Clinical trial NCT03897036
Conditions: Carcinoma, Basal Cell
Keywords: Advanced Basal Cell Carcinoma laBCC Locally Advanced Basal Cell Carcinoma mBCC Metastatic Basal Cell Carcinoma
Sponsor: Senhwa Biosciences, Inc.
Start date: 2019-04-16; Completion date: 2024-01-25
Enrollment: 25 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is to determine the recommended phase II dose (RP2D) and schedule of CX-4945 when administered orally twice daily for 28 consecutive days, in a 4-week (28 days) cycle, in patients with locally advanced or metastatic basal cell carcinoma (BCC). The safety and tolerability of CX-4945, preliminary evidence of antitumor effect, and the effect of CX-4945 treatment on the Hh signaling pathway will also be evaluated in this study.

Detailed description:
Basal cell carcinomas require the hedgehog (Hh) pathway for growth. Hh binding relieves the inhibitory effect of PTCH1 on Smoothened (SMO). Signal transduction by SMO then leads to the activation and nuclear localization of GLI1 transcription factors and induction of Hh target genes, many of which are involved in proliferation, survival, and angiogenesis. Hedgehog pathway inhibitors, such as vismodegib6 and sonidegib phosphate, target the G-protein-coupled receptor Smoothened (SMO) and are recommended as first-line treatment for advanced BCC or mBCC by the National Comprehensive Cancer Network. CK2 affects the terminal-most Hh signaling components. Given the roles of CK2 on the terminal step of the hedgehog signaling pathway, CK2 inhibition is unlikely to be overcome by downstream mutations within this pathway. These data thus suggest an immediately practical application of CX-4945 in Hh-driven tumors and possibly tumors resistant to SMO inhibitors.

Arms: arm 1: CX-4945 capsules at 1000mg BID x 28 days/cycle arm 2: CX-4945 capsules at 1000mg BID x 28 days/cycle
Interventions: intervention 1: CX-4945
Intervention descriptions: intervention 1: API powder-in-capsule in 200 mg strength

Protocol documents:
Prot_000.pdf: 
Senhwa Biosciences, Inc.  
 
Study Protocol CX-4945-07    Version: 6.0 
CONFIDENTIAL INFORMATION              06 April 2022 
1 
 
 
 
 
 
STUDY PROTOCOL 
 
 
Title: A Phase I, Multi-Center, Open-Label, Treatment Duration Increment, Expansion, Safety, 
and Pharmacodynamic Study of CX-4945 Administered Orally Twice Daily to Patients with 
Advanced Basal Cell Carcinoma 
 
Protocol Number:  CX-4945-07 
 
Study Drug: CX-4945 
 
IND: 102181 
 
NCT: 03897036 
 
Medical Monitor: Nina Baluja, MD 
 
Sponsor: Senhwa Biosciences, Inc. 10F, No.225, Section 3, Pei-Hsin Road, Hsin-Tien District, 
New Taipei City 23143, Taiwan R.O.C. 
 
 
Protocol Version 
Amendment # 
Amendment Date 
6.0 
Amendment 3.0 
06 April 2022 
 
 
 
Supersedes: 
5.0
Amendment 2.0
25 September 2020
4.0
Amendment 1.0
27 November 2018
3.0
Original
19 September 2018


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2. 
TREATMENT SCHEMA 
 
 
 
 
Patients with metastatic/locally 
advanced/unresectable Basal Cell 
Carcinoma (BCC)
(3-6 patients)
Starting dose and schedule:
CX-4945 twice daily dosing in 28-
day cycles
Determine RP2D of CX-4945
Expansion at RP2D - 20 patients;  10 
patients with metastatic BCC and 10 
patients with locally advanced BCC


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3. TABLE OF CONTENTS 
 
1. 
TITLE PAGE ......................................................................................................................1 
2. 
TREATMENT SCHEMA ..................................................................................................2 
3. 
TABLE OF CONTENTS ...................................................................................................3 
4. 
LIST OF ACRONYMS, ABBREVIATIONS, AND DEFINITIONS OF TERMS........6 
5. 
CLINICAL RESEARCH ETHICS ...................................................................................7 
5.1. 
INSTITUTIONAL REVIEW BOARD (IRB) .....................................................................7 
5.2. 
ETHICAL CONDUCT OF STUDY ...................................................................................7 
5.3. 
PATIENT INFORMATION AND CONSENT ..................................................................7 
6. 
SIGNATURE PAGE...........................................................................................................8 
7. 
INTRODUCTION ..............................................................................................................9 
7.1. 
BACKGROUND ................................................................................................................9 
7.2. 
BACKGROUND ON THE MOLECULE ..........................................................................9 
7.3. 
RATIONALE FOR DOING THIS STUDY ..................................................................... 13 
7.4. 
DOSING REGIMEN AND STARTING DOSE ............................................................... 14 
8. 
STUDY OBJECTIVES ..................................................................................................... 14 
9. 
INVESTIGATIONAL PLAN .......................................................................................... 14 
9.1. 
STUDY DESIGN AND PLAN ......................................................................................... 14 
9.2. 
OUTCOME MEASURES ................................................................................................. 15 
9.3. 
DEFINITION OF DLT ..................................................................................................... 16 
9.4. 
SAFETY PLAN ................................................................................................................ 16 
10. 
SELECTION OF STUDY POPULATION ..................................................................... 18 
10.1. 
PATIENT SELECTION ................................................................................................... 18 
10.1.1. 
Inclusion Criteria ............................................................................................. 18 
10.1.2. 
Exclusion Criteria............................................................................................ 20 
10.2. 
ENROLLMENT AND REGISTRATION PROCEDURES ............................................. 21 
10.2.1. 
Enrollment Procedures .................................................................................... 21 
10.2.2. 
Registration Procedures................................................................................... 21 
10.3. 
PATIENT DISCONTINUATION .................................................................................... 21 
10.4. 
PATIENT REPLACEMENT ............................................................................................ 21 
11. 
STUDY TREATMENT .................................................................................................... 22 
11.1. 
STUDY DRUG DESCRIPTION AND ALLOCATION .................................................. 22 
11.2. 
IDENTITY OF INVESTIGATIONAL PRODUCT ......................................................... 22 
11.3. 
ADMINISTRATION INSTRUCTION............................................................................. 23 
11.4. 
STORAGE AND HANDLING OF TEST ARTICLE ...................................................... 24 
11.5. 
CONCOMITANT AND EXCLUDED THERAPIES ....................................................... 24 
11.6. 
DOSE MODIFICATION FOR CX-4945 ......................................................................... 25 
11.7. 
PREMEDICATION .......................................................................................................... 25 
11.8. 
VITAMIN D SUPPLEMENT ........................................................................................... 26 
12. 
STUDY ASSESSMENTS ................................................................................................. 26 
12.1. 
DEFINITION OF STUDY ASSESSMENTS ................................................................... 26 


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12.2. 
SCREENING AND PRETREATMENT ASSESSMENTS .............................................. 30 
12.3. 
ASSESSMENTS DURING TREATMENT ..................................................................... 30 
12.4. 
STUDY COMPLETION/EARLY TERMINATION VISIT ............................................. 31 
13. 
STUDY DISCONTINUATION – STUDY STOPPING RULES .................................. 31 
14. 
ASSAY METHODS .......................................................................................................... 31 
14.1. 
EVALUATION OF HH PATHWAY STATUS USING QRT-PCR IN FRESH FROZEN 
TISSUE OR FORMALIN FIXED PARAFFIN EMBEDDED ......................................... 31 
15. 
STATISTICAL CONSIDERATIONS ............................................................................ 31 
15.1. 
SAFETY ANALYSES ...................................................................................................... 31 
15.2. 
EFFICACY ANALYSES ................................................................................................. 32 
15.3. 
ANALYSIS OF THE CONDUCT OF THE STUDY ....................................................... 32 
15.4. 
LENGTH OF TRIAL ........................................................................................................ 32 
15.5. 
HANDLING OF MISSING CLINICAL DATA............................................................... 32 
15.6. 
SAMPLE SIZE CONSIDERATIONS .............................................................................. 33 
15.7. 
DATA QUALITY ASSURANCE .................................................................................... 33 
16. 
ASSESSMENT OF SAFETY ........................................................................................... 33 
16.1. 
SAFETY VARIABLES AND DEFINITIONS ................................................................. 33 
16.1.1. 
Adverse Event ................................................................................................. 34 
16.1.2. 
Serious Adverse Event .................................................................................... 34 
16.1.3. 
Other Protocol Reportable Events – Pregnancy Reporting ............................. 35 
16.2. 
METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY 
PARAMETERS ................................................................................................................ 35 
16.2.1. 
Adverse Event Reporting Period ..................................................................... 36 
16.2.2. 
Assessment of Severity and Causality of Adverse Events .............................. 36 
16.3. 
PROCEDURES FOR RECORDING ADVERSE EVENTS ............................................ 37 
16.3.1. 
Recording Adverse Events on the eCRF ......................................................... 37 
16.4. 
EXPEDITED REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS 
AND OTHER PROTOCOL REPORTABLE EVENTS ................................................... 39 
16.4.1. 
Reporting Requirements for Fatal/Life-Threatening SAEs Related to         
Investigational Product ................................................................................... 39 
16.4.2. 
Reporting Requirements for All SAEs and Other Protocol Reportable Events...
 ........................................................................................................................ 39 
16.5. 
TYPE AND DURATION OF FOLLOW-UP OF PATIENTS AFTER ADVERSE 
EVENTS ........................................................................................................................... 40 
16.6. 
POST-STUDY ADVERSE EVENTS ............................................................................... 40 
17. 
INVESTIGATOR REQUIREMENTS ............................................................................ 40 
17.1. 
STUDY INITIATION ....................................................................................................... 40 
17.2. 
STUDY COMPLETION ................................................................................................... 41 
17.3. 
INFORMED CONSENT FORMS .................................................................................... 41 
17.4. 
COMMUNICATION WITH THE INSTITUTIONAL REVIEW BOARD OR ETHICS 
COMMITTEE ................................................................................................................... 42 
17.5. 
STUDY MONITORING REQUIREMENTS ................................................................... 43 
17.6. 
CASE REPORT FORMS .................................................................................................. 43 
17.7. 
SOURCE DATA DOCUMENTATION ........................................................................... 43 
17.8. 
STUDY DRUG ACCOUNTABILITY AND DISPOSITION OF UNUSED STUDY 
DRUG ............................................................................................................................... 44 
17.9. 
CONFIDENTIALITY OF DATA ..................................................................................... 44 
17.10. 
RETENTION OF RECORDS ........................................................................................... 45 
17.11. 
PUBLICATION AGREEMENT ...................................................................................... 45 
17.12. 
PROTOCOL ADHERENCE ............................................................................................ 45 


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18. 
ADMINISTRATIVE STRUCTURE ............................................................................... 45 
19. 
REFERENCES ................................................................................................................. 46 
APPENDIX A STUDY FLOWCHART ................................................................................................... 47 
APPENDIX B RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.0 
(RECIST) ........................................................................................................................... 50 
APPENDIX C COMPOSITE TUMOR RESPONSE CRITERIA FOR PATIENTS WITH 
LOCALLY ADVANCED BASAL CELL CARCINOMA ............................................ 55 
APPENDIX D DEFINITION OF WOMEN OF CHILDBEARING POTENTIAL AND 
ACCEPTABLE AND UNACCEPTABLE FORMS OF CONTRACEPTION ........... 58 
APPENDIX E VITAMIN D DOSING RECOMMENDATION1 ........................................................... 60 
APPENDIX F MEDICATIONS WITH THE POTENTIAL TO INTERACT WITH CX-4945 ........ 61 
APPENDIX G GUIDELINES FOR TISSUE BIOPSY IN PATIENTS WITH LOCALLY 
ADVANCED BASAL CELL CARCINOMA ................................................................. 62 
APPENDIX H DIGITAL PHOTOGRAPHIC PROCEDURES FOR SERIAL 
PHOTOGRAPHIC DOCUMENTATION OF BASAL CELL CARCINOMA .......... 67 
APPENDIX I ECOG PERFORMANCE STATUS ................................................................................ 68 
APPENDIX J EQUATION FOR CALCULATING AN ESTIMATED GLOMERULAR 
FILTRATION RATE ....................................................................................................... 69 
APPENDIX K HEDGEHOG PATHWAY ANTAGONISTS IN USE OR WITH POTENTIAL 
INTERACTION OF THE HEDGEHOG PATHWAY.................................................. 70 
 
 
 


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4. LIST OF ACRONYMS, ABBREVIATIONS, AND DEFINITIONS OF TERMS 
AE(s)
Adverse Event(s)
ALT
Alanine aminotransferase 
ANC
Absolute neutrophil count
API
Active pharmaceutical ingredient
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase 
BCC 
Bid 
BUN 
CBC 
CFR 
CR 
CRF 
CRO 
CT 
CTCAE 
DLT 
ECOG 
GCP 
HH 
HNSTD
Basal cell carcinoma 
Twice daily (bis in die) 
Blood urea nitrogen  
Complete blood count 
Code of Federal Regulations 
Complete Response 
Case Report Form 
Contract (Clinical) Research Organization 
Computerized (Axial) Tomography 
Common Terminology Criteria for Adverse Events 
Dose limiting toxicity 
Eastern Cooperative Oncology Group 
Good Clinical Practice 
Hedgehog 
Highest non-severely toxic dose
INR 
IRB 
IV 
LDH
International Normalized Ratio (for coagulation) 
Institutional Review Board 
Intravenous 
Lactate dehydrogenase 
mBCC 
MRI 
NPO 
PD
Metastatic basal cell carcinoma 
Magnetic resonance imaging 
nil per os (nothing by mouth) 
Progressive Disease
PK 
PR 
PT 
Qid 
RECIST 
RP2D 
SAE(s) 
SD 
SDV 
SMO
Pharmacokinetics 
Partial Response 
Prothrombin Time 
Four times daily (quarter in die) 
Response Evaluation Criteria in Solid Tumors 
Recommended Phase 2 Dose 
Serious Adverse Event(s) 
Stable Disease 
Source Data Verification 
Smoothened
SQ 
TEAE 
ULN 
WNL 
Subcutaneous 
Treatment Emergent Adverse Event 
Upper Limit of Normality (For lab values) 
Within normal limits 
 


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5. 
CLINICAL RESEARCH ETHICS 
5.1. 
INSTITUTIONAL REVIEW BOARD (IRB) 
 
This study will be conducted in compliance with current Good Clinical Practices (GCP) 
and Title 21 Part 56 of the United States of America Code of Federal Regulations 
(CFR) relating to Institutional Review Boards (IRBs). 
 
5.2.ETHICAL CONDUCT OF STUDY 
This study will be conducted in accordance with GCP of the International Conference 
on Harmonization (ICH) and the ethical principles of the Declaration of Helsinki. 
 
5.3. PATIENT INFORMATION AND CONSENT 
This study will be conducted in compliance with Title 21 Part 50 of the Code of Federal 
Regulations pertaining to patient informed consent.  Prior to initiating any study-related 
tests or procedures, patients will be required to grant their written consent to participate 
in the study after being informed of the nature and purpose of the study, 
participation/termination conditions, and the potential risks and benefits.   
 


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6. SIGNATURE PAGE 
 
Investigator Agreement:  I confirm that I have read this Protocol and all applicable 
amendments included in the Protocol, and I agree to conduct the study as outlined 
herein. 
 
Signature:  
 
 
 
Date:  
 
 
 
 
Investigator Name (print): _______________________________________  
 


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7. INTRODUCTION 
7.1. 
BACKGROUND 
Advanced Basal Cell Carcinoma 
 
Basal cell carcinoma (BCC) is the most common cancer in the United States1. It is 
estimated that BCCs occur in 2 million Americans each year; this exceeds the 
incidence of all other cancers combined 2-4. Almost all of these cases are small 
BCCs that can be effectively treated by dermatologists using several surgical 
modalities. However, locally advanced (unresectable) or metastatic BCC (mBCC) 
have a poor prognosis, with a mean survival ranging from 8 months to 3.6 years 5.  
 
