor 19 (FGF19), play a critical role in HCC.  Addition of H3B-6527 to 
FGF19-overexpressing HCC cell lines leads to dose-dependent inhibition of FGF19/FGFR4 
signaling and concomitant reduction in the viability of cells.  H3B-6527 dosing in mice leads 
to inhibition of FGF19/FGFR4 signaling and tumor regression in FGF19-overexpressing 
HCC cell line-derived xenografts and HCC patient-derived xenografts.  
These genetic analyses along with preclinical findings support the investigation of H3B-6527 
in patients with advanced HCC.   
This first-in-human study is an open-label, multicenter, Phase 1, dose-finding study that will 
be conducted in 2 parts:  a Dose Escalation Phase and a Dose Expansion phase.  The primary 
objectives are to determine the maximum tolerated dose (MTD) of H3B-6527 and to assess 
the safety and tolerability of H3B-6527 as a single agent in subjects with advanced HCC.  
7.1 
Indication 
Liver cancers occur predominantly in developing regions, most commonly in China, with 
83% of the estimated 782,000 new cancer cases worldwide occurring in developing regions 
in 2012, according to the World Health Organization (WHO).  Liver cancers are more 
common in men than in women, ranking as the fifth most common cancer among men and 
ninth among women.  Globally, liver cancer is the second most common cause of cancer 


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deaths, estimated to be responsible for approximately 746,000 deaths in 2012 (9.1% of the 
total).  Whereas mortality rates have decreased over the past several decades in many cancer 
types, the mortality rates for liver cancers, including bile duct cancers, have doubled over 
that same time period (Llovet, et al., 2015). 
The most common type of primary liver cancer is HCC, accounting for up to 90% of all 
primary liver cancers worldwide (Llovet, et al., 2015).  The main risk factors for liver cancer 
are hepatitis B virus (HBV), hepatitis C virus (HCV), and chronic hepatitis and cirrhosis 
secondary to alcohol use and other causes, with HBV and HCV being the most common 
causes (GBD 2013 Mortality and Causes of Death Collaborators, 2015).   
Most patients with liver cancers are diagnosed at intermediate or advanced disease stages, 
where curative approaches are often not feasible (Llovet, et al., 2015).  For patients with 
advanced disease, treatment options are limited.  Thus, the prognosis for those with advanced 
disease is poor. 
The molecular targeted agent sorafenib, a multireceptor kinase inhibitor, currently is 
considered the standard of care for unresectable HCC in the US, EU, and multiple countries 
in the rest of the world (Nexavar USPI, 2015).  In a Phase 3, double-blind, randomized, 
placebo-controlled clinical study in patients with unresectable HCC, sorafenib was associated 
with significant prolongation of survival versus placebo (median survival 10.7 versus 
7.9 months, respectively; P<0.001) as well as significant prolongation of time to progression 
(5.5 versus 2.8 months, respectively; P <0.001) (Nexavar USPI, 2015).  However, in clinical 
practice, sorafenib demonstrates only modest efficacy and is associated with toxicity in 
patients with HCC (Cheng, et al., 2012). 
Enhanced fibroblast growth factor receptor (FGFR) expression is commonly observed in 
various types of human malignancies (Tiong, et al., 2013).  Signaling through the fibroblast 
growth factor family is involved in fibrosis and its progression to cirrhosis of the liver, which 
is a risk factor for the development of HCC.  Several alterations in FGFR signaling correlate 
with the outcomes of HCC patients, suggesting that signaling through this family of proteins 
contributes to the development or progression of HCC tumors (Cheng, et al., 2012).  The 
main FGFRs expressed in liver tissues are FGFR3 and FGFR4 (Cheng, et al., 2012). 
Recent genomic studies have identified FGF19 as a driver oncogene in HCC.  FGF19 is a 
gut-secreted hormone that acts in the liver through FGFR4 to regulate bile acid synthesis.  
Consistent with the notion that FGF19 is a driver oncogene in HCC, transgenic mice 
overexpressing FGF19 form liver tumors and genetic ablation of FGFR4 prevented tumor 
formation.  These data suggest that targeting HCC, which is dependent on FGFR4 signaling, 
would have therapeutic benefit in patients with altered FGF19 signaling, although tumor 
regression has also been observed in patient-derived xenograft models of HCC with 
undetectable levels of FGF19.  While a number of pan-FGFR inhibitors are being clinically 
evaluated, their application to FGFR4-dependent HCC may be limited by their FGFR1-3-
related dose-limiting toxicities (DLTs). 


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7.1.1 
H3B-6527 
7.1.1.1 
Therapeutic Pathway 
H3B-6527 is a selective FGFR4 inhibitor being developed for the treatment of 
FGF19/FGFR4-driven HCC.  Biochemical selectivity assays showed that H3B-6527 is 
>250-fold more selective towards FGFR4 compared to other kinases tested.  The addition of 
H3B-6527 to FGF19-amplified HCC cell lines led to dose-dependent inhibition of 
FGF19/FGFR4 signaling and concomitant reduction in the viability of cells.  Importantly, 
these effects were only observed in FGF19-altered HCC cell line models.   
H3B-6527 dosing in mice leads to pharmacodynamic modulation and tumor regression in 
FGF19-altered HCC cell line-derived xenografts.  In addition, ongoing preclinical studies in 
HCC patient-derived xenograft mouse models showed that both FGF19-altered (detectable) 
and FGF19-unaltered (undetectable) models respond to H3B-6527.  In particular, significant 
tumor growth inhibition relative to vehicle control was seen with H3B-6527 at oral doses of 
100 and 300 mg/kg twice daily (BID) in the HEP3B xenograft model and at oral doses of 
300 mg/kg and 500 mg/kg BID in the JHH7 model.   
Genetic analyses along with nonclinical study findings support the investigation of 
H3B-6527 in patients with advanced HCC.   
7.1.1.2 
Clinical Experience with H3B-6527 
The current study represents the first clinical investigation of H3B-6527. 
7.1.1.3 
Common Serious Adverse Events Expected to Occur in the Study Population in 
the Absence of Study Drug Exposure 
Common serious adverse events (SAEs) expected to occur in this study population include 
hepatobiliary dysfunction, ascites, gastrointestinal hemorrhage, fatigue, abdominal pain and 
renal failure.  The current study represents the first clinical investigation of H3B-6527; 
therefore, the clinical safety profile of this investigational agent is unknown.  Based on 
nonclinical studies, AEs potentially associated with H3B-6527 may include corneal atrophy, 
hepatocellular hypertrophy, hepatobiliary toxicity, gastrointestinal toxicity, and focal 
mineralization with associated hyperphosphatemia.  Additional details can be found in the 
Investigator’s Brochure. 
7.2 
Study Rationale 
This first-in-human study is an open-label, multicenter, Phase 1, dose-finding study that will 
be conducted in 2 parts:  a Dose Escalation phase (Part 1) and a Dose Expansion phase 
(Part 2).  The primary objectives are to determine the MTD and/or the recommended Phase 2 
dose (RP2D) of H3B-6527 and to assess the safety and tolerability of H3B-6527 as a single 
agent in subjects with advanced HCC. 


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H3B-6527 will be supplied as 50-, 100-, and 200-mg capsules and will be administered orally 
as a single-agent dose in 21-day cycles without a break; this is supported by nonclinical data 
showing tumor growth inhibition and regressions in human HCC xenograft models grown in 
nude mice.  In addition, nonclinical safety evaluations with once daily (QD) dosing in mice 
and dogs have shown evidence of on-target pharmacology (eg, changes in circulating bile 
acid).  The starting dose of 300 mg (first-in-human dose) is the human equivalent dose 
(HED) of 1/6th the highest non-severely toxic dose (HNSTD) in dog.  The maximum single 
dose proposed in the current study is 2000 mg.  It is also limited by the maximum number of 
capsules required to reach this dose. 
The Dose Escalation Phase will follow a standard 3+3 cohort design.  The dose will be 
escalated in successive cohorts based on a modified Fibonacci schema.  The RP2D will be 
selected based on an integrated evaluation of available safety, tolerability, efficacy, 
pharmacokinetic (PK), and pharmacodynamic data for all dose levels on the defined 
schedule.  The following considerations will help guide selection. 
1. The RP2D must have <2/6 subjects experiencing a DLT at that dose (<33% DLT 
rate). 
2. The overall safety profile, including AEs assessed as related to study drug treatment 
but not considered dose-limiting, as well as the nature, type, timing, and frequency of 
toxicities. 
3. Tumor response(s). 
4. Demonstration of proof of principle with respect to in vivo biologic activity.  Mouse 
studies have shown an approximate 100-fold increase in cytochrome P450 
(CYP) 7A1 tumor levels at efficacious doses.  The proof of principle for H3B-6527 
could be a robust increase in CYP7A1 tumor expression in humans. 
Safety, tumor response, PK, and pharmacodynamic assessments will be performed on all 
subjects. 
8 
STUDY OBJECTIVES 
8.1 
Primary Objectives 
The primary objectives of this study are to: 
• Determine the MTD and/or RP2D of H3B-6527 in subjects with advanced HCC 
• Assess the safety and tolerability of H3B-6527 as a single agent administered orally. 


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8.2 
Secondary Objectives 
The secondary objectives of this study are to: 
• Evaluate the PK profile of H3B-6527  
• Evaluate the preliminary antitumor activity of H3B-6527 at the RP2D and schedule in 
subjects with advanced HCC, who are FGF19-positive as determined by the 
Sponsor-designated laboratory. 
8.3 
Exploratory Objectives 
The exploratory objectives of this study are to: 
• Explore biomarkers and their correlation with safety and efficacy endpoints  
• Assess the pharmacodynamic effects of H3B-6527 on FGF19, Ki67, bile acids, and 
other FGFR4-related biomarkers in blood  
• Explore the relationship between PK and pharmacodynamics 
• Exposure to H3B-6527 in tumor samples may be assessed 
• Explore the metabolite profile of H3B-6527 in plasma and urine. 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is an open-label, multicenter, Phase 1 study that will be conducted in 2 parts:  a Dose 
Escalation phase (Part 1) and a Dose Expansion phase (Part 2).  Approximately 30 to 128 
subjects are planned for enrollment.  H3B-6527 will be administered by mouth (PO) in 
21-day cycles without break to examine both QD and BID dose schedules, with flexibility to 
also examine additional alternate dosing schedules (eg, daily for 2 consecutive weeks every 
3 weeks [dosing on Days 1-14 of a 21-day cycle]).   
During both parts of the study, subjects will be administered the study drug with food based 
on the Healthy Volunteers Food-Effect study (Study H3B 6527-A001-001:  A Randomized 
Phase 1 Food-Effect Study of H3B-6527 in Healthy Subjects).  The starting dose of study 
drug when given with food was agreed upon with the Safety Review Committee (SRC) to 
meet the criteria that it be no more than one-half of the previously determined safe total daily 
dose level.  Any additional dose escalation will follow the procedures outlined in 
Section 9.1.1. 
The objective of Part 1, the Dose Escalation phase is to determine the MTD and/or RP2D of 
H3B-6527 in subjects with HCC.  The total number of subjects to be enrolled will depend on 
the observed safety profile, which will determine the number of subjects per dose cohort, as 


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well as the number of dose escalations required to achieve the MTD and/or RP2D of H3B-
6527.   
This study makes provision for exploring a BID schedule of H3B-6527; the criteria to 
evaluate H3B-6527 at the BID dose schedule will be based on an integrated evaluation of 
safety, tolerability, clinical benefit, PK, and pharmacodynamic data, for all QD dose levels 
tested.  In this case, a new cohort of 3 subjects will be enrolled and treated with a BID dose.  
The initial total daily dose given BID will be equal to a total daily dose that has been well 
tolerated as a QD dose (DLT rate <33% in a cohort of 3-6 subjects).   
During Part 2, the Dose Expansion phase, a sample size of 40 subjects per dose schedule will 
be enrolled to examine both QD and/or BID dosing of H3B-6527 based on the recommended 
dose determined from Part 1, the Dose Escalation Phase.  When both dose schedules are 
accruing subjects, an alternating enrollment schema into QD and BID dose schedule will be 
followed.  
Safety, tumor response, PK, and pharmacodynamic assessments will be performed on every 
subject; see Section 9.5 for details. 
 
 
 
Figure 1: Overall Study Design 
BID = twice daily, HCC = hepatocellular carcinoma, QD = once daily. 
Part 1: 
Dose Escalation Phase
H3B-6527 QD dose schedule:
5 treatment cohorts of sequential 
escalating doses of 300, 600, 1000, 
1400, and 2000 mg; 
6 subjects per cohort, 
N=up to 30
H3B-6527 BID dose schedule:
3 treatment cohorts;
total daily starting dose equal to the 
safest total dose in QD dose schedule; 
3 to 6 subjects per cohort, 
N=up to 18
Part 2:
Dose Expansion Phase
HCC FGF19-positive subjects
QD dose schedule
N= 40
HCC FGF19-positive subjects
BID dose schedule
N= 40


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9.1.1 
Study Parts 
9.1.1.1 
Dose Escalation (Part 1) 
The objective of Part 1, the Dose Escalation phase, is to determine the MTD/RP2D of 
H3B-6527 in subjects with advanced HCC.  The selection of the RP2D will be based on an 
integrated evaluation of safety, tolerability, and clinical benefit, including PK and 
pharmacodynamic data.  The total number of subjects to be enrolled will depend on the 
observed safety profile, which will determine the number of subjects per dose cohort, as well 
as the number of dose escalations required to achieve the MTD and/or RP2D of H3B-6527.  
Assuming 5 dose levels will be studied for the QD dose schedule and 3 dose levels for the 
BID dose schedule and a maximum of 6 subjects will be enrolled per dose level, 
approximately 30 to 48 subjects may be accrued during dose escalation.  Subjects enrolled 
into Part 1, Dose Escalation phase, are not required to be FGF19-positive.  
The criteria to evaluate at the BID dose schedule will be based on an integrated evaluation of 
safety, tolerability, clinical benefit, PK, and pharmacodynamic data, for all QD dose levels 
tested.  In this case, a new cohort of 3 subjects will be enrolled and treated with a BID dose.  
The initial total daily dose given BID will be equal to a total daily dose that has been well 
tolerated as a QD dose (DLT rate <33% in a cohort of at least 3 subjects).  If BID dosing of 
H3B-6527 is well tolerated in this initial cohort, then dose escalation may continue with BID 
dosing, following the same dose escalation rules applied to QD dosing.  Additional cohorts of 
subjects may be enrolled to evaluate a less frequent dosing schedule (eg, daily for 
2 consecutive weeks every 3 weeks [dosing on Days 1-14 of a 21-day cycle]).   
Due to the potential for dropouts during the first cycle of treatment (eg, because of early 
disease progression), a cohort may initially be expanded to include up to 2 additional 
subjects.  However, if these additional subjects are to be enrolled, they must start treatment 
≤14 days after the third subject enrolled in the cohort was first dosed with H3B-6527.  The 
decision to dose escalate may still be made after the third subject enrolled to the dose level in 
question has completed the first cycle of treatment.  However, if under these circumstances 
the decision is made to enroll subjects to a higher dose level, and one of the additional 
subjects treated at the preceding dose level experiences a DLT in the first cycle of treatment, 
then further enrollment of subjects to the higher dose level will be suspended until it can be 
determined whether the preceding dose level exceeds the MTD.  In the meantime, subjects 
enrolled to the higher dose level may continue treatment at that dose if they are tolerating it 
well, and if continuing treatment is considered appropriate for the toxicity in question. 
For dose escalation purposes, toxicities assigned as DLTs during the first cycle will be 
assessed.  After 3-6 subjects in a cohort have completed Cycle (C) 1, all available safety data 
will be reviewed by the SRC, consisting of Sponsor personnel and investigators, and the 
decision to proceed to the next dose cohort will be made jointly.  If different dose schedules 
are explored, decisions regarding dose escalation will be made based on review of data from 
subjects enrolled in cohorts on the same schedule, however, safety data from alternate 
schedules may be considered by the SRC.  Toxicities will be graded using the National 
Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. 


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Once a subject has completed C3 at the initially assigned dose schedule and dose level (QD 
or BID), intrapatient dose escalation will be allowed.  Only subjects who have not progressed 
on treatment and did not have a dose reduction or interruption because of a drug-related AE, 
will be permitted to escalate to the highest dose level that has completed DLT assessment 
within that dose schedule and has been shown to be safe (no DLT in the first 3 subjects or no 
more than 1 DLT in 6 subjects).  Subjects on the intrapatient dose escalation will not be 
included in the DLT analysis at the higher dose level.  The investigator and the medical 
monitor must agree that dose escalation is appropriate for the subject prior to escalating their 
H3B-6527 dose level.   
The starting dose of 300 mg QD (first-in-human dose) is the HED of 1/6th the HNSTD in 
dog.  Dose escalation will follow a modified Fibonacci design such that the magnitude of the 
escalation will decrease as the dose level nears the HED of the HNSTD in dogs 
(HED ≈ 2000 mg). 
 
Table 1 
Dose Cohorts in H3B-6527 Dose-Escalation 
Dose Level 
Initial No. of Subjects 
H3B-6527 Total Daily Dose 
-1 
3 
150 mg 
  1a 
3 
300 mg  
2 
3 
600 mg  
3 
3 
1000 mg 
4 
3 
1400 mg  
5 
3 
2000 mg  
These total daily dose levels may be evaluated in QD or BID dose schedules, including intermediate dose 
levels, and in expansion of an existing dose level of up to 12 evaluable subjects following discussions 
between the Sponsor and the investigators, if supported by evolving safety, tolerability, PK, and 
pharmacodynamic data. 
BID = twice daily, PK = pharmacokinetic, QD = once daily. 
a:  Planned starting dose level in QD schedule. 
 
Refer to Section 9.4.4.1 for details regarding the dose-escalation procedure. 
The MTD is defined as the highest dose at which no more than 1 of 6 subjects experiences a 
DLT in the dose cohort.  (Note that at least 6 subjects must be treated at the dose level 
potentially considered to be the MTD before that dose level can be considered the MTD).  
Therefore, if ≥2 subjects within a cohort experience a DLT and the previous dose level did 
not enroll 6 subjects, enrollment will move down to the previous dose level and continue 
until 6 subjects are enrolled, and the same guidelines for determining the MTD will be 
followed. 
The RP2D may not exceed the MTD and will be agreed upon by the SRC, based on an 
integrated evaluation of safety, tolerability, clinical benefit, PK, and pharmacodynamic data, 
for all dose levels tested.  Clinically significant toxicities (eg, chronic Grade 2 toxicities) or 
AEs that meet the definition of dose limiting but occurring after C1 (dose-modifying events, 


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DME) may be considered when determining the RP2D.  Once the MTD/RP2D is reached, at 
least 6 HCC subjects must be enrolled at the RP2D (regardless of the total number of subjects 
enrolled at that dose level) to proceed with dose expansion. 
To be evaluable for a DLT, subjects must have completed safety assessments through 
predose on C2 Day 1 and must have received at least 17 of 21 (approximately 80%) study 
days within C1, unless due to a DLT.  Subjects who discontinue from the study for reasons 
other than DLT before completing C1 are to be replaced.  Subjects who experience toxicities 
meeting DLT criteria during C1 will be discontinued from treatment.  In rare cases, an 
exemption to study discontinuation for a DLT in 1st cycle may be considered after discussion 
between the treating physician, Sponsor and study medical monitor.  Subjects who 
experience toxicities meeting DLT criteria may, at the discretion of the investigator and after 
discussion with the Sponsor, be allowed to continue study drug at a reduced dose if this is 
judged to be in the best clinical interest of the subject.  The Sponsor will communicate 
information about DLTs or safety concerns rapidly to all sites as per the separate Dose 
Escalation Plan, which also details the format and timelines of the Dose Escalation review 
meetings, and the communication of dose level decisions to all sites. 
9.1.1.1.1 
DEFINITION OF DOSE-LIMITING TOXICITIES OR DOSE-MODIFYING EVENTS 
DLTs are defined as any of the toxicities listed in Table 2 occurring during C1 Phase 1 only 
and judged by the investigator as related to study drug (ie, assessed as unrelated to disease, 
intercurrent illness, or concomitant medications).  Any event that occurs in C2 or beyond 
(including any cycle in Phase 2) will be considered a DME. 
Table 2 
Definition of Dose-Limiting Toxicity (Cycle 1 Phase 1 Only) or 
Dose-Modifying Event (Cycle 2 or Beyond and Any Cycle in 
Phase 2) 
TOXICITY 
CRITERIA 
Hematology 
• 
Febrile neutropenia  
• 
CTCAE Grade 4 neutropenia that does not resolve to Grade ≤2 within 7 days  
• 
CTCAE Grade 3 thrombocytopenia requiring transfusion 
• 
CTCAE Grade 3 thrombocytopenia and clinically significant bleeding  
• 
CTCAE Grade 4 thrombocytopenia 
• 
CTCAE Grade 3 anemia if transfused or if lasting for more than 7 days 
• 
CTCAE Grade 4 anemia of any duration 
Gastrointestinal 
• 
CTCAE Grade 3 nausea, vomiting and/or diarrhea lasting more than 72 hours 
despite the use of optimal anti-emetic/antidiarrheal treatment 
• 
CTCAE Grade 4 diarrhea and/or vomiting irrespective of prophylaxis or 
appropriate treatment 
Renal 
• 
CTCAE Grade ≥3 serum creatinine  
Hepatic 
• 
CTCAE Grade 3 bilirubin (>3.0 × ULN) and/or AST/ALT ≥10 × ULN  
• 
For subjects with a starting AST/ALT within the normal range for the local 
laboratory, an elevation AST/ALT ≥ 5 × ULN for the local laboratory 


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Table 2 
Definition of Dose-Limiting Toxicity (Cycle 1 Phase 1 Only) or 
Dose-Modifying Event (Cycle 2 or Beyond and Any Cycle in 
Phase 2) 
TOXICITY 
CRITERIA 
• 
For subjects with an abnormal value ≥ ULN at baseline based on the local 
laboratory ranges, an AST/ALT elevation ≥ 10 × ULN for the local laboratory 
Other AEs not listed 
above 
• 
Nonhematologic toxicities of CTCAE Grade ≥3 except for the following: 
- 
CTCAE Grade 3 fatigue lasting less than 1 week  
- 
Isolated CTCAE Grade 3 elevations in biochemistry laboratory values 
without associated clinical symptoms that last for ≤7 days.  This includes 
electrolyte abnormalities that respond to medical intervention. 
• 
H3B-6527-related, CTCAE Grade 2 nonhematologic toxicities that, in the 
opinion of the treating investigator, require a dose reduction or discontinuation 
of study drug, or lead to a failure to complete at least 17 days of study drug 
administration in C1, may be deemed dose-limiting if agreed upon by the 
participating investigator and the Sponsor. 
AE = adverse event, ALT = alanine aminotransferase, AST = aspartate aminotransferase, C = Cycle, CTCAE 
= Common Terminology Criteria for Adverse Events, ULN = upper limit of normal. 
 
As described in Table 2, any subject with an increase in alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) to ≥2 × the baseline value or with a bilirubin level of 
>3 × the upper limit of normal (ULN) must have repeat testing 1 week later.  If either the ALT 
or bilirubin level increase further, testing will be repeated at 1-week intervals until the values 
return to baseline levels. 
The only instance in which the AST/ALT and/or bilirubin changes will not be considered a 
DLT is if there is unequivocal evidence that these increases are due to progression of the 
underlying disease or the intrahepatic malignancy.  In these cases, determination of a non-
DLT event will be made jointly by the Sponsor and the investigator(s). 
For any dose-limiting hepatic toxicity that does not return to baseline within 7 days, an 
abdominal computed tomography (CT) scan must be performed to assess whether it is related 
to disease progression. 
9.1.1.2 
Expansion (Part 2) 
Prior to starting Part 2 of the study, the investigators and the Sponsor will use safety, 
efficacy, PK, and pharmacodynamic data obtained during the Dose Escalation Phase, as well 
as clinical judgement, to jointly determine the dose schedules to be studied.  
During Part 2, the Dose Expansion phase, approximately 40 subjects per dose schedule will 
be enrolled to examine QD and/or BID dose schedules.  Subjects enrolled into Part 2, Dose 
Expansion phase, must be FGF19-positive as defined by Sponsor-designated laboratory.   
Part 2 of the study is designed to better characterize the safety, tolerability and preliminary 
antitumor activity of the study drug when provided at the RP2D and schedule.  For a 
reference of the precision of objective response rate (ORR) estimates, the associated 2-sided 
95% CIs for ORR up to 30% for 40 subjects is provided.  See Section 9.7.2 for additional 


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information.  When both dose schedules are accruing subjects, an alternating enrollment 
schema into QD and BID dose schedule will be followed. 
9.1.2 
Study Phases 
The study will be conducted in the following 4 phases:  Pretreatment Phase, Treatment 
Phase, Extension Phase, and Follow-up Phase. 
9.1.2.1 
Pretreatment Phase 
This pretreatment phase will last no longer than 28 days and includes: 
• A Screening Period to establish protocol eligibility. 
• A Baseline Period to establish disease characteristics before treatment. 
9.1.2.2 
Treatment Phase 
The Treatment Phase will last for 1 treatment cycle of 21 days.   
Subjects who are receiving study drug at the end of the Treatment Phase will continue to 
receive study drug in the Extension Phase (see Section 9.1.2.3). 
9.1.2.3 
Extension Phase  
In the Extension Phase, subjects will continue to receive the same treatment and dose they 
received during the Treatment Phase, provided termination criteria are not met.   
In both the Treatment and Extension Phases, subjects will discontinue study drug at the time 
of progressive disease (PD), development of unacceptable toxicity, withdrawal of consent, or 
termination of the study program by the Sponsor.  However, subjects may continue to receive 
study treatment, as long as there is demonstrated clinical benefit, as judged by the 
investigator after discussion with the Sponsor, or until the end of the study.  Disease 
progression will be determined by the investigator following relevant modified Response 
Evaluation Criteria in Solid Tumors (mRECIST) guidelines.  The mRECIST for this protocol 
harmonizes the original mRECIST criteria (Lencioni and Llovet 2010) using triphasic liver 
CT/magnetic resonance imaging (MRI; optimized for precontrast, arterial phase, and portal 
venous phase) and elements of Response Evaluation Criteria in Solid Tumors, Version 1.1 
(Eisenhauer, et al., 2009). 
9.1.2.4 
Follow-Up Phase 
After the Off-treatment Visit (OTV), all subjects who discontinue study treatment, regardless 
of their reasons for doing so, will be followed for survival via telephone (for those subjects 
who experience PD or initiate a new anticancer therapy) or office visit (for those subjects still 
undergoing tumor assessments).  Subjects will be followed for survival approximately every 
12 weeks for up to 12 months or until 6 cycles after last patient in, death, loss to follow-up, 
or withdrawal of consent, whichever occurs first.  Subjects who discontinue study drug and 


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have not experienced PD will continue to undergo tumor assessments every 6 weeks until 
documented PD or another anticancer therapy is initiated.   
The data cutoff for the primary analysis will occur once the last subject completes 6 cycles of 
investigational therapy. Subjects will be allowed to continue treatment until progression or 
the end of therapeutic benefit from the study drug as determined by Sponsor discussion with 
investigator.  
The end of the study is defined as when the last ongoing subject completes their off treatment 
visit.  The off treatment visit should occur 30 days after final dose with a window of ±3 days.  
The maximum estimated period for each subject on treatment is anticipated to be 
approximately 4 months.  However, subjects may continue to receive study treatment, as long 
as they demonstrate clinical benefit as judged by the investigator after discussion with the 
Sponsor or until the end of the study. 
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 pharmacodynamic effects 
(Ahn, 1998; ICH E8, 1997; Gatsonis and Greenhouse, 1992; Dillman and Koziol, 1992); 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, a traditional 3+3 dose escalation design will 
be used.  The dose escalation scheme to be followed is based on a modified Fibonacci 
sequence schema, which is commonly employed in Phase 1 dose-finding oncology studies 
(Storer, 1989).  An integrated evaluation of safety, tolerability, PK, and pharmacodynamic 
data will be utilized to select the RP2D dose schedule to be employed during 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 H3B-6527.  After identification of 
the MTD, the potential antitumor activity of H3B-6527 will be evaluated in Part 2, the 
Expansion phase, to determine whether there are any tolerability issues or antitumor activity 
associated with the use of H3B-6527 in subjects with HCC. 
It is recommended that the effect of food intake on the rate and extent of absorption of an 
orally administered investigational drug be investigated as early as possible during drug 
development to optimize dose finding and to ensure optimal food recommendations for study 
drug administration.  The decision was made to allow study drug administration in 
conjunction with a meal, and this was informed by the Healthy Volunteers Food-Effect study 
(H3B-6527-A001-001).  The starting dose of study drug when given with food was agreed 
upon with the SRC to meet the criteria that it be no more than one-half of the previously 


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determined safe total daily dose level.  Any additional dose escalation will follow the 
procedures outlined in Section 9.1.1. 
Since the study drug is to be administered with food, all subjects will be required to fast 
2 hours prior to pharmacodynamic assessments and have a meal prior to or in conjunction 
with study drug administration.  
9.3 
Selection of Study Population 
Approximately 30 to 128 subjects are planned to be enrolled in this study:  30 to 48 during 
Part 1, the Dose Escalation phase, and up to 80 subjects in the Expansion phase (40 subjects 
per dose schedule).  The total number of subjects to be enrolled in the Dose Escalation phase 
will be dependent upon the observed safety profile, which will determine the number of 
subjects per dose cohort, as well as the number of dose escalations required to achieve the 
MTD of H3B-6527 and establish the RP2D.  The total number of subjects in the Dose 
Expansion Phase will be dependent on whether data collected during the Dose Escalation 
Phase of the study can clearly differentiate between one dosing schedule (QD or BID) or 
whether both schedules will continue being evaluated during the Dose Expansion phase.  
Subjects who do not meet all the inclusion criteria or who meet any of the exclusion criteria 
will not be eligible for enrollment in the study. 
9.3.1 
Inclusion Criteria 
In order to be eligible for participation in this study, subject must: 
1. Be ≥18 years of age. 
2. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 
3. Have an HCC diagnosis with the following criteria: 
• Confirmed by available pathology records or current biopsy (confirmed diagnosis 
may be made by histological examination or by noninvasive criteria according to the 
European Association for the Study of the Liver or the American Association for the 
Study of Liver Disease Guidelines) 
• Advanced, unresectable, or recurrent 
• Progressing since the last antitumor therapy 
• Child-Pugh A classification 
• No clinically significant ascites 
• Must have received at least one prior standard-of-care therapy, unless contraindicated. 
4. Must be FGF19-positive, as determined by a Sponsor-designated laboratory from a fresh 
tumor sample prior to enrollment in the Dose Expansion phase.  
5. Have completed any prior chemotherapy, monoclonal antibody or immunotherapy (eg, 
tumor vaccine, cytokine, or growth factor given to control the cancer) at least 4 weeks or 


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5 half-lives (whichever is shorter) before study drug administration, and all AEs must 
have either returned to Baseline or resolved to Grade 0 or 1. 
6. Have completed any prior definitive radiation therapy at least 3 weeks before study drug 
administration; any prior focal radiotherapy at least 2 weeks before study drug 
administration; and irradiated lesions should show evidence of size increase as defined in 
inclusion criterion #7 if they are intended to be followed as target lesions; any 
radiopharmaceutical therapy (strontium, samarium, and yttrium) must have been 
completed 8 weeks before study drug administration. 
7. Have tumor tissue available as follows: 
a. Part 1, Dose Escalation:  Tumor tissue (screening acquisition or archival tissue if 
available) is requested but not mandated. 
b. Part 2, Dose Expansion:  Fresh tumor tissue must be available (collected up to 
8 weeks before administration of H3B-6527 on C1 Day 1).  Archival tissue if 
available is requested but not mandated. 
8. Have measurable disease as follows:  
a. Part 1, Dose Escalation:  Subjects may have measurable or nonmeasurable disease as 
defined by mRECIST.   
b. Part 2, Expansion:  Subjects must have measurable disease meeting the following 
criteria: 
 i. Subjects with HCC:  At least 1 measurable target lesion according to 
mRECIST that meets the following criteria: 
• Hepatic lesion 
- The lesion can be accurately measured in at least one dimension as ≥1.0 cm 
- The lesion is suitable for repeat measurement 
- The lesion shows intratumoral arterial phase enhancement on 
contrast-enhanced CT or MRI 
• Nonhepatic lesion 
- Lymph node lesion that measures at least one dimension as ≥1.5 cm in the 
short axis, except for porta hepatis lymph node that measures ≥2.0 cm in the 
short axis 
- Non-nodal lesion that measures ≥1.0 cm in the longest diameter 
Lesions previously treated with radiotherapy or locoregional therapy must show 
radiographic evidence of disease progression by mRECIST to be deemed a target 
lesion. 
9. Have left ventricular ejection fraction >50% on echocardiography or multiple-gate 
acquisition (MUGA) scan. 
10. Have adequate renal function defined as serum creatinine <1.5 × ULN (or calculated 
creatinine clearance ≥50 mL/min per the Cockcroft and Gault formula). 
11. Have adequate bone marrow function including: 


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a. Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5 × 109/L) 
b. Platelet counts ≥75,000/mm3 (≥75 × 109/L) 
c. Hemoglobin ≥9.0 g/dL (may have been transfused) 
12. Have adequate liver function including:  
a. Adequate blood coagulation as evidenced by an International Normalized Ratio ≤1.5. 
b. Total bilirubin ≤1.5 × ULN. 
c. ALT and AST ≤5 × ULN. 
d. No evidence of biliary duct obstruction unless obstruction controlled by local 
treatment or, the biliary tree can be decompressed by endoscopic or percutaneous 
stenting with subsequent reduction in bilirubin to ≤1.5 × ULN. 
13. Females must not be lactating or pregnant at Screening or Baseline (as documented by a 
negative beta-human chorionic gonadotropin [ß-hCG] test with a minimum sensitivity of 
25 IU/L or equivalent units of ß-hCG).  A separate baseline assessment is required if a 
negative screening pregnancy test was obtained more than 72 hours before the first dose 
of study drug. 
NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group and without other known or suspected cause) or have been sterilized surgically (ie, 
bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at 
least 1 month before dosing). 
14. Females of childbearing potential should avoid becoming pregnant and use highly 
effective contraception while on treatment and for at least 1 month after finishing 
treatment.  Females of childbearing potential must not have had unprotected sexual 
intercourse within 30 days before study entry and must agree to use a highly effective 
method of contraception (eg, sexual abstinence, an intrauterine device, a contraceptive 
implant, an oral contraceptive, or have a vasectomized partner with confirmed 
azoospermia) throughout the entire study period and for 30 days after study drug 
discontinuation.  Sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatment.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the subject.  Periodic abstinence (calendar, symptothermal, and post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method are not acceptable methods of contraception.  Female condom and male condom 
should not be used together.  Females who are using hormonal contraceptives must have 
been on a stable dose of the same hormonal contraceptive product for at least 4 weeks 
before dosing and must continue to use the same contraceptive during the study and for 
30 days after study drug discontinuation.  Women using oral hormonal contraceptives 
should add a barrier method. 
15. Be willing and able to comply with all aspects of the protocol. 


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16. Provide written informed consent prior to any study-specific Screening procedures. 
 
9.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Other malignancy active within the previous 2 years except for basal or squamous cell 
skin cancer, stage 1 prostate cancer, superficial bladder cancer, or carcinoma in situ of the 
cervix or breast that has completed curative therapy. 
2. Current evidence of corneal disorder/keratopathy including but not limited to corneal 
epithelial thinning, bullous/band keratopathy, corneal abrasion, inflammation/ulceration, 
or keratoconjunctivitis (to be confirmed by ophthalmological examination).  Pre-existing 
cataract is not a reason for exclusion. 
3. Brain or subdural metastases are not eligible, unless they have completed local therapy 
and have discontinued the use of corticosteroids for this indication 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. 
4. Genetic diseases of the liver that may complicate review of safety data. 
5. Known human immunodeficiency virus infection. 
6. Uncontrolled significant active infections, except HBV or HCV.  Subjects with HBV are 
eligible, but should be taking appropriate antiviral medication if indicated.  Subjects with 
HCV are eligible but must not be taking any concomitant treatment for HCV while 
receiving H3B-6527.   
7. Major surgery or other locoregional treatment within 4 weeks before the first dose of 
study drug or radionuclide treatment (eg, 90Yttrium intra-arterial treatment) within 
8 weeks before the first dose of drug administration. 
8. 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-6527.  Subjects with prior gastric resection are eligible. 
9. Use of any drug that is a strong inhibitor or inducer of the CYP3A4 enzyme or the 
P-glycoprotein transporter within at least 2 weeks before the start of study drug and 
during the conduct of the study unless there is an emergent or life-threatening medical 
condition that requires it. 
10. Use of any drug known to prolong corrected QT (QTc) interval within at least 2 weeks 
before the start of the study drug and during the conduct of the study. 
11. Treatment with proton pump inhibitors that cannot be discontinued 3 days prior to the 
start of study drug and during the course of the study; antacids are permitted except for 
calcium carbonate antacids (eg, Tums®).   
12. Use of other investigational drugs within 28 days or at least 5 half-lives (whichever is 
shorter) before study drug administration. 
13. Previous treatment with a selective FGF19-FGFR4 targeted therapy. 


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14. Use of any live vaccines against infectious diseases (eg, influenza, varicella) within 4 
weeks (28 days) of initiation of study therapy. 
15. Presence of gastric or esophageal varices requiring active treatment.   
16. A clinically significant electrocardiogram (ECG) abnormality, including a marked 
baseline prolonged QTc interval (eg, a repeated demonstration of a QTc interval 
>450 ms). 
17. Significant cardiovascular impairment:  history of congestive heart failure greater than 
New York Heart Association Class II, uncontrolled arterial hypertension, unstable 
angina, myocardial infarction, or stroke within 6 months of the first dose of study drug; 
or cardiac arrhythmia requiring medical treatment (including oral anticoagulation). 
18. Any other major illness, medical condition, or concomitant medication that, in the 
Investigator’s judgment, will substantially increase the risk associated with the subject’s 
participation in this study or would compromise the subject’s ability to safely complete 
the study. 
19. Males who have not had a successful vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
practicing highly effective contraception throughout the study period or for 90 days after 
study drug discontinuation).  No sperm donation is allowed during the study period or for 
90 days after study drug discontinuation  
20. Hypersensitivity to the study drug or to any of the excipients. 
21. Intolerance or hypersensitivity to both CT and MRI contrast material that would preclude 
the ability to acquire the triphasic liver imaging required by the protocol. 
22. Inorganic phosphorus > ULN for the institution.  Note:  Subjects may be on treatment for 
hyperphosphatemia, but the levels must be normal at screening to participate in this 
study.  Subjects with high levels on screening may subsequently be treated and 
rescreened and, should they have stable levels for 2 weeks prior to study, may enter the 
study. 
23. Total or ionized serum calcium > ULN for the institution.  Note:  Subjects may be on 
treatment for hypercalcemia, but the levels must be normal at screening to participate in 
this study.  Subjects with high levels on screening may subsequently be treated and 
rescreened and, should they have stable levels for 2 weeks prior to study, may enter the 
study. 
24. Endocrine changes that may result in increases in calcium or phosphate, including, but 
not limited to, hyperparathyroidism and tumoral calcinosis. 
25. Past medical history and/or current evidence of tumoral calcinosis or tissue calcification. 
26. Use of calcium or vitamin D supplements or systemic corticosteroids.  The duration 
between the last systemic corticosteroid administration and the first dose of study drug 
should be at least 2 weeks. 
27. Hereditary problems of galactose intolerance, the Lapp lactase deficiency, or 
glucose-galactose malabsorption. 
 


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9.4 
Treatments 
9.4.1 
Treatments Administered 
All subjects will receive H3B-6527 at their assigned dose daily PO.  For the purposes of this 
study, a cycle length is defined as 21 days. 
9.4.2 
Guidelines for Continuation of Treatment 
Study drug should continue to be administered as planned unless a DLT has occurred.  
Subjects who experience a DLT during C1 will be discontinued from treatment.  In rare 
cases, an exemption to study discontinuation for a DLT in 1st cycle may be considered after 
discussion between the treating physician, Sponsor and study medical monitor.  If a subject 
should experience a DLT or DME (ie, an AE meeting the criteria for a DLT but occurring 
after C1) during the study then study treatment will be interrupted and subjects may, at the 
discretion of the investigator, and after discussion with the Sponsor, be allowed to continue 
study drug at a reduced dose, if the following criteria are met: 
• ANC ≥1.0 × 109/L (1,000/mm3) 
• Platelet count ≥75 × 109/L (75,000/mm3) 
• All other nonhematologic treatment-related toxicities are Grade 0 or 1 (except alopecia) 
or return to baseline level 
• Clinical benefit is being received, and  
• Evidence of an otherwise favorable risk/benefit profile.  
The magnitude of the dose reduction cannot be specified a priori since the actual doses 
evaluated and the dose-toxicity relationship will not be known until there is clinical 
experience with H3B-6527; however, a minimum reduction of 33% must be taken.  The dose 
chosen will require discussion and agreement between the investigator and Sponsor 
following review of the relevant clinical data. 
Dose reductions are allowed for all subjects.  However, once the H3B-6527 dose has been 
reduced for a given subject, no re-escalation will be permitted for that subject.  
A maximum of 2 dose reductions will be allowed as needed, but study treatment should not 
be resumed in the case of the following treatment-related events: 
• Occurrence of a DLT in C1 except upon agreement with investigator, Sponsor and 
medical monitor.  A dose reduction must be taken if treatment is resumed. 
• CTCAE Grade 3 or 4 cardiac event 
• Nonhematologic events of Grade 4 severity 
• Dose delay of ≥21 days for a treatment-related event in C2 and beyond. 
 


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9.4.3 
Identity of Investigational Product 
H3B-6527 drug product for clinical studies is supplied as Swedish orange, opaque, 
hypromellose shell capsules, size 4 containing 50 mg, size 2 containing 100 mg, or size 0 
containing 200 mg of H3B-6527 drug substance.  The composition ratio of the capsule 
content is the same for the 3 strengths. 
H3B-6527 capsules (28) are packaged in a 50-mL high-density polyethylene bottle with 2 g 
of desiccant and closed with a polypropylene screw cap. 
9.4.3.1 
Chemical Name, Structural Formula of H3B-6527 
Test drug code: 
H3B-6527 
Generic name: 
Not assigned 
Chemical name: 
N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-
methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-1-
yl)phenyl)acrylamide 
Molecular formula: C29H34Cl2N8O4 
Molecular weight: 629.54 
Structural formula: The structural formula is as follows: 
 
9.4.3.2 
Comparator Drug 
Not applicable. 
9.4.3.3 
Labeling for Study Drug 
H3B-6527 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.  Study drug labels will not bear any statement that is false or misleading in any 
NH
H
N
N
N
N
N
Me
H
N
O
Cl
Cl
OMe
OMe
N
Me
O
Chemical Formula: C29H34Cl2N8O4
Molecular Weight: 629.54


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manner or represents that the study drug is safe or effective for the purposes for which it is 
being investigated. 
9.4.3.4 
Storage Conditions 
Study drug will be stored in accordance with the labeled storage conditions.  At the study 
center, study drug is to be stored refrigerated at 2-8°C.   
Subjects will be instructed to store study drug at home according to the storage requirements 
listed on the drug supply label.  
While at the study center and at home, the study participants will be instructed to take 
capsules immediately after removal from refrigerated conditions, in order to limit the time 
out of the required storage conditions. 
9.4.4 
Method of Assigning Subjects to Treatment Groups 
The dose level to which a subject is assigned is dependent on the study part and cohort into 
which the subject is enrolled. 
9.4.4.1 
Dose Escalation Scheme (Part 1) 
The starting dose of H3B-6527 is 300 mg QD. 
H3B-6527 doses will be escalated sequentially after the SRC, with appropriate representation 
from the Sponsor and participating investigators, reviews safety data collected during C1 
from the subject(s) enrolled at the current dose level. 
Subjects who do not receive study drug for at least 17 of 21 days (approximately 80%; not 
necessarily consecutively) during the first cycle for reasons not considered to be a DLT by 
both the investigators and the Sponsor will be replaced.  The subjects who are replaced will 
not be considered evaluable for DLT assessments. 
Based on the interim evaluation of the safety and tolerability data of the previous dose level, 
the Sponsor may decide to initiate accrual at an intermediate dose level.  The SRC may be 
convened earlier at the discretion of the Sponsor if important safety issues arise requiring the 
attention of the committee.   
Up to 3 subjects initially are to be enrolled.  After 3 subjects complete C1 and have safety 
evaluations performed through C2 Day 1, and: 
• None of these 3 subjects experience a DLT (see Section 9.1.1.1.1), then enrollment of 
the next cohort may commence with approval from the SRC. 
• 1 of 3 subjects within a cohort experiences a DLT (see Section 9.1.1.1.1), then up to 
3 additional subjects are to be enrolled sequentially at that dose level.  If none of the 


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additional 3 subjects has a DLT (ie, 1 of 6 subjects has a DLT), then enrollment at the 
next scheduled dose may commence with approval from the SRC. 
• If ≥2 subjects within a cohort experience a DLT (see Section 9.1.1.1.1), then the DLT 
dose level will have been reached and the previous lower dose level will be 
considered the MTD.  Note that at least 6 subjects must be treated at the dose level 
potentially considered to be the MTD before that dose level can definitely be 
considered the MTD.  Therefore, if ≥2 subjects within a cohort experience a DLT and 
the previous dose level did not enroll 6 subjects, enrollment will move down to the 
previous dose level and continue until 6 subjects are enrolled, and the same guidelines 
for determining the MTD will be followed.  
- Once the MTD or RP2D is established, additional subjects will be treated in the 
Expansion phase of the study (Part 2), which is designed to better characterize the 
safety, tolerability and preliminary antitumor activity of the study drug when 
provided at the RP2D and schedule. 
Due to the potential for dropouts during the first cycle of treatment (eg, because of early 
disease progression), a cohort may initially be expanded to include up to 2 additional 
subjects.  However, if these additional subjects are to be enrolled, they must start treatment 
≤14 days after the third subject enrolled in the cohort was first dosed with H3B-6527.  The 
decision to dose escalate may still be made after the third subject enrolled to the dose level in 
question has completed the first cycle of treatment.  However, if under these circumstances 
the decision is made to enroll subjects to a higher dose level, and one of the additional 
subjects treated at the preceding dose level experiences a DLT in the first cycle of treatment, 
then further enrollment of subjects to the higher dose level will be suspended until it can be 
determined whether the preceding dose level exceeds the MTD.  In the meantime, subjects 
enrolled to the higher dose level may continue treatment at that dose if they are tolerating it 
well, and if continuing treatment is considered appropriate for the toxicity in question.  
Although decisions regarding dose escalation will be made based on review of data from C1, 
safety data will also be collected from all subjects continuing treatment and this will be 
reviewed periodically by the SRC.  Any detected cumulative toxicity may require later dose 
reductions or other action as appropriate, including further refinement of the RP2D. 
The dose escalation procedure is summarized in Table 3. 
Table 3 
Summary of Dose Escalation Procedure 
Observed Safety Outcomes  
Action 
Dose Escalation Cohorts (n=3-6 each) 
No DLT 
• 
Escalate to the next planned dose level. 
DLT in 1 of 3 subjects 
• 
Expand cohort up to 6 subjects. 
No additional DLT in 6 subjects 
• 
Escalate to the next planned dose level. 
DLT in ≥2 subjects 
• 
MTD reached; stop dose escalation.   
• 
Possibly explore intermediate doses for the RP2D. 
Note:  DLT is defined in Section 9.1.1.1.1. 
DLT = dose-limiting toxicity, MTD = maximum tolerated dose, RP2D = recommended Phase 2 dose. 