Basal cell carcinomas require the hedgehog (Hh) pathway for growth. The Hh 
ligand in the extracellular space binds to Patched (PTCH1), a 12-pass 
transmembrane receptor on the surface of cells. Hh binding relieves the inhibitory 
effect of PTCH1 on Smoothened (SMO), a 7-pass transmembrane domain protein 
and a member of the G-protein coupled receptor superfamily. Signal transduction 
by SMO then leads to the activation and nuclear localization of GLI1 transcription 
factors and induction of Hh target genes, many of which are involved in 
proliferation, survival, and angiogenesis. Hedgehog pathway inhibitors, such as 
vismodegib6 and sonidegib phosphate, target the G-protein–coupled receptor 
Smoothened (SMO) and are recommended as first-line treatment for advanced 
BCC or mBCC by the National Comprehensive Cancer Network7. While initial 
response rates are about 50% in advanced and metastatic BCC, resistance to Hh 
inhibitor therapy generally develops within 6 to 8 months8. Better therapies are thus 
urgently required. 
 
The mechanisms of both acquired and intrinsic resistance to Hedgehog inhibitors 
is largely due to reactivation of the Hedgehog pathway with mutations in pathway 
components, primarily in SMO8.  
 
CK2 is a highly conserved serine/threonine protein kinase ubiquitously distributed 
in the cytoplasmic and nuclear compartments of multiple cell types9-11 . 
 
CK2 affects the terminal-most Hh signaling components by promoting Gli2 
stability and Gli2’s interaction with target genes Gli1, Ccnd1, Ptch1.  Targeting 
CK2 circumvents challenges of emergence of resistance and a priori resistance seen 
with existing small molecule inhibitors targeting upstream at SMO12.  Given the 
roles of CK2 on the terminal step of the hedgehog signaling pathway, CK2 
inhibition is unlikely to be overcome by downstream mutations within this 
pathway12. These data thus suggest an immediately practical application of CX-
4945 in Hh-driven tumors and possibly tumors resistant to SMO inhibitors. 
 
7.2. 
BACKGROUND ON THE MOLECULE 
CX-4945 is a highly selective, small molecule inhibitor of CK2 with a molecular 
weight of 371.75 and an empirical formula of C19H11ClN3NaO2.  


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CX-4945, the molecule to be evaluated in this Phase I study, has oral bioavailability 
and potent anti-tumor activity in a variety of primary human xenografts and tumor 
cell line xenograft models (see the CX-4945 Investigator Brochure). 
 
Three phase I clinical trials of CX-4945 in cancer patients have been conducted to 
date, and there is 1 ongoing phase I/II study of CX-4945 in combination with 
standard chemotherapy agents.  
 
All patients in the completed trials had advanced and/or relapsed or refractory 
cancer and had undergone previous cancer treatments. The median age of the 
patients was ≥60 years, and all were taking concomitant medications during the 
studies. 
 
CX-4945 was generally well-tolerated when administered following a twice-daily 
(bid) or four times-daily (qid) oral dosing schedule for 21 days followed by 7 days 
of rest. Most adverse events reported were mild to moderate in severity. The most 
common toxicities associated with CX-4945 were gastrointestinal disorders, 
including diarrhea, nausea and vomiting. Other frequently reported drug-related 
adverse events were hypokalemia and fatigue. Severe adverse events related to CX-
4945 were diarrhea, hypokalemia, hyponatremia, hypophosphatemia and 
lymphopenia. 
 
Most toxicities related to CX-4945 were manageable with drug discontinuation, use 
of antidiarrheal medication and potassium supplementation. 
 
The highest planned dose, 1000 mg bid, was found to be safe and tolerable. At this 
dose, 1 out of 12 patients experienced DLT, grade 4 hypokalemia. 
 
Generally, dose dependent peak plasma concentrations and AUC have been 
observed in the pharmacokinetic studies at steady state during both the twice daily 
and four-times daily administration of CX-4945. The observed terminal half-life at 
steady state is approximately 15 hours. 
 
Dose-proportional (Cmax and AUC) biomarker effects have been observed in CX-
4945-treated patients, including reduced phosphorylation of Akt and p21 in PBMCs 
beginning with the 300 mg bid dose level and 300 mg qid dose level. Reduced 
levels of plasma IL-6 and IL-8 have also been observed. 
 
Safety and pharmacokinetic data supported increasing the frequency of dosing from 
twice daily (BID) for 21 days followed by 7 days rest to 28 days of a 28-day cycle. 
 
Completed Study in Patients with Solid Tumors 
 
Two open-label, multicenter, dose-escalation, safety, PK, and pharmacodynamic 
studies (C4-08-001, C4-10-001) of CX-4945 have been completed in patients with 
advanced cancers or lymphoproliferative disorders known to overexpress CK2 that 


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had failed standard therapies (surgery, radiotherapy, endocrine therapy, 
chemotherapy) or for which effective therapy was not available. The eligible 
cancers included solid tumors (lung cancer, renal cell cancer, breast cancer 
[including inflammatory breast cancer], head and neck cancer [squamous cell], 
prostate cancer), Castleman’s disease (multi-centric disease), and multiple 
myeloma. However, all enrolled patients had solid tumors. 
 
In both studies, CX-4945 was administered either twice daily (bid) or 4 times daily 
(qid) for 21 days followed by a 7-day rest period in 28-day cycles. The drug was 
taken in a fed state, with at least 6 ounces (180 mL) of water. Patients were enrolled 
in the following oral capsule bid cohorts: 90 mg (3 patients), 160 mg (3 patients), 
300 mg (4 patients), 460 mg (7 patients), 700 mg (3 patients), and 1000 mg (12 
patients). There was an additional bid cohort of 200 mg (3 patients) in which the 
drug was administered as an amorphous spray dried dispersion. Patients were 
enrolled in the following oral capsule qid cohorts: 300 mg (3 patients), 500 mg (3 
patients), 600 mg (6 patients), and 800 mg (5 patients).  
 
The median age was 65.0 years for patients in the bid cohorts and 60.0 years for 
patients in the qid cohorts. 
 
All patients were taking concomitant medication during the study. The most 
frequently used medications for patients in the bid cohorts included analgesics 
(79.4%), antidiarrheal, intestinal anti-inflammatory, or infectious agents (64.7%), 
psycholeptics (64.7%), drugs for acid-related disorders (61.8%), vitamins (61.8%), 
mineral 
supplements 
(58.8%), 
antithrombotic 
agents 
(55.9%), 
and 
antiemetics/antinauseants (52.9%). The most frequently used medications for 
patients in the qid cohorts included antidiarrheal, intestinal anti-inflammatory, and 
infectious agents (82.4%), analgesics (76.5%), antiemetics/antinauseants (70.6%), 
blood substitutes and perfusion solutions (58.8%), mineral supplements (58.8%), 
and psycholeptics (58.8%). 
 
There were no remarkable changes in ECGs, weight, or vital signs during the study. 
 
A total of 51 patients were treated with CX-4945: 34 patients followed a twice-
daily (bid) dosing regimen and 17 patients followed a four-times-daily (qid) dosing 
regimen. Most bid cohort patients (97.1%) and all qid cohort patients (100.0%) 
reported treatment-emergent adverse events (TEAEs). Drug-related TEAEs were 
reported in 64.7% (bid) and 76.5% (qid) of patients. Severe (grade 3 or greater) 
TEAEs were reported in 50.0% (bid) and 76.5% (qid) of patients. Severe drug-
related TEAEs were reported in 11.8% (bid) and 41.2% (qid) of patients. 
 
In general, more drug-related events were reported in the qid cohort, possibly due 
to the aggressive dosing and higher total dose administered to qid patients. 
However, patients in both dosing cohorts had similar toxicity profiles. 
 


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Overall, TEAEs were predominantly gastrointestinal disorders, including diarrhea 
(70.6%), nausea (35.3%) and vomiting (33.3%); other frequently reported TEAEs 
were hypokalemia (25.5%), fatigue (21.6%), dizziness (19.6%), anorexia (17.6%), 
headache (17.6%), abdominal pain (15.7%), upper abdominal pain (11.8%), back 
pain (11.8%), and lymphopenia (11.8%). 
 
The most frequently reported (≥10%) drug-related TEAEs were gastrointestinal 
disorders: diarrhea (58.8%), nausea (17.6%), and vomiting (15.7%). Other 
frequently reported drug-related TEAEs were hypokalemia (17.6%) and fatigue 
(11.8%). 
 
Most TEAEs were grade 1 or grade 2 severity. The most frequently reported 
(≥10%) severe (grade 3 or greater) TEAEs were diarrhea, hypokalemia, and 
lymphopenia (11.8% each). Severe TEAEs considered to be related to CX-4945 
were 
diarrhea 
(11.8%), 
hypokalemia 
(7.8%), 
hyponatremia 
(3.9%), 
hypophosphatemia (2.0%), and lymphopenia (2.0%). Drug-related severe TEAEs 
were only reported in the 460 mg bid, 1000 mg bid, 600 mg qid, and 800 mg qid 
dose cohorts. 
 
Thirteen patients (25.5%) reported SAEs, of which only 1, grade 4 hypokalemia, 
was considered to be probably related to CX-4945. 
 
Two patients reported dose-limiting toxicities: grade 4 hypokalemia (1000 mg bid 
dose cohort) and grade 3 diarrhea (800 mg qid dose cohort). Two patients died due 
to disease progression that was considered to be unrelated to CX-4945.  
 
Completed Study in Patients with Multiple Myeloma 
 
This was an open-label, dose-escalation, safety, PK, and pharmacodynamic study 
(C4-09-001) of CX-4945 in patients with relapsed or refractory multiple myeloma. 
Patients must have received at least 2 prior therapies for multiple myeloma, which 
could be inclusive of autologous stem cell transplant, and for whom other approved 
standard therapy was not available. 
 
CX-4945 was administered as oral capsules daily for 21 days followed by a 7-day 
rest period in 28-day cycles. The drug was taken 1 hour after meals, with at least 6 
ounces (180 mL) of water. A total of 11 patients with multiple myeloma received 
CX-4945 at 1 of the following doses: 300 mg, 500 mg, or 600 mg qid; 800 mg or 
1000 mg bid. 
 
The median patient age in the qid and bid cohorts was 72.0 and 74.5 years, 
respectively. 
 
All patients were taking concomitant medication during the study. The most 
frequently used medications were antidiarrheal, intestinal anti-inflammatory, or 
anti-infectious agents (72.7%) and drugs for acid-related disorders (72.7%). 


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ECGs, performance status, weight, and vital signs were monitored throughout the 
study. There were no notable changes or observations. 
 
All 11 patients reported TEAEs. Ten patients (90.9%) reported drug-related 
TEAEs, 8 patients (72.7%) reported TEAEs of grade 3 or greater severity, of which 
1 patient (9.1%) had a drug-related grade 3 or greater TEAE. There was no apparent 
difference in TEAEs reported in the bid and qid dosing regimens.  
 
Patients 
experienced 
mostly 
mild 
(<grade 
3) 
TEAEs, 
predominantly 
gastrointestinal or general disorders. The most frequently reported TEAEs 
considered to be related to CX-4945 were diarrhea (90.9%), fatigue (45.5%), and 
nausea (27.3%). Eight out of 11 patients (4 patients from each dosing regimen) 
reported grade 3 or greater TEAEs. Hypokalemia and hemoglobin decrease were 
the only severe TEAEs reported by multiple patients (2 patients). One patient (1000 
mg bid) reported drug-related grade 3 diarrhea, which occurred 13 days after the 
first dose. 
 
Ongoing Study in Patients with Cholangiocarcinoma 
 
A phase I/II study (S4-13-001) of CX-4945 in combination with gemcitabine plus 
cisplatin is ongoing in patients with cholangiocarcinoma. CX-4945 is administered 
orally twice daily on Days 0, 1, and 2 and on Days 7, 8, and 9, with the 
administration of intravenous cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on 
Days 1 and 8. The doses administered have been 200, 400, 600, 800, and 1000 mg 
per dose (twice daily). Treatment repeats every 21 days in the absence of disease 
progression or unacceptable toxicity. The most frequently reported AEs associated 
with the combination drug regimen have been diarrhea, nausea, fatigue, anemia, 
vomiting, and white blood cell (WBC) count decrease. Reportable serious adverse 
events (SAEs) have been grade 3 anemia, grade 3 ovarian vein thrombosis, and 
grade 3 elevated alanine aminotransferase (ALT) and gamma-glutamyl 
transpeptidase (GGT). 
 
7.3. 
RATIONALE FOR DOING THIS STUDY 
Previous Phase I clinical trials have evaluated the MTD and DLTs of CX-4945 
when administrated orally BID or QID for 21 days followed by 7 days of rest.  
 
Although no complete or partial response was reported, 6 out of the 51 patients with 
advanced solid tumors experienced tumor reductions from baseline. 
 
In this study, we plan to test a more dose intense schedule, 28-day continuous CX-
4945 dosing in order to optimize pharmacodynamic effects and thus optimize anti-
tumor effects. 
 


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7.4. 
DOSING REGIMEN AND STARTING DOSE 
CX-4945 will be administered twice a day on a continuous basis. Each cycle will 
be 28 days (4 weeks) in duration and the first cycle will be used as the DLT 
observation period. 
 
The starting dose will be 1000 mg BID (2000 mg total daily dose). This starting 
dose is based on three completed Phase I studies where patients were administered 
CX-4945 following a twice-daily (BID) or four-times-daily (QID) dosing regimen 
for 21 days followed by 7 days of rest. A total of 12 patients were treated at the 
1000 mg bid dose level. Grade 3 or greater hypokalemia and hyponatremia 
associated to CX-4945 were reported but no drug-related severe diarrhea was noted. 
At the 1000 mg bid dose level, 1 out of 12 patients had DLT, grade 4 hypokalemia.  
 
8. STUDY OBJECTIVES 
Primary Objective 
The primary objective of this study is to determine the recommended phase II dose 
(RP2D) and schedule of CX-4945 when administered orally twice daily for 28 
consecutive days, in a 4-week (28 days) cycle, in patients with locally advanced or 
metastatic basal cell carcinoma (BCC).  
 
Secondary Objectives 
• 
To establish the safety and tolerability of CX-4945 in this patient population.  
• 
To assess preliminary evidence of antitumor effects in this patient population 
by documentation of objective responses using standardized criteria. 
• 
To evaluate the effect of CX-4945 treatment on the Hh signaling pathway using 
qRT-PCR in fresh-frozen tissue from patients with locally advanced BCC 
obtained at baseline and following CX-4945 treatment. 
 
9. INVESTIGATIONAL PLAN 
9.1. 
STUDY DESIGN AND PLAN 
This is an open label, multicenter, treatment duration increment trial Phase I run- 
in study followed by two expansion cohorts to evaluate the safety, 
pharmacodynamic and preliminary antitumor activity of CX-4945 in patients with 
advanced basal cell carcinoma. All patients will receive CX-4945 until evidence of 
progression, intolerable toxicities most probably attributable to CX-4945, or 
withdrawal from the study. Day 1 of the study will be defined as the first day a 
patient receives CX-4945 (for the list of study assessments, please see the Study 
Flowchart in Appendix A). 
 
This study population will consist of patients ≥ 18 years old with a histologically 
confirmed diagnosis of advanced BCC (metastatic BCC [mBCC] or locally 
advanced BCC as defined as follows) which has progressed on smoothened 


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inhibitor or that are intolerant to smoothened inhibitor (see Section 10.1.1, 
Inclusion Criteria). 
 
Patients with mBCC are required to have histologic confirmation of a distant BCC 
metastasis (e.g., lung, liver, lymph nodes, or bone).  
 
Patients with locally advanced BCC are required to have disease that is considered 
inoperable or to have a medical contraindication to surgery (see Section 10.1.1, 
Inclusion Criteria). 
 
Patients with nevoid BCC syndrome (Gorlin syndrome) may enroll in this study 
but must meet the criteria for locally advanced or metastatic disease listed above.  
 
In the phase I treatment duration increment part of the study, the 28-day continuous 
dosing of CX-4945 [1000 mg twice daily] will be explored. Dose cohort will 
initially include a minimum of 3 patients. A standard 3+3 design will be used. If no 
DLTs are seen in the 3 patients, the treatment duration increment part will be closed 
and the expansion cohorts will be opened.  
 
If 1 patient out of 3 experiences a dose-limiting toxicity (DLT), up to 3 additional 
patients will be recruited (for a maximum of 6). If there are < 2/6 patients with 
DLT, this will be declared the dose for the Recommended Phase II Dose (RP2D), 
the Phase I will be closed and two expansion cohorts will be opened. If 2 out of 3, 
or 2 out of 6, patients experience DLT, the previous Phase I oral dosing regimen of 
1000 mg BID (total daily dose 2000 mg) for 21 days followed by 7 days of rest will 
be selected for the expansion cohorts. The expansion cohorts will include 10 
patients with locally advanced BCC and 10 patients with metastatic BCC. 
 
During the treatment duration increment part, the first patient enrolled at the 28-
day continuous dosing schedule must receive ≥ 75% planned doses with no 
observed DLTs before a second patient and a third patient are treated one week 
apart in that cohort.  If no patient in the cohort experiences a Dose Limiting Toxicity 
(DLT) after the completion of Day 28 of the final patient in the cohort, then the 
Expansion Cohorts may proceed with the 28-day continuous dosing schedule.  
 
Patients that have experienced a DLT may be offered the option to continue at the 
previous Phase I oral dosing regimen of 1000 mg bid (total daily dose of 2000 mg) 
for 21-day followed by 7 days of rest if this is considered safe by the Investigator 
and the Sponsor. 
 
9.2. 
OUTCOME MEASURES 
 
Primary Outcome Measure: 
The primary endpoint for this study is the determination of RP2D. 
 
 
Secondary Outcome Measures: 
The secondary outcome measures are the following: 


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• The number and attribution of all adverse events (including vital signs, physical 
findings, and clinical laboratory results) in patients who received any amount 
of study drug. 
• The objective response will be assessed separately for patients with mBCC and 
locally advanced BCC. For patients with mBCC, RECIST will be used (see 
Appendix B). For patients with locally advanced BCC, a composite response 
endpoint will be used that incorporates externally visible tumor dimension and 
tumor ulceration, as well as RECIST for lesions with a RECIST-measurable 
component (see Appendix C). In patients achieving a clinical response, tumor 
biopsies will be used in the final determination of complete versus partial 
response. 
• Absence of residual BCC in patients with locally advanced BCC achieving a 
clinical response to CX-4945, as measured by pathological review.  
• The changes in GLI1 expression in fresh-frozen tissue as measured by qRT-
PCR. 
 
9.3. 
DEFINITION OF DLT 
Dose limiting toxicity (DLT) will be defined as any of the following drug related 
adverse events occurring during Cycle 1: 
 Grade 3 or 4 non-hematologic toxicity (excluding inadequately managed 
nausea and vomiting, alopecia or grade 3 fatigue lasting < 7 days), 
 Grade 4 myelosuppression ≥ 7 days, febrile neutropenia or ≥ grade 3 
thrombocytopenic bleeding, 
 Other toxicity of concern to the investigators including toxicities requiring 
delays ≥ 14 days.  
 
9.4. 
SAFETY PLAN 
A number of measures will be taken to ensure the safety of patients participating in 
this study. Patients enrolled in this trial will be evaluated clinically and with 
standard laboratory tests before and at regular intervals during their participation in 
this study. Safety evaluations will consist of tumor assessments performed every 8 
weeks, and routine hematology, serum chemistry, and urinalysis profiles will be 
obtained for all patients. 
 
The study period will begin on Day 1 and will continue until documented disease 
progression. 
 
All enrolled patients who are treated with at least 1 dose of CX-4945 will be 
monitored for adverse events. Adverse events will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE, Version 5.0). 
 
If a treatment interruption occurs, and it is determined that CX-4945 will be re-
started, the dose modification plan in Section 11.6 will be followed.  
 


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Treatment with CX-4945 may be interrupted for up to 2 weeks for evaluation of an 
intolerable toxicity finding or up to 4 weeks for a planned surgical procedure. The 
Medical Monitor must be consulted in cases where study drug will be interrupted. 
In general, when treatment is held because of drug related adverse effects for > 2 
weeks without recovery to the degree required for restarting treatment, the patient 
should go off protocol therapy.  
 
Intolerable toxicities are defined as new (not present at baseline) Grade 3 or 4 
adverse events considered related to CX-4945 that are likely to be life-threatening 
or irreversible, and when in the opinion of the investigator, the risk outweighs the 
benefit of continued treatment with CX-4945. The following adverse events are not 
considered intolerable: 
• Grade 3 or 4 events that in the opinion of the investigator are more likely related 
to ongoing or recent procedures or concomitant medications other than CX-
4945 
• 
Hematologic or metabolic/chemistry laboratory abnormalities that are found on 
routine testing and are not considered clinically significant 
• 
Musculoskeletal abnormalities, skin ulceration, fracture, debridement or wound 
care, and dental or periodontal disease related to underlying medical conditions 
(e.g., basal cell carcinoma, nevoid basal cell carcinoma [Gorlin] syndrome) 
• 
Nausea, vomiting, or diarrhea that are adequately controlled after optimization 
of medical management. 
• 
Grade 3 infection that is transient and treatable or manageable 
• 
Grade 3 sterility 
• 
Asymptomatic thromboembolism found incidentally on imaging and managed 
with anti-coagulation therapy 
 
Patients with an asymptomatic or tolerable severe adverse event may continue to 
receive study drug, provided that the adverse event is manageable and the patient 
and the investigator agree that continued study participation is acceptable. 
 
The teratogenic potential of CX-4945 has not been investigated. Women who are 
pregnant or nursing are excluded from this study. 
 
Women of childbearing potential are defined in Appendix D, and those enrolled in 
this study are required to have a negative serum pregnancy test at screening, 
followed by urine pregnancy tests on Day 1 and every 4 weeks while in the study. 
If a urine pregnancy test is positive, it must be confirmed with a serum pregnancy 
test. If pregnancy is confirmed with serum pregnancy test, the subject should be 
discontinued from the study and complete the early termination visit. Women of 
childbearing potential are required to use two effective methods of contraception 
(including one barrier method) during the study and for 6 months after 
discontinuation of CX-4945. During the study, the investigator must confirm the 
use of two acceptable contraceptive methods and the patient’s understanding of the 
teratogenic potential of CX-4945, as well as document a negative pregnancy test 


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prior to dispensing CX-4945 to a woman of childbearing potential. Not all methods 
of contraception are acceptable; see Appendix D. 
 
Male patients (including those who have undergone vasectomy) with female 
partners of childbearing potential should use a latex condom during any sexual 
contact and should advise their partners to use an additional method of 
contraception during the study and for at least 6 months after discontinuation of 
CX-4945. 
 
10. SELECTION OF STUDY POPULATION 
10.1. PATIENT SELECTION 
Eligible patients with locally advanced and metastatic BCC who are in 
conformance with the following inclusion and exclusion criteria may enroll in this 
study. 
 
10.1.1. Inclusion Criteria 
 
 
Patients must meet the following criteria to be eligible for study entry: 
 
1. Signed, written IRB-approved informed consent. 
2. Men and women age ≥ 18 years 
3. ECOG Performance status 0 or 1 (see Appendix I) 
4. For patients with mBCC, histologic confirmation of distant BCC metastasis 
(e.g., lung, liver, lymph nodes, or bone), with metastatic disease that is RECIST 
measurable using CT or MRI 
 
Phase I Expansion 
If a patient with locally advanced BCC also has a tumor that is not contiguous 
with cutaneous BCC, e.g., regional lymph nodes (if confirmed on biopsy as 
BCC and RECIST measurable), the patients should be considered as having 
mBCC and should be enrolled in the mBCC cohort 
 
5. For patients with locally advanced BCC, histologically confirmed disease with 
at least one lesion that was 10 mm or more in at least 1 dimension by color 
photograph that is considered to be inoperable or medical contraindication to 
surgery (see below), in the opinion of a Mohs dermatologic surgeon, head and 
neck surgeon, or plastic surgeon 
6. Acceptable medical contraindications to surgery include: 
a. BCC that has recurred in the same location after two or more surgical 
procedures and curative resection is deemed unlikely. 
b. Anticipated substantial morbidity and/or deformity from surgery (e.g., 
removal of all or part of a facial structure, such as nose, ear, eyelid, eye; or 
requirement for limb amputation). 
c. Other conditions considered to be medically contraindicating must be 
discussed with the Medical Monitor before enrolling the patient. 
 


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7. For all patients, smoothened inhibitor should have been previously 
administered for their locally advanced or metastatic BCC, unless smoothened 
inhibitor is inappropriate (e.g., patient has received a smoothened inhibitor but 
became intolerant to the therapy). For patients whose BCC has been treated 
with smoothened inhibitor, disease must have progressed after treatment. 
8. For patients with locally advanced BCC, radiotherapy should have been 
previously administered for their locally advanced BCC, unless radiotherapy is 
contraindicated or inappropriate (e.g., hypersensitivity to radiation due to 
genetic syndrome such as Gorlin syndrome, limitations because of location of 
tumor, or cumulative prior radiotherapy dose). For patients whose locally 
advanced BCC has been irradiated, disease must have progressed after 
radiation. 
9. Previous Therapy 
o Surgery: Previous surgery is permitted provided that a minimum of 28 days 
(4 weeks) have elapsed between any major surgery and date of registration, 
and that wound healing has occurred. 
o Cytotoxic Chemotherapy: There is no limit to the number of prior regimens 
received. 
o Other Systemic Therapy: Previous treatment with Hh pathway antagonists 
is not allowed (except for Smoothened inhibitors). There is no limit to the 
other prior therapies received (see Appendix K). 
 
Patients must have recovered (to baseline or ≤ grade 1) from all reversible 
toxicity related to prior chemotherapy or systemic therapy and have 
adequate washout as follows:  
 
Longest of one of the following: 
 Two weeks, 
 5 half-lives for investigational agents, 
o For anti-cancer therapies with half-lives > 8 days, a 
washout period of at least 28 days will be acceptable, 
 Standard cycle length of standard therapies. 
 
10. Patients with nevoid BCC syndrome (Gorlin syndrome) may enroll in this study 
but must meet the criteria for locally advanced or metastatic disease listed 
above. 
 
11. For patients with locally advanced BCC, willingness to consent to biopsy of 
tumor(s) at baseline and during the study, as mandated by the protocol. 
12. Adequate hematopoietic capacity, as defined by the following: 
- 
Hemoglobin ≥ 9.0 g/dL and not transfusion dependent 
- 
Platelets ≥ 100,000/mm3 
- 
Absolute neutrophil count ≥ 1500 cells/mm3 
13. Adequate hepatic function, as defined by the following: 
- 
AST and ALT ≤ 2.5 times upper limit of normal (ULN) or ≤ 5 times 
ULN if liver metastases are present 


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- 
Total bilirubin ≤ 1.5 x ULN or within 3x the ULN for patients with 
Gilbert disease 
- 
Albumin ≥ 3.0 g/dL 
14. Adequate renal function, as defined by the following: 
- 
Renal: calculated creatinine clearance >45 mL/min for patients between 
18 and 70 years old with abnormal, increased, creatinine levels 
(Cockcroft-Gault formula; Appendix J). For patients who are greater 
than 70 years old, investigator judgment may be used to assess the renal 
risk of study participation. 
15. Women/men of childbearing potential must have agreed to use two effective 
contraceptive methods while on study and for 6 months after the last dose of 
CX-4945 (see Appendix D for definition of women of childbearing potential 
and acceptable and unacceptable methods of contraception)  
 
10.1.2. Exclusion Criteria 
 
 
Patients who meet the following criteria will be excluded from study entry:  
 
1. Pregnant or nursing women.  NOTE:  Women of child-bearing potential and 
men must agree to use adequate contraception (hormonal or barrier method 
of birth control; or abstinence) prior to study entry and for the duration of 
study participation.  Should a man father a child, or a woman become 
pregnant or suspect she is pregnant while participating in this study, he or 
she should inform the treating physician immediately. 
2. Concurrent non–protocol-specified anti-tumor therapy (e.g., chemotherapy, 
other targeted therapy, radiation therapy, or photodynamic therapy) 
 
- For patients with multiple cutaneous BCCs at baseline that are not 
designated by the investigator as target lesions, treatment of these non-
target BCCs with surgery may be permitted but must be discussed with the 
Medical Monitor prior to any surgical procedure. 
 
- For patients with locally advanced BCC whose target lesion(s) is/are 
inoperable at baseline but is/are later deemed potentially operable because 
of tumor response to CX-4945, surgery with curative intent may be 
permitted but must be discussed with the Medical Monitor prior to any 
surgical procedure. 
 
3. History of other malignancies within 3 years of Day 1, except for tumors 
with a negligible risk for metastasis or death, such as adequately treated 
squamous-cell carcinoma of the skin, ductal carcinoma in situ of the breast, 
or carcinoma in situ of the cervix. 
4. Active or uncontrolled infections or with serious illnesses or medical 
conditions which would not permit the patient to be managed according to 
the protocol.  
5. History of other disease, metabolic dysfunction, physical examination 
finding, or clinical laboratory finding giving reasonable suspicion of a 


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disease or condition that contraindicates use of an investigational drug or 
that might affect interpretation of the results of the study or renders the 
patient at high risk from treatment complications. 
6. Difficulty with swallowing oral medications. 
7. Chronic diarrhea (excess of 2-3 stools/day above normal frequency). 
 
10.2. ENROLLMENT AND REGISTRATION PROCEDURES 
10.2.1. Enrollment Procedures 
A signed, Institutional Review Board (IRB) approved, informed consent must be 
obtained from patients before any study-specific procedures or registration can 
occur. 
 
10.2.2. Registration Procedures 
Prior to registration and any study-specific evaluations being performed, all 
patients must have given written informed consent for the study and must have 
completed the pre-study evaluations.   
 
Upon signing the informed consent, the patient will be given a screening number. 
Once the patient has been confirmed eligible to be enrolled in the study, a patient 
identification number will be assigned via the Medidata RAVE (refer to the eCRF 
completion guidelines for specific instructions) that will be used on all 
documentation for the subject throughout the study.  Patient identification numbers 
will be assigned in ascending order, and numbers will not be omitted or reused. 
Investigator will verify that patients are eligible per the protocol specific Inclusion 
and Exclusion criteria. No patient is allowed to begin study treatment prior to 
registration and assignment of a patient identification number.  The maximum 
allowable time between registration and the first administration of study treatment 
is 7 calendar days.  
 
10.3. PATIENT DISCONTINUATION 
The investigator has the right to discontinue a patient from the study for any 
medical condition that the investigator determines may jeopardize the patient’s 
safety if he or she continues in the study; for reasons of noncompliance (e.g., missed 
doses, visits); if the patient becomes pregnant; or if the investigator determines it is 
in the best interest of the patient. 
 
Please see the Study Flowchart provided in Appendix A for assessments that are to 
be performed for patients who prematurely withdraw from the study during the 
treatment period. 
 
10.4. PATIENT REPLACEMENT 
If a patient is not evaluable for toxicity for Cycle 1, that patient will be replaced to 
ensure the minimum number of patients are evaluable. Patients must receive ≥ 75% 


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planned dose to be considered evaluable for toxicity unless study drug was held or 
discontinued for toxicity and/or DLT has occurred. 
 
All patients who are removed from the study for any reason other than for adverse 
events or for disease progression (e.g., voluntary discontinuation at the patient’s 
request, or a severe violation of the study protocol) will be replaced.  Data from 
these removed patients will be included in the overall safety analysis but will not 
be included in the assessment of relative dose intensity.    
 
11. STUDY TREATMENT 
11.1. STUDY DRUG DESCRIPTION AND ALLOCATION 
Senhwa Biosciences Inc. will supply study drug.  At the time of delivery to the site, 
the Investigator, designee, or Pharmacist will sign a Drug Receipt Form or 
Investigational Product Packing Slip to confirm the supplies for the study have been 
received. This form will specify lot numbers, quantities shipped/delivered, date of 
receipt and condition of the product upon receipt.   
 
Study drug must be stored in a secure, limited-access location. Accountability for 
study drug is the responsibility of the Investigator, designee or pharmacist.   
 
Study drug must only be dispensed by a Pharmacist or medically qualified staff and 
is to be dispensed only to patients enrolled in this trial.  Once study medication is 
dispensed to any patient, it can only be administered to that patient and study drug 
remaining in the dispensed bottle should not be used for another patient.  All 
dispensed bottles of study drug will be returned by a patient at the next visit for 
drug accountability and compliance review.  
 
11.2. IDENTITY OF INVESTIGATIONAL PRODUCT 
CX-4945 is a synthetically derived small molecule. The API is isolated as an off-
white to yellow solid that is slightly soluble in water. CX-4945 is provided as sodium 
salt with no excipients and encapsulated in size 1 opaque hard-shell gelatin capsules. 
The capsules are formulated for immediate release of CX-4945. 
 