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If PK, pharmacodynamic, or safety data for H3B-6527 suggest that it may be preferable to 
administer H3B-6527 BID rather than QD, then the dose escalation procedure may be 
repeated for BID dosing.  In this event, a new cohort of 3 subjects will be enrolled and 
treated with a BID dose; the initial total daily dose given BID will be equal to a total daily 
dose that has been well tolerated as a QD dose (DLT rate <33% in a cohort of 3-6 subjects).  
If BID administration of H3B-6527 is well tolerated in this initial cohort, then dose 
escalation may continue with BID dosing, following the same dose escalation rules applied to 
QD administration.   
Furthermore, additional cohorts of subjects may be enrolled to evaluate a less frequent dosing 
schedule (eg, daily for 2 consecutive weeks every 3 weeks [dosing on Day -14 of a 21-day 
cycle]).   
9.4.4.2 
Expansion (Part 2) 
In the Dose Expansion Phase, all subjects will receive H3B-6527 at the MTD or RP2D for a 
specific schedule as identified in the Dose Escalation Phase of the study. 
9.4.5 
Selection of Doses in the Study 
The starting dose of H3B-6527, 300 mg (first-in-human dose), is the HED of 1/6th the 
HNSTD in dog.  Dose escalation will follow a modified Fibonacci design such that the 
magnitude of the escalation will decrease as the dose level approaches the HED of the 
HNSTD in dogs (HED ≈2000 mg). 
9.4.6 
Selection and Timing of Dose for Each Subject 
H3B-6527 will be supplied as 50-, 100-, and 200-mg capsules.  The starting dose will be 
300 mg/day PO, with escalation of total daily doses in successive cohorts to a maximum 
planned dose of 2000 mg (see Section 9.1.1.1).   
During Parts 1 and 2, subjects will be instructed to take the dose in conjunction with a meal 
at approximately the same time each day (see Section 9.2).   
Capsules should be swallowed whole.  Dosing should not be repeated if a subject vomits.  
For subjects on a QD schedule, a dose missed by >8 hours should be skipped.  For subjects 
on a BID schedule a dose missed by >4 hours should be skipped. 
9.4.7 
Blinding 
The study will not be blinded. 
9.4.8 
Prior and Concomitant Therapy 
Any medication (including over-the-counter medications) or therapy administered to the 
subject during the study (starting at the date of informed consent) will be recorded on the 
Prior & Concomitant Medication Case Report Form (CRF) or Non-Pharmacological 


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Procedures CRF.  The investigator will record on the Adverse Event CRF any AE for which 
the concomitant medication/therapy was administered.   
9.4.8.1 
Prohibited Concomitant Therapy and Procedures 
The following therapies and procedures are prohibited during study participation: 
• Other investigational drugs. 
• Other antitumor therapies such as chemotherapy, surgical resection, or antitumor 
immunotherapy. 
• Proton pump inhibitors. 
• Radiotherapy for central metastases (eg, vertebral, mediastinal) will not be allowed; 
the need for such radiotherapy while on study will be seen as an indication of disease 
progression and the subject should be withdrawn from therapy.  However, palliative 
radiotherapy for up to 2 local peripheral metastases not being used as target lesions is 
allowed but the need for such therapy may be an indication of PD and should be 
discussed with the Sponsor prior to implementation.   
• Drugs that are strong inhibitors or inducers of CYP3A4 enzyme (see list in Table 4) 
or P-glycoprotein transporter. 
• Drugs that raise serum calcium and phosphorus levels (eg, vitamin D supplements, 
calcium dietary supplements, calcium antacids) or systemic corticosteroids.  The 
duration between the last systemic corticosteroid administration and the first dose of 
study drug should be at least 2 weeks.  If a short-term course of systemic 
corticosteroids is required while on treatment, then study drug must be held while the 
subject receives systemic corticosteroid treatment.  If the subject has not progressed 
in the interim, resumption of treatment with H3B-6527 may be considered following 
discontinuation of steroid treatment and a 2-week washout period. 
 
Table 4 
Inducers and Strong Inhibitors of CYP3A4 
INDUCERS 
Carbamazepine, efavirenz, nevirapine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. 
John’s Wort, troglitazone 
STRONG INHIBITORS 
Indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone 
Source:  Indiana University Department of Medicine.  http://medicine.iupui.edu/clinpharm/ddis/clinical-
table Accessed September 7, 2016 
 


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9.4.8.2 
Permitted Concomitant Therapy and Procedures 
Medications and treatments other than those specified in Section 9.4.8.1, including palliative 
and supportive care for disease-related symptoms, are permitted during the study.  Subjects 
should be closely monitored, and treatment is to be instituted for disease-related symptoms, 
as appropriate. 
• Growth Factors:  Subjects receiving recombinant erythropoietin or darbepoietin-α 
prior to study start may continue to receive pretreatment doses.  Following initiation 
of study treatment, the use of erythropoietic and granulocyte growth factors is 
permitted in accordance with local practice or guidelines.  American Society for 
Clinical Oncology guidelines may be implemented at the discretion of the treating 
physician. 
• Management of diarrhea:  Subjects should be instructed to take loperamide, 4 mg, at 
the occurrence of the first loose stool and then 2 mg every 2 hours until they are 
diarrhea-free for at least 12 hours.  During the night, subjects may take 4 mg of 
loperamide every 4 hours.  Subjects should be advised to avoid dehydration through 
adequate fluid intake.  Bile acid sequestrants may be utilized in the case of bile acid 
diarrhea. 
Medications for the treatment of AEs or cancer symptoms, eg, packed red blood cells and 
pain medications, are allowed.  Additionally, medications (not addressed above) used to treat 
underlying medical conditions at study entry including antiemetics and antidiarrheals will be 
allowed to continue. 
Management of hyperphosphatemia or hypercalcemia:  Phosphorus and calcium will be 
measured at screening, before the first dose, every week with safety labs during C1, and on 
Day 1 and Day 8 for C2 and beyond.  Please note that a treatment cycle is 21 days.  Subjects 
with elevated levels of phosphorus or calcium at screening, as defined as being over the ULN 
on local lab ranges, may not participate in this study and should be referred for management 
of such.  If successfully controlled, subjects may be rescreened.  During study participation, 
any confirmed levels of phosphorus above 7 mg/dL, or calcium equal to or above Grade 2 
hypercalcemia as per CTCAE, Version 4.03, will result in the dose of H3B-6527 being held 
for 14 days.  The hyperphosphatemia and / or hypercalcemia should be managed by local 
practice, with medication, diet change and potential referral as necessary.  After 14 days of 
holding the drug, if the phosphorus level has returned to 5.5 mg/dL or lower, and the calcium 
is less than or equal to a Grade 1 elevation, the subject may begin taking H3B-6527 again at 
one dose level lower than their original dose and should continue other measures initiated 
during the drug holiday, such as phosphorus lowering agents, while on study.  If a subject 
should experience hyperphosphatemia above 7 mg/dL or hypercalcemia equal to or above 
Grade 2 again on study, then study therapy will be discontinued.  


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9.4.9 
Treatment Compliance 
A diary will be provided to subjects on C1 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. 
9.4.10 
Drug Supplies and Accountability 
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator or designee until the following documentation has been received 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 
• A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol 
• An investigator-signed and dated Food and Drug Administration (FDA) Form 1572, 
where applicable 
• Financial Disclosure form(s) for the PI and all subinvestigators listed on FDA Form 
1572, where applicable 
• A signed and dated curriculum vitae of the PI including a copy of the PI’s current 
medical license (in the US) or medical registration number on the CV 
• A signed and dated clinical studies agreement 
The investigator and the study staff will be responsible for the accountability of all study 
drug (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 drug to be used other than as 
directed by this protocol.  Study drug will not be dispensed to any individual who is not 
enrolled in the study.   
The site must maintain an accurate and timely record of the following:  receipt of all study 
drug, dispensing of study drug to the subject, collection and reconciliation of unused study 
drug that are either returned by the subjects or shipped to site but not dispensed to subjects, 


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and return of reconciled study drug to the Sponsor or (where applicable) destruction of 
reconciled study drug at the site.  This includes, but may not be limited to, (a) documentation 
of receipt of study drug, (b) study drug dispensing/return reconciliation log, (c) study drug 
accountability log, (d) all shipping service receipts, (e) documentation of returns to the 
Sponsor, and (f) certificates of destruction for any destruction of study drugs/study supplies 
that occurs at the site.  All forms will be provided by the Sponsor.  Any comparable forms 
that the site wishes to use must be approved by the Sponsor. 
The study drug and inventory records must be made available, upon request, for inspection 
by a designated representative of the Sponsor or a representative of a health authority (eg, 
FDA, Medicines and Healthcare products Regulatory Agency).  As applicable, all unused 
study drug and empty and partially empty containers from used study drug are to be returned 
to the investigator or designee by the subject and together with unused study drug that were 
shipped to the site but not dispensed to subjects are to be returned to the Sponsor’s 
designated central or local depot(s) during the study or at the conclusion of the study, unless 
provision is made by the Sponsor for destruction of study drug and containers at the site.  
Destruction at the site will only occur under circumstances where regulation or supply type 
prohibits the return of study drug 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 drug that are to be returned to the Sponsor’s 
designated central or local depot(s) must be boxed and sealed and shipped back to the central 
or local depot(s) following all local regulatory requirements.  In some regions, study drug 
may be removed from the site and hand delivered to the central or local depot by Sponsor 
representatives.  Where study drugs are approved for destruction at the site, destruction will 
occur following the site’s standard procedures and certificates of destruction will be provided 
to the Sponsor. 
Drug accountability will be reviewed during site visits and at the completion of the study. 
9.5 
Study Assessments 
9.5.1 
Assessments 
Subjects will be evaluated for study eligibility during the Pretreatment period, within 28 days 
before the first H3B-6527 dose.  All subjects must provide written informed consent before 
any study-related samples are collected or evaluations performed in this study, up to 8 weeks 
before the first dose of study drug.   
9.5.1.1 
Pretreatment Assessments 
9.5.1.1.1 
SCREENING 
Subjects in the Dose Expansion phase will be evaluated for FGF19 expression.  A fresh 
tumor biopsy (for determining FGF19 expression levels by a Sponsor designated laboratory), 
the signing of the ICF, and the collection of blood samples for pharmacodynamic analysis 
(same day as fresh tumor biopsy) will be required up to 8 weeks before administration of 


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H3B-6527 on C1 Day 1, in order to enroll in the Dose Expansion Phase of the study.  The 
28-day Screening Period will begin when any of the remaining screening assessments are 
performed.  The entire Pretreatment Phase must be completed within 8 weeks of study drug 
administration on C1 Day 1.  Subjects enrolled in the Dose Escalation phase are not required 
to be FGF19-positive. 
9.5.1.1.2 
DEMOGRAPHY 
The subjects’ demographic information will be collected during Screening.  Demographic 
information includes date of birth (or age), sex, race/ethnicity. 
9.5.1.1.3 
MEDICAL HISTORY 
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit and updated at Baseline, prior to administration of the first H3B-6527 dose.  The 
medical history will also include cancer history (including the subject’s primary tumor type, 
date of and stage at diagnosis, method of diagnosis, etiology) extent of disease (including 
portal vein invasion/thrombosis), and all previous treatments, including radiation therapy, 
and response to such treatment.  As part of the subject’s cancer history, study centers are to 
submit a local histology or cytology report obtained prior to enrollment, if available.  
9.5.1.2 
Efficacy Assessments 
9.5.1.2.1 
TUMOR IMAGING 
All subjects are required to undergo chest, abdomen, and pelvis imaging at baseline and all 
follow-up time points.  Contrast-enhanced CT scan of the chest and contrast-enhanced CT 
scan or MRI of the abdomen, pelvis, and any other areas of disease, as clinically indicated, 
will be acquired at Screening and at all imaging time points.  A liver CT scan or MRI must 
be performed using triphasic scanning techniques optimized to capture precontrast, arterial, 
and portal venous phases.  Copies of all tumor imaging scans must be retained by the 
investigators.  If requested by the Sponsor or by the health authorities, these copies will be 
sent to an imaging core laboratory designated by the Sponsor for quality assessment, 
archiving, and potential future review.  Historical standard-of-care scans conducted within 
28 days prior to study drug administration may be used as screening/baseline imaging if 
scanning parameters are consistent with the requirements for this protocol as separately 
defined by the imaging core laboratory. 
MRI scans (optimized for precontrast, arterial phase, and portal venous phase) may be used 
instead of CT scans for imaging of the abdomen and pelvis.  However, the chest must be 
imaged using CT; and chest disease must be followed by CT scan (ie, chest x-ray for 
response assessment is not allowed).  If iodinated intravenous (IV) contrast is 
contraindicated, chest CT scan should be performed without IV contrast.   
Imaging studies are to be repeated during the Treatment Phase and Extension Phase every 
6 weeks, or more frequently if clinically indicated, until disease progression, withdrawal of 


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consent, or the subject receives another anticancer therapy.  The same method of assessment 
used during Screening must be used at all subsequent time points. 
After initiation of treatment, if a subject is unable to undergo a contrast CT due to allergy or 
renal insufficiency, a chest CT scan without contrast, combined with MRI images of the 
remaining anatomy with gadolinium contrast, is preferred if tolerated by the subject.  If it is 
determined that neither CT scan nor MRI IV contrast can be tolerated by the subject, a chest 
CT scan without contrast combined with high quality T1 and T2 weighted MRI images of the 
remaining anatomy, should be provided.  Importantly, such a modality switch will render the 
subsequent measurements of target lesions, especially typical hepatic target lesions, 
inadequate and the target lesion disease should be followed as not evaluable or potentially 
progressing (if sufficient evidence is available). 
CT and MRI scans should be of diagnostic quality acquired on spiral or multidetector CT 
with oral and IV contrast.  Low-dose, noncontrast CT transmission scans from positron 
emission tomography/CT scanner are not acceptable.  Spiral or multidetector CT scans 
should be performed with a 5-mm contiguous slice reconstruction algorithm.  If MRI scans 
are acquired, contiguous 5-mm slice thickness with minimal gap are also recommended.  
Ultrasound should not be used for radiographic assessment.  A chest x-ray or skeletal x-ray 
that clearly demonstrates a new metastatic lesion may be used to document progression in 
lieu of the CT/MRI scans. 
A brain scan should be performed for all subjects to assess potential central nervous system 
disease and/or metastases as clinically indicated.  For eligible subjects with previously 
treated brain metastases, a brain scan will be required at all tumor assessment time points (eg, 
every 6 weeks).  For all subjects, a follow-up brain scan must be performed to confirm a 
complete response (CR) within 1 week following response confirmation.   
If a subject discontinues treatment prior to C3 Day 1 (ie, 6 weeks after the first study drug 
dose on C1 Day 1), the scans for tumor assessment should be performed as close as possible 
to C3 Day 1, but before another anticancer therapy is initiated. 
If a subject discontinues study treatment due to radiographic evidence of PD, then imaging 
studies are not required at the OTV.   
During the Follow-up Period, subjects who discontinue study treatment without objective 
evidence of PD will continue to have tumor assessments (including brain scans as clinically 
indicated) performed every 6 weeks from the date of last tumor assessment, or sooner if 
clinically indicated, until PD is documented. 
The tumor assessment schedule should not be affected by interruptions in therapy or any 
other events. 
Tumor assessments will be performed following mRECIST guidance (Appendix 1) for HCC 
using triphasic liver CT/MRI (optimized for precontrast, arterial phase, and portal venous 
phase).  


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9.5.1.2.2 
SURVIVAL 
After the OTV, all subjects who discontinue study treatment, regardless of their reasons for 
doing so, will be followed for survival via telephone (for those subjects who experience PD 
or initiate a new anticancer therapy) or office visit (for those subjects still undergoing tumor 
assessments).  Subjects will be followed for survival approximately every 12 weeks for up to 
12 months or until 6 cycles after last patient in, death, loss to follow-up, or withdrawal of 
consent, whichever occurs first.     
9.5.1.3 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments 
Tumor tissue samples and blood samples for pharmacodynamics, pharmacogenomics (PG), 
and other biomarker assessments will be collected, as indicated in Table 6 and Table 7 except 
where prohibited by regional or local laws.   
Instructions for the processing, storage, and shipment of PK, pharmacodynamic, PG, and 
other biomarker samples will be provided in the Laboratory Manual. 
9.5.1.3.1 
PHARMACOKINETIC ASSESSMENTS 
Blood samples for PK assessments are to be collected from all subjects according to the 
schedule designated in Table 6 and Table 7.  A protocol deviation will be reported only when 
a PK time point is not collected (missing) or blood is drawn on the wrong study day.  
For subjects in Part 1, dose escalation, an aliquot of blood from the sample collected at each 
PK time point will be transferred for use for exploratory assessment of the metabolite profile 
of H3B-6527. 
Plasma concentrations of H3B-6527 will be determined using a validated assay.   
Additionally, urine samples for assessment of the metabolite profile of H3B-6527 will be 
collected during C1 from subjects in Part 1, dose escalation, only, according to the schedule 
designated in Table 6. 
The total urine volume collected during each designated interval is to be documented in the 
CRF. 
During the Dose Expansion phase, H3B-6527 levels in tumor tissue may be analyzed using a 
nonvalidated assay such as matrix-assisted laser desorption/ionization.  During the Dose 
Escalation Phase, the investigators and Sponsor may agree that determination of H3B-6527 
exposure in tumor tissue is required to guide dosing decisions.  In this scenario, biopsies of 
tumor tissue will be obtained from all consenting subjects. 
9.5.1.3.2 
PHARMACODYNAMIC AND OTHER BIOMARKER ASSESSMENTS IN BLOOD 
Blood samples for determination of biomarkers (in serum and/or plasma) will be collected 
from all subjects at the time points designated in Table 6 and Table 7. 


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Such samples may be analyzed for FGF19 (ligand of H3B-6527’s target FGFR4), bile acids, 
circulating tumor cells, alpha-fetoprotein, and other exploratory biomarker candidates (both 
protein and nucleic acids) using global proteomic/metabolomics/genomic methods, enzyme-
linked immunosorbent assay, multiplex bead-based immunoassay, or other assays/methods.  
These blood biomarker samples may be used for exploratory analysis for evaluation of 
response-related and/or safety-related outcomes, as well as for potential use in diagnostic 
development.  Retrospective testing for potential subject stratification markers may also be 
explored.   
During the dose escalation phase, results from biomarker studies may be used to aid the 
selection of the RP2D and schedule, and for monitoring drug efficacy.  When new research 
results emerge, the parameters and methods for the pharmacodynamic biomarker analysis 
may change. 
9.5.1.3.3 
PHARMACODYNAMICS AND BIOMARKERS IN TISSUE 
Archival Tumor Tissue Collection 
For all subjects, an archival tumor tissue block or slide obtained before the first planned dose 
is to be collected, if available, any time during the study.  Archival tumor tissue may be used 
for assessment of mutations and other exploratory biomarkers. 
Screening Tumor Biopsy 
Subjects in Part 1, the Dose Escalation phase, may have a fresh tumor sample, collected 
during Screening if an archival sample is not available; however, this is not a requirement for 
study participation. 
For all subjects in the Expansion phase, the signing of the ICF, the collection of blood 
samples for pharmacodynamic analysis (same day as fresh tumor biopsy), and a fresh tumor 
tissue sample (for determining FGF19 expression levels by a Sponsor designated laboratory) 
is required to be collected up to 8 weeks before administration of the first dose of H3B-6527 
on C1 Day 1.  The 28-day Screening Period will begin when any of the remaining screening 
assessments are performed. 
Additional Tumor Tissue Samples 
In the event a subject is required to have a repeat tumor biopsy for medically indicated 
reasons, freshly obtained biopsy tissue from the procedure should be collected and shipped to 
H3 Biomedicine or a predesignated laboratory for exploratory biomarker analysis. 
9.5.1.3.4 
PHARMACOGENOMIC ASSESSMENTS 
A blood sample will be collected at baseline for PG analysis.  If the sample cannot be 
collected at baseline, it may be collected at any time point thereafter.   


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This sample may be used to evaluate the role of deoxyribonucleic acid (DNA) sequence 
variability on the absorption, distribution, metabolism, and elimination (ADME) of 
H3B-6527. 
Furthermore, genomic DNA extracted from blood samples may be used to confirm whether 
the DNA sequence variants observed in DNA extracted from tumor material are limited to 
the tumor.   
DNA will not be used to determine or predict risks for diseases that an individual subject 
does not currently have.  Any sample or derivatives (DNA, ribonucleic acid, and protein) 
may be stored for up to 15 years to assist in any research scientific questions related to H3B-
6527 or cancer. 
9.5.1.4 
Safety Assessments 
Safety assessments include monitoring and recording all AEs, including SAEs; clinical 
laboratory tests (including hematology, coagulation parameters, clinical chemistry (including 
total bile acids, cholesterol, triglycerides), and urinalysis); and periodic measurement of vital 
signs, ECGs, MUGA/echocardiogram, and ophthalmic and physical examinations.  
Additionally, QTc intervals will be evaluated during the Dose Escalation phase. 
AEs will be assessed using the National Cancer Institute CTCAE, Version 4.03. 
9.5.1.4.1 
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS 
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 is H3B-6527.   
The criteria for identifying AEs in this study are: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE) 
• Any new disease or exacerbation of an existing disease.  However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE.  
• Any deterioration in nonprotocol-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 pretreatment 
(Baseline) 


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• An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not 
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the OTV (ie, within 30 days after the last study drug 
dose).  Subjects who fail Screening primarily due to AE(s) must have the AE(s) leading to 
screen failure reported on the Screening Disposition CRF.  Serious AEs (SAEs) will be 
collected for 30 days after the last dose  
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 (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QT corrected for heart rate using 
Fridericia’s formula (QTcF) interval is >450 ms and there is an increase of >60 ms from 
baseline.  Any ECG abnormality that the investigator considers as an AE should be reported 
as such. 
All AEs must be followed for 28 days or 5 × the half-life, (whichever is longer) after the 
subject’s last dose, or until resolution, whichever comes first.  All SAEs must be followed to 
resolution or, if resolution is unlikely, to stabilization. 
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment. 
Assessing Severity of Adverse Events 
AEs will be graded on a 5-point scale according to CTCAE, Version 4.03 (Appendix 2).  
Investigators will report CTCAE grades for all AEs (for both increasing and decreasing 
severity). 
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
• Temporal relationship of the onset of the event to the initiation of the study treatment 
• The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
• Whether the event is known to be associated with the study treatment or with other 
similar treatments 


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• The presence of risk factors in the study subject known to increase the occurrence of the 
event 
• The presence of nonstudy, 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. 
9.5.1.4.2 
SERIOUS ADVERSE EVENTS AND OTHER EVENTS OF INTEREST 
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.  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 1 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. 