CX-4945 capsules will be supplied in 200 mg strength in 60 cc wide mouth, white, 
high-density polyethylene (HDPE) plastic bottles. Each bottle is individually heat 
sealed with foil liner capped with 33 mm white plastic child resistant cap.  Each 
bottle will contain fifteen (15) capsules that also contains a single Canister Sorb-IT 
desiccant (1 gram) labeled in blue ink “Do Not Eat” and a low moisture polyester 
coil.  The label of the bottle includes information bearing the drug identification, 
conditions for storage, protocol number, capsule lot number, packaging batch 
number, manufacturing date, and caution statement.  Drug supplies will be shipped 
between 15°C-30°C (59°F-86°F) temperature and should continue to be stored 
under the same conditions upon arrival. 
 


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Intact bottles should be stored in the recommended storage temperature. If the 
packaging is damaged or if there is anything unusual about the appearance or 
attributes of the study drug, it should not be used.  The boxes or bottles in question 
should be saved, and the problem immediately reported to Senhwa. 
 
11.3. ADMINISTRATION INSTRUCTION 
Patients will receive 1000 mg of CX-4945 twice daily by mouth, beginning on Day 
1, and continuously until one of the following occurs: 
 
- 
Disease Progression:  
If the investigator’s assessment of progressive disease is equivocal, and in 
the investigator’s opinion the patient is still deriving benefit from 
treatment, treatment with CX-4945 should be continued, and the patient 
should be re-evaluated at the next tumor assessment timepoint. 
- 
Intolerable toxicity most probably attributable to CX-4945. 
- 
Withdrawal from the study. 
 
Patients will be instructed to take oral antiemetic prophylaxis at least 1 hour prior 
to taking the study drug. Other oral medications should be taken at least one hour 
before or 2 hours after ingesting the dose of CX-4945 capsules.  
 
Patients will take five 200-mg CX-4945 capsules twice daily, two hours after the 
morning meal and two hours after the evening meal (dinner) with water. Patients 
are advised to take 1 capsule at a time with a pause in between each.  This method 
may prevent a clumping effected in the stomach, so patient can take as much as 10 
minutes to swallow each capsule.   
 
The study drug will be taken on an empty stomach with at least six ounces (180 
mL) of water.  After CX-4945 administration, all patients will be NPO (except for 
water) for 2 hours, after which, the patient may eat.  
 
At each study visit, patients will be given enough capsules for dosing until the next 
study visit. The investigator is required to confirm that any woman of childbearing 
potential has a negative pregnancy test, understands the teratogenic potential of 
CX-4945, and is using two forms of acceptable contraception, including one barrier 
method, prior to dispensing CX-4945. 
 
When CX-4945 capsules are dispensed, each patient will be provided with specific 
dosing instructions, including the number of capsules to take at each morning and 
evening dose. The number of containers and capsules being dispensed, the patient 
number, and the date dispensed will be recorded on the Case Report Form. 
 
The patients will be instructed to store the study drug in the original containers at 
room temperature in a safe location. Each patient will be shown the desiccant 
container found in each bottle of study medication and instructed not to remove or 
eat this desiccant. Patients will be instructed to avoid storing the study drug in areas 


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of excessive heat (vehicle glove box) or excessive moisture (bathroom medicine 
cabinets).  Patients will be instructed on the use of the dosing record form and will 
be asked to keep a dosing record for all dose administrations. 
 
Patients will be instructed to bring the dosing record form and all unused study 
medication and empty study medication containers at each study visit, as 
applicable. At each visit, the dosing record will be reviewed and the amount of used 
and unused study medication that is returned will be recorded. Every effort will be 
made to obtain all dispensed containers. If such effort fails, a dated note of the 
reason for the failure will be recorded.   
 
If a patient misses a dose, he or she should be instructed not to take or make up that 
dose and to resume dosing with the next scheduled dose. Missed doses will not be 
made up and should be documented in the dosing record form.  
 
If a patient is suspected to be pregnant, CX-4945 must be immediately 
discontinued. If it is subsequently confirmed that the patient is not pregnant, dosing 
may be resumed. If pregnancy is confirmed with serum pregnancy test, the subject 
should be discontinued from the study and complete the early termination visit.  
 
11.4. STORAGE AND HANDLING OF TEST ARTICLE  
The stability of test materials used in this study will be known and monitored to 
ensure suitability for use throughout the study.  CX-4945 capsules should be stored 
in their original containers and should be protected from moisture, freezing, bright 
light, and heat. Drug supplies must be stored in a secure, lockable area.  
 
The pharmacy or medically qualified staff will prepare and dispense CX-4945 
capsules to enrolled patients.   The number of containers and capsules being 
dispensed, the patient number, patient initials, and the date dispensed will be 
recorded. The patient will be instructed to store the study drug in the original 
containers at room temperature between 15°C-30°C (59°F-86°F), in a safe location.  
 
11.5. CONCOMITANT AND EXCLUDED THERAPIES 
  
Concomitant Therapy 
Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days preceding the screening 
evaluation and the end of study visit. All concomitant medications should be 
reported to the investigator and recorded on the appropriate electronic Case Report 
Form (eCRF). 
 
Excluded Therapy 
 
Although no specific concomitant medications are prohibited during this study, 
concomitant medications should be used with care, and the risk–benefit profile of 
each agent should be taken into consideration. Concomitant medications that may 


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potentially interact with CX-4945 are listed in Appendix F. This is not necessarily 
a complete list; other medications may also interact with CX-4945. 
 
11.6. DOSE MODIFICATION FOR CX-4945  
The most common drug related adverse events reported for CX-4945 are 
predominantly gastrointestinal disorders, including nausea, vomiting and diarrhea. 
 
Toxicities related to CX-4945  
Event Grade 
(CTCAE 5.0)
Dose Interruption 
Dose Reduction 
Dose for subsequent cycle 
Grade 1 
Treat on time 
No change 
No change 
Grade 2 
Hold until ≤ Grade 1 
Resume at same 
dose
No change 
Grade 3 
Hold until < Grade 2 
Reduce by 1 dose 
level (200 mg) 
If toxicity remains <Grade 
2, dose re-escalation can be 
considered at the discretion 
of the Investigator. If dose 
is re-escalated and toxicity 
(≥ Grade 3) recurs, institute 
permanent dose reduction.
Grade 4 
Hold until < Grade 2 
Reduce by 1 dose 
level (200 mg). 
 
Permanent 
discontinuation 
can be considered 
at the 
Investigator’s 
discretion
 
 
 
11.7. PREMEDICATION 
Antiemetic (mandatory) 
CX-4945 has been observed to be moderately emetogenic from previous Phase I 
studies. All patients enrolled in this study will self-administer an oral 5-HT3 
antagonist daily, at least 1 hour prior to taking the CX-4945 capsules or a 5-HT3 
antagonist transdermal patch at least 24 hours prior to taking the CX-4945 capsules 
every 7 days. If a patient prefers 5-HT3 antagonist transdermal patch, the patient is 
expected to apply the patch approximately 24 hours before the day 1 visit. If missed 
the patch, the patient is suggested taking the oral 5-HT3 antagonist 1 hour before 
taking CX-4945 on day 1 and continue taking the oral 5-HT3 antagonist for 7 days 
in order to switch to antagonist patch. 
 


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Medications within the 5-HT3 antagonist class are interchangeable depending on 
availability and tolerability.  Dose(s) of the antiemetic medication, either intensity 
or frequency can be adjusted as clinically indicated.  Patient should receive enough 
supply to cover the entire treatment of each cycle.   
 
5-HT3 antagonist (choose one)
- 
Dolasetron 100 mg PO daily 
- 
Granisetron 1 mg PO twice daily; the first 1 mg dose should be given up to 1 hour before CX-
4945 (with second 1 mg dose 12 hours later) or 3.1 mg/24-h transdermal patch every 7 days 
- 
Ondansetron 8 mg PO twice daily; the first 8 mg dose should be given up to 1 hour before CX-
4945 (repeat dose 8 hours after the initial dose)
 
The use of additional antiemetics as necessary to manage breakthrough nausea and 
vomiting will be permitted. Details of any premedication or concomitant 
medication given to manage or prevent adverse events should be recorded on 
electronic case report forms (eCRFs). 
 
Diarrhea (recommended): 
- 
All patients should be advised to obtain an adequate supply of Loperamide 
(IMODIUM®) with explicit instructions for the management of diarrhea. 
- 
Early diarrhea or abdominal cramps occurring within the first 24 hours is treated 
with atropine 0.3 - 1.2 mg IV or SC. Prophylactic atropine may be required for 
subsequent treatments.  
- 
Late diarrhea has a median onset of 2 days post-treatment with CX-4945 and must 
be treated with Loperamide (e.g., IMODIUM®). Instruct patient to have 
Loperamide on hand and start treatment at the first poorly formed or loose stool, or 
earliest onset of more frequent stool than usual:  
o 4 mg stat  
o then 2 mg every 2 hours until diarrhea-free for 12 hours  
o may take 4 mg every 4 hours at night  
 
11.8. VITAMIN D SUPPLEMENT 
BCC patients are at high risk for developing vitamin D deficiency from prolonged 
reduction in sun exposure. Patients found to have serum 25-hydroxyvitamin D 
(25[OH]D) concentration lower than 20 ng/mL during the screening period should 
receive Vitamin D supplement. Institute of Medicine (IOM) favors maintaining the 
serum 25(OH)D concentration between 20 and 40 ng/mL (50 to 100 nmol/L). See 
Appendix E for Vitamin D dosing recommendation. 
 
12. STUDY ASSESSMENTS 
12.1. DEFINITION OF STUDY ASSESSMENTS 
The study period will begin on Day 1, and patients will be followed until disease 
progression, death, or withdrawal of consent from the study. 
 


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Screening tests and evaluations will be used to determine the eligibility of each 
patient for study inclusion. All patients must provide written informed consent 
before any study-specific procedures and assessments are performed and any 
exclusionary medications are discontinued for the purposes of establishing 
eligibility. Screening evaluations will be performed within the 14 days preceding 
Day 1, unless otherwise specified (for list of study assessments, see the study 
flowchart in Appendix A). Results of tests or examinations performed as standard 
of care prior to obtaining informed consent prior to study entry may be used rather 
than repeating required tests. 
 
a. Physical Examination 
 
The initial complete physical examination should include the evaluation of the head, 
eyes, ears, nose, and throat (HEENT); cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurological systems. Height and 
weight will also be recorded. Subsequent limited physical examinations for 
assessment of toxicity may be restricted to evaluation of specific systems or areas 
of interest, including those with previously abnormal findings or associated with 
symptomatic or laboratory evidence of toxicity. Changes from baseline 
abnormalities should be recorded at each subsequent physical examination. New or 
worsened abnormalities should be recorded as adverse events if appropriate. 
 
b. Vital Signs 
 
Vital signs will include measurements of pulse, systolic and diastolic blood pressure 
while the patient is in a seated position, respiratory rate, and temperature. Vital signs 
will be recorded at screening and at regular intervals throughout the study, including 
at the end of the study or early termination, as appropriate. 
 
c. Electrocardiographic Assessment 
 
Twelve-lead electrocardiograms (ECGs) are required at screening. 
 
d. Vitamin D level Assessment 
 
Measurement of serum 25-hydroxyvitamin D (25[OH]D or calcidiol) is required at 
screening. Follow-up 25(OH)D measurements will be performed every three 
months.  
 
e. Tumor and Response Assessments 
 
Baseline Assessments 
 
For patients with mBCC, computed tomography (CT) or magnetic resonance 
imaging (MRI) of the chest, abdomen, and pelvis must be performed for all patients. 
For patients with known involvement of the head and/or neck, CT or MRI of the 


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head and neck is also required. Additional areas of known tumor involvement (e.g., 
limbs) should also be evaluated on CT or MRI. The same imaging modality used at 
baseline must be used throughout the study. Baseline imaging studies must be 
performed within the 14 days preceding Day 1. Patients with mBCC are required to 
have disease that is measurable by RECIST using CT or MRI. 
 
For patients with locally advanced BCC, CT or MRI of the area(s) involved by the 
locally advanced tumor(s) should be performed at baseline for all patients to 
determine whether a RECIST-measurable component is present in externally 
visible lesions. Measurements of externally visible tumor dimension, assessment of 
tumor ulceration, description of the lesion at baseline, digital photography of target 
lesion(s), and a baseline tumor biopsy must be performed in accordance with biopsy 
guidelines (see Appendices C and G). Baseline imaging studies must be performed 
within the 14 days preceding Day 1. If locally advanced BCC lesions with a 
RECIST measurable component are identified, the same imaging modality used at 
baseline must be used throughout the study. 
 
 
Tumor Assessments during Treatment, End of Study, or Early Termination 
 
During treatment, tumor assessments will be performed every 8 weeks and at the 
study completion or early termination visit, as appropriate. 
 
For patients with mBCC, response assessments by the investigator will be 
categorized as complete response, partial response, stable disease, or progressive 
disease using RECIST. Objective responses using RECIST should be confirmed on 
repeat assessments 4 or more weeks after initial documentation of response. The 
same imaging modality (CT or MRI) used to define measurable disease sites at 
baseline must be used throughout the study (e.g., the same contrast protocol for CT 
scans). All patients are required to have imaging of the chest, abdomen, and pelvis; 
any additional areas imaged during screening (e.g., head or neck, limbs) should also 
be imaged at each tumor assessment. If the investigator’s assessment of progressive 
disease is equivocal, and in the investigator’s opinion the patient is still deriving 
benefit from treatment, treatment with CX-4945 should be continued, and the 
patient should be re-evaluated at the next tumor assessment timepoint.  
 
For patients with locally advanced BCC, response assessments by the investigator 
will be categorized as response, stable disease, or progressive disease using the 
composite tumor assessment criteria (see Appendix C). Measurements of externally 
assessable tumor, assessment of tumor ulceration, description of the lesion and any 
changes since the previous assessment, and digital photography of target lesion(s) 
will be performed. If the patient has a target lesion(s) containing a RECIST-
measurable component by CT or MRI, radiographic assessment is also required and 
should be incorporated into the response assessment according to Appendix C. If 
the investigator’s assessment of progressive disease is equivocal, and in the 
investigator’s opinion the patient is still deriving benefit from treatment, treatment 


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with CX-4945 should be continued, and the patient should be re-evaluated at the 
next tumor assessment timepoint.  
 
f. Tumor Biopsy 
 
Representative tumor biopsies are required from patients with locally advanced 
BCC at screening, at week 8, and again either at the time of investigator-assessed 
clinical or clinical/RECIST response (if before 24 weeks), or at 24 weeks if the 
patients are still in the study without evidence of progression. At any time during a 
patient’s participation in the study, an optional tumor biopsy may be requested to 
clarify the response status of the patient. In addition, biopsy of any accessible target 
lesion(s) is highly recommended at the time of progression and will be used for 
exploratory molecular and histologic analyses. The sites, number, and technique of 
representative biopsies will be determined by the investigator on the basis of the 
size and location of the accessible lesions. It is recommended that any areas 
suspicious for residual disease be biopsied, as well as areas which appear to be free 
of disease. These biopsies will be reviewed by site’s pathologist. For additional 
details regarding the guidelines for tissue biopsy, see Appendix G. 
 
g. Laboratory Assessments 
 
Local Laboratory Assessments. Samples for hematology, serum chemistry, 
urinalysis, and pregnancy will be analyzed at the study site’s local laboratory. 
 
• 
Hematology (hemoglobin, hematocrit, platelet count, red blood cell [RBC] 
count, white blood cell [WBC] count, and percent or absolute differential 
count [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and 
other cells]) 
• 
Serum chemistry (including glucose, blood urea nitrogen [BUN], 
creatinine, sodium, potassium, magnesium, bicarbonate, calcium, total 
protein, albumin, total bilirubin, alkaline phosphatase, AST, and ALT) 
• 
Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood) 
• 
Pregnancy test:  
All women of childbearing potential (including those who have had a tubal 
ligation) will have a serum pregnancy test at screening, followed by urine 
pregnancy tests on Day 1, and every 4 weeks. A positive urine pregnancy 
test must be confirmed with a serum pregnancy test. 
 
Central Laboratory Assessments. Samples tissue of locally advanced BCC 
patients in the expansion phase obtained at baseline and 8-week visits will be sent 
to a central laboratory for analysis. 
 