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The following hospitalizations are not considered to be SAEs because there is no “AE” (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 post study drug administration) 
• Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry 
If possible, a blood sample for PK analysis should be drawn at the first report of an SAE or a 
severe unexpected AE and at its resolution. 
9.5.1.4.3 
LABORATORY MEASUREMENTS 
Clinical laboratory tests to be performed, including hematology, chemistry, coagulation 
parameters, and urinalysis, are summarized in Table 5.  The Schedules of 
Procedures/Assessments (Table 6 and Table 7) show the visits and time points at which 
blood for clinical laboratory tests and urine for urinalysis will be collected in the study.  
Clinical laboratory tests will be performed by the local laboratory.  Laboratory certification 
as available will be included in the final clinical study report for this study. 
Screening laboratory assessments may be used as the Baseline assessment if performed 
within 72 hours before the first study drug dose.  All hematology, blood chemistry (including 
pregnancy test, as applicable) and urinalysis samples are to be obtained prior to study drug 
administration and results reviewed prior to administration/dispensing of study drug at the 
beginning of each treatment cycle (refer to Section 9.4.2).  Total bile acids will be collected 
with blood chemistries but, due to potentially long turnaround times, results are not required 
for individual subject treatment decisions prior to the start of each cycle.  However, results 
should be reviewed when available.  Additionally, total bile acids will be reviewed in 
aggregate to look for any potential safety trends as outlined in the existing safety review plan.  
The primary purpose of this retrospective review is to look for a potential correlation with 
clinical observations of related signs and symptoms. 
Subjects should be in a seated or supine position during blood collection.   


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Table 5 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands/segs, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils) 
Coagulation Parameters 
Prothrombin time or INR and activated partial thromboplastin time   
Chemistry 
 
 Electrolytes 
Chloride, potassium, sodium  
 Liver function tests 
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, total bilirubin 
 Renal function tests 
Blood urea nitrogen, creatinine 
 Other 
Albumin, calcium, carbon dioxide, cholesterol, glucose, lactate 
dehydrogenase, inorganic phosphorus, total protein, triglycerides, 
uric acid, total bile acids, AFP 
Urinalysis 
Appearance, specific gravity, and pH and semi-quantitative dipstick 
evaluation of glucose, protein, bilirubin, ketones, leukocytes, and 
blood.   
If dipstick evaluation is positive for leukocytes, protein, or blood, a 
microscopic examination of sediment is to be performed. 
AFP = alpha-fetoprotein, INR = International Normalized Ratio, RBC = red blood cell, Segs = segmented cells, 
WBC = white blood cell. 
 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.4.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF. 
9.5.1.4.4 
VITAL SIGNS AND WEIGHT MEASUREMENTS 
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], heart rate 
[HR; beats per minute], respiratory rate [RR; per minute], body temperature [in centigrade]), 
and weight (kg) will be obtained as designated in the Schedule of Procedures/Assessments 
(Table 6 and Table 7) by a validated method.  BP, HR, and RR will be measured after the 
subject has been sitting for 5 minutes.  All BP measurements should be performed on the 
same arm, preferably by the same person.   
Height (cm) is to be measured during Screening only. 
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed prior to drawing blood samples in order to maximize 
the accuracy of blood sampling times while minimizing the potential effects of blood 
drawing on recordings obtained during safety assessments. 


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Amendment 09:  30 Sep 2020 
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9.5.1.4.5 
PHYSICAL EXAMINATIONS 
Comprehensive and symptom-directed physical examinations and ophthalmic examinations 
will be performed as designated in the Schedule of Procedures/Assessments (Table 6 and 
Table 7).  Documentation of the physical examination will be included in the source 
documentation at the site.  Significant findings during the Pretreatment Period will be 
recorded on the Medical History and Current Medical Conditions CRF.  Changes from 
pretreatment physical examination findings that meet the definition of an AE will be 
recorded on the Adverse Events CRF. 
Comprehensive Physical Examination 
A comprehensive physical examination will include evaluations of the head, eyes, ears, nose, 
throat, neck, chest (including heart and lungs), abdomen, limbs, skin, and a complete 
neurological examination.  The subject will be queried regarding physical status and 
subjective symptoms as well.  A urogenital examination will only be required in the presence 
of clinical symptoms related to this region. 
Symptom-directed Physical Examination 
The subject must be queried regarding changes in physical status since the last examination 
and a symptom-directed physical examination accordingly conducted. 
Ophthalmic Examination 
As part of the ophthalmological examination, a visual acuity test, funduscopic examination 
(mydriatic test if necessary), slit-lamp examination (fluorescein staining will be performed if 
necessary), and an anterior eye optical coherence tomography (OCT) for assessing the 
corneal epithelium will be performed.  The central corneal thickness will be measured as part 
of the anterior eye OCT and recorded on the CRF.  Any clinically significant changes in 
OCT will be captured and recorded as AEs.  The ophthalmological examination may be 
completed within 7 days prior to Day 1 of each applicable cycle.  Ophthalmic examinations 
performed within 8 weeks of C1 Day 1 can be used in the event of a rescreen. 
9.5.1.4.6 
ELECTROCARDIOGRAMS AND HOLTER MONITORING 
For all subjects, 12-lead ECGs will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 6 and Table 7).  In the event of any alteration, or if clinically 
necessary, an echocardiogram and/or cardiac enzymes should be performed. 
In Part 1, Dose Escalation, the effects of H3B-6527 on cardiovascular repolarization will be 
evaluated via 12-lead continuous Holter/ECG monitoring on C1 Day 1 and on Day 8.  The 
continuous Holter monitoring must begin at least 1 hour prior to dose on C1 Days 1 and 8 
and will continue through 10 hours postdose for all subjects regardless of dose schedule (QD 
or BID) in the Dose Escalation Phase of the study. 
Additionally, Holter monitoring/ECGs (12-lead) are to be collected 1 hour before the first 
dose (at 3 time points) and at 0.5, 1, 2, 4, 6, 8, and 10 hours postdose on C1 Days 1 and 8.  At 
each of these time points, subjects should be supinely resting for at least 10 minutes before 


Clinical Study Protocol  
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Amendment 09:  30 Sep 2020 
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and 5 minutes after the nominal time.  When coinciding, blood collection, vital signs, and 
12-lead safety ECGs should be performed immediately after the time window for ECG 
extraction.   
Screening & baseline ECGs will be performed as singles.  However, if clinically indicated, 
triplicates will be performed at screening and baseline.  All other ECGs after 
screening/baseline will be performed as singles. 
Individual ECGs will be extracted from the Holter recordings at specified time points per 
ECG manual and will be evaluated by a central laboratory.  QT intervals will be measured 
from Lead II and will be corrected for QTcF correction factors.  The primary QTc parameter 
will be QTcF.  Secondary parameters (QT corrected for heart rate using Bazett’s formula 
[QTcB], QT, QRS, PR, and heart rate) and wave forms (T waves) will be evaluated. 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 9.5.1.4.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF. 
For ECG abnormalities meeting the criteria of an SAE (see Section 9.5.1.4.2), the site must 
fax or email the SAE report including the ECG report to the Sponsor using the SAE form 
(see Section 9.5.4.1). 
9.5.1.4.7 
ECOG PERFORMANCE STATUS 
ECOG performance status is to be determined as designated in the Schedule of 
Procedures/Assessments (Table 6 and Table 7).   
The ECOG performance status scale, with corresponding Karnofsky performance status 
score equivalents, is presented in Appendix 3. 
9.5.1.4.8 
ECHOCARDIOGRAM/MUGA 
MUGA scans or echocardiograms will be performed during the Pretreatment Phase, at the 
OTV (±1 week), and if clinically indicated during treatment.  MUGA scans or 
echocardiograms performed within 8 weeks of C1 Day 1 can be used in the event of a 
rescreen.  MUGA scans and echocardiograms will be performed locally in accordance with 
the institution’s standard practice. 
9.5.1.4.9 
PREGNANCY TEST 
A serum pregnancy test (β-hCG) will be performed during Screening for all premenopausal 
women and postmenopausal women who have been amenorrheic for less than 12 months.  A 
urine or serum pregnancy test will be performed before the first H3B-6527 dose and at the 
OTV. 


Clinical Study Protocol  
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Amendment 09:  30 Sep 2020 
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9.5.2 
Schedule of Procedures/Assessments 
Table 6 presents the schedule of procedures/assessments for the Dose Escalation phase of the 
study.  Table 7 presents the schedule of procedures assessments to be performed during the 
Dose Expansion Phase of the study. 


Clinical Study Protocol  
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Amendment 09:  30 Sep 2020 
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Table 6 
Schedule of Assessments in H3B-6527-G000-101 – Dose Escalation Cohort 
Phase 
Pretreatmenta 
Treatment 
Extension 
 
 
Period 
Screening 
Baseline 
Cycle 1 
Cycle 2 and Beyond 
Off-Treatmentb,c 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6, 8, etc. 
7, 9, etc. 
98 
99 
Day 
-28 to -1 
-3 to -1 
1 
8 (±3) d 
15 (±3) 
1 (±3) 
8 (±3) 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
Informed consent 
Xa 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
Prior and concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examinatione 
X 
X 
X 
X 
X 
X 
X 
X 
 
Ophthalmologic examinationf 
X 
 
 
X 
 
X 
 
X 
 
Echocardiogram / MUGAg  
X 
 
If clinically indicated 
X 
 
Pregnancy testh 
X 
 
X 
 
 
 
 
X 
 
Vital signsi 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
X 
X 
 
 
X 
 
X 
 
12-lead ECGsj 
X 
X 
X 
 
 
X 
 
X 
 
ECG Holter monitoringk 
 
 
X 
X 
 
 
 
 
 
AFP biomarker assessment 
 
X 
Every 6 weeks through Cycle 6 
with tumor assessment 
 
 
 
 
Hematologyl 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood chemistryl 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation parametersl  
X 
X 
X 
 
 
X 
 
X 
 
Urinalysism 
X 
 
X 
 
 
X 
 
X 
 
PG blood samplen 
 
X 
 
 
 
 
 
 
 
Metabolite profiling urine 
sampleso 
 
 
 
X 
 
 
 
 
 
PK and metabolite profiling 
blood samplesp 
 
 
X 
X 
X 
 
 
 
 


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Phase 
Pretreatmenta 
Treatment 
Extension 
 
 
Period 
Screening 
Baseline 
Cycle 1 
Cycle 2 and Beyond 
Off-Treatmentb,c 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6, 8, etc. 
7, 9, etc. 
98 
99 
Day 
-28 to -1 
-3 to -1 
1 
8 (±3) d 
15 (±3) 
1 (±3) 
8 (±3) 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
Pharmacodynamic blood sampleq 
 
X 
X 
X 
X 
X 
X 
X 
 


Clinical Study Protocol  
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Amendment 09:  30 Sep 2020 
Confidential 
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Table 6 Schedule of Assessments in H3B-6527-G000-101 – Dose Escalation Cohort 
Phase 
Pretreatmenta 
Treatment 
Extension 
 
 
Period 
Screening 
Baseline 
Cycle 1 
Cycle 2 and Beyond 
Off-Treatmentb,c 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6, 8, etc. 
7, 9, etc. 
98 
99 
Day 
-28 to -1 
-3 to -1 
1 
8 (±3) d 
15 (±3) 
1 (±3) 
8 (±3) 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
Pharmacodynamic blood sample 
for CTC/cf-nucleic acidr 
 
X 
X 
X 
X 
X 
X 
X 
 
Archival tumor block or slidess 
 
X 
 
 
 
 
 
 
 
Fresh tumor tissue biopsyt 
X 
 
 
 
 
 
 
 
 
Brain scanu 
If clinically indicated 
Tumor assessments: CT or 
MRIv,w,x 
X 
 
Every 6 weeks or sooner if clinically indicated 
X 
X 
Adverse Events 
Continuous from date of consent until off-treatment visit 
 
H3B-6527 administrationy 
 
 
Continuous 21-day cycles of H3B-6527 daily dosing.y 
 
 
Survival statusz 
 
 
 
 
 
 
 
 
X 
AFP = alpha-fetoprotein, ALT = alanine aminotransferase, AST = aspartate aminotransferase, β-hCG = beta-human chorionic gonadotropin, BID = twice daily, BP = blood 
pressure, BUN = blood urea nitrogen, C = Cycle, CF = cell-free, CR = complete response, CRF = case report form, CT = computed tomography, CTC = circulating tumor cell, 
ECG = electrocardiograms, ECOG = Eastern Cooperative Oncology Group, GGT = gamma-glutamyl transferase, HR = heart rate, ICF = informed consent form; IV = intravenous, 
LDH = lactate dehydrogenase, mRECIST = modified Response Evaluation Criteria In Solid Tumors, MRI = magnetic resonance imaging, MUGA = multigated acquisition, 
OCT = optical coherence tomography, OTV = off-treatment visit, PD = progressive disease; PG = pharmacogenomics, PK = pharmacokinetic, QD = once daily, RBC = red blood 
cell, RR = respiratory rate, WBC = white blood cell. 
a: 
The Screening Period extends from Day -28 to Day -1, except for signing of the ICF, which may be up to 8 weeks before the first dose of study drug.  The baseline 
assessments may be performed from Day -3 to Day -1 (before the first dose of H3B-6527).  Screening assessments may be used as baseline assessments if performed within 
72 hours of the first dose of study medication. 
b: 
Subjects who discontinue study treatment for reasons other than PD will be followed until PD or death.  All anticancer therapies will be collected.  The Sponsor may choose 
to stop the collection of therapies after the first anticancer treatment. 
c: 
The OTV should occur 30 days after the final dose of study drug with a window of ± 3 days. 
d: 
Blood samples for PK analysis and urine samples must be obtained on Day 8.  The window of ±3 days does not apply to this visit for these samples. 
e: 
A comprehensive physical examination will be performed during Screening and at the OTV.  A symptom-directed physical examination will be performed on Day 1 of all 
treatment cycles and at any time during the study, as clinically indicated. 
 


Clinical Study Protocol  
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Amendment 09:  30 Sep 2020 
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Table 6 Schedule of Assessments in H3B-6527-G000-101 – Dose Escalation Cohort 
____________________________________________________________________________________________________________ 
f: 
Ophthalmic examination by an ophthalmologist will be performed at Screening (or within 7 days prior to Day 1 of each applicable cycle), on C1 Day 8, C2 Day 1, and on 
Day 1 of all subsequent cycles (through C6), and at the off-treatment visit.  Ophthalmic examinations performed within 8 weeks of C1 Day 1 can be used in the event of a 
rescreen.  After C6, OCT will be required only on Day 1 of every other cycle.  As part of the ophthalmological examination, a visual acuity test, funduscopic examination 
(mydriatic test if necessary), slit-lamp examination (fluorescein staining will be performed if necessary), and an anterior eye OCT for assessing the central corneal thickness 
will be performed.  The central corneal thickness will be measured as part of the anterior eye OCT and recorded on the CRF. 
g: 
MUGA scans or echocardiograms will be performed during the Pretreatment Phase, during the OTV (window of ±1 week), and if clinically indicated during treatment.  
MUGA scans or echocardiograms performed within 8 weeks of C1 Day 1 can be used in the event of a rescreen.  MUGA scans and echocardiograms will be performed 
locally in accordance with the Institution’s standard practice. 
h: 
A serum pregnancy test (β-hCG) will be performed during Screening for all premenopausal women and postmenopausal women who have been amenorrheic for less than 
12 months.  A urine or serum pregnancy test will be performed before the first H3B-6527 dose and at the OTV. 
i: 
Vital signs include BP, HR, RR, and body temperature, as well as weight.  BP, HR, and RR will be collected after the subject has been sitting for 5 minutes.  Height will be 
measured during Screening only. 
j: 
Screening and baseline ECGs will be performed as singles.  However, if clinically indicated, triplicates will be performed at screening and baseline.  All other ECGs after 
screening/baseline will be performed as singles.   
k: 
Continuous Holter monitoring will begin at least 1 hour prior to dosing through 10 hours post-dose on C1 Days 1 and 8.  Subjects should be supinely resting for at least 
10 minutes prior to and 5 minutes after the following time points, pre-dose (3 time points within 1 hour of dose) and 0.5, 1, 2, 4, 6 ,8 and 10 hours postdose.  When 
coinciding, blood draws, vital signs and 12-lead safety ECGs should be performed immediately after the time window for ECG extraction. 
l: 
Hematology and blood chemistry samples will be obtained before drug administration.  Screening assessments may be used as baseline assessments if performed within 
72 hours of the first dose of study medication.  Hematology includes hemoglobin, hematocrit, RBC count, platelet count, WBC and differential.  Chemistry includes albumin, 
alkaline phosphatase, total bilirubin, BUN, calcium, carbon dioxide, chloride, creatinine, glucose, inorganic phosphorus, potassium, total protein, GGT, LDH, ALT, AST, 
cholesterol, triglycerides, sodium, uric acid, and total bile acids.  Total bile acids will be collected with blood chemistries but, results are not required for individual subject 
treatment decisions prior to the start of each cycle, but should be reviewed once available.  Coagulation parameters (prothrombin time or International Normalized Ratio, and 
activated partial thromboplastin time) will be collected at within 72 hours of dosing on Day 1 of each cycle, and at the OTV. 
m: Urine samples will be obtained before drug administration.  Analysis will include assessment of appearance, specific gravity and pH as well as a semi-quantitative “dipstick” 
evaluation of glucose, protein, bilirubin, ketones, leukocytes and blood.  Microscopic examination of sediment will be performed if urinalysis is positive for leukocytes, 
proteins, or blood.   
n: 
Blood samples will be collected at baseline for PG analyses.  If it cannot be collected at the designated time point, it may be collected at a time point after baseline. 
o: 
Urine will be collected for exploratory metabolite profiling on Day 8, at the following collection intervals:  0 to 6 hours, 6 to 12 hours and 12 to 24 hours.  Total urine volume 
collected during each interval will be recorded.   
p: 
For QD dosing, blood samples for PK analysis will be collected in C1 on Day 1 and Day 8 at predose (0 hours), 0.5, 1, 2, 4, 6, 8, 10, and 24 hours (immediately prior to the 
next dose); and at Day 15 predose (0 hours).  An aliquot of blood from each collection time point will be used for exploratory H3B-6527 metabolite profiling.  For BID 
dosing, blood samples for PK analysis will be collected on C1 on Day 1 and Day 8 at predose (0 hours), 0.5, 1, 2, 4, 6, 8, and 10 hours (immediately prior to the next daily 
dose), and at Day 15 predose (0 hours).  The ±3 day-window does not apply to the PK sampling on Day 8. 
q: 
Blood samples for pharmacodynamic analysis (eg, circulating proteins, total bile acids) will be collected prior to dosing (all subjects will be required to fast 2 hours prior to 
pharmacodynamic assessments) at the following time points:  Baseline, predose (0 hours) on C1 Day 1, Day 8, and Day 15, and Day 1 and Day 8 of subsequent cycles 
through cycle 6, and at the OTV. 


Clinical Study Protocol  
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Amendment 09:  30 Sep 2020 
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Table 6 Schedule of Assessments in H3B-6527-G000-101 – Dose Escalation Cohort 
____________________________________________________________________________________________________________ 
r: 
Blood samples for nucleic-acid and CTC/cf based pharmacodynamic analysis will be collected prior to dosing (all subjects will be required to fast 2 hours prior to blood 
sample collection) at the following time points:  Baseline, predose (0 hours) on C1 Day 1, Day 8, and Day 15, and Day 1 and Day 8 of subsequent cycles through cycle 6, and 
at the OTV. 
s: 
An archival tumor tissue block or slide (if available) must be obtained any time during the study.  Archival tumor tissue may be used for assessment of mutations and other 
exploratory biomarkers. 
t: 
Subjects may have a fresh tumor sample collected during Screening if an archival sample is not available; however, this is not a requirement for study participation for the 
Dose Escalation Phase.  In the event that a subject is required to have a repeat tumor biopsy for medically indicated reasons, freshly obtained biopsy tissue from the procedure 
should be collected and shipped to H3 Biomedicine or a predesignated laboratory for exploratory biomarker analysis as per instructions in the laboratory manual. 
u: 
Screening CT/MRI of the brain should be performed as clinically indicated.  For eligible subjects with previously treated brain metastases, a brain scan will be required at all 
tumor assessment time points.  For all subjects, a follow-up brain scan must be performed to confirm a CR within 1 week following response confirmation. 
v: 
Tumor assessments will be performed based on mRECIST.  CT scans (with oral and intravenous contrast) of chest, abdomen, pelvis and other known sites of disease will be 
obtained at Screening (within 28 days prior to C1/Day 1), every 6 weeks during the Treatment and Extension phases, and as clinically indicated.  Subjects will also have 
triphasic liver CT or MRI performed (optimized for precontrast, arterial phase, and portal venous phase).  Historical standard-of-care scans conducted within 28 days prior to 
dosing may be utilized as baseline imaging if scanning parameters are consistent with the requirements for this protocol. 
w: MRI scans (optimized for precontrast, arterial phase, and portal venous phase) may be used instead of CT scans for imaging of the abdomen and pelvis.  However, the chest 
must be imaged using CT; and chest disease must be followed by CT (ie, chest x-ray for response assessment is not allowed).  If iodinated IV contrast is contraindicated, chest 
CT scan should be performed without IV contrast.  The same method of assessment must be used at all time points as used at Screening.   
x: 
The first radiological assessment of tumor response status will be performed at Week 6, unless there is clinical indication warranting earlier radiologic imaging.  If subjects 
discontinue study treatment for radiographic evidence of disease progression, tumor assessments are not required at the off-treatment assessment.  During the Follow-up 
Period, subjects who discontinue study treatment without objective evidence of disease progression, tumor assessments (including brain scans as clinically indicated) will 
continue to be performed every 6 weeks from the date of last tumor assessment, or sooner if clinically indicated, until documented disease progression or initiation of another 
anticancer therapy. 
y: 
H3B-6527 should be taken daily at the assigned schedule and dose in conjunction with a meal.  On visit days, subjects should not take study medication before evaluations are 
performed.   
z: 
Subjects who discontinue study treatment will be followed for survival.  Survival follow-up will be conducted approximately every 12 weeks for up to 12 months or until 6 
cycles after last patient in, death, loss to follow-up, or withdrawal of consent, whichever occurs first. 
 


Clinical Study Protocol  
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H3 Biomedicine, Inc. 
Amendment 09:  30 Sep 2020 
Confidential 
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Table 7 
Schedule of Assessments in Study H3B-6527-G000-101 – Expansion Cohorts 
Phase 
Pretreatmenta 
Treatment 
Extension 
 
Period 
Screening 
Baseline 
Cycle 1 
Cycle 2 and 
Beyond 
Off 
Treatmentb,c 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6, 8, 
etc. 
7, 9, etc. 
98 
99 
Day 
-28 to -1 
-3 to -1 
1 
8 (±3) 
15 (±3) 
1 (±3) 
8 (±3) 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
Informed consent 
Xa 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examinationd 
X 
X 
X 
X 
X 
X 
X 
X 
 
Ophthalmologic examinatione 
X 
 
 
X 
 
X 
 
X 
 
Echocardiogram / MUGAf 
X 
 
If clinically indicated 
X 
 
Pregnancy testg 
X 
 
X 
 
 
 
 
X 
 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
X 
X 
 
 
X 
 
X 
 
12-lead ECGi 
X 
X 
X 
 
 
X 
 
X 
 
AFP biomarker assessment 
 
X 
Every 6 weeks through cycle 6 
with tumor assessment 
 
 
 
 
Hematologyj 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood chemistryj 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation parametersj 
X 
X 
X 
 
 
X 
 
X 
 
Urinalysisk 
X 
 
X 
 
 
X 
 
X 
 
PG blood samplel 
 
X 
 
 
 
 
 
 
 
PK blood samplesm 
 
 
 
X 
X 
 
 
 
 
Pharmacodynamic blood samplen 
Xa 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacodynamic blood sample for 
CTC/cf-nucleic acido 
X 
X 
X 
X 
X 
X 
X 
X 
 


Clinical Study Protocol  
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Amendment 09:  30 Sep 2020 
Confidential 
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Table 7 
Schedule of Assessments in Study H3B-6527-G000-101 – Expansion Cohorts 
Phase 
Pretreatmenta 
Treatment 
Extension 
 
Period 
Screening 
Baseline 
Cycle 1 
Cycle 2 and 
Beyond 
Off 
Treatmentb,c 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6, 8, 
etc. 
7, 9, etc. 
98 
99 
Day 
-28 to -1 
-3 to -1 
1 
8 (±3) 
15 (±3) 
1 (±3) 
8 (±3) 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
Archival tumor block or slidesp 
 
X 
 
 
 
 
 
 
 
Fresh tumor tissue biopsyq 
Xa 
 
 
 
 
 
 
 
 
Brain scanr 
If clinically indicated 
Tumor assessments: CT or MRIs,t,u 
X 
 
Every 6 weeks or sooner if clinically indicated 
X 
X 
Adverse Events 
Continuous from date of consent until off-treatment visit 
H3B-6527 administrationv 
 
 
Continuous 21-day cycles of H3B-6527 daily dosing. 
 
 
Survival statusw 
 
 
 
 
 
 
 
 
X 
AFP = alpha-fetoprotein, ALT = alanine aminotransferase, AST = aspartate aminotransferase, β-hCG = beta-human chorionic gonadotropin, BID = twice daily, BP = blood 
pressure, BUN = blood urea nitrogen, C = Cycle, CF = cell-free, CR = complete response, CRF = case report form, CT = computed tomography, CTCs = circulating tumor cells, 
ECG = electrocardiograms, ECOG = Eastern Cooperative Oncology Group, GGT = gamma-glutamyl transferase, HR = heart rate, ICF = informed consent form, IV = intravenous, 
LDH = lactate dehydrogenase, mRECIST = modified Response Evaluation Criteria In Solid Tumors, MRI = magnetic resonance imaging, MUGA = multigated acquisition, 
OCT = optical coherence tomography, OTV = off treatment visit, PD = progressive disease, PG = pharmacogenomics, PK = pharmacokinetic, QD = once daily, RBC = red blood 
cell, RR = respiratory rate, WBC = white blood cell. 
a: 
The Screening Period extends from Day -28 to Day -1, except for signing of the ICF, the fresh tumor tissue biopsy, and the blood samples for pharmacodynamic analysis, 
which may be up to 8 weeks before the first dose of study drug.  The 28-day Screening Period will begin when any of the remaining screening assessments are performed.  
The baseline assessments may be performed from Day -3 to Day -1 (before the first dose of H3B-6527).  Screening assessments may be used as baseline assessments if 
performed within 72 hours of the first dose of study medication.   
b: 
Subjects who discontinue study drug for reasons other than PD will be followed until PD or death.  All anticancer therapies will be collected (the Sponsor may choose to stop 
the collection of therapies after the first anticancer treatment). 
c: 
The OTV should occur 30 days after the final dose of study drug with a window of ± 3 days.  
d: 
A comprehensive physical examination will be performed during Screening and at the OTV.  A symptom-directed physical examination will be performed on Day 1 of all 
treatment cycles and at any time during the study, as clinically indicated. 


Clinical Study Protocol  
H3B-6527-G000-101 
 
 
H3 Biomedicine, Inc. 
Amendment 09:  30 Sep 2020 
Confidential 
Page 91 of 126 
 
Table 7 Schedule of Assessments in Study H3B-6527-G000-101 – Expansion  
________________________________________________________________________________________________________________________________ 
e: 
Ophthalmic examination will be performed by an ophthalmologist at Screening (within 7 days of Day 1 of each applicable cycle), on C1 Day 8, C2 Day 1, and on Day 1 of all 
subsequent cycles (through C6), and at the off-treatment visit.  Ophthalmic examinations performed within 8 weeks of C1 Day 1 can be used in the event of a rescreen.  After 
C6, ophthalmic examination will be required on Day 1 of every other cycle.  As part of the ophthalmological examination, a visual acuity test, funduscopic examination 
(mydriatic test if necessary), slit-lamp examination (fluorescein staining will be performed if necessary), and an anterior eye OCT for assessing the central corneal thickness 
will be performed.  The central corneal thickness will be measured with the anterior eye OCT and recorded on the CRF. 
f: 
MUGA scans or echocardiograms will be performed during the Pretreatment Phase, during the OTV (window of ±1 week), and if clinically indicated during treatment.  
MUGA scans or echocardiograms performed within 8 weeks of C1 Day 1 can be used in the event of a rescreen.  MUGA scans and echocardiograms will be performed 
locally in accordance with the Institution’s standard practice. 
g: 
A serum pregnancy test (β-hCG) will be performed during Screening for all premenopausal women and postmenopausal women who have been amenorrheic for less than 
12 months.  A urine or serum pregnancy test will be performed before the first H3B-6527 dose and at the OTV. 
h: 
Vital signs include BP, HR, RR, and body temperature, as well as weight.  BP, HR, and RR will be collected after the subject has been sitting for 5 minutes.  Height will be 
measured during Screening only. 
i: 
Screening and baseline ECGs will be performed as singles.  However, if clinically indicated, triplicates will be performed at screening and baseline.  All other ECGs after 
screening/baseline will be performed as singles.  
j: 
Hematology and blood chemistry samples will be obtained before drug administration.  Screening assessments may be used as baseline assessments if performed within 
72 hours of the first dose of study medication.  Hematology includes hemoglobin, hematocrit, RBC count, platelet count, WBC and differential.  Chemistry includes albumin, 
alkaline phosphatase, total bilirubin, BUN, calcium, carbon dioxide, chloride, creatinine, glucose, inorganic phosphorus, potassium, total protein, GGT, LDH, ALT, AST, 
cholesterol, triglycerides, sodium, uric acid, and total bile acids.  Total bile acids will be collected with blood chemistries but, results are not required for individual subject 
treatment decisions prior to the start of each cycle, but should be reviewed once available.  Coagulation parameters (prothrombin time or International Normalized Ratio, and 
activated partial thromboplastin time) will be collected at within 72 hours of Day 1 of each cycle, either at the Screening or Baseline visit, as well at the OTV. 
k: 
Urine samples will be obtained before drug administration.  Analysis will include assessment of appearance, specific gravity and pH as well as a semi-quantitative “dipstick” 
evaluation of glucose, protein, bilirubin, ketones, leukocytes and blood.  Microscopic examination of sediment will be performed if urinalysis is positive for leukocytes, 
proteins, or blood.   
l: 
A blood sample will be collected at Baseline for PG analyses.  If it cannot be collected at the designated time point, it may be collected at a time point after baseline.   
m: For QD dosing, blood samples for PK analysis will be collected in C1 on Day 8, at predose (0 hours), 0.5, 1, 2, 4, 6, 8, 10, and 24 hours (immediately prior to the next dose), 
and predose (0 hours) on Day 15.  For BID dosing, blood samples for PK analysis will be collected on C1 on Day 8 at predose (0 hours), 0.5, 1, 2, 4, 6, 8, and 10 hours, and at 
Day 15 predose (0 hours).  The ±3 day-window does not apply to the PK sampling on Day 8. 
n: 
Blood samples for pharmacodynamic analysis (eg, circulating proteins, bile acids) will be collected prior to dosing (all subjects will be required to fast 2 hours prior to 
pharmacodynamic assessments) at the following time points:  same day as fresh tumor biopsy, Baseline, predose (0 hours) on C1 Day 1, Day 8, and Day 15, and Day 1 and 
Day 8 of subsequent cycles.  In addition, if a second biopsy is performed on a day other than C2 Day 1, the blood sample should also be collected on the same day as the 
biopsy.  Samples will be collected through cycle 6 and at the end of treatment visit for all remaining patients.  
o: 
Blood samples for nucleic acid- and CTC/cf-based pharmacodynamic analysis will be collected prior to dosing (all subjects will be required to fast 2 hours prior to blood 
sample collection) at the following time points:  Screening, Baseline, predose (0 hours) on C1 Day 1, Day 8, and Day 15, and Day 1 and Day 8 of subsequent cycles.  Samples 
will be collected through cycle 6 and at the end of treatment visit for all remaining patients.  


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Table 7 Schedule of Assessments in Study H3B-6527-G000-101 – Expansion  
 ________________________________________________________________________________________________________________________________ 
p: 
An archival tumor tissue block or slide obtained before the first planned dose in this study is to be collected, if available, any time during the study.  Archival tumor tissue 
may be used for assessment of mutations and other exploratory biomarkers.  
q: 
A fresh tumor tissue sample is required to be collected up to 8 weeks before administration of H3B-6527 on C1 Day 1, for determination of FGF19 expression levels by 
Sponsor-designated laboratory.  Freshly obtained biopsy tissue from the procedure should be collected and shipped to H3 Biomedicine or a predesignated laboratory. 
r: 
Screening CT/MRI scans of the brain should be performed as clinically indicated.  For eligible subjects with previously treated brain metastases, a brain scan will be required 
at all tumor assessment time points.  For all subjects, a follow-up brain scan must be performed to confirm a CR within 1 week following response confirmation.   
s: 
Tumor assessments will be performed based on mRECIST.  CT scans (with oral and intravenous contrast) of chest, abdomen, pelvis and other known sites of disease will be 
obtained at Screening (within 28 days prior to C1/Day 1), every 6 weeks during the Treatment and Extension parts, and as clinically indicated.  Subjects will also have 
triphasic liver CT or MRI performed (optimized for precontrast, arterial phase, and portal venous phase).  Historical standard-of-care scans conducted within 28 days prior to 
dosing may be used as baseline imaging if scanning parameters are consistent with the requirements for this protocol. 
t: 
MRI scans (optimized for precontrast, arterial phase, and portal venous phase) may be used instead of CT scans for imaging of the abdomen and pelvis.  However, the chest 
must be imaged using CT scans; and chest disease must be followed by CT scans (ie, chest x-ray for response assessment is not allowed).  If iodinated IV contrast is 
contraindicated, chest CT scan should be performed without IV contrast.  The same method of assessment must be used at all time points as used at Screening.   
u: 
The first radiological assessment of tumor response status will be performed at Week 6, unless there is clinical indication warranting earlier radiologic imaging.  If subjects 
discontinue treatment for radiographic evidence of disease progression, tumor assessments are not required at the off-treatment assessment.  During the Follow-up Period, 
subjects who discontinue study treatment without objective evidence of disease progression, tumor assessments (including brain scans as clinically indicated) will continue to 
be performed every 6 weeks from the date of last tumor assessment, or sooner if clinically indicated, until documented disease progression or initiation of another anticancer 
therapy. 
v: 
On C1 Day 1, all subjects in the Expansion phase, will take H3B-6527 daily in conjunction with a meal.  On visit days, subjects should not take study medication before 
evaluations are performed.   
w: Subjects who discontinue treatment will be followed for survival.  Survival follow-up will be conducted approximately every 12 weeks for up to 12 months or until 6 cycles 
after last patient in, death, loss to follow-up, or withdrawal of consent, whichever occurs first. 


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9.5.2.1 
Description of Procedures/Assessments Schedule 
The schedules of assessments are presented in Table 6 and Table 7, and details regarding the 
assessments to be performed are presented in Section 9.5.1. 
9.5.3 
Appropriateness of Measurements 
Planned assessments are standard measurements for this type of study and are considered 
appropriate.  Per the US FDA guidance, demographic data, complete subject medical 
histories, including cancer treatment history, and baseline disease status are to be for all 
subjects prior to administration of the first dose of study drug (FDA Guidance for Industry 
2001; European Medicines Agency 2011).  Study drug administration data, including dose 
interruptions and modifications and the associated reason(s), also are to be documented 
(FDA Guidance for Industry 2001; European Medicines Agency 2011). 
AEs and SAEs will be monitored in this study in accordance with ICH GCP guidelines to 
ensure the safety of subjects.  Furthermore, additional safety assessments conducted during 
this study, including physical examinations, ECGs, vital signs assessments, and clinical 
laboratory tests, are widely used and generally recognized as reliable, accurate, and relevant.  
These tests and procedures also will be monitored in accordance with ICH GCP guidelines. 
Tumor response and progression will be assessed using standard criteria for the assessment 
of disease response in solid tumors. 
The effects of H3B-6527 in FGF19 and other FGFR4-related biomarkers and any correlation 
with safety and antitumor activity will be evaluated during the study.   
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations 
9.5.4.1 
Reporting of Serious Adverse Events 
All SAEs, 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 
when the investigator becomes aware of the event. 
SAEs, regardless of causality assessment, must be collected through the OTV (ie, 30 days 
after the last study drug 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. 
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. 


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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 follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the Sponsor. 
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. 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding 
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 30 days of last study treatment or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment must be reported. 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion is considered to be an SAE and should be reported in the same time frame and in the 
same format as all other SAEs (see Section 9.5.4.1). 
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome. 
Study drug must be discontinued immediately for any subject who becomes pregnant during 
the study. 


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9.5.4.3 
Reporting of Events Associated with Special Situations 
9.5.4.3.1 
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. 
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and reported using the procedures detailed in Section 9.5.4.1 even if 
the AEs do not meet serious criteria.  Abuse is always to be captured as an AE.  If the AE 
associated with an overdose, misuse, abuse, or medication error does not meet serious 
criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF 
9.5.4.4 
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. 
9.5.4.5 
Breaking the Blind 
Not applicable. 
9.5.4.6 
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. 


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All studies that are conducted within any European country will comply with European GCP 
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. 
9.5.5 
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 study drug and study participation 
at any time for any reason.  All subjects who discontinue study drug are to complete the 
Off-Treatment visit, as indicated in the Schedule of Procedures/Assessments Table 6 and 
Table 7).   
Study drug is to be discontinued for the following reasons: 
• Progression of disease that, in the opinion of the investigator, precludes further study 
treatment.  (After consultation with the Sponsor, H3B-6527 may be continued for a 
subject who has met the criteria for PD but, in the investigator’s opinion, is receiving 
benefit.) 
• Occurrence of an unacceptable AE. 
• Subjects who do not receive study drug for at least 17 of 21 days (approximately 80%, 
not necessarily consecutively) during the first cycle for reasons not considered to be a 
DLT by both the investigators and the Sponsor will be replaced.  The subjects who are 
replaced will not be considered evaluable for DLT assessments.  
• Subject requires use of a prohibited concomitant medication or therapy. 
• General or specific changes in the subject’s condition unacceptable for further treatment 
within the study parameters, in the judgment of the investigator. 
• Non-compliance.  
• Lost to follow-up. 
• Subject, investigator, or Sponsor request.  
The reason for study drug discontinuation is to be documented in the CRF. 
Subjects who discontinue study drug for reasons other than PD are to continue to have tumor 
measurements and disease response assessments performed every 6 weeks until the 
development of PD.  After development of PD, subjects who discontinue study treatment, 
regardless of their reasons for doing so, will be followed for survival approximately every 12 
weeks for up to 12 months or until 6 cycles after last patient in, death, loss to follow-up, or 
withdrawal of consent, whichever occurs first.  However, subjects may continue to receive 
study treatment, as long as they demonstrate clinical benefit as judged by the investigator 
after discussion with the Sponsor or until the end of the study. 
Study participation also may be discontinued for any of the following reasons: 


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• Subject withdrawal of consent 
• Non-compliance 
• Lost to follow-up 
• Sponsor request 
• Closure of the study by the Sponsor. 
The reason for study discontinuation is to be documented in the CRF. 
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed by 
mail, telephone, or other means to gather information such as the reason for failure to return, 
the status of treatment compliance, the presence or absence of AEs, and clinical courses of 
signs and symptoms. 
9.5.6 
Abuse or Diversion of Study Drug 
Not applicable. 
9.5.7 
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. 
9.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
Standard Operating Procedures, working practice documents, and applicable regulations and 
guidelines.  Site audits may 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.   
9.6.1 
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 


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clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 
1572 must sign the completed CRF to attest to its accuracy, authenticity, and completeness. 
Completed, original CRFs are the sole property of H3 Biomedicine and should not be made 
available in any form to third parties without written permission from H3 Biomedicine, 
except for authorized representatives of H3 Biomedicine or appropriate regulatory 
authorities. 
9.6.2 
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. 
9.7 
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.  Statistical analyses will be performed 
using WinNonlin and SAS software or other validated statistical software as required.  
Details of the statistical analyses will be included in a separate statistical analysis plan. 
9.7.1 
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 statistical analysis plan, which will be finalized before 
database lock. 
9.7.1.1 
Study Endpoints 
The primary study endpoints are: 
• Occurrence of DLTs as a function of the dose of H3B-6527 for determination of the 
MTD and RP2D. 
• Safety/tolerability:  the type and frequency of AEs, SAEs using CTCAE, 
Version 4.03, as well as changes in clinical laboratory values, ECG parameters, and 
vital sign measurements. 
Secondary study endpoints are: 
• PK:  standard primary PK parameters including, but not limited to, the area under the 
plasma concentration-time curve from time 0 through the last measurable point 
(AUC0−t), maximum observed plasma concentration (Cmax) and time of maximum 
observed plasma concentration (tmax).   
• Preliminary antitumor activity:  Response will be determined by the investigator 
using mRECIST (Appendix 1).  The following endpoints will be determined: 


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- ORR, defined as the proportion of subjects achieving a best overall confirmed 
response of partial response (PR) or CR (PR + CR), from first dose date until 
disease progression/recurrence.   
- Duration of response, defined as the time from the date of first documented 
CR/PR until the first documentation of disease progression as determined by the 
investigator or death, whichever comes first.   
- Progression-free survival (PFS), defined as the time from first dose date to the 
date of the first documentation of disease progression as determined by the 
investigator or death (whichever occurs first).   
- Overall survival (OS), defined as the time from first dose date to the date of death. 
- Time to response, defined as the time from first dose date to the date of first 
documented CR/PR. 
Exploratory study endpoints include: 
• Correlation of biomarker expression levels with antitumor activity and safety 
• Expression levels of biomarkers in blood and tumor samples 
• Correlation of biomarker expression levels with H3B-6527 exposure in plasma 
• H3B-6527 levels in tumor tissue may be assessed 
• H3B-6527 metabolites in plasma and urine 
9.7.1.2 
Definitions of Analysis Sets 
Analyses will be performed using the following analysis sets: 
• Full Analysis Set, which will include all subjects who receive at least 1 dose of study 
drug.  This will be the primary analysis set for efficacy evaluations, as well as for 
demographic and baseline characteristics.  The summary of efficacy will be based on 
this set for HCC subjects.   
• Safety Analysis Set, which will include all subjects who received at least 1 dose of 
study drug.  This will be the analysis set for all safety evaluations except DLT results. 
• PK Analysis Set, which will include all subjects who have received at least 1 dose of 
study drug and have at least 1 evaluable plasma concentrations. 
• Pharmacodynamics Analysis Set, which will include all subjects who have received 
at least 1 dose of study drug and have evaluable pharmacodynamic data. 


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• PK/Pharmacodynamics Analysis Set, which will consist of all subjects in the Safety 
Analysis Set that also have evaluable plasma PK and pharmacodynamic pretreatment 
assessment and at least 1 posttreatment assessment. 
• Response Evaluable Set, which will consist of those HCC subjects who have 
received at least 1 dose of study drug and have measurable disease at baseline and at 
least 1 postbaseline evaluation.  
9.7.1.3 
Subject Disposition 
The numbers 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. 
9.7.1.4 
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. 
9.7.1.5 
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 WHO Drug Dictionary.  The number (percentage) of subjects 
who took prior and concomitant medications will be summarized on the Full Analysis Set by 
study part and cohort and overall, Anatomical Therapeutic Chemical class (ie, anatomical 
class, therapeutic class, pharmacologic class, chemical class), and WHO Drug Dictionary 
preferred term (PT).  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 30 days after the subject’s last dose.  All 
medications will be presented in subject data listings. 
9.7.1.6 
Efficacy Analyses 
The efficacy analyses will be performed at the time of data cutoff for primary analysis.  
ORR, response duration, time to response, PFS, and OS will be listed and descriptively 
summarized as appropriate.  All efficacy parameters will be summarized for the Full 
Analysis Set for HCC subjects.  In addition, ORR, duration of response, and time to response 
will also be summarized for the Response Evaluable Set as appropriate.  
ORR will be reported in summary tables. 
For response duration and time to response, summary statistics (median Q1, Q3 and range) 
will be generated on subjects achieving a best overall response of PR or CR (PR + CR).  The 
summary statistics will be generated using Kaplan-Meier estimate. 


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For PFS, subjects who do not have progression of disease or death information will be treated 
as right-censored observations at the time of the last response evaluation.  The PFS censoring 
rules will follow the FDA guidance.  PFS will be reported in both summary tables and 
plotted with Kaplan-Meier curve.   
For OS, time of death will be censored for subjects who are without death information at the 
time of OS analysis.  OS will be reported in both summary tables and plotted with Kaplan-
Meier curve. 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
9.7.1.7.1 
PHARMACOKINETIC ANALYSES 
Plasma concentrations of H3B-6527 will be tabulated and summarized by dose level, day, 
and time.  H3B-6527 PK parameters will be derived from plasma concentrations by 
noncompartmental analysis using actual times.  Minimally, the following PK parameters will 
be calculated:  Cmax, tmax, AUC0-t, accumulation ratio (Racc); and if data permit, area under 
the plasma concentration-time curve extrapolated to infinity (AUC0-inf), terminal 
elimination half-life (t½), apparent total body clearance (CL/F), and apparent volume of 
distribution during the terminal phase (Vz/F). 
9.7.1.7.2 
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES 
Pharmacodynamics, PG and other biomarker analyses may be performed and reported 
separately.  Details of these analyses will be described in a separate analysis plan. 
9.7.1.8 
Safety Analyses 
Evaluation of safety will be performed on the Safety Analysis Set except for the 
determination of the MTD during the dose escalation.  The determination of the MTD will be 
based on all DLT-evaluable subjects enrolled in the Dose Escalation part. 
Subjects who do not receive study drug for at least 17 of 21 days (approximately 80%; not 
necessarily consecutively) during the first cycle for reasons not considered to be a DLT by 
both the investigators and the Sponsor will be replaced.  The subjects who are replaced will 
not be considered evaluable for DLT assessments. 
Safety data to be evaluated include AEs, clinical laboratory results, vital signs, ECGs, and the 
results of ophthalmic examinations. 
Safety parameters will be summarized using descriptive statistics (mean, standard deviation, 
median, Q1, Q3, and range for continuous variables; numbers and percentages for categorical 
measures). 
The effects of H3B-6527 on cardiovascular repolarization will be evaluated via 12-lead 
continuous Holter/ECG monitoring on C1 Day 1 and on Day 8 in the Dose Escalation phase 


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of the study only.  Individual ECGs will be extracted from the Holter recordings at specified 
time points per ECG manual and will be evaluated by a central laboratory.  QT intervals will 
be measured from Lead II and will be corrected for QTcF correction factors.  The primary 
QTc parameter will be QTcF; secondary parameters (QTcB, QT, QRS, OTcB, PR, and heart 
rate) and waveforms (T waves) will be evaluated. 
9.7.1.8.1 
EXTENT OF EXPOSURE 
Descriptive statistics for subjects treated, including the duration of treatment, the number of 
cycles received, and the number of subjects requiring dose changes, will be presented.  A 
by-subject listing of the date of study drug administration and the dose administered will be 
presented. 
9.7.1.8.2 
ADVERSE EVENTS 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  AEs will be coded to the MedDRA (Version 18.0 or higher) lower level term 
closest to the verbatim term.  The linked MedDRA PT and primary system organ class (SOC) 
are also captured in the database. 
A treatment-emergent adverse event (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 were treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings. 
The TEAEs will be summarized overall and by study part and cohort.  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 a 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 TEAEs leading to death will be summarized by 
MedDRA SOC and PT overall and for each study part and cohort.  A subject data listing of 
all AEs leading to death will be provided. 