• 
Sample analysis (fresh frozen tissue or formalin fixed paraffin embedded): 
Tumor histology will be reviewed and Hh pathway target gene (GLI1) and 
reference gene expression profiling will also be performed on the tumor 
tissue sample obtained from patients with locally advanced BCC at baseline 


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and at 8 weeks following CX-4945 treatment in order to evaluate the effect 
of CX-4945 treatment on the Hh signaling pathway.  
 
h. Early Termination or End of Study Assessments 
 
Patients who discontinue from the study will be asked to return to the clinic within 
30 days of the last dose of CX-4945 for a follow-up visit. In patients with locally 
advanced BCC, biopsy of tumor at the time of progression for submittal for 
pathology review is strongly encouraged. 
 
i. Follow-up Off Protocol Treatment 
 
All patients will be seen at 4 weeks after completion of protocol therapy. Thereafter, 
continued follow-up is not required for patients who go off protocol treatment with 
progressive disease, except to document ongoing toxicities (until resolved to < 
grade 2) and late toxicities (including second malignancies). For patients who go 
off protocol treatment with CR, PR, or SD ongoing, follow-up will be required 
every 3 months until relapse (see Appendix A for investigations to be performed). 
Death report will be required on all patients unless advised by the Sponsor and due 
within 2 weeks of knowledge of death (see Section 16.3.1).  
 
12.2. SCREENING AND PRETREATMENT ASSESSMENTS 
Screening tests and evaluations will be used to determine the eligibility of each 
patient for study inclusion. All patients must provide written informed consent (one 
for study participation and a separate informed consent detailing teratogenic risk) 
before any study-specific procedures and assessments are performed and any 
exclusionary medications are discontinued for the purposes of establishing 
eligibility. Screening evaluations will be performed within the 14 days preceding 
Day 1, unless otherwise specified (for list of study assessments, see the study 
flowchart in Appendix A). Results of tests or examinations performed as standard 
of care prior to obtaining informed consent and within 14 days prior to study entry 
may be used rather than repeating required tests. Please see the Study Flowchart 
provided in Appendix A for the schedule of screening and pretreatment 
assessments. 
 
12.3. ASSESSMENTS DURING TREATMENT 
All visits must occur within ± 3 days from the scheduled date, unless otherwise 
noted. All assessments will be performed on the day of the specified visit unless a 
time window is specified. Assessments scheduled on the day of study drug 
administration (Day 1) of each cycle should be performed prior to study drug 
administration, unless otherwise noted. 
 
Please see the Study Flowchart provided in Appendix A for the schedule of 
treatment period assessments. 
 


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12.4. STUDY COMPLETION/EARLY TERMINATION VISIT 
Patients who discontinue from the study will be asked to return to the clinic 
within 30 days of the last dose of CX-4945 for a follow-up visit. 
 
 
Please see the Study Flowchart provided in Appendix A for assessment to be 
performed at the study completion/early termination visit. 
 
13. STUDY DISCONTINUATION – STUDY STOPPING RULES 
The sponsor has the right to terminate this study at any time.  Reasons for 
terminating the study may include the following: 
 
1. The incidence or severity of adverse events in this or other studies indicates 
a potential health hazard to patients. 
2. A decision on the part of the Sponsor to suspend or discontinue testing, 
evaluation, or development of the product. 
3. Patient enrollment is unsatisfactory. 
4. Data recording is inaccurate or incomplete. 
5. The Investigator fails to comply with pertinent regulations of appropriate 
regulatory authorities or there are persistent serious violations of the 
protocol.    
 
14. ASSAY METHODS 
14.1. EVALUATION OF HH PATHWAY STATUS USING QRT-PCR IN 
FRESH FROZEN TISSUE OR FORMALIN FIXED PARAFFIN 
EMBEDDED 
Transcripts for Hh pathway target gene, GLI1, and reference genes will be 
quantitated by TaqMan® qRT-PCR. RNA will be extracted from fresh frozen tissue 
or formalin fixed paraffin embedded using commercially available reagents and 
reverse transcribed in the presence of random hexamers (TaqMan® reverse 
transcription reagents).  PCR will be conducted using the Life Technologies 
QuantStudio Quantitative Real-Time PCR (qPCR) Machine.  Expression levels of 
GLI1 will be quantitated using the [Δ]Ct method.  
 
15. STATISTICAL CONSIDERATIONS 
15.1. SAFETY ANALYSES 
Unless otherwise noted, all safety analyses will be performed using the all treated 
patient population. Safety will be assessed through summaries of laboratory test 
results, all adverse events, including serious adverse events, study drug−related 
adverse events, and adverse events leading to discontinuation of CX-4945. All 
treatment-emergent adverse events will be mapped to thesaurus terms and graded 
according to the NCI CTCAE, version 5.0. 
 


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Relative dose intensity (expressed as a percentage) defined for each cycle as the 
ratio between ‘actual dose/actual duration’ over ‘intended dose/intended duration’ 
will be assessed for all patients enrolled in the expansion cohorts. Patients who are 
removed from the study for any reason other than for adverse events or for disease 
progression will not be included in the relative dose intensity assessment.  
 
15.2. EFFICACY ANALYSES 
Unless otherwise noted, all efficacy analyses will be performed using the all treated 
patient population, defined as all enrolled patients who receive any amount of study 
drug. Patients for whom the pathologist’s interpretation of baseline biopsy is not 
consistent with BCC will not be included in the efficacy analyses. More details 
regarding analyses involving missing or uninterpretable biopsies can be found in 
Section 15.5. 
 
Patients with measurable disease will be evaluated for clinical benefit as determined 
by objective response. Objective response will be determined as a function of a 
radiographic, photographic and pathological review (See Appendices B, C, G and 
H). Objective response is defined as a complete or partial response determined on 
two consecutive assessments ≥ 4 weeks apart. The objective response observed in 
this trial will be described separately for the mBCC and locally advanced BCC.  
 
The endpoint of the Hh pathway signaling study is the relative expression of Gli1 
in fresh-frozen tissues as measured by qRT-PCR. The relative expression of Gli1 
will be summarized by [Δ]Ct. Patients with missing or unevaluable results will be 
excluded from these analyses. The fresh-frozen tissues will be sent to Oncocyte 
Corporation for analysis. 
 
15.3. ANALYSIS OF THE CONDUCT OF THE STUDY 
The number of patients who are enrolled will be tabulated by center. Major protocol 
deviations, study discontinuation reasons, and exposure will be summarized for all 
enrolled patients. 
 
15.4. LENGTH OF TRIAL 
This study is expected to remain open until approximately 25 months following the 
first treatment of the first patient with CX-4945. The final analysis will commence 
at least 9 months following the first treatment of the last enrolled patient in the 
expansion cohort. All outstanding study data will be collected from Senhwa’s 
designated CROs (hereafter referred to as the CRO) and sites, and data queries will 
be resolved. After data queries are resolved, the database will be locked and the 
final analysis will be performed and described in the Clinical Study Report. 
 
15.5. HANDLING OF MISSING CLINICAL DATA 
Patients without interpretable baseline tissue, as determined by the pathologist, or 
by pathology report from the study site documenting a pathologist’s determination 


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of BCC, will be excluded from the efficacy analyses. No imputations will be made 
for missing data. The data will be analyzed as observed cases only. 
 
15.6. SAMPLE SIZE CONSIDERATIONS 
In the treatment duration increment part of the study, a 3+3 study design will be 
utilized, therefore approximately 3-6 patients will be enrolled to define the RP2D.  
 
In the expansion part of the study, a total sample size of 20 patients is proposed; 10 
patients with local advanced BCC and 10 patients with metastatic BCC. Assume 
that CX-4945 is of no interest if its true response is 5% or lower, the proposed 
sample size for each sub-population will provide an 80% confidence interval of 
(5.5%, 45.0%) given that there are 2 responses out of the 10 patients. This would 
provide adequate evidence to suggest that additional studies with this agent may be 
warranted. 
 
15.7. DATA QUALITY ASSURANCE 
The CRO will perform oversight of the data management of this trial. The CRO 
will produce an EDC Study Specification document that describes the quality 
checking to be performed on the data. Central Laboratory data will be sent directly 
to the CRO, using its standard procedures to handle and process the electronic 
transfer of these data. eCRFs and data queries documentation will be maintained in 
the EDC system’s audit trail. System backups for data stored at the CRO and 
records retention for the study data will be consistent with the CRO’s standard 
procedures. 
 
16. ASSESSMENT OF SAFETY 
16.1. SAFETY VARIABLES AND DEFINITIONS 
Safety assessments will consist of monitoring and recording protocol-defined 
adverse events (AEs) and serious adverse events (SAEs); measurement of protocol-
specified hematology, clinical chemistry, and urinalysis variables; measurement of 
protocol-specified vital signs; and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study drug. 
 
Senhwa Biosciences is responsible for reporting relevant SAEs to the Competent 
Authority, other applicable regulatory authorities, and participating investigators, 
in accordance with regulatory requirements. 
 
Senhwa Biosciences or its designee is responsible for reporting unexpected fatal or 
life-threatening events associated with the use of the study drug to the regulatory 
agencies and competent authorities by telephone or facsimile within 7 calendar days 
after being notified of the event. Senhwa Biosciences or its designee will report 
other relevant SAEs associated with the use of the study drug to the appropriate 
competent authorities (according to local guidelines), investigators, and central 
IRBs/ECs (except in the United States where investigators are responsible for 


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reporting to their IRBs per local requirements) by a written safety report within 15 
calendar days of notification. 
 
16.1.1. Adverse Event 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product or other protocol-
imposed intervention, regardless of attribution. 
 
This includes the following: 
• 
AEs not previously observed in the patient that emerge during the 
protocol-specified AE reporting period, including signs or 
symptoms associated with advanced BCC that were not present 
prior to the AE reporting period (see Section 16.2.1) 
• 
Complications that occur as a result of protocol-mandated 
interventions (e.g., invasive procedures such as biopsies) 
• 
AEs that occur prior to assignment of study treatment that are related 
to a protocol-mandated intervention (e.g. invasive procedures such 
as biopsies, medication washout, or no treatment run-in). 
• 
Preexisting medical conditions (other than the condition being 
studied), judged by the investigator to have worsened in severity or 
frequency or changed in character during the protocol-specified AE 
reporting period. 
 
16.1.2. Serious Adverse Event 
 
 
An SAE is any AE that is any of the following: 
• 
Is fatal (i.e., the AE actually causes or leads to death) 
• 
Is life threatening (i.e., the AE, in the view of the investigator, places 
the patient at immediate risk of death) 
• 
Requires or prolongs inpatient hospitalization 
• 
Results in persistent or significant disability/incapacity (i.e., the AE 
results in substantial disruption of the patient’s ability to conduct 
normal life functions) 
• 
Results in a congenital anomaly/birth defect in a neonate/infant born 
to a mother exposed to the investigational product(s) 
• 
Is considered a significant medical event by the investigator (e.g., 
may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above) 
 
All AEs that do not meet any of the criteria for serious should be regarded as non-
serious AEs. 
 
The terms “severe” and “serious” are not synonymous. Severity refers to the 
intensity of an AE (as in mild, moderate, or severe pain); the event itself may be of 
relatively minor medical significance (such as severe headache). “Serious” is a 
regulatory definition and is based on patient or event outcome or action criteria 


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usually associated with events that pose a threat to a patient’s life or vital functions. 
Seriousness (not severity) serves as the guide for defining regulatory reporting 
obligations. 
 
Severity and seriousness should be independently assessed when recording AEs and 
SAEs on the eCRF. 
 
16.1.3. Other Protocol Reportable Events – Pregnancy Reporting 
If a patient becomes pregnant during the course of the study, the investigational 
agent should be discontinued immediately.  
 
Pregnancy itself - occurring in female participants, and female partners of male 
participants - is not regarded as an AE unless there is a suspicion that the IP under 
study may have interfered with the effectiveness of a contraceptive medication. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and 
documented even if the patient was discontinued from the study.  
 
The investigator is required to report to the CRO any pregnancy occurring in female 
participants, and female partners of male participants. Pregnancies occurring up to 
6 months after the last dose of study treatment must also be reported. 
 
The investigator should report the pregnancy in a timely manner, within 24 hours 
of learning. All follow-up reports must be submitted to the CRO in a timely manner. 
For pregnant partner of trial participant (and pregnant participants, if required by 
local policy), a copy of the signed signature page of the pregnancy follow-up 
consent must be submitted to the CRO.  
 
If the pregnancy results in death (e.g. spontaneous abortion, stillbirth); is life-
threatening; requires inpatient hospitalization or prolongation of existing 
hospitalization; results in persistent or significant disability/incapacity; is a 
congenital anomaly/birth defect, then an SAE report must be additionally submitted 
as described above. Please note, hospitalization for labor/delivery alone does not 
constitute an ‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
Refer to Section 16.4.2 for SAE reporting instructions. 
 
16.2. METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY 
PARAMETERS 
The investigator is responsible for ensuring that all AEs and SAEs (as defined in 
Section 16.1) are recorded on the eCRF and reported to the CRO in accordance 
with protocol instructions. 
 


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16.2.1. Adverse Event Reporting Period 
After informed consent, but prior to initiation of study drug, only SAEs caused by 
a protocol-mandated intervention will be collected (e.g., SAEs related to invasive 
procedures such as biopsies, medication washout, or no treatment run-in). 
 
After initiation of study drug, all AEs and SAEs regardless of attribution will be 
collected until 30 days following the last administration of study treatment or study 
discontinuation/termination, whichever is later. After this period, investigators 
should report only SAEs that are felt to be related to prior study treatment (see 
Section 16.6). Additional guidance is provided for pregnancy events occurring 
within 6 months after the last dose of CX-4945 in Section 16.1.3. 
 
16.2.2. Assessment of Severity and Causality of Adverse Events 
Investigators will seek information on AEs and SAEs at each patient contact. All 
AEs and SAEs, whether reported by the patient or noted by authorized study 
personnel, will be recorded in the patient’s medical record and on the appropriate 
AE/SAE eCRF. 
 
For each AE and SAE recorded on the applicable eCRF, the investigator will make 
an assessment of seriousness (see Section 16.1.2 for seriousness criteria), severity, 
and causality. 
 
The following criteria provides guidance for grading AE severity. The AE grading 
(severity) scale found in the CTCAE, v5.0, will be used for AE reporting. 
 
1. Mild: 
Nuisance, barely noticeable. 
2. Moderate: 
Uncomfortable, troublesome symptoms not significantly 
interfering with daily activities or sleep. 
3. Severe/Disabling: 
Symptoms significantly interfere with daily activities or sleep.  
4. Life threatening: 
Event places the patient at risk of death. 
5. Fatal: 
Event caused the death of the patient. 
 
To ensure consistency of causality assessments, investigators should apply the 
following general guidelines: 
 
 
Is the AE/SAE suspected to be caused by the investigational product based on 
facts, evidence, science-based rationales, and clinical judgment?


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YES 
The temporal relationship of the AE/SAE to investigational 
product administration makes a causal relationship possible, 
AND other drugs, therapeutic interventions or underlying 
conditions do not provide sufficient explanation for the AE/SAE.
NO 
The temporal relationship of the AE/SAE to investigational 
product administration makes a causal relationship unlikely, OR 
other drugs, therapeutic interventions or underlying conditions 
provide a sufficient explanation for the AE/SAE.
 
Note: The investigator’s assessment of causality for individual AE reports is part 
of the study documentation process. Regardless of the “Yes” or “No” causality 
assessment for individual AE reports, the Sponsor will promptly evaluate all 
reported SAEs against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators and applicable 
regulatory authorities. 
 
16.3. PROCEDURES FOR RECORDING ADVERSE EVENTS 
16.3.1. Recording Adverse Events on the eCRF 
Investigators should use correct medical terminology/concepts when recording AEs 
or SAEs on the eCRF and should avoid colloquialisms and abbreviations. Only one 
medical concept should be recorded in the event field on the AE/SAE eCRF page. 
 
A. Diagnosis versus Signs and Symptoms 
If known, a diagnosis should be recorded on the eCRF rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as an AE or SAE 
on the eCRF. If a diagnosis is subsequently established, it should be reported as 
follow-up information. 
 
B. Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause. For example, if severe 
diarrhea is known to have resulted in dehydration, it is sufficient to record only 
diarrhea as an AE or SAE on the eCRF. 
 
However, medically significant AEs occurring secondary to an initiating event that 
are separated in time should be recorded as independent events on the eCRF. For 
example, if a severe gastrointestinal hemorrhage leads to renal failure, both events 
should be recorded separately on the eCRF. 
 
C. Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between 
patient evaluation timepoints. Such events should only be recorded once on the 


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eCRF unless their severity increases. If a persistent AE becomes more severe, it 
should be recorded again on an AE/SAE eCRF. 
 
A recurrent AE is one that occurs and resolves between patient evaluation 
timepoints and subsequently recurs. All recurrent AEs should be recorded on an 
AE/SAE eCRF. 
 
D. Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities that require active management 
will be recorded as AEs or SAEs on the eCRF (e.g., abnormalities that require study 
drug dose modification, discontinuation of study treatment, more frequent follow-
up assessments, further diagnostic investigation, etc.). 
 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × the upper limit of normal associated 
with cholecystitis), only the diagnosis (e.g., cholecystitis) needs to be recorded on 
the AE/SAE eCRF. 
 
If the clinically significant laboratory abnormality is not a sign of a disease or 
syndrome, the abnormality itself should be recorded as an AE or SAE on the eCRF. 
If the laboratory abnormality can be characterized by a precise clinical term, the 
clinical term should be recorded as the AE or SAE. For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.” 
 
Observations of the same clinically significant laboratory abnormality from visit to 
visit should not be repeatedly recorded as AEs or SAEs on the eCRF, unless their 
severity, seriousness, or etiology changes. 
 
E. Deaths 
Deaths that occur during the protocol-specified AE reporting period (see Section 
16.2.1) that are attributed by the investigator solely to progression of advanced 
BCC will be recorded only on the Study Discontinuation eCRF. All other on-study 
deaths, regardless of attribution, will be reported to the Clinical Safety Management 
at the CRO within 24 hours of learning of the events.  Refer to Section 16.4.2 for 
reporting instructions.  
 
When recording a death on an SAE eCRF, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept 
on the SAE eCRF. If the cause of death is unknown and cannot be ascertained at 
the time of reporting, record “Unexplained Death” on the SAE eCRF. 
 
F. Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be recorded on the Medical and Surgical History eCRF. A 
preexisting medical condition should be recorded as an AE or SAE only if the 
frequency, severity, or character of the condition worsens during the study. When 


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recording such events on an AE/SAE eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors (e.g., 
“more frequent headaches”). 
 
G. Worsening of Advanced Basal Cell Carcinoma 
Worsening and/or progression of advanced BCC should not be recorded as an AE 
or SAE. These data will be captured as efficacy assessment data only. 
 
H. Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE unless specifically instructed otherwise in this 
protocol. 
 
 
There are some hospitalization scenarios that do not require reporting as an SAE 
when there is no occurrence of an AE. These scenarios include a planned 
hospitalization or prolonged hospitalization to: 
 
• Perform an efficacy measurement for the study 
• Undergo a diagnostic or elective surgical procedure for a preexisting 
medical condition that has not changed 
• Receive scheduled therapy for the target disease of the study 
 
I. Pregnancy 
Pregnancy is reportable event. The CRO must be notified within 24 hours of 
learning of the pregnancy to facilitate outcome follow-up. Please refer to Section 
16.1.3 for additional specific instructions. 
 
16.4. EXPEDITED REPORTING REQUIREMENTS FOR SERIOUS ADVERSE 
EVENTS AND OTHER PROTOCOL REPORTABLE EVENTS 
16.4.1. Reporting 
Requirements 
for 
Fatal/Life-Threatening 
SAEs 
Related 
to 
Investigational Product 
Any life-threatening (i.e., imminent risk of death) or fatal AE that is attributed by 
the investigator to the investigational product will be reported to the Clinical Safety 
Management at the CRO within 24 hours of learning of the events.  Refer to Section 
16.4.2 for reporting instructions.  
 
16.4.2. Reporting Requirements for All SAEs and Other Protocol Reportable Events  
Investigators will submit reports of all SAEs, regardless of attribution, and other 
protocol reportable events to the Clinical Safety Management at the CRO within 24 
hours of learning of the events. For initial SAE and other protocol reportable events, 
investigators may fax, phone or email the events to the Clinical Safety 
Management. A phoned SAE report must be followed by a written report as soon 
as possible. The SAE information will be entered to the EDC system as soon as 
possible. The study supplied reporting form along with any medical comments from 
medical monitor will be sent to Sponsor.  


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Relevant follow-up information should be submitted to the CRO as soon as it 
becomes available and/or upon request. 
 
Email:  Safety-Inbox@novellaclinical.com, or  
 
Country Name
Telephone Number 
Fax Number 
Worldwide Toll 
1-919-313-7111
1-919-313-1412
USA (Toll Free) 
1-866-758-2798
1-866-761-1274
 
 
16.5. TYPE AND DURATION OF FOLLOW-UP OF PATIENTS AFTER 
ADVERSE EVENTS 
The investigator should follow all unresolved AEs and SAEs until the events are 
resolved or stabilized, the patient is lost to follow-up, or it has been determined that 
the study treatment or participation is not the cause of the AE/SAE. Resolution of 
AEs and SAEs (with dates) should be documented on the appropriate AE/SAE 
eCRF and in the patient’s medical record to facilitate source data verification 
(SDV). 
 
For some SAEs, the CRO may follow-up by telephone, fax, electronic mail, and/or 
a monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant 
report, or autopsy report). 
 
16.6. POST-STUDY ADVERSE EVENTS 
At the last scheduled visit, the investigator should instruct each patient to report to 
the investigator any subsequent SAEs that the patient’s personal physician believes 
could be related to prior study treatment. 
 
The investigator should notify the CRO of any death or other SAE occurring at any 
time after a patient has discontinued or terminated study participation if felt to be 
related to prior study treatment. The CRO should also be notified if the investigator 
should become aware of the development of cancer or of a congenital anomaly in 
a subsequently conceived offspring of a patient that participated in this study (refer 
to Section 16.1.3). The investigator should report these events following the 
reporting procedures specified in the Section 16.4. If the CRO or the EDC is no 
longer available, the investigator should report the event directly to Sponsor Drug 
Safety via safety@senhwabio.com  
 
17. INVESTIGATOR REQUIREMENTS 
17.1. STUDY INITIATION 
The following documentation must be received by the Sponsor prior to initiation 
of the trial: 
 


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1. Original US FDA Form 1572 (for all studies conducted under US 
Investigational New Drug [IND] regulations), signed by all Principal 
Investigators.  The names of any sub-investigators must appear on this form.  
Investigators must also complete all regulatory documentation as required by 
local and national regulations. 
2. Current curricula vitae of the Principal Investigator and all sub-investigators. 
3. Institutional Review Board (IRB) membership list and/or Department of Health 
and Human Services number. 
4. Written documentation of IRB approval of protocol (identified by protocol 
number or title and date of approval) and informed consent document 
(identified by protocol number or title and date of approval). 
5. A copy of the IRB-approved informed consent document. 
6. Current laboratory certification of the laboratory performing the analysis 
(issuing agency and expiration date), as well as current normal laboratory 
ranges for all laboratory tests. 
7. A signed Clinical Research (Protocol) Agreement. 
8. Certified translations of IRB approval letters, pertinent correspondence, and 
approved informed consent document (when applicable). 
9. Financial disclosure form for Principal Investigator and all sub-investigators. 
 
17.2. STUDY COMPLETION 
The following data and materials are required by the Sponsor before the study can 
be considered complete or terminated: 
 
1. Laboratory findings, clinical data, and all special test results from screening 
through the end of the study follow-up period. 
2. eCRFs properly completed by appropriate study personnel and signed and dated 
by the investigator. 
3. Completed drug accountability records. 
4. Copies of protocol amendments and IRB approval/notification, if appropriate. 
5. A summary of the study prepared by the Principal Investigator (an IRB 
summary close letter is acceptable). 
 
17.3. INFORMED CONSENT FORMS 
A sample Informed Consent Form will be provided to each site. Please note that 
the patient must sign the Study Informed Consent in order to participate in this 
study. The Sponsor or its designee must review and approve any proposed 
deviations from the sample Informed Consent Form or any alternate consent form 
proposed by the site (collectively, the “Consent Form”) before IRB/EC submission. 
Patients must be re-consented to the most current version of the Consent Form 
during their participation in the study. The final IRB/EC-approved Consent Form 
must be provided to the Sponsor for regulatory purposes.  


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The Consent Form must be signed by the patient or the patient’s legally authorized 
representative before his or her participation in the study. The case history for each 
patient shall document the informed consent process and that written informed 
consent was obtained prior to participation in the study. A copy of each signed 
Consent Form must be provided to the patient or the patient’s legally authorized 
representative. If applicable, it will be provided in a certified translation of the local 
language. 
 
All signed and dated Consent Forms must remain in each patient’s study file and 
must be available for verification by study monitors at any time. 
 
The Informed Consent Forms should be revised whenever there are changes to 
procedures outlined in the informed consent or when new information becomes 
available that may affect the willingness of the patient to participate. For any 
updated or revised Consent Forms, the case history for each patient shall document 
the informed consent process and that written informed consent was obtained for 
the updated/revised Consent Forms for continued participation in the study. The 
final revised IRB/EC-approved Informed Consent Forms must be provided to the 
Sponsor for regulatory purposes. 
 
If the site utilizes a separate Authorization Form for patient authorization to use and 
disclose personal health information under the U.S. Health Insurance Portability 
and Accountability Act (HIPAA) regulations, the review, approval, and other 
processes outlined above apply except that IRB/IEC review and approval may not 
be required per study site policies. 
 
17.4. COMMUNICATION WITH THE INSTITUTIONAL REVIEW BOARD 
OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the 
patient and relevant supporting information must be submitted to the IRB/EC for 
review and approval before the study is initiated. In addition, any patient 
recruitment materials must be approved by the IRB/EC. 
 
The Principal Investigator is responsible for providing written summaries of the 
status of the study to the IRB/EC annually or more frequently in accordance with 
the regulatory requirements and policies and procedures established by the IRB/EC. 
Investigators are also responsible for promptly informing the IRB/EC of any 
protocol changes or amendments and of any unanticipated problems involving risk 
to human patients or others. 
 
In addition to the requirements to report protocol-defined AEs to the Sponsor, 
investigators are required to promptly report to their respective IRB/EC all 
unanticipated problems involving risk to human patients. Some IRBs/ECs may 
want prompt notification of all SAEs, whereas others require notification only 


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about events that are serious, assessed to be related to study treatment, and are 
unexpected. Investigators may receive written IND safety reports or other safety-
related communications from the Sponsor or its designee. Investigators are 
responsible for ensuring that such reports are reviewed and processed in accordance 
with regulatory requirements and with the policies and procedures established by 
their IRB/EC and archived in the site’s Study File. 
 
17.5. STUDY MONITORING REQUIREMENTS 
Site visits will be conducted by an authorized representative of the Sponsor to 
inspect study data, patient’s medical records, and CRFs in accordance with current 
standard operating procedures of the Sponsor or its CRO. 
 
The Principal Investigator will permit authorized representatives of the Sponsor 
(including its CRO), the US FDA, and the respective national and local authorities 
to inspect facilities and records relevant to this study. 
 
17.6. CASE REPORT FORMS 
Data collected during the study will be entered in the patient’s eCRF by the 
investigational site staff. The staff will keep records of the patient’s visit in the files 
considered as source documents for the site, e.g., hospital chart, research chart. The 
Investigator will be responsible for the recording of all data on the eCRF and for 
submitting the data to the Sponsor or their designee in a timely manner. Should any 
value be significantly different from normal, the Investigator will comment in the 
appropriate sections provided in the eCRF.  
 
The Investigator will provide access to his/her original records to permit a 
representative from the Sponsor to verify the proper transcription of data. To 
facilitate photocopying, entries on original records must be written legibly in black 
ink only.  Erroneous entries will be crossed out with a single line, so as to remain 
legible.  The correct value will be entered above the error and then initialed and 
dated by the person authorized to make the correction.   
 
17.7. SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing SDV to confirm that critical protocol data 
(i.e., source data) entered on the eCRFs by authorized site personnel are accurate, 
complete, and verifiable from source documents. 
 
Source documents are where patient data are recorded and documented for the first 
time. They include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, patient diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient 
files, and records kept at the pharmacy, laboratories, and medico-technical 
departments involved in a clinical trial. 


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Source documents that are required to verify the validity and completeness of data 
entered on the eCRFs must never be obliterated or destroyed. 
 
To facilitate SDV, the investigator(s) and institution(s) must provide the Sponsor 
direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also 
allow inspection by applicable regulatory authorities. 
 
17.8. STUDY DRUG ACCOUNTABILITY AND DISPOSITION OF UNUSED 
STUDY DRUG 
The Investigator must maintain accurate records demonstrating dates and amount 
of study drug received, lot numbers, to whom dispensed (patient-by-patient 
accounting) and accounts of any study drug accidentally or deliberately destroyed.   
 
CX-4945 inventory forms and drug accountability will be examined and reconciled 
periodically by the study monitor throughout the course of the study and at the end 
of the study.  All partially used or empty containers returned by patients who will 
no longer participate in the trial should be disposed of at the study site according to 
institutional standard operating procedures after the monitor has completed drug 
accountability record review for these articles.  The sponsor will request 
documentation of the accountability and disposal procedures. Unopened, expired, 
or unused study drug should be returned with the appropriate accountability and 
shipment forms as directed by the sponsor or the CRO at the end of the trial, overall 
inventory and accountability of study drug will be conducted.  Any missing 
containers must be explained. 
 
All CX-4945 drug product required for completion of this study will be provided 
by the Sponsor.  The recipient will provide written acknowledgement of receipt 
after checking for shipment content and condition.  All damaged or expired supplies 
will be replaced. 
 
All partially used or empty containers should be disposed of at the study site 
according to institutional standard operating procedure.   
 
 
17.9. CONFIDENTIALITY OF DATA 
Patients’ medical information obtained during this study is confidential, and 
disclosure to third parties other than those noted below is prohibited. 
 
Upon the patient’s permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his or her 
care and welfare. 
 


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Data generated by this study must be available for inspection by representatives of 
the FDA, national and local health authorities, the Sponsor and its designated CRO, 
and the IRB.   
 
Doctors, hospitals and other health care professionals, their employers, insurance 
companies, or others who handle individuals' health care information associated 
with the conduct of this study are responsible for maintaining the privacy of that 
information in accordance with the Health Insurance Portability and Accountability 
Act of 1996 (HIPAA).  Data collected from the Investigator by the Sponsor’s 
designated CRO will be maintained in confidentiality and will only be reviewed 
during internal quality checks or external audits by regulatory authorities.   
 
17.10. RETENTION OF RECORDS 
US regulations (21 CFR 312.62[c]) require that records and documents pertaining 
to the conduct of this study and the distribution of investigational drug, including 
CRFs, patient informed consent forms, laboratory test results, and medical records, 
must be retained by the Principal Investigator for 2 years beyond the FDA’s 
approval date of CX-4945 ’s marketing application.  If no marketing application is 
filed, these records and documents must be kept for 2 years beyond the date when 
the FDA and the applicable national and local health authorities are notified by the 
Sponsor of the discontinuation of further development of CX-4945.  The Sponsor 
or its CRO will inform the Principal Investigator should either of these events 
occur.   
 
17.11. PUBLICATION AGREEMENT 
The Investigator agrees that no interim publications regarding the study or this 
study’s patients will occur without the written agreement of Senhwa Biosciences. 
 
17.12. PROTOCOL ADHERENCE 
Each Investigator must adhere to the protocol as detailed in this document and 
agrees that any changes to the protocol must be approved first by the Sponsor, and 
then by the IRB before being enacted.  Each Investigator must agree to enroll only 
those patients who meet all protocol eligibility criteria. 
 
18. ADMINISTRATIVE STRUCTURE 
Senhwa Biosciences Inc., will sponsor this study. A contract research organization 
(CRO) will perform study management, including project management, statistical 
programming, clinical monitoring, medical monitoring, data monitoring, and data 
management. One hundred percent source document verification will be conducted 
for all enrolled patients. Approximately 26 patients will be enrolled at 
approximately 6 sites in the United States. 
 