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The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and PT overall and for each study part and cohort.  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 overall and for each study part and cohort.  A 
subject data listing of all AEs leading to discontinuation from study drug will be provided. 
In DLT-evaluable subjects, the number (percentage) of subjects with DLT will be presented 
by dose level for Dose Escalation phase of the study.  Listing of subjects with DLT will be 
provided. 
9.7.1.8.3 
LABORATORY VALUES 
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.4.3, the actual value and the change 
from baseline to each postbaseline visit and to the end of treatment (defined as the last on-
treatment value) will be summarized by visit and study part and dose cohort using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.4.3 will be summarized using 
frequencies (number and percentage of subjects), and changes from baseline to each 
postbaseline visit and to end of treatment 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 postbaseline CTCAE 
grade will be tabulated by cycle and overall for selected laboratory parameters to include at 
least hemoglobin, white blood cell count, ANC, lymphocytes, platelet count, AST, ALT, 
bilirubin, creatinine, alkaline phosphatase, and electrolytes.  Shift tables will also be 
produced for these parameters based on the baseline CTCAE grade and the maximum 
CTCAE grade overall and by cycle. 
9.7.1.8.4 
VITAL SIGNS 
Changes in vital sign parameters (including systolic and diastolic BP, HR, RR, and 
temperature) and body weight will be summarized over time, and any abnormal values will 
be tabulated.   
9.7.1.8.5 
ELECTROCARDIOGRAMS AND HOLTER MONITORING 
For all subjects, 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, 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: 


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Absolute QTc interval prolongation: 
• QTc interval >450 ms 
• QTc interval >480 ms 
• QTc interval >500 ms 
Change from baseline in QTc interval: 
• QTc interval increases from baseline >30 ms 
• QTc interval increases from baseline >60 ms 
All ECG abnormalities will be listed on a per-subject basis. 
9.7.2 
Determination of Sample Size 
Dose Escalation Phase (Part 1) 
It is anticipated that selection of the RP2D will be based on an integrated evaluation of 
safety, tolerability, clinical benefit, PK, and pharmacodynamic data.  The total number of 
subjects to be enrolled is dependent upon the observed safety profile, which will determine 
the number of subjects per dose cohort, as well as the number of dose escalations required to 
achieve the MTD and/or RP2D.  For each dose schedule of QD and BID, assuming 5 dose 
levels for QD dose schedule and 3 dose levels for the BID dose schedule will be studied and 
a maximum of 6 subjects will be enrolled per dose level, then between 30 to 48 subjects may 
be accrued during dose escalation. 
Dose Expansion Phase (Part 2) 
A total of approximately 40 to 80 subjects will be enrolled in the Dose Expansion phase.  
Prior to starting the Dose Expansion phase, the investigators and the Sponsor will use safety, 
efficacy, PK, and pharmacodynamic data obtained during the Dose Escalation Phase, as well 
as clinical judgement, to jointly determine the dose schedules to be studied.  
During Part 2, the Dose Expansion phase, a sample size of 40 evaluable subjects per dose 
schedule will be enrolled to examine QD and/or BID dosing of H3B-6527 based on the 
recommended dose determined from Part 1 (Table 8).  For a reference of the precision of 
ORR estimates, the associated 2-sided 95% CIs for ORR up to 30% (40 subjects) are 
provided in Table 9.  
This study makes provision for exploring a BID schedule of H3B-6527 during the Dose 
Expansion phase if evaluation of the PK, pharmacodynamics, or safety of H3B-6527 
suggests that it may be preferable to administer H3B-6527 BID rather than QD.  When both 
dose schedules are accruing subjects, an alternating enrollment schema into QD and BID 
schedule will be followed.  


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Table 8 
Treatment Arms for Part 2, Dose Expansion 
Treatment Arm 
Number of Subjects 
1:  Subjects with advanced HCC who are FGF19-positive to 
receive H3B-6527 QD for 21-day cycles 
40 subjects 
2:  Subjects with advanced HCC who are FGF19-positive to 
receive H3B-6527 BID for 21-day cycles 
40 subjects 
BID = twice daily, HCC = hepatocellular carcinoma. 
 
 
 


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Table 9 
2-sided 95% Confidence Interval for ORR estimate up to 30%  
(40 subjects) 
ORR (N=40) 
2-sided 95% CI 
5% (2 responders in 40 subjects) 
(0.006, 0.169) 
7.5% (3 responders in 40 subjects) 
(0.016, 0.204) 
10% (4 responders in 40 subjects) 
(0.028, 0.234) 
12.5% (5 responders in 40 subjects) 
(0.042, 0.268) 
15% (6 responders in 40 subjects) 
(0.057, 0.298) 
17.5% (7 responders in 40 subjects) 
(0.073, 0.328) 
20% (8 responders in 40 subjects) 
(0.091, 0.356) 
22.5% (9 responders in 40 subjects) 
(0.108, 0.385) 
25% (10 responders in 40 subjects) 
(0.127, 0.412) 
27.5% (11 responders in 40 subjects) 
(0.146, 0.439) 
30% (12 responders in 40 subjects) 
(0.166, 0.465) 
CI = confidence interval, ORR = objective response rate. 
 
Within each treatment arm, if both QD and BID dose schedules are studied, an evaluation 
using efficacy, safety, PK, pharmacodynamic data will be performed and the investigators 
and Sponsor will jointly determine if one dose schedule is better than the other.  
9.7.3 
Interim Analysis 
There will be interim analyses to define the MTDs and/or RP2Ds prior to initiating the 
Expansion phase of the study.  Other interim analyses may be performed to determine if a 
different dosing schedule (eg, BID) or frequency (eg, 2-weeks on/1-week off) may be 
preferable.  Database locks are not required to perform these analyses.  Safety and PK 
summaries may be provided periodically.   
9.7.4 
Other Statistical/Analytical Issues 
Not applicable. 


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10 REFERENCE LIST 
Ahn C. An evaluation of phase 1 cancer clinical trial designs. Stat Med. 1998;17(14):1537-
1549. 
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 [published 28 May 2009 (v4.03: June 14, 2010)].  Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.  
Cheng AL, Guan Z, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib 
in patients with advanced hepatocellular carcinoma according to baseline status: subset 
analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer. 2012 Jul;48(10):1452-65. 
Dillman RO and Koziol JA. Phase 1 cancer trials: limitations and implications. Mol Biother. 
1992;4(3):117-121. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).  
Eur J Cancer.  2009;45(2):228-247. Available from:  
http://linkinghub.elsevier.com/retrieve/pii/S0959804908008733. 
European Medicines Agency, Guideline on the evaluation of anticancer medicinal products 
in man. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-
guideline-evaluation-anticancer-medicinal-products-man-revision-4_en.pdf. 
Food and Drug Administration, Guidance for Industry, Cancer Drug and Biological Products 
- Clinical Data in Marketing Applications. Available from: 
https://www.fda.gov/media/71270/download. 
Gatsonis C and Greenhouse JB. Bayesian methods for phase 1 clinical trials.  Stat Med. 
1992;11(10):1377-1389. 
GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age–
sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a 
systematic analysis for the Global Burden of Disease Study 2013. Lancet. 
2015;385(9963):117–171. 
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation 
of Medicinal Products, Committee for Proprietary Medicinal Products, International Council 
for Harmonisation of Pharmaceuticals for Human Use 
Indiana University Department of Medicine.  Cytochrome P450 Drug Interaction Table. 
Available from:  http://medicine.iupui.edu/clinpharm/ddis/clinical-table.  Accessed 
07 Sep 2016. 


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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. 
Lencioni R and Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular 
carcinoma. Semin Liver Dis. 2010 Feb;30(1):52-60. 
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced 
hepatocellular carcinoma.  N Engl J Med. 2008 Jul 24;359(4):378-90. 
Llovet JM, Villanueva A, Lachenmayer A, Finn RS. Advances in targeted therapies for 
hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol. 2015 Jul;12(7):408-24. 
Mor V, Laliberte L, Morris JN, Wiemann M. The Karnofsky Performance Status Scale: an 
examination of its reliability and validity in a research setting. Cancer. 1984;53:2002-2007. 
Nexavar® United States Prescribing Information, Revised July 2015. Available from: 
https://dailymed.nlm.nih.gov/dailymed/index.cfm.  Accessed 09 Sep 2016. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982:5(6):649-655. 
Principles of the World Medical Association Declaration of Helsinki (64th WMA General 
Assembly, Fortalenza Brazil, October 2013) 
Storer BE. Design and analysis of phase 1 clinical trials. Biometrics. 1989;45(3):925-937. 
Tiong KH, Mah LY, Leong CO. Functional roles of fibroblast growth factor receptors 
(FGFRs) signaling in human cancers. Apoptosis (2013) 18:1447–1468. 


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) 
11.1 Changes to the Protocol 
There are to be no changes to the protocol without written approval from the Sponsor.  
Protocols will be followed as written. 
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 CA 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 CRA representing the Sponsor 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 IRB/IEC review. 


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In accordance with ICH E6, Section 1.52, source documents include, but are not limited to 
the following: 
• Clinic, office, or hospital charts 
• Copies or transcribed health care provider notes which have been certified for accuracy 
after production 
• Recorded data from automated instruments such as x-rays and other imaging reports (eg, 
sonograms, CT scans, MRIs, 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 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.   


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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, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the Sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product. 
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 the 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 drug 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 CRA representing the Sponsor 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/CRO and the Institution/investigator.  The review is aimed at protecting 
the Sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each investigator and the Sponsor or CRO, as appropriate. 
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 nonuse 
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 nonuse 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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12 APPENDICES 


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Appendix 1 
Modified Response Evaluation Criteria in Solid Tumors  
Tumor assessments will be performed following Modified Response Evaluation Criteria in 
Solid Tumors guidance (Lencioni and Llovet, 2010) using triphasic liver computed 
tomography (CT)/magnetic resonance imaging (MRI; optimized for precontrast, arterial 
phase, and portal venous phase) and elements of Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (Eisenhauer, et al., 2009).  
Quantitative and Qualitative Assessments of Tumor Burden 
The disease burden during Screening will be categorized into target and nontarget lesions.  
Within the target and nontarget categories are typical hepatic lesions, atypical hepatic lesions, 
and nonhepatic lesions. 
• Typical hepatic lesions are lesions that display hypervascularity in the arterial phase 
and “wash-out” in the portal venous phase of contrast-enhanced CT or MRI imaging. 
• Atypical hepatic lesions are lesions that are not showing the distinctive enhancement 
pattern but are considered to be malignant. 
• Nonhepatic lesions are all nodal and non-nodal lesions outside of the liver. 
Selection and Measurement of Target Lesions  
A maximum of 2 target lesions per organ and 5 target lesions in total, representative of all 
involved organs, may be selected.  Target lesions are lesions that can be accurately measured 
in at least 1 dimension and whose minimum lesion size is as follows: 
• Typical hepatic target lesions:  The longest diameter of the viable tumor must 
measure ≥1 cm or ≥2 times the slice thickness/reconstruction interval (if the slice 
thickness/reconstruction interval is >5 mm). 
• Atypical hepatic target lesions:  The longest diameter must measure ≥1 cm or 
≥2 times the slice thickness/reconstruction interval (if the slice 
thickness/reconstruction interval is >5 mm).   
• Nonhepatic non-nodal target lesions:  The longest diameter must measure ≥1 cm or 
≥2 times the slice thickness/reconstruction interval (if the slice 
thickness/reconstruction interval is >5 mm).   
• Nonhepatic nodal target lesions (lymph nodes):  The short axis must measure ≥1.5 cm 
with exception of porta hepatis lymph nodes that need to be ≥2.0 cm in the short axis 
(regardless of modality/scanner type and slice thickness/reconstruction interval). 
If typical and atypical liver lesions are present, preference should be given to typical liver 
lesions when selecting targets.  Target lesions are measured at every time point and a single 
Sum of Diameters (SOD) will be determined by adding the longest diameters of all 


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non-nodal lesions and short axes (ie, widest dimensions perpendicular to the long axis) of 
nodal nonhepatic lesions.  For typical hepatic lesions the longest diameters will include only 
the viable tissue, while for all other target lesions all tumor tissue (whether necrotic or not) 
will be included in the SOD.  Note that hypovascular tissue should not be considered as 
necrotic (nonviable) tissue.  While hypovascular tissue will still show contrast uptake 
(although less than what would be observed in a hypervascular lesion), necrotic tissue will 
show complete absence of any contrast enhancement.  Quantitative determinations of average 
Hounsfield Units (HU) in the tissue of interest both precontrast and postcontrast may be 
used, if needed, to support the subjective assessment:  necrotic (nonviable) tissue will show 
no change in HU between the phases, while hypovascular tissue will yield an increase in HU 
(although less than what would be observed in a hypervascular lesion) between precontrast 
and postcontrast images of the same region.   
Target lesions are assessed as complete response (CR), partial response (PR), stable disease 
(SD), progressive disease (PD), or not evaluable (NE) at every time point based on the SOD. 
Selection and Assessment of Nontarget Lesions 
Nontarget lesions are all other lesions, including malignant portal vein thrombosis, 
infiltrative type, and diffuse type hepatocellular carcinoma (HCC) with ill-defined lesion 
borders and truly nonmeasurable lesions.  Nontarget lesions will be assessed qualitatively, 
and the possible assessments are CR, Non-CR/Non-PD (NN), and PD.   
If a hepatic nontarget lesion exhibits an enhancement pattern that is consistent with HCC, the 
determination of CR, NN, PD, or NE will be dependent on the enhancing portion of the 
lesion.   
If pleural effusions or ascites selected as nontarget lesions at Baseline are stable in size or 
minimally enlarging, they will be assessed as NN.  A cytopathological confirmation of any 
effusion that appears or worsens on treatment is required when the measurable tumor has met 
criteria for response or SD. 
New Lesions 
New lesions are defined as: 
• Unequivocally new nonhepatic lesions seen at follow-up, without a corresponding 
lesion on the baseline imaging 
• New typical hepatic lesions displaying intratumoral arterial enhancement 
(hypervascularization in the arterial phase and washout in the portal venous phase on 
contrast-enhanced CT or MRI) that measure ≥1 cm in the longest diameter 
• New atypical hepatic lesions ≥1 cm in the longest diameter that show interval growth 
in subsequent scans of at least 1 cm 


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Any lesion that meets the requirements for unequivocal new lesions will trigger PD.  Any 
lesion that does not meet the above criteria (eg, <1 cm in longest diameter and/or does not 
show typical HCC vascular enhancement pattern) should be considered an equivocal new 
lesion.  If an equivocal lesion is later determined to be unequivocal, the time point of 
progression will be the time point the lesion was first noted as equivocal. 
Table 10 
Overall Response Assessments per mRECIST 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Time Point Response 
CR 
CR 
No 
CR 
CR 
NN 
No 
PR 
CR 
NE 
No 
PR 
PR 
NE 
No 
PR 
PR 
CR 
No 
PR 
PR 
NN 
No 
PR 
SD 
NE 
No 
SD 
SD 
CR 
No 
SD 
SD 
NN 
No 
SD 
PD 
Any 
Yes/No 
PD 
Any 
PD 
Yes/No 
PD 
Any 
Any 
Yes 
PD 
NE 
Non-PD 
No 
NE 
CR 
No nontarget lesions 
identified 
No 
CR 
PR 
No nontarget lesions 
identified 
No 
PR 
SD 
No nontarget lesions 
identified 
No 
SD 
CR = complete response, mRECIST = modified Response Evaluation Criteria In Solid Tumors, NE = not 
evaluable, NN = non-CR/non-PD, PD = progressive disease, PR = partial response, SD = stable disease. 
 
 
 


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Appendix 2 
Common Terminology Criteria for Adverse Events 
(v4.03) 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE), Version 4.03 [published 28 May 2009 (Version 4.03:  14 June 2010)] provides 
descriptive terminology to be used for adverse event reporting in clinical trials.  A brief 
definition is provided to clarify the meaning of each adverse event (AE) term.  To increase 
the accuracy of AE reporting, all adverse event terms in CTCAE, Version 4.03 have been 
correlated with single-concept, Medical Dictionary for Regulatory Activities (MedDRA) 
terms. 
CTCAE, Version 4.03 grading refers to the severity of the AE.  CTCAE Grades 1 through 5, 
with unique clinical descriptions of severity for each AE, are based on this general guideline: 
Grade 
CTCAE Status 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2 
Moderate: minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL.a 
3 
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care ADL.b 
4 
Life-threatening consequences: urgent intervention indicated. 
5 
Death related to adverse event. 
ADL = activities of daily living, CTCAE = Common Terminology Criteria for Adverse Events, NCI = National Cancer 
Institute. 
a:  Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
b:  Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
Adapted from the Cancer Therapy Evaluation Program, NCI.  CTCAE v4.03.  Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html (Accessed 25 Jun 2015). 
 
For further details regarding MedDRA, refer to the MedDRA website at: 
http://www.meddra.org/.  CTCAE, Version 4.03 is available online at:  
http://evs.nci.nih.gov/ftp1/CTCAE/About.html (Accessed 25 Jun 2015). 


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Appendix 3 
Eastern Cooperative Oncology Group Performance 
Status and Karnofsky Performance Status Scale 
ECOGa 
Karnofskyb 
Score 
Criterion 
% 
Criterion 
0 
Normal activity 
100 
Normal; no complaints; no evidence 
of disease 
 
 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease 
1 
Symptoms but ambulatory 
80 
Normal activity with effort; some 
signs or symptoms of disease 
 
 
70 
Cares for self; unable to carry on 
normal activity or do active work 
2 
In bed <50% of time 
60 
Requires occasional assistance but is 
able to care for most of his/her needs 
 
 
50 
Requires considerable assistance and 
frequent medical care 
3 
In bed >50% of time 
40 
Disabled, requires special care and 
assistance 
 
 
30 
Severely disabled; hospitalization is 
indicated though death is not 
imminent 
4 
100% bedridden 
20 
Very sick; hospitalization is necessary 
 
 
10 
Moribund; fatal processes progressing 
rapidly 
5 
Dead 
0 
Dead 
ECOG = Eastern Cooperative Oncology Group. 
a: 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al.  Toxicity and response 
criteria of the Eastern Cooperative Oncology Group.  Am J Clin Oncol.  1982;5:649-655. 
b: Mor V, Laliberte L, Morris JN, Wiemann M.  The Karnofsky Performance Status Scale:  an examination of 
its reliability and validity in a research setting.  Cancer.  1984;53:2002-2007. 


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Appendix 4 
Pharmacokinetic Sample Collection, Handling, and 
Shipping 
Blood Samples 
Samples will be processed following the procedures below.  Each plasma sample will be 
identified by protocol number, subject number, nominal day and time of sampling, and 
specimen matrix.   
1. Draw blood samples from the median antebrachial vein and transferred into tubes 
containing sodium heparin. 
2. Mix the blood and anticoagulant by gently inverting the tube 8 to 10 times and then place 
on water ice (crushed ice). 
3. Within approximately 30 minutes of collection, centrifuge samples for 15 minutes at 
2500 rpm at 4 °C. 
4. Pipette the separated plasma equally, at least 1.5 mL each, into two 5 mL polypropylene 
tubes (Tubes marked as A and B).  If the required volume of blood cannot be collected, a 
minimum of 1.5 mL of plasma must be transferred into Tube A and the remaining 
volume transferred to Tube B. 
5. Store samples in an upright position at approximately –20 °C until samples are 
transferred for analysis to the designated bioanalytical laboratory. 
6. After plasma separation, the remaining buffy coat and red blood cell layers should be 
discarded by the study institution in a proper manner. 
Urine Samples (for Metabolite Profiling) 
1. Subjects must void their urine just prior to the administration of study drug.   
2. Urine will be collected in containers.  During each collection period, the urine samples 
will be stored in a refrigerator at approximately 4 °C. 
3. At the end of each collection interval, weight the collected urine and measure total 
volume of urine.  Record the total volume in the case report form. 
4. Mix the contents of each urine container gently to obtain a homogeneous solution. 
5. Transfer approximately an aliquot of 8 mL each into the 13-mL polypropylene tubes 
(Tubes marked as A and B). 
6. Store urine samples in an upright position at approximately -20 °C until samples are 
transferred for analysis to the designated bioanalytical laboratory. 
7. The remaining urine will be appropriately discarded by the study institution in a proper 
manner.   


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Appendix 5 
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research 
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacodynamics, pharmacogenomics (PG) (separate consent required), and other 
biomarker analysis.  These samples may be used for discovery and validation to identify 
biomarkers that may be used for exploratory evaluation of response and/or safety-related 
outcomes as well as for use in diagnostic development. 
The PG samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential adverse events related to study treatment, and to explore the role of 
genetic variability in response.  Samples may be analyzed to determine a subject’s genotypes 
or sequence for a number of genes or noncoding regulatory regions.  The research may 
include the investigation of polymorphisms in genes that are likely to influence the study 
drug PK or therapeutic response. 
Collection of the pharmacodynamic, PG, and other biomarker samples will be bound by the 
sample principles and processes outlined in the main study protocol.  Sample collection for 
pharmacodynamic, PG, and other biomarker analysis is required as per the study protocol 
unless the collection and use of the samples is prohibited by specific country laws. 
Sample Collection and Handling 
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic deoxyribonucleic acid (DNA) blood sample cannot be obtained 
at the prespecified visit, the sample can be taken at any study center visit at the discretion of 
the investigator and site staff. 
Security of the Samples, Use of the Samples, Retention of the Samples 
Sample processing, for example DNA and/or ribonucleic acid extraction, genotyping, 
sequencing, or other analysis will be performed by a laboratory under the direction of the 
Sponsor.  Processing, analysis, and storage will be performed at a secure laboratory facility 
to protect the validity of the data and maintain subject privacy. 
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the Sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The Sponsor will not sell the samples to a third party. 
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed. 