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19. REFERENCES 
1. Miller DL, Weinstock MA. Nomelanoma skin cancer in the united states: 
incidence. J Am Acad Dermatol 1994; 30:774-778. 
2. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2016. CA Cancer J Clin 2016; 
66:7-30. 
3. Asgari MM, Moffet HH, Ray GT, Quesenberry CP. Trends in basal cell 
carcinoma incidence and identification of high-risk groups, 1998-2012. JAMA 
Dermatol 2015; 151:976-981. 
4. Roger HW, Weinstock MA, Feldman SR, Coldiron BM. Incidence estimate of 
nonmelanoma skin cancer (keratinocyte carcinomas) in the U.S. population, 2012. 
JAMA Dermatol 2015; 151:1081-1086. 
5. Wysong A, Aasi SZ, Tang JY. Update on metastatic basal cell carcinoma: a 
summary of published cases from 1981 through 2011. JAMA Dermatol. 2013; 
149(5):615–616. [PubMed: 23677097] 
6. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in 
advanced basal-cell carcinoma. N Engl J Med. 2012; 366(23):2171–2179. 
[PubMed: 22670903]  
7. National Comprehensive Cancer Network. [June 28, 2018] Basal cell skin cancer. 
2015. 
https://www.nccn.org/store/login/login.aspx?ReturnURL=http://www.nccn.org/pr
ofessionals/physician_gls/pdf/nmsc.pdf. 
8. Pricl S., Cortelazzi B., Dal Col V., Marson D., Laurini E., Fermeglia M., 
Licitra L., Pilotti S., Bossi P., Perrone F., (2015), Smoothened (SMO) receptor 
mutations dictate resistance to vismodegib in basal cell carcinoma, Molecular 
Oncology, 9, doi: 10.1016/j.molonc.2014.09.003. 
9. Duncan, J. S.; Litchfield, D. W., Too much of a good thing: The role of protein 
kinase CK2 in tumorigenesis and prospects for therapeutic inhibition of CK2. 
Biochim Biophys Acta 2007. 
10. Meggio, F.; Pinna, L. A., One-thousand-and-one substrates of protein kinase 
CK2? Faseb J 2003, 17, (3), 349-68. 
11. Pagano, M. A.; Cesaro, L.; Meggio, F.; Pinna, L. A., Protein kinase CK2: a 
newcomer in the 'druggable kinome'. Biochem Soc Trans 2006, 34, (Pt 6), 1303-6. 
12. Purzner et al. Unpublished data. 


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APPENDIX A 
STUDY FLOWCHART 
Assessment or 
Procedure 
Screening 
 
 
Day 
1 
 
Treatment 
4 weeks 
after 
completion 
of protocol 
therapy 
3 month 
follow-up 
(only 
required 
for pts 
without 
confirmed 
PD and 
ongoing 
toxicities 
n)
Days –14 
to –1 
Every 
4 
Weeks 
( ± 3 
Days) 
Every 
8 
Weeks 
( ± 3 
Days) 
Week 
8 
( ± 3 
Days) 
Every 
Week 
12 
( ± 3 
Days) 
Clinical 
Response 
if 
before 
Wk 24 
Week 
24 
( ± 3 
Days) 
Informed Consent a 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion
X
Medical, surgical, 
and cancer history, 
and demographics
X 
 
 
 
 
 
 
 
 
 
Complete physical 
examination b
X 
 
 
 
 
 
 
 
 
 
Limited physical 
examination
 
 
X 
 
 
 
 
 
X 
 
Weight and Vital 
Signs c 
X 
X 
X 
 
 
 
 
 
X 
 
ECOG 
Performance 
Status (Appendix I)
X 
X 
X 
 
 
 
 
 
X 
 
12-Lead 
Electrocardiogram
X 
 
 
 
 
 
 
 
 
 
Tumor 
Assessments d
X 
 
 
X 
 
 
 
 
X 
Xr,s 
Digital 
photographs e
X 
 
 
X 
 
 
 
 
X 
 
Tumor biopsy f
X
Xf
Xf
Xf
Xf
Hematology g 
X 
 
X 
 
 
 
 
 
Xq 
Xq 
Serum Chemistry h
X
X
Xq
Xq
Urinalysis i
X
Serum vitamin D 
level j
X 
 
 
 
 
X 
 
 
 
 
Serum or urine 
pregnancy test k
X 
X 
X 
 
 
 
 
 
X 
 
CX-4945 
accountability l
 
 
X 
 
 
 
 
 
X 
 
Dispense CX-4945 l 
 
X 
X 
 
 
 
 
 
 
 
Concomitant 
medications m
X 
X 
X 
 
 
 
 
 
X 
 
Evaluation of 
Adverse Events
 
Xn
 
X
 
X
 
 
 
 
 
X 
Xn 
Cancer-related 
medical or 
surgical 
procedures o
 
X 
X 
 
 
 
 
 
X 
 
Dispense 
antiemetics and 
loperamide p 
(IMODIUM®)
 
X 
X 
 
 
 
 
 
 
 
BCC = basal cell carcinoma  
 
Note: Results of tests or examinations performed as standard of care prior to obtaining informed consent and within 14 days prior to 
study entry may be used rather than repeating required tests. 
 


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a.  
All patients must provide written informed consent prior to any study-specific 
procedure being performed and any exclusionary medications are discontinued for 
the purposes of establishing eligibility. Patients will sign two informed consent  
forms: one for study participation, and a separate consent detailing teratogenic 
risk. 
b.  
A complete physical exam includes evaluation of the head, eyes, ears, nose and 
throat; cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems. 
c.  
Vital signs include pulse, systolic and diastolic blood pressure while the patient is 
in a seated position, respiratory rate, and temperature. 
d.  
Tumor assessments must be performed at screening and every 8 weeks thereafter. 
Assessments should include an evaluation of all sites of disease. Patients in the 
metastatic BCC cohort will undergo tumor assessments per the Response 
Evaluation Criteria in Solid Tumors (see Appendix B). Patients in the locally 
advanced BCC cohort will undergo tumor assessments per the composite tumor 
response criteria (see Appendix C). 
e.  
Instructions for obtaining digital photographs are given in Appendix H. 
f.  
For patients with locally advanced BCC, a baseline tumor biopsy must be 
performed in accordance with guidelines (see Appendix G). Perform biopsy again 
on Week 8. Repeat biopsy either at best clinical response if achieved prior to 
Week 24 or at Week 24. A tumor biopsy is recommended at the time of 
progression. 
g. 
Hematology consists of hemoglobin, hematocrit, platelet count, red blood cell 
(RBC) count, white blood cell (WBC) count, and percent or absolute differential 
count (neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells). 
h. 
Serum chemistry includes glucose, blood urea nitrogen (BUN), creatinine, 
sodium, potassium, magnesium, bicarbonate, calcium, total protein, albumin, total 
bilirubin, alkaline phosphatase, AST, and ALT. 
i. 
Urinalysis includes pH, specific gravity, glucose, protein, ketones, and blood. 
j. 
Measurement of serum 25-hydroxyvitamin D (25[OH]D or calcidiol) is required 
at screening. Follow-up 25(OH)D measurements will be performed every three 
months. Patients found to have serum 25-hydroxyvitamin D (25[OH]D) 
concentration lower than 20 ng/mL during the screening period should receive 
vitamin D supplement. 
k. 
For women of childbearing potential, including those who have had a tubal 
ligation. A serum pregnancy test is required at screening and urine pregnancy 
tests will be performed at specified subsequent visits. If a urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test.  
l.  
Dispense, administer, and maintain drug accountability of CX-4945. For women 
of childbearing potential, the investigator must confirm the patient’s negative 
pregnancy test, the patient’s understanding of the teratogenic potential of CX-
4945, and the use of two acceptable methods of contraception prior to dispensing 
CX-4945. 


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m. 
The recording of concomitant medications will begin at the time of informed 
consent and continues through the end of the study period. Record all concomitant 
medications administered to the patient within the 14 days preceding Day 1. 
n.  
The reporting period for adverse events (AEs) will begin at the time of informed 
consent signed and continues until 30 days after the last dose of CX-4945. During 
screening (i.e., after informed consent, but prior to initiation of study drug), only 
SAEs related to protocol-mandated procedures should be reported. At the end of 
the study period, any patient with an ongoing AE or SAE leading to CX-4945 
discontinuation will be followed until the event resolves, the investigator assesses 
the event as stable, or the patient is lost to follow-up. 
o. 
The recording of cancer-related medical and surgical procedures begins on Day 1 
and continues through the end of the study period. 
p.  
Patient should receive enough antiemetic medication or patch and loperamide 
(IMODIUM®) supply within 72 hours of the treatment visit to cover the entire 
treatment of each cycle. 
q. 
At 4 weeks then every 3 months thereafter only to follow abnormal results felt 
related until resolved to ≤ Grade 2. 
r. 
Patients with a CR or PR should have scans repeated after 4 weeks to confirm 
response. 
s. 
Every three months until relapse or progression for patients with CR, PR, SD 
response. 


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APPENDIX B 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.0 
(RECIST) 
 
1. Introduction 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST) are 
below. 1 Modifications to the RECIST for the purposes of this study are also described. For 
this protocol, RECIST will be used to evaluate tumor lesions on standard radiologic 
imaging modalities (computed tomography [CT] or magnetic resonance imaging [MRI]) 
in non-skin organs, such as metastatic disease in lymph node, soft tissue, lung, or liver, or 
subcutaneous disease in patients with locally advanced disease. Evaluation of externally 
measurable lesions (such as visible locally advanced lesions) for patients with locally 
advanced disease will be performed using the criteria listed in Appendix C. 
2. Measurability of Tumor Lesions at Baseline 
2.1. Definitions 
At baseline, tumor lesions will be categorized as follows: measurable (lesions that can be 
accurately measured in at least one dimension [longest diameter to be recorded] as 20 mm 
with conventional imaging techniques or as 10 mm with spiral CT scan [see Section 2.2]) 
or nonmeasurable (all other lesions, including small lesions [longest diameter < 20 mm 
with conventional techniques or < 10 mm with spiral CT scan] and truly nonmeasurable 
lesions). 
All measurements should be recorded in metric notation by use of a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of treatment. Lesions 
considered to be truly non-measurable include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, abdominal masses that are not confirmed and followed by imaging 
techniques, and cystic lesions. 
Tumor lesions that are situated in a previously irradiated area may be considered 
measurable if an increase in the size of that tumor lesion has been documented since the 
time of irradiation. 
2.2. Specifications by Methods of Measurements 
The same imaging-based method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow up. CT and 
MRI are acceptable (see below). Imaging-based evaluation is preferred to evaluation by 
clinical examination when both methods have been used to assess the anti-tumor effect of 
a treatment. 
1 Therasse P, Arbuck SG, Eisenhauser EA, et al. New guidelines to evaluate the response to 


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treatment in solid tumors. J Natl Cancer Inst 2000; 92:205–16. 
 
2.2.1. Clinical examination. For lesions that are only evaluable on clinical examination in 
patients with locally advanced disease, refer to criteria for evaluation in Appendix C. 
2.2.2. Chest X-ray. Lesions on chest X-rays are not acceptable as measurable lesions. 
2.2.3. CT and MRI. CT and MRI are the best currently available and most reproducible 
methods for measuring target lesions selected for response assessment. Conventional CT 
and MRI should be performed with contiguous cuts of 10 mm or less in slice thickness. 
Spiral CT should be performed by use of a 5-mm contiguous reconstruction algorithm; this 
specification applies to the tumors of the chest, abdomen, and pelvis, while head and neck 
tumors and those of the extremities usually require specific protocols. More details 
concerning the use of these methods of assessment for objective tumor response evaluation 
are provided in Appendix I.2 
2.2.4. Ultrasound. Ultrasound should not be used to measure tumor lesions. 
2.2.5. Endoscopy and laparoscopy. These techniques should not be used to measure 
tumor lesions. 
2.2.6. Tumor markers. Tumor markers should not be used to measure tumor lesions. 
3. Tumor Response Evaluation 
3.1. Baseline Evaluation 
3.1.1. Assessment of overall tumor burden and measurable disease. To assess objective 
response, it is necessary to estimate the overall tumor burden at baseline to which 
subsequent measurements will be compared. Only patients with measurable disease at 
baseline should be included in protocols where objective tumor response is the primary 
endpoint. Measurable disease is defined by the presence of at least one measurable lesion 
(as defined in Section 2.1). If the measurable disease is restricted to a solitary lesion, its 
neoplastic nature should be confirmed by cytology/histology. 
3.1.2. Baseline documentation of “target” and “nontarget” lesions. All measurable 
lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of 
all involved organs, should be identified as target lesions and recorded and measured at 
baseline. Target lesions should be selected on the basis of their size (those with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A sum of the longest diameter for all target lesions will be 
calculated and reported as the baseline sum longest diameter. The baseline sum longest 
diameter will be used as the reference by which to characterize the objective tumor 
response. 


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All other lesions (or sites of disease) should be identified as nontarget lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up. 
3.2. Response Criteria 
3.2.1. Evaluation of target lesions. This section provides the definitions of the criteria 
used to determine objective tumor response for target lesions. The criteria have been 
adapted from the original WHO Handbook, taking into account the measurement of the 
longest diameter only for all target lesions: 
Complete Response—the disappearance of all target lesions; Partial Response at least a 
30% decrease in the sum of the longest diameter of target lesions, taking as reference the 
baseline sum longest diameter; Progressive Disease—at least a 20% increase in the sum of 
the longest diameter of target lesions, taking as reference the smallest sum longest diameter 
recorded since the treatment started or the appearance of one or more new lesions; Stable 
Disease—neither sufficient shrinkage to qualify for partial response nor sufficient increase 
to qualify for progressive disease, taking as reference the smallest sum longest diameter 
since the treatment started. If the investigator’s assessment of progressive disease is 
equivocal, and in the investigator’s opinion the patient is still deriving benefit from 
treatment, treatment with CX-4945 should be continued, and the patient should be re-
evaluated at the next tumor assessment timepoint. 
3.2.2. Evaluation of nontarget lesions. This section provides the definitions of the criteria 
used to determine the objective tumor response for nontarget lesions: complete response—
the disappearance of all nontarget lesions; incomplete response/stable disease—the 
persistence of one or more nontarget lesion(s); and progressive disease—the appearance of 
one or more new radiographically identified lesions and/or unequivocal progression of 
existing nontarget lesions. A new radiographically identified lesion is defined as a lesion 
that has not previously been seen in prior imaging studies, and that has increased in size to 
either a diameter larger than the size of the slice thickness being used for that imaging 
modality or at least 5 mm, whichever is larger. 
3.2.3. Evaluation of best overall response. The best overall response is the best response 
recorded from the start of treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started). In general, the patient's best response assignment will depend on the achievement 
of both measurement and confirmation criteria (see Section 3.5.1). Table 1 provides overall 
responses for all possible combinations of tumor responses in target and nontarget lesions 
with or without the appearance of new lesions. 
 
2 See Appendix I of the Therasse et al. 2000 article. 
 


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Table 1. Overall responses for all possible combinations of tumor responses in target and 
nontarget lesions with or without the appearance of new lesions 
RECIST Best Overall Response: Patients with Measurable Disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PR = partial response; SD = stable disease; and PD = progressive disease. See 
text for more details. 
Note: If the investigator’s assessment of progressive disease is equivocal, and in the 
investigator’s opinion the patient is still deriving benefit from treatment, treatment with 
CX-4945 should be continued, and the patient should be re-evaluated at the next tumor 
assessment timepoint. 
 Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration.” Every effort should be made to 
document the objective disease progression, even after discontinuation of 
treatment. 
 In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (fine-
needle aspiration/biopsy) before confirming the complete response status. 
 
3.2.4. Frequency of tumor re-evaluation. Frequency of tumor re-evaluation while on 
treatment is defined in this study as every 8 weeks. 
 
3.3. Confirmatory Measurement/Duration of Response 
 
3.3.1. Confirmation. The main goal of confirmation of objective response in clinical trials 
is to avoid overestimating the response rate observed. This aspect of response evaluation 
is particularly important in nonrandomized trials where response is the primary endpoint. 
In this setting, to be assigned a status of partial response or complete response, changes in 
tumor measurements must be confirmed by repeat assessments that should be performed 
no less than 4 weeks after the criteria for response are first met. 
 


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In the case of stable disease, measurements must have met the stable disease criteria at least 
once after study entry at a minimum interval of 8 weeks. 


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APPENDIX C 
COMPOSITE TUMOR RESPONSE CRITERIA FOR PATIENTS WITH 
LOCALLY ADVANCED BASAL CELL CARCINOMA 
 
For all patients with locally advanced basal cell carcinoma (BCC), externally visible target 
lesions will be chosen by the investigator and must include any lesions that are both 
externally visible and measurable according to the Response Evaluation Criteria in Solid 
Tumors (RECIST). The externally visible component of all target lesions should be at least 
10 mm in the longest dimension, to facilitate accurate and reproducible measurement. 
Standardized digital photographs of the externally visible component of all target lesions 
must be obtained at baseline and at the time of each tumor assessment (see Appendix H). 
For patients with a target lesion that contains both an externally visible and a RECIST-
measurable component, appropriate imaging studies (computed tomography or magnetic 
resonance imaging) will be used to assess the RECIST component of tumor response (see 
Appendix B). Investigators must also provide a clinical description of the target lesion(s) 
at baseline and at each tumor assessment, as well as comments on any changes in the 
lesion(s) since the previous assessment. 
 