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It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the International Council for Harmonisation E15 
guidelines) in order to maintain subject privacy.   
Right to Withdraw 
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, H3 Biomedicine will destroy the samples.  
Information from any assays that have already been completed at the time of withdrawal of 
consent will continue to be used as necessary to protect the integrity of the research project. 
Subject Privacy and Return of Data 
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All pharmacodynamics and other biomarker 
samples will be single-coded.  Genomic DNA samples used to explore the effects on PK, 
treatment response, and safety will be single coded.  Genomic DNA samples that will be 
stored for long-term use (defined as 15 years after the completion of the study) will be double 
coded.  Double coding involves removing the initial code (subject identification [ID]) and 
replacing with another code such that the subject can be re-identified by use of 2 code keys.  
The code keys are usually held by different parties.  The key linking the sample ID to the 
subject number will be maintained separately from the sample.  At this point, the samples 
will be double-coded, the first code being the subject number.  Laboratory personnel 
performing genetic analysis will not have access to the “key.”  Clinical data collected as part 
of the clinical study will be cleaned of subject identifying information and linked by use of 
the sample ID “key.” 
The Sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection. 
The Sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include: 
• Clinical research organizations retained by the Sponsor  
• Independent ethics committees or institutional review boards that have responsibility for 
this research study  
• National regulatory authorities or equivalent government agencies 
At the end of the analysis, results may be presented in a final report which may include part 
or all of the coded data, in listing or summary format.  Other publication (eg, in peer-
reviewed scientific journals) or public presentation of the study results will only include 


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summaries of the population in the study, and no identified individual results will be 
disclosed. 
Given the research nature of the pharmacodynamics, PG, and other biomarker analysis, it 
will not be possible to return individual data to subjects.  The results that may be generated 
are not currently anticipated to have clinical relevance to the subjects or their family 
members.  Therefore, these results will not be disclosed to the subjects or their physicians. 
If at any time, pharmacodynamics, PG, and/or other biomarker results are obtained that may 
have clinical relevance, Institutional Review Board/Independent Ethics Committee review 
and approval will be sought to determine the most appropriate manner of disclosure and to 
determine whether or not validation in a Clinical Laboratory Improvement Amendments 
(CLIA)-certified setting will be required.  Sharing of research data with individual subjects 
should only occur when data have been validated by multiple studies and testing has been 
done in CLIA-approved laboratories. 
 
 


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Appendix 6 
Child Pugh Classification Scoring 
1.* 
Child Pugh Classification 
Assessment 
[Child Pugh classification 
Assessment] 
Not Done 
Done, Enter Date of Assessment 
               Req / Req / Req (2016-2020) 
2. 
Total Serum Bilirubin 
[Total Serum Bilirubin] 
Bilirubin <2 mg/dL (1 point) 
Bilirubin 2 to 3 mg/dL (2 points) 
Bilirubin >3 mg/dL (3 points) 
3. 
Serum Albumin 
[Serum Albumin] 
Albumin >3.5 g/dL (1 point) 
Albumin 2.8 to 3.5 g/dL (2 points) 
Albumin <2.8 g/dL (3 points) 
4. 
INR 
[INR] 
INR <1.70 (1 point) 
INR 1.7 to 2.30 (2 points) 
INR >2.30 (3 points 
5. 
Ascites 
[Ascites] 
Absent (1 point) 
Mild (2 points) 
Moderate (3 points) 
6. 
Encephalopathy 
[Encephalopathy] 
Grade 0: Normal consciousness, personality, neurological 
examination, 
electroencephalogram (1 point) 
Grade 1: Restless, sleep disturbed, irritable/agitated, 
tremor, impaired handwriting, 5 cps (cycles per second) 
waves (2 points) 
Grade 2: Lethargic, time-disoriented, inappropriate, 
asterixis, ataxia, slow triphasic waves (2 points) 
Grade 3: Somnolent, stuporous, place-disoriented, 
hyperactive reflexes, rigidity, slower waves (3 points) 
Grade 4: Unrousable, coma, no personality/behaviour, 
decerebrate, slow 2 to 3 cps deactivity (3 points) 
7. 
Child Pugh Score [read-only] 
[Child Pugh Score] 
 
 
8. 
Child-Pugh classification 
[read-only] 
[Child-Pugh classification] 
Child Pugh Class A : 5 to 6 points 
Child Pugh Class B : 7 to 9 points 
Child Pugh Class C : 10 to 15 points 
CPS = cycles per second, INR = International Normalized Ratio. 


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PROTOCOL SIGNATURE PAGE 
Study Protocol Number: H3B-6527-G000-101 
Study Protocol Title: 
An Open-Label Multicenter Phase 1 Study to Evaluate the 
Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 
in Subjects With Advanced Hepatocellular Carcinoma 
Investigational Product 
Name: 
H3B-6527 
IND Number: 
128686 
EudraCT Number: 
2016-001915-19 
 
SIGNATURES 
 
 
 
__
_ 
 
 
 
 
 
______________ 
H3 Biomedicine, Inc. 
 
Date 
 
 
_
Oncology Business Group 
Eisai, Inc. 
 
 
 
 
______________ 
Date 
 
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE 
 
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 Registration of 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 
 

SAP_001.pdf: 
 
Statistical Analysis Plan 
H3B-6527-G000-101 
 
 
H3 Biomedicine and Eisai  
Amendment 0.2 
CONFIDENTIAL 
 
Page 1 of 24  
 
 
 
 
 
            
 
 
 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
H3B-6527-G000-101 
 
Study Protocol Title: 
An Open-Label Multicenter Phase 1 Study to Evaluate the Safety, 
Pharmacokinetics and Pharmacodynamics of H3B-6527 in 
Subjects With Advanced Hepatocellular Carcinoma.  
 
 
Approval Date: 
Original SAP                08 Feb 2017 
Amendment 0.1            08 Nov 2017 
Amendment 0.2            07 Oct 2020 
 
 
 
 
 
 
 
 
 
 


 
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SIGNATURE PAGE 
 
 
Author:  
Eisai Biostatistics 
 
Signature 
Date:  ______________ 
 
Approval 
 
Biostatistic
y: 
Eisai Biostatistics 
Signature 
Date: ________________ 
 
Study Director: 
 
H3 Biomedicine 
 
 
 
 
 
 
Signa
Date: ________________ 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................3 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................5 
3 
INTRODUCTION .............................................................................................................7 
3.1 
Study Objectives ......................................................................................................7 
3.1.1 
Primary Objectives .........................................................................................7 
3.1.2 
Secondary Objectives .....................................................................................7 
3.1.3 
Exploratory Objectives ..................................................................................7 
3.2 
Overall Study Design and Plan ................................................................................8 
3.2.1 
Study Design ..................................................................................................8 
3.2.2 
Dose Escalation (Part 1) .................................................................................9 
3.2.3 
Expansion (Part 2)........................................................................................11 
3.2.4 
Subject Participation Phases ........................................................................11 
4 
DETERMINATION OF SAMPLE SIZE ........................................................................12 
5 
STATISTICAL METHODS ............................................................................................14 
5.1 
Study Endpoints .....................................................................................................14 
5.1.1 
Primary Endpoints .......................................................................................14 
5.1.2 
Secondary Endpoints ...................................................................................14 
5.1.3 
Exploratory Endpoints .................................................................................15 
5.2 
Study Subjects ........................................................................................................15 
5.2.1 
Definitions of Analysis Sets.........................................................................15 
5.2.2 
Subject Disposition ......................................................................................16 
5.2.3 
Protocol Deviations ......................................................................................16 
5.2.4 
Demographic and Other Baseline Characteristics .......................................16 
5.2.5 
Prior and Concomitant Therapy ...................................................................17 
5.2.6 
Treatment Compliance .................................................................................17 
5.3 
Data Analysis General Considerations ..................................................................17 
5.3.1 
Pooling of Centers........................................................................................17 
5.3.2 
Adjustments for Covariates..........................................................................17 
5.3.3 
Multiple Comparisons/Multiplicity .............................................................17 
5.3.4 
Examination of Subgroups ...........................................................................17 
5.3.5 
Handling of Missing Data, Drop-outs, and Outliers ....................................17 
5.4 
Efficacy Analyses ..................................................................................................18 
5.4.1 Analysis of Efficacy Endpoints Based on Tumor Response ..............................18 
5.4.2 Analysis of Overall Survival ...............................................................................19 
5.5 
PHARMACOKINETIC, PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER 
BIOMARKERS ANALYSES ........................................................................................19 


 
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5.6 
Safety Analyses ......................................................................................................20 
5.6.1 
Extent of Exposure .......................................................................................20 
5.6.2 
Adverse Events ............................................................................................21 
5.6.3 
Laboratory Values ........................................................................................21 
5.6.4 
Vital Signs ....................................................................................................22 
5.6.5 
Electrocardiograms ......................................................................................22 
5.6.6 
Other Safety Analyses ..................................................................................22 
5.7 
Other Analyses .......................................................................................................23 
5.8 
Exploratory Analyses .............................................................................................23 
6 
INTERIM ANALYSES ...................................................................................................23 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................23 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING ...............................23 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................23 
10  STATISTICAL SOFTWARE ..........................................................................................24 
11  MOCK TABLES, LISTINGS AND GRAPHS ...............................................................24 
12  REFERENCES ................................................................................................................24 
 
 


 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
Adverse event 
ATC 
Anatomical therapeutic class 
AUC 
Area under curve  
AUC(0-inf) 
AUC from time point 0 extrapolated to infinity 
AUC(0-t) 
AUC from time point 0 through the last measurable point 
BID 
Twice Daily 
Cx 
Cycle x 
CI 
Confidence interval 
CL/F 
Apparent Total Body Clearance Following Oral 
Administration 
Cmax 
Maximum Observed Plasma Concentration 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common terminology criteria for adverse event 
DLT 
Dose limiting toxicities 
DME 
Dose modifying events 
DOR 
Duration of response 
ECGs 
Electrocardiograms 
FAS 
Full analysis set 
HCC 
Hepatocellular carcinoma 
ICC 
Intrahepatic cholangiocarcinoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute  
ORR 
Objective response rate 
OS 
Overall survival 
OTV 
Off-treatment visit 
PG 
Pharmacogenetic 


 
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Abbreviation 
Term 
PD 
Progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PT 
Preferred term 
Q1 and Q3 
The first and the third quartiles 
QD 
Once daily 
QTc 
Corrected QT interval 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
Racc 
Accumulation Ratio 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SI 
Système International 
SRC 
Safety review committee 
SOC 
System organ class 
t1/2 
Terminal elimination half-life 
TEAE 
Treatment-emergent adverse event 
TLG 
Tables, listings, and graphs 
tmax 
Time of maximum observed plasma concentration 
VZ/F 
Apparent volume of distribution during  the terminal phase 
WHO DD 
World Health Organization Drug Dictionary 
 


 
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3 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned statistical analysis and reporting for 
Clinical Study Protocol H3B-6527-G000-101 titled “An Open-Label, Multicenter Phase I 
Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 in 
Subjects with Advanced Hepatocellular Carcinoma”. 
This SAP amendment is based on SAP Amendment 0.1 dated on 08 Nov 2017 and the protocol 
Amendment 09 dated on 30 Sep 2020. In the event of future amendments to the protocol, this 
SAP amendment will be modified to account for changes relevant to the statistical analysis. 
3.1 
Study Objectives 
3.1.1 Primary Objectives 
The primary objectives are to:  
• Determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose 
(RP2D) of H3B-6527 in subjects with advanced hepatocellular carcinoma (HCC). 
• Assess the safety and tolerability of H3B-6527 as a single agent administered orally. 
3.1.2 
Secondary Objectives 
The secondary objectives are to:  
• Evaluate the pharmacokinetic (PK) profile of H3B-6527.  
• Evaluate the preliminary antitumor activity of H3B-6527 at the RP2D and schedule in 
subjects with advanced HCC, who are FGF19-positive, as determined by the 
Sponsor-designated laboratory. 
3.1.3 
Exploratory Objectives 
The exploratory objectives are to:  
• Explore biomarkers and their correlation with safety and efficacy endpoints. 
• Assess the pharmacodynamic effects of H3B-6527 on FGF19, Ki67, pERK, bile acids 
and CYP7A1 and other FGFR4-related biomarkers in blood and tumor samples. 
• Explore the relationship between PK and pharmacodynamics. 
• Exposure to H3B-6527 in tumor samples may be assessed. 
• Explore the metabolite profile of H3B-6527 in plasma and urine. 


 
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3.2 
Overall Study Design and Plan 
3.2.1 
Study Design 
This is an open-label, multicenter, Phase 1 study that will be conducted in 2 parts, a Dose 
Escalation phase (Part 1) and a Dose Expansion phase (Part 2). Dose escalation will follow a 
standard 3+3 cohort design until the MTD/RP2D is determined in this population. 
Approximately 30 to 128 subjects are planned for enrollment. H3B-6527 will be administered 
by mouth in 21-day cycles without break to examine both QD (once daily) and BID (twice 
daily) dose schedules.  
During both parts of the study, subjects will be administered the study drug with food based 
on the Healthy Volunteers Food-Effect study (Study H3B 6527-A001-001: A Randomized 
Phase 1 Food-Effect Study of H3B-6527 in Healthy Subjects). 
 
This study makes provision for exploring a BID schedule of H3B-6527; the criteria to evaluate 
a BID schedule will be based on an integrated evaluation of safety, tolerability, clinical benefit, 
PK, and pharmacodynamic data, for all QD dose levels tested. In this case, a new cohort of 3 
subjects will be enrolled and treated with a BID dose. The initial total daily dose given BID 
will be equal to a total daily dose that has been well tolerated as a QD dose (dose limiting 
toxicities (DLT) rate <33% in a cohort of 3-6 subjects).  
 
Figure 1: Overall Study Design 
 
Part 1: 
Dose Escalation Phase
H3B-6527 QD dose schedule:
5 treatment cohorts of sequential 
escalating doses of 300, 600, 1000, 
1400, and 2000 mg; 
6 subjects per cohort, 
N=up to 30
H3B-6527 BID dose schedule:
3 treatment cohorts;
total daily starting dose equal to the 
safest total dose in QD dose schedule; 
3 to 6 subjects per cohort, 
N=up to 18
Part 2:
Dose Expansion Phase
HCC FGF19-positive subjects
QD dose schedule
N= 40
HCC FGF19-positive subjects
BID dose schedule
N= 40


 
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3.2.2 
Dose Escalation (Part 1) 
The objective of the Dose Escalation phase is to determine the MTD and/or RP2D of H3B-
6527 in subjects with advanced HCC. Intrahepatic cholangiocarcinoma (ICC) subjects were 
also enrolled from protocol Amendement 5 to Amendment 7.  
For dose-escalation purposes, toxicities assigned as DLTs during the first cycle will be 
assessed. After 3-6 subjects in a cohort have completed Cycle 1 (C1), 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. Toxicities 
will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. 
Once a subject has completed C3 at the initially assigned dose schedule and dose level (QD or 
BID), intrapatient dose escalation will be allowed. 
H3B-6527 will be tested in sequential escalating dose cohorts (n=3 to 6) at the dose levels 
listed in the Table 1.   
Table 1 
Dose Cohorts in H3B-6527 Dose Escalation Phase 
Dose level 
Initial No. of Subjects 
H3B-6527 Total Daily 
Dose 
-1 
3 
150 mg 
1a 
3 
300 mg 
2 
3 
600 mg 
3 
3 
1000 mg 
4 
3 
1400 mg 
5 
3 
2000 mg 
These total daily (dose levels may be evaluated in QD or BID) dose schedules, including intermediate levels, differing MTDs 
by sub-population (e.g., disease indication or ethnicity), and in expansion of an existing dose level up to 12 evaluable subjects 
following discussion between the Sponsor and the investigators, if supported by evolving safety, tolerability, PK, and 
pharmacodynamic data. 
a: Planned starting dose level in QD schedule. 
 
Subjects will be assigned to a dose level in the order of study entry. Initially, 3 subjects will 
be enrolled at the starting dose level. If 2 of the 3 subjects experience a DLT then the dose 
level -1 (150 mg) will be explored. If 1 of the 3 subjects experiences a DLT then the dose 
will be expanded to 6 subjects. If ≥2 of 6 subjects in the starting dose cohort experience a 
DLT during the first cycle, then the dose level -1 (150 mg) will be explored. 
Dose escalation to the next higher dose may proceed if no DLT is observed in C1 among the 
first 3 subjects accrued to a cohort. If 1 of 3 subjects in the cohort experienced a DLT, up to a 
total of 6 subjects will be enrolled. If 2 or more of the 3-6 subjects in a cohort experience a 


 
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DLT, dose-escalation will cease, and additional subjects will be treated at a lower dose level. 
Dose escalation will continue until a dose level where 2 or more of 6 subjects experience a 
DLT. 
To be evaluable for a DLT, subjects must have completed safety assessments through 
predose on C1 Day 1 and must have received at least 17 of 21 (80%) study days within C1, 
unless due to a DLT.  Subjects who discontinue from the study for reasons other than DLT 
before completing C1 are to be replaced.   
Definitions of DLT and MTD 
The DLTs are defined as any of the toxicities listed in Table 2 occurring during C1 and judged 
by the investigator as related to study drug (i.e., assessed as unrelated to disease, intercurrent 
illness, or concomitant medications). 
Table 2 
Dose-Limiting Toxicity Definition 
TOXICITY  
CRITERIA 
Hematology 
 
Febrile neutropenia 
 
CTCAE Grade 4 neutropenia that does not resolve to Grade ≤2 within 7 
days 
 
CTCAE Grade 3 thrombocytopenia requiring transfusion 
 
CTCAE Grade 3 thrombocytopenia and clinically significant bleeding 
 
CTCAE Grade 4 thrombocytopenia 
 
CTCAE Grade 3 anemia if transfused or if lasting for more than 7 days 
 
CTCAE Grade 4 anemia of any duration 
Gastrointestinal 
 
CTCAE Grade 3 nausea, vomiting and/or diarrhea lasting more than 72 
hours despite the use of optimal anti-emetic/antidiarrheal treatment 
 
CTCAE Grade 4 diarrhea and/or vomiting irrespective of prophylaxis or 
appropriate treatment 
Renal 
 
CTCAE Grade ≥3 serum creatinine 
Hepatic 
 
CTCAE Grade 3 bilirubin (>3.0 × the upper limit of normal (ULN)) 
and/or alanine aminotransferase (ALT) ≥10 × ULN 
 
For subjects with a starting ALT within the normal range for the local 
laboratory, an elevation ALT ≥ 5 × ULN for the local laboratory 
 
For subjects with an abnormal value ≥ ULN at baseline based on the 
local laboratory ranges, an ALT elevation ≥ 10 × ULN for the local 
laboratory 
Other AEs not listed  
above 
 
Non-hematologic toxicities of CTCAE Grade ≥3 except for the following. 
- 
CTCAE Grade 3 fatigue lasting less than 1 week, 
- 
Isolated CTCAE Grade 3 elevations in biochemistry laboratory values 
without associated clinical symptoms that last for ≤7 days. This 
includes electrolyte abnormalities that respond to medical 
intervention. 
 
H3B-6527-related, CTCAE Grade 2 nonhematologic toxicities that, in the 
opinion of the treating investigator, require a dose reduction or 
discontinuation of study drug, or lead to the subject’s failure to complete 
at least 17 days of study drug administration in C1, may be deemed to be 


 
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dose-limiting if agreed upon by participating investigators and the 
Sponsor. 
 AE = adverse event, ALT = alanine aminotransferase, AST = aspartate aminotransferase, C = Cycle, CTCAE = 
Common Terminology Criteria for Adverse Events, ULN = upper limit of normal.  
 
The MTD is defined as the highest dose at which no more than 1 of 6 subjects experiences a 
DLT in the dose cohort. (Note that at least 6 subjects must be treated at the dose level 
potentially considered to be the MTD before that dose level can be considered the MTD).   
The RP2D may not exceed the MTD and will be agreed upon by the SRC based on an 
integrated evaluation of safety, tolerability, clinical benefit, PK, and pharmacodynamic data, 
for all dose levels tested. Clinically significant toxicities (eg, chronic Grade 2 toxicities) or 
adverse events (AEs) that meet the definition of dose limiting but occurring after C1 (dose 
modifying events, DME) may be considered when determining the RP2D. Once the 
MTD/RP2D is reached, at least 6 HCC subjects must be enrolled at the RP2D (regardless of 
the total number of subjects enrolled at that dose level) in order to proceed with dose 
expansion.  
 
3.2.3 
Expansion (Part 2) 
Prior to starting Part 2 of the study, the investigators and the Sponsor will use safety, 
efficacy, PK, and pharmacodynamic data obtained during the Dose Escalation Phase, as well 
as clinical judgement, to jointly determine the dose schedules to be studied.  
During Part 2, the Dose Expansion phase, approximately 40 subjects per dose schedule will 
be enrolled to examine QD and/or BID dose schedules.  Subjects enrolled into Part 2, Dose 
Expansion phase, must be FGF19-positive as defined by Sponsor-designated laboratory.   
When both dose schedules are accruing subjects, an alternating enrollment schema into QD 
and BID dose schedule will be followed.  
3.2.4 
Subject Participation Phases 
The study will be conducted in the following 4 phases:  Pretreatment Phase, Treatment 
Phase, Extension Phase, and Follow-up Phase. 
Pretreatment Phase 
Pretreatment Phase will last no longer than 28 days and includes a Screening Period to obtain 
informed consent and establish protocol eligibility and a Baseline Period to establish disease 
characteristics before treatment.  
Treatment Phase 


 
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Treatment phase will last for 1 treatment cycle of 21 days. Subjects who are receiving study 
drug at the end of the Treatment Phase will continue to receive study drug in the Extension 
Phase. 
Extension Phase 
In the Extension Phase, subjects will continue to receive the same treatment and dose they 
received during the Treatment Phase, provided termination criteria are not met. 
In Treatment and Extension phases, subjects will discontinue study drug at the time of disease 
progression, development of unacceptable toxicity, withdrawal of consent or termination of 
the Sponsor. However, subjects may continue to receive study treatment as long as there is 
demonstrated clinical benefit as judged by the investigator after discussion with the Sponsor 
or until the end of the study. Disease progression will be determined by the investigator 
following relevant Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines for 
ICC and modified RECIST (mRECIST) for HCC. The mRECIST for this protocol harmonizes 
the original mRECIST criteria (Lencioni and Llovet 2010) using triphasic liver computed 
tomography (CT)/magnetic resonance imaging (MRI; optimized for precontrast, arterial phase, 
and portal venous phase) and elements of RECIST 1.1 (Eisenhauer et al., 2009). 
Follow-up Phase 
After the Off-treatment Visit, all subjects who discontinue study treatment, regardless of their 
reasons for doing so, will be followed for survival approximately every 12 weeks for up to 12 
months or until 6 cycles after last patient in, death, loss to follow-up, or withdrawal of consent, 
whichever occurs first. Subjects who discontinue study drug without PD (progressive disease) 
will continue to undergo tumor assessments every 6 weeks until documented PD or another 
anticancer therapy is initiated.   
The data cutoff for the primary analysis will occur once the last subject completes 6 cycles of 
investigational therapy.   
The end of study is defined as when the last ongoing subject completes their off treatment visit.   
The schedules of assessments are presented in Table 6 and Table 7 of the Protocol. 
4 
DETERMINATION OF SAMPLE SIZE 
Dose Escalation Phase (Part 1) 
It is anticipated that selection of the RP2D will be based on an integrated evaluation of 
safety, tolerability, clinical benefit, PK, and pharmacodynamic data. The total number of 
subjects to be enrolled is dependent upon the observed safety profile, which will determine 
the number of subjects per dose cohort, as well as the number of dose escalations required to 
achieve the MTD and/or the RP2D. For each dose schedule of QD and BID, assuming 5 dose 
levels for QD dose schedule and 3 dose levels for the BID dose schedule will be studied and 
a maximum of 6 subjects will be enrolled per dose level, then between 30 to 48 subjects may 
be accrued during dose escalation. 
Dose Expansion Phase (Part 2) 


 
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A total of approximately 40 to 80 subjects will be enrolled in the Dose Expansion phase.  
Prior to starting the Dose Expansion phase, the investigators and the Sponsor will use safety, 
efficacy, PK, and pharmacodynamic data obtained during the Dose Escalation Phase, as well 
as clinical judgement, to jointly determine the dose schedules to be studied.  
During Part 2, the Dose Expansion phase, a sample size of 40 evaluable subjects per dose 
schedule will be enrolled to examine QD and/or BID dosing of H3B-6527 based on the 
recommended dose determined from Part 1 (Table 3).  For a reference of the precision of 
ORR estimates, the associated 2-sided 95% CIs for ORR up to 30% (40 subjects) are 
provided in Table 4. 
This study makes provision for exploring a BID schedule of H3B-6527 during the Dose 
Expansion phase if evaluation of the PK, pharmacodynamics, or safety of H3B-6527 
suggests that it may be preferable to administer H3B-6527 BID rather than QD.  When both 
dose schedules are accruing subjects, an alternating enrollment schema into QD and BID 
schedule will be followed.  
Table 3. 
Treatment Arms for Part 2, Dose Expansion 
Treatment Arm 
Number of Subjects 
1: Subjects with advanced HCC who are FGF19-
positive to receive H3B-6527 QD for 21-day cycles 
40 subjects 
2: Subjects with advanced HCC who are FGF19-
positive to receive H3B-6527 BID for 21-day cycles 
40 subjects 
 
 
Table 4. 
2-sided 95% CI for ORR estimate up to 30%  
(40 subjects) 
ORR (N=40) 
2-sided 95% CI 
5% (2 responders in 40 subjects) 
(0.006, 0.169) 
7.5% (3 responders in 40 subjects) 
(0.016, 0.204) 
10% (4 responders in 40 subjects) 
(0.028, 0.234) 
12.5% (5 responders in 40 subjects) 
(0.042, 0.268) 
15% (6 responders in 40 subjects) 
(0.057, 0.298) 
17.5% (7 responders in 40 subjects) 
(0.073, 0.328) 
20% (8 responders in 40 subjects) 
(0.091, 0.356) 
22.5% (9 responders in 40 subjects) 
(0.108, 0.385) 
25% (10 responders in 40 subjects) 
(0.127, 0.412) 
27.5% (11 responders in 40 subjects) 
(0.146, 0.439) 
30% (12 responders in 40 subjects) 
(0.166, 0.465) 


 
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Within each treatment arm, if both QD and BID dose schedules are studied, an evaluation 
using efficacy, safety, PK, pharmacodynamic data will be performed and the investigators 
and Sponsor will jointly determine if one dose schedule is better than the other.  
5 
STATISTICAL METHODS 
All statistical analyses and summary information are to be generated according this SAP. Any 
deviations from this SAP will be documented in the clinical study report (CSR).  
Unless otherwise stated, tables, listings, and graphs (TLGs) for Dose Escalation (Part 1) will 
be broken down by dose cohort, for Expansion (Part 2) by QD/BID dose schedule.  
5.1 
Study Endpoints 
5.1.1 
Primary Endpoints 
 Occurrence of DLTs as a function of the dose of H3B-6527 for determination of the 
MTD and RP2D. 
 Safety/tolerability: the type and frequency of AEs, serious adverse events (SAEs) using 
CTCAE, Version 4.03, as well as changes in clinical laboratory values, 
electrocardiogram (ECG) parameters and vital sign measurements. 
5.1.2 
Secondary Endpoints 
 PK: standard primary PK parameters including, but not limited to, the area under the 
plasma concentration-time curve from 0 through last measurable point (AUC0-t), 
maximum observed plasma concentration (Cmax) and time of maximum observed 
plasma concentration (tmax). 
 Preliminary antitumor activity: Response will be determined by the investigator using 
mRECIST/RECIST 1.1. The following endpoints will be determined: 
- Objective response rate (ORR), defined as the proportion of subjects achieving a 
best overall confirmed response of partial or complete response (partial response 
[PR] + complete response [CR]) from first dose date until disease 
progression/recurrence.  
- Duration of response (DOR), defined as the time from the date of first documented 
CR/PR until the first documentation of disease progression as determined by the 
investigator or death, whichever comes first. If a subject had no record of disease 
progression or did not die before the data cut-off date, then the subject will be 
censored at the last available tumor assessment. 
- Progression free survival (PFS), defined as the time from first dose date to the date 
of the first documentation of disease progression as determined by the investigator 
or death, whichever occurs first. 


 
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- Overall survival (OS), defined as the time from first dose date to the date of death. 
- Time to response, defined as the time from first dose date to the date of first 
documented CR/PR. 
5.1.3 
Exploratory Endpoints 
• Correlation of biomarker expression levels with antitumor activity and safety. 
• Expression levels of biomarkers in blood and tumor samples. 
• Correlation of biomarker expression levels with H3B-6527 exposure in plasma. 
• H3B-6527 levels in tumor tissue may be assessed. 
• H3B-6527 metabolites in plasma and urine. 
5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
Full Analysis Set (FAS) will include all subjects who received at least 1 dose of study drug. 
This will be the primary analysis set for demographic and baseline characteristics. Efficacy 
analysis will be based on FAS for HCC subjects only. 
Safety Analysis Set will include all subjects who received at least 1 dose of study drug. This 
will be the analysis set for all safety evaluations except DLT results. 
DLT Analysis Set will include all subjects in Dose Escalation phase (Part 1) who are evaluable 
for a DLT. To be evaluable for a DLT, subjects must have completed safety assessments through 
predose on C2 Day 1 and must have received at least 17 of 21 (approximately 80%) study days 
within C1, unless due to a DLT. This will be the analysis set for analyzing DLT results only. 
PK Analysis Set will include all subjects who have received at least 1 dose of study drug and 
have at least 1 evaluable plasma concentration.  
Pharmacodynamics Analysis Set will include all subjects who have received at least 1 dose 
of study drug and have evaluable pharmacodynamic data. 
PK/Pharmacodynamics Analysis Set will consist of all subjects in the Safety Analysis Set 
that also have evaluable plasma PK and pharmacodynamic pretreatment assessment and at 
least 1 post treatment assessment. 
Response Evaluable Set will consist of those HCC subjects who have received at least 1 dose 
of study drug and have measurable disease at baseline and at least 1 post-baseline evaluation. 
The number (percentage) of subjects enrolled in the study and included in each analysis set 
will be summarized. 
A listing of subjects included in each analysis set will be provided. 


 
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5.2.2 
Subject Disposition 
The number (percentage) of subjects who screened for participation, discontinued study drug 
and discontinued from the study will be summarized, along with the primary reason for 
screening failure and/or discontinuation. 
Listings of all subjects screened for participation, discontinued study drug and discontinued 
from the study, including primary reasons for screening failure and/or discontinuation will be 
provided. 
5.2.3 
Protocol Deviations 
All major protocol deviations will be determined prior to database lock and will be agreed 
upon by a review of individual subject data. The summary table and listing of major protocol 
deviations will be provided using data in the clinical database. 
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the FAS will be summarized using 
descriptive statistics. They include: 
 age (years) and age group (<65 years, >=65 years) 
 sex (male, female) 
 race (White, Black or African American, Asian [Japanese, Chinese, Other Asian], 
American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, and 
Other)  
 ethnicity (Hispanic or Latino, not Hispanic or Latino) 
 height (cm)  
 weight (kg)   
 ECOG performance status. 
The number (percentage) of subjects of previous anti-cancer medications, previous 
radiotherapy and tumor diagnosis assessed in the baseline for the FAS will be summarized, 
respectively.  
Listings of demographics, tumor diagnosis, Child-Pugh classification, previous anti-cancer 
medications and previous radiotherapy will be provided. 
Medical history 
The number (percentage) of subjects reporting a history of any medical condition will be 
summarized for the FAS. The medical history and current medical condition at baseline will 
be summarized as appropriate. Reported medical conditions will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA), version 19.0 or later.  
A listing of medical and surgical history will be provided. 


 
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5.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded on the case report form (CRF) will be coded 
using the World Health Organization Drug Dictionary (WHO DD) 2016 or current. The 
number (percent) of subjects who have taken prior and concomitant medications will be 
summarized on the FAS by Anatomical Therapeutic Chemical (ATC) Classification and WHO 
DD preferred term. Prior medications will be defined as medications that stopped prior to 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 30 days after the subject’s last dose.  
All medications will be presented in subject data listings. 
5.2.6 
Treatment Compliance 
Subjects with treatment related protocol deviations will be summarized. 
5.3 
Data Analysis General Considerations 
5.3.1 
Pooling of Centers  
Subjects from all centers will be pooled for all analyses. 
5.3.2 
Adjustments for Covariates 
Not applicable. 
5.3.3 
Multiple Comparisons/Multiplicity 
Not applicable. 
5.3.4 
Examination of Subgroups 
No formal subgroup analyses are planned.  Exploratory subgroup analyses may be performed 
as needed. 
5.3.5 
Handling of Missing Data, Drop-outs, and Outliers 
In general, missing or incomplete data, including dates, will be treated as missing or 
incomplete and no data imputation will be applied. Data that are potentially spurious or 
erroneous will be queried and examined during the review of the study data. 
For efficacy data summarized for the FAS for HCC subjects, subjects who start trial therapy 
and drop out prior to any tumor response assessment for any reason will be considered as 
nonresponders and will be included in the denominator when calculating the response rate. 
Some numerical laboratory data may contain a “<” or “>” or letters, the numerical value will 
be used for calculation and analysis in tables and figures and the complete character records in 
listings. 


 
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5.4 
Efficacy Analyses 
Efficacy analyses will be based on the FAS for HCC subjects only and/or Response Evaluable 
Set. 
5.4.1 Analysis of Efficacy Endpoints Based on Tumor Response 
ORR, duration of response (DOR), time to response and PFS will be analyzed on the FAS for 
HCC subjects and Response Evaluable Set as appropriate. 
The exact 95% confidence intervals of ORR will be calculated using Clopper-Pearson method. 
DOR and time to response will be for subjects who have achieved a best response of CR or PR 
only. Censoring rules for PFS will follow the FDA guidance and are specified in Table 5. PFS 
will be reported in both summary tables and plotted with Kaplan-Meier curve. 
Table 5 
Censoring Rules for PFS 
No. 
Situation 
Date of Event (Progression/Death) or 
Censoring 
Outcome 
1 
No baseline tumor assessments 
Date of first dose  
Censored 
 
2 
Progression documented between 
scheduled visits 
 
Date of first radiologic PD assessment 
 
Event 
 
3 
 
No progression 
Date of last adequate 
radiologic assessment 
 
Censored 
 
4 
 
New anticancer treatment started 
Date of last adequate radiologic 
assessment prior to or on date of 
new anticancer treatment 
 
Censored 
5 
Death before first PD assessment 
Date of death 
Event 
6 
Death between adequate assessment 
visits* 
Date of death 
Event 
 
7 
 
Death or progression after more 
than one missed visit/tumor 
assessment** 
Date of last adequate 
radiologic assessment before 
missed tumor assessments 
 
Censored 
CR = complete response, PD = progressive disease, PR = partial response, SD =stable disease, 
* Adequate tumor assessment is radiologic assessment of CR, PR, SD, non-CR/non-PD or PD 
at regular interval as defined in the protocol. 
** More than one missed visit/adequate tumor assessment is defined as having either one of the following 
two durations being longer than 14 weeks - 1 day, which is 97 days ( = ((6+1) x 2 x 7) – 1) for subjects on the 
every 6 week tumor assessment schedule: 
a.  Duration between two consecutive tumor assessments 
b. Duration between the last adequate tumor assessment and death or PD 
The priority of the censoring rules is as follows,  
1.  If the subject had PD or death, the following sequence will be applied: 
• 
If a subject did not have a baseline tumor assessment (No. 1), the subject will be censored on the date 
of first dose. 
 
If the subject died within 97 days (14 weeks -1 day) following first dose and did not receive a new 
anticancer treatment, it will be counted as PFS event at the date of death.  


 
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 
If a subject had new anticancer treatment before PD or death (No. 4), the subject will be censored on the 
date of the last adequate tumor assessment prior to or on the date of new anticancer treatment.  
• 
If a subject missed two or more tumor assessments before PD or death (No. 7), the subject will be 
censored on the date of the last adequate tumor assessment before PD or death.  Note that if a subject 
is censored by both this criterion and the anticancer treatment criterion, the earliest censoring date will be 
used. 
•    Otherwise, if a subject had an event (No. 2, No. 5, or No. 6), the earliest event date will be used. 
2.  If a subject did not have PD or death, the censoring date will be the earliest censoring date if the subject 
met multiple censoring criteria (No. 1, No. 3, No. 4, No. 7). 
 
A listing of target lesion response, non-target lesion response, new lesion and overall response 
at each assessment time point will be provided. Best overall response will be identified in the 
listing. 
5.4.2 Analysis of Overall Survival 
OS will be summarized, estimated and plotting using Kaplan-Meier method on the FAS for 
HCC subjects. Time of death will be censored for subjects who are without death information 
at the time of OS analysis. Censoring rules for OS are specified in Table 6. 
Table 6  
Censoring Rules for Overall Survival Endpoint 
Situation 
Event Date or Censoring 
Outcome 
Death during study 
Date of death 
Death 
Death after data cut-off 
Date of data cut-off 
Censored  
Subject still alive at data cut-off 
Date of data cut-off 
Censored  
Subject lost to follow-up before data 
cut-off 
Date last known to be 
alive  
Censored  
 
A listing of PFS and OS will be provided. 
5.5 
PHARMACOKINETIC, PHARMACODYNAMIC, PHARMACOGENOMIC, AND 
OTHER BIOMARKERS ANALYSES 
Pharmacokinetic Analysis  
Plasma concentrations of H3B-6527 will be tabulated and summarized by dose level, day, and 
time.  H3B-6527 PK parameters will be derived from plasma concentrations by 
noncompartmental analysis using actual times.  Minimally, the following PK parameters will 
be calculated: Cmax, tmax, AUC(0-t), accumulation ratio (Racc); and if data permit, area under the 
plasma concentration-time curve extrapolated to infinity (AUC(0-inf)), terminal elimination half-
life (t1/2), apparent total body clearance (CL/F), and apparent volume of distribution during the 
terminal phase (Vz/F). More details will be described in a separate PK analysis plan.  


 
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Pharmacodynamics, Pharmacogenetics (PG) and other biomarker analyses will be performed 
and reported separately. Details of these analyses will be described in separate analysis plans.  
5.6 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set and “as treated” basis 
except the evaluation of DLT and determination of the MTD. The number (percentage) of 
DLT will be summarized on and the determination of the MTD will be based on DLT 
Analysis Set in the Dose Escalation part.  
Subjects who do not receive study drug for at least 17 of 21 days (80%; not necessarily 
consecutively) during the first cycle for reasons not considered to be a DLT by both the 
investigators and the Sponsor will be replaced.  The subjects who are replaced will not be 
considered evaluable for DLT assessments. 
Safety data include all AEs, SAEs, clinical laboratory tests, vital signs, ECGs, 
MUGA/echocardiogram, and ophthalmic examinations.  
Safety parameters will be summarized using descriptive statistics (mean, standard deviation, 
median, Q1, Q3, and range for continuous variables; numbers and percentages for categorical 
measures). 
The effects of H3B-6527 on cardiovascular repolarization will be evaluated via 12-lead 
continuous cardiac Holter monitoring around first dose administration on C1 Day 1 and Day 8 
in the dose escalation part of the study only. Individual ECGs will be extracted from the Holter 
recordings at specified time points per ECG manual and will be evaluated by a central 
laboratory. QT intervals will be measured from Lead II and will be corrected for heart rate 
(QTc) using Fredericia’s (QTcF) correction factors. The primary QTc parameter will be QTcF; 
secondary parameters (QTc corrected using Bazett’s formula [QTcB], QT, QRS, PR, and heart 
rate) and wave forms (T waves) will be evaluated.   
5.6.1 Extent of Exposure 
The extent of exposure of study drug will be summarized for the Safety Analysis Set by number 
of cycles/days on treatment, duration of treatment, total dose, the number of cycles received 
and the number of subjects requiring dose reductions, treatment delay and treatment 
discontinuation due to AEs. A subject listing of study drug administration by cycle/visit will 
be provided. 
The treatment compliance will be summarized for the Safety Analysis Set by dose intensity 
and received dose as percentage of planned starting dose. 
Duration of treatment (days) = last dose date of study drug– first dose date of study drug+1. 
Dose intensity (mg/day) = total dose received during the study / (duration of treatment in days) 
Received dose as percentage of planned starting dose (%) = 100 x dose intensity (mg/day) / 
planned starting dose (mg/day). 
Listings of study drug administration by cycle/visit and treatment exposure will be provided. 


 
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5.6.2 
Adverse Events 
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 19.0 or higher) lower level term (LLT) closest to the verbatim term. The linked 
MedDRA preferred term (PT) and primary system organ class (SOC) are also captured in the 
database. 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during treatment 
up to 28 days after last dose, having been absent before treatment or:  
 reemerges during treatment, having been present before treatment but stopped before 
treatment, or 
 worsens in severity during treatment relative to before treatment state, when the AE was 
continuous. 
Only TEAEs will be included in summary tables.  
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 a SOC and PT, even if the subject 
experienced more than one TEAE within a specific SOC and PT. The number (percentage) of 
subjects with TEAEs will also be summarized by highest CTCAE grade. 
The number (percentage) of subjects with TEAEs, the number (percentage) of subjects with 
TEAEs leading to death, the number (percentage) of subjects with SAEs, and the number 
(percentage) of subjects with TEAEs leading to discontinuation from study drug will be 
summarized by MedDRA SOC and PT.  
Also, the TEAEs will be summarized by relationship to study drug (Yes or No) and by CTCAE 
grade.  
To assess the MTD and DLT, the number (percentage) of subjects with DLT events in each 
dose level will be summarized. 
All AEs will be presented in subject data listings. In addition, listings of DLTs, SAEs, AEs 
leading to death and AEs leading to discontinuation from study drug will be provided. 
5.6.3 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative laboratory parameters, the actual value and the change from baseline to 
each post baseline visit and to the end of treatment (defined as the last on-treatment value) will 
be summarized by visit. Qualitative parameters will be summarized using frequencies (number 
and percentage of subjects), and changes from baseline to each post-baseline visit and to end 
of treatment will be reported using shift tables. Percentages will be based on the number of 
subjects with both non-missing baseline and relevant post-baseline results. 
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, white blood cell count, ANC, lymphocytes, platelet count, AST, ALT, bilirubin, 


 
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creatinine, alkaline phosphatase, and electrolytes. Shift tables will also be produced for these 
parameters based on the baseline CTCAE grade and maximum CTCAE grade overall and by 
cycle. 
Listings of laboratory results will be provided.  
5.6.4 
Vital Signs 
Descriptive statistics for vital sign parameters (i.e. systolic and diastolic blood pressure, heart 
rate, respiratory rate, temperature, and weight) and changes from baseline will be summarized 
over time.  
A listing of vital sign measurements will be provided. 
5.6.5 
Electrocardiograms 
Descriptive statistics for ECG parameters (i.e. QTcF, QTcB, QT, QRS, heart rate and 
waveforms) and changes from baseline will be summarized over time. 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, the number (percentage) of subjects with at least 1 post baseline abnormal ECG 
result in QTcF during the treatment period will be summarized. Clinically abnormal ECG 
results in QTcF will be categorized as follows: 
Absolute QTc interval prolongation: 
 QTc interval > 450 ms 
 QTc interval > 480 ms 
 QTc interval > 500 ms 
Change from baseline in QTc interval: 
 QTC interval increases from baseline > 30 ms 
 QTC interval increases from baseline > 60 ms 
Listings of ECG results, ECG abnormalities and Holter recordings will be provided. 
5.6.6 
Other Safety Analyses 
ECOG performance status will be summarized by visit. Shift tables will present changes from 
baseline in ECOG performance status to worst post-baseline visit. 
Ophthalmologic examination will be summarized for left eye and right eye  by visual acuity 
test and central corneal thickness as continuous variables, and by funduscopic examimation 
and slit-lamp examination in terms of normality (normal/abnormal) and clinically significant 
at each  visit..  
Listings of ECOG, MUGA/echocardiogram, and ophthalmologic examinations will be 
provided.     


 
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5.7 
Other Analyses 
Other analyses may be conducted as appropriate. 
5.8 
Exploratory Analyses 
Exploratory analyses may be conducted as appropriate. More details will be given in a separate 
analysis plan if necessary. 
6 
INTERIM ANALYSES 
There will be interim analyses to define the MTDs and/or RP2Ds prior to initiating the 
Expansion phase of the study. Other interim analyses may be performed to determine if a 
different dosing schedule (eg, BID) or frequency (eg, 2-weeks on/1-week off) may be 
preferable. Database locks are not required to perform these analyses.  Safety and PK 
summaries may be provided periodically. 
7 
CHANGES IN THE PLANNED ANALYSES 
SAP Amendment 0.1: DLT analysis set is defined for the evaluation of DLTs. 
SAP amendment 0.2: Efficacy summaries will only include HCC subjects. Efficacy listings 
will include both HCC and ICC subjects who were enrolled prior to Protocol Amendment 8.  
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
The Baseline value will be defined as the last non-missing measurement prior to the first dose 
of the study drug. A Baseline value doesn’t have to be collected in the Baseline period. 
Descriptive statistics for continuous variables will be reported using number of non-missing 
measurements (n), mean, standard deviation (SD), median, the first quartile (Q1), the third 
quartile (Q3), minimum and maximum.  
Descriptive statistics for categorical variables will be summarized as number (percentage) of 
subjects.  
P-values will be presented with 3 decimal places or “< .001”, rates will be presented with 1 
decimal place or 0, CIs of rates will be reported as two-sided and calculated using Clopper-
Pearson method, and time-to-event variables will be estimated using Kaplan-Meier method. 
Further definitions and conventions for data handling will be presented in “Programming 
Specifications”. 
9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 


 
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10 
STATISTICAL SOFTWARE 
All statistical analyses will be performed using SAS 9.4, or later. 
11 
MOCK TABLES, LISTINGS AND GRAPHS 
The shells of TLGs in the study report  will be provided in a separate document which will 
show the content and format of TLGs in detail. Additionally, the Global Study Report 
Template gives the standard numbering structure for Section 14 tables, figures, and for 
Appendix 16.2 listings.  
12 
REFERENCES 
1. E.A. Eisenhauer, P. Therasse, J. Bogaerts, et al. New response evaluation criteria in solid 
tumors: Revised RECIST guideline (version 1.1), European Journal of Cancer 45 (2009)    
228-247. 
2. Riccardo Lencioni, MD, and Josep M. Llovet, M.D. Modified RECIST (mRECIST) 
Assessment for Hepatocellular Carcinoma, SEMINARS IN LIVER DISEASE/VOLUME 
30, NUMBER 1 2010.