All patients will undergo baseline and on-study biopsies of target lesions per Appendix G; 
in patients achieving a clinical response, histologic analysis of on-study biopsies will be 
used for final determination of complete versus partial response (see below). 
 
Clinical Response Criteria (for all patients with locally advanced BCC) 
 
A. Externally Visible Tumor Dimension 
 
The externally visible component of target lesion(s) will be measured in the longest 
dimension at each tumor assessment and will be documented using standardized digital 
photography. If the border of the tumor is no longer visible but a scar is present, the 
dimensions of the scar should be measured. 
 
Response criteria for tumor dimension are as follows: 
 Complete Response (CR): all target lesion(s) no longer visible, maintained for at 
least 4 weeks 
 Partial Response (PR): decrease of 30% or greater in the sum of the longest 
dimension of target lesion(s), maintained for at least 4 weeks 
 Stable Disease (SD): not meeting criteria for CR, PR, or progressive disease (PD) 
 Progressive Disease (PD): increase of ≥ 20% in the sum of the longest dimension 
of target lesion(s) 
 
B. Tumor Ulceration (only for patients whose target lesion[s] are ulcerated at 
baseline) 
 
Response criteria are as follows: 


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 CR: re-epithelialization of the entire baseline area of ulceration of target lesion(s), 
maintained for at least 4 weeks 
 PR: there are no criteria for PR 
 SD: not meeting criteria for CR or PD 
 PD: new ulceration of target lesion(s), not related to (i.e., in a location separate 
from) tissue biopsy or other known trauma, persisting without evidence of healing 
for at least 2 weeks 
 
Overall Clinical Responses for All Possible Combinations of 
Tumor Responses for Locally Advanced BCC
Externally Visible 
Tumor Dimension 
Tumor Ulceration 
(If Applicable) 
New Lesions a 
Clinical Response 
CR or PR 
Non-PD 
No 
Response b 
SD 
CR 
No 
Response b 
SD 
SD 
No 
SD 
PD 
Any 
Any 
PD c 
Any 
PD 
Any 
PD c 
Any 
Any 
Yes  
PD c 
CR = complete response; PD = progressive disease; SD = stable disease. 
 
a See above for definitions. 
b In patients achieving clinical response, histologic analysis of biopsies will be used for final 
determination of CR vs. PR; see below and Appendix G. 
c If the investigator’s assessment of progressive disease is equivocal, and in the investigator’s 
opinion the patient is still deriving benefit from treatment, treatment with CX-4945 should be 
continued, and the patient should be re-evaluated at the next tumor assessment timepoint. 
 
Clinical plus RECIST (for patients with locally advanced BCC whose target 
lesion[s] have both externally visible and RECIST-measurable components) 
 
See Appendix B for RECIST; also see Section C above with respect to the criteria for 
new skin lesions. 
 
Clinical Response 
RECIST 
Response 
Clinical + RECIST 
Response 
Response 
Non-PD 
Response a 
SD 
CR or PR 
Response a 
SD 
SD 
SD 
PD 
Any 
PD b 
Any 
PD 
PD b 
CR = complete response; PD = progressive disease; PR = partial response; 
RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease. 
 
a In patients achieving clinical response, histologic analysis of biopsies will be used for final 
determination of CR vs. PR; see below and Appendix G. 


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b If the investigator’s assessment of progressive disease is equivocal, and in the investigator’s 
opinion the patient is still deriving benefit from treatment, treatment with CX-4945 should be 
continued, and the patient should be re-evaluated at the next tumor assessment timepoint. 
 
In patients with a clinical response, histologic analysis of biopsies will be used for final 
determination of CR (absence of residual BCC) versus PR (residual BCC present); see 
Appendix G.  
 
In addition, if all previously inoperable target lesions are rendered operable with clear 
margins obtained at the time of surgery, this will be considered a PR. If the investigator 
deems a previously inoperable lesion to be potentially operable, the Medical Monitor 
should be consulted prior to any surgical procedure 


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APPENDIX D 
DEFINITION OF WOMEN OF CHILDBEARING POTENTIAL AND 
ACCEPTABLE AND UNACCEPTABLE FORMS OF CONTRACEPTION 
 
Women of childbearing potential are defined as follows: 
 Patients with regular menses 
 Patients with amenorrhea, irregular cycles, or using a contraceptive method that 
precludes withdrawal bleeding 
 Women who have had a tubal ligation 
 
Women are considered not to be of childbearing potential for the following reasons: 
 The patient has undergone hysterectomy and/or bilateral oophorectomy. 
 The patient is post-menopausal defined by amenorrhea for at least 1 year in a 
woman > 45 years old. 
 Women of childbearing potential are required to use two forms of acceptable 
contraception, including one barrier method, during their participation in the study 
and for 6 months following discontinuation of CX-4945. 
 
The following are acceptable forms of barrier contraception: 
 Latex condom (always used with spermicide) 
 Diaphragm (always used with spermicide) 
 Cervical cap (always used with spermicide) 
 
The following are acceptable forms of secondary contraception, when used with a barrier 
method: 
 Tubal ligation 
 Partner’s vasectomy 
 Hormonal contraception including birth control pills, patches, rings, or injections, 
with the exception of the progesterone-only “minipill” 
 Intrauterine device (non–progesterone T) 
 Vaginal sponge (containing spermicide) 
 
In addition, 100% commitment to abstinence is considered an acceptable form of 
contraception. 
 
The following are unacceptable forms of contraception for women of childbearing 
potential: 
 IUD progesterone T 
 Progesterone-only “minipill” 
 Female condom 
 Natural family planning (rhythm method) or breastfeeding 
 Fertility awareness 


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 Withdrawal 
 Cervical shield 


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APPENDIX E 
VITAMIN D DOSING RECOMMENDATION1 
 
 Institute of Medicine (IOM) favors maintaining the serum 25(OH)D concentration 
between 20 and 40 ng/mL (50 to 100 nmol/L)2. 
 
 For patients with severe vitamin D deficiency (25[OH]D <10 ng/mL [25 nmol/L]), the 
recommended approach is to treat with 50,000 international units of vitamin D2 or D3 
orally once per week for six to eight weeks, and then 800 international units of vitamin 
D3 daily thereafter.  
 
 For individuals with serum 25(OH)D levels in the range of 10 to 20 ng/mL (25 to 50 
nmol/L), supplement initially with 800 to 1000 international units daily.  
 
 For individuals with serum 25(OH)D levels in the range of 20 to 30 ng/mL (50 to 75 
nmol/L), the recommended approach is to supplement with 600 to 800 units of vitamin 
D3 daily. 
 
 Cholecalciferol (vitamin D3) is recommended, when available, rather than 
ergocalciferol (vitamin D2) for vitamin D supplementation. 
 
 Follow-up 25(OH)D measurements should be made approximately three months after 
initiating maintenance therapy to confirm that the target level has been achieved. 
 
 
1 Dawson-Hughes, B. (2017). Vitamin D deficiency in adults: Definition, clinical manifestations, and 
treatment. UpToDate. Retrieved June 28, 2018, from 
https://www.uptodate.com/contents/vitamin-d-deficiency-in-adults-definition-clinical-manifestations-and-
treatment. 
 
2 Ross AC, Manson JE, Abrams SA, et al. The 2011 Report on Dietary Reference Intakes for Calcium and 
Vitamin D from the Institute of Medicine: What Clinicians Need to Know. The Journal of Clinical 
Endocrinology and Metabolism. 2011;96(1):53-58. doi:10.1210/jc.2010-2704. 


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APPENDIX F 
MEDICATIONS WITH THE POTENTIAL TO INTERACT WITH CX-4945 
 
CX-4945 was tested in a non-GLP in vitro Cytochrome P450 inhibition assay in human 
liver microsomes with the following five key CYP450 isoenzymes: CYP1A2, CYP2C9, 
CYP2C19, CYP2D6 and CYP3A4. The concentration range of CX-4945 was from 0.0229 
to 50 μM. Using recombinant CYP450 enzymes and industry-accepted CYP450 substrates, 
CX-4945 had a moderate inhibitory effect on CYP1A2, as the IC50 value was in excess of 
10 μM. CX-4945 had a weak inhibitory effect on CYP2C9 and CYP3A4-testosterone as 
the IC50 values were in excess of 50 μM. There was no detectable inhibition for CYP2C19 
and CYP2D6. CYP3A4-midazolam exhibited positive cooperativity for this assay. The 
results suggest minimal risk for drug-drug interaction in patients. CX-4945 did not inhibit 
any of the CYP450 isoforms tested at the concentrations likely to be achieved in clinic. 
This result suggests that CX-4945 will not inhibit CYP450 and can be co-administered 
with drugs that are metabolized via this pathway. 
 
Initial preliminary pharmacokinetic findings suggest that co-administration of warfarin and 
HMG-CoA reductase inhibitors (statins) results in an increased exposure to the study drug. 
This tendency toward an increased drug exposure has been observed in four separate CX-
4945-treated patients who were concomitantly taking warfarin and a statin medication. 
While this observation did not appear to present additional safety concerns for these 
patients, these findings introduced variability that complicated the interpretation of the 
pharmacokinetic data. Use of warfarin and statins with CX-4945 should be documented in 
the eCRFs. 


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APPENDIX G 
GUIDELINES FOR TISSUE BIOPSY IN 
PATIENTS WITH LOCALLY ADVANCED BASAL CELL CARCINOMA 
 
Representative tumor biopsies are required for patients in the locally advanced basal 
cell carcinoma (BCC) cohort at the following timepoints: 
 
• 
At screening, Week 8 and 
• 
Either at the investigator’s assessment of best clinical response or best 
clinical/RECIST response, if occurring prior to 24 weeks,  
 
or  
 
At 24 weeks, if patient is still in study and is without evidence of progression 
 
Required 
Tumor Biopsy 
Screening 
(Day -14 to -1) 
Week 8 ( ± 3 
Days) 
Clinical 
Response if 
before Wk 24 
Week 24 
( ± 3 
Days) 
At disease 
progression 
Tumor biopsy 
for Hh pathway 
measurement 
(for laBCC 
patients in 
expansion cohort 
only)
X 
X 
 
 
 
Tumor biopsy 
for tumor 
response 
assessment
X 
 
X 
X 
X1 
1Recommended for all locally advanced BCC patients. 
 
At any time during a patient’s participation in the study, an optional tumor biopsy may be 
requested to clarify the response status of a patient. In addition, biopsy of any accessible 
target lesion(s) is highly recommended at the time of progression. 
 
The sites, number, and technique of representative biopsies will be determined by the 
investigator on the basis of the size and location of the accessible lesions. It is 
recommended that any areas suspicious for residual disease be biopsied, as well as areas 
which appear to be free of disease. These biopsies will be reviewed by site’s pathologist. 
 
Two separate biopsies should be obtained rather than splitting the biopsies for response 
assessment and Hh pathway activity measurement.  
 
For Hh pathway activity measurement, at least one and up to two punch biopsies of at least 
4 mm in size, or 14-gauge or larger core needle biopsies should be obtained. It is 
recommended that approximately 0.1 cm3 of the tissue specimen, which should yield 
sufficient mRNA for this study. Tumor samples should immediately be snap frozen in 


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either liquid nitrogen or dry ice following surgical resection and stored at −80°C or below 
in a proper pre-cooled cryovial. It is highly recommended that biopsies should be snap 
frozen immediately and to be maintained frozen. Samples should be transported to 
Oncocyte Corporation per the “Sample Storage and Shipping Instructions” attached to this 
Guideline.  
 
For tumor response assessment, at least one and up to five punch biopsies of at least 3 mm 
in size, or 14-gauge or larger core needle biopsies, as determined by the investigator, should 
be obtained. For large, accessible lesions in the skin and/or soft tissues, punch biopsies of 
3 to 4 mm are strongly recommended to allow for optimal assessment of residual disease. 
 
Biopsies for tumor response assessment should be fixed and paraffin embedded according 
to site standards.  
 
The site pathologist’s assessment will be used in the determination of response. The 
hematoxylin- and eosin-stained slides will be reviewed by site’s pathologist to determine 
whether residual BCC is present. Epithelial rests or tumors consisting of epithelium with 
abnormal follicular differentiation, while not necessarily definitive evidence of residual 
BCC, will be interpreted as residual BCC. 
 
If a biopsy obtained after administration of CX-4945 cannot be interpreted because of 
technical issues (e.g., crush artifact), then additional biopsies will be requested, if available. 
Patients experiencing a clinical response whose biopsies show no evidence of residual BCC 
on biopsy will be considered to have a complete response; those experiencing a clinical 
response, but whose biopsies show evidence of residual BCC, will be considered to have a 
partial response. 


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Sample Storage and Shipping Instructions 
(Refer to the most current version of the Pharmacodynamics Manual)  


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Tissue Biopsy Specimen Submission Form 
(Refer to the most current version of the Pharmacodynamics Manual) 


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Specimen Shipment Notification Form 
 
(Refer to the most current version of the Pharmacodynamics Manual) 


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APPENDIX H 
DIGITAL PHOTOGRAPHIC PROCEDURES FOR SERIAL PHOTOGRAPHIC 
DOCUMENTATION OF BASAL CELL CARCINOMA 
 
(Refer to the most current version of the Photo Manual) 


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APPENDIX I 
ECOG PERFORMANCE STATUS 
 
GRADE
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; 
up and about more than 50% of waking hours
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5
Dead


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APPENDIX J 
EQUATION FOR CALCULATING AN ESTIMATED GLOMERULAR 
FILTRATION RATE 
 
The Cockcroft and Gault formula: 
 
CrCl (mL/min) =  
 
(140 - Age) x Weight x 0.85 (if female) 
 
72 x Serum Creatinine 
Abbreviations/ Units: 
CrCl (creatinine clearance) = mL/minute 
Age = years 
Weight = kg 
Serum creatinine = mg/dL 
[If serum creatinine is in μmol/L, multiply the above Cockcroft and Gault equation with 
1.4 for females or 1.23 for males] 


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APPENDIX K 
HEDGEHOG PATHWAY ANTAGONISTS IN USE OR WITH POTENTIAL 
INTERACTION OF THE HEDGEHOG PATHWAY 
The table below lists experimental compounds in columns under the designation of 
specific target of the Hedgehog pathway.  
 
This is not necessarily a complete list; other medications may also interact with Hh 
pathway. 
  
Target 
Inhibitor 
Gli
ATO
Gli
GANT58, 61
Gli
HPI 1-4
Gli
Glabrescione B
Gli
JQ1
PKA
Imiquimod
RARβ/RARγ
Tazarotene
aPKC
PSI
Abbreviations: Hh, Hedgehog; BCC, basal cell carcinoma; PKA, protein kinase A; aPKC, 
atypical protein kinase C ι/λ; RARβ/RARγ, retinoic acid receptor β/γ; ATO, arsenic trioxide; 
PSI, specific peptide inhibitor; Gli, Gli transcription factors. 


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Senhwa Biosciences, Inc. 
 
 
Protocol CX-4945-07 Version 6.0 
 
 
Approved by  
 
 
 
 
John Soong, MD, Chief Medical Officer 
Date
 
 
 

SAP_001.pdf: 
Senhwa Biosciences/ Protocol: CX-4945-07 
IQVIA Biotech (Confidential) Project # UYA26114 
 
 
 
 
 
Senhwa Biosciences 
Protocol #: CX-4945-07 
IQVIA Study #: UYA26114 
 
 
 A Phase I, Multi-Center, Open-Label, Treatment Duration Increment, Expansion, Safety, and 
Pharmacodynamic Study of CX-4945 Administered Orally Twice Daily to Patients with 
Advanced Basal Cell Carcinoma 
 
Statistical Analysis Plan, version 1.0 
 
Document last saved: 1-May-2023 5:12 PM 
 
 
 
Prepared by: 
 
 
 
 
 
_____________________________ 
Jin Wei 
Director, Biostatistics 
IQVIA Biotech 
 
 
 
 
 
Approved by: 
 
 
 
 
 
_____________________________ 
Daniel McCormick 
Senior Director, Clinical Operations 
Senhwa Biosciences, Inc. 
02-May-2023 | 14:25:40 EDT
03-May-2023 | 07:58:02 EDT


Senhwa Biosciences/ Protocol: CX-4945-07 
IQVIA Biotech (Confidential) Project # UYA26114 
 
 
Table of Contents 
Table of Contents ...........................................................................................................................2 
List of Abbreviations and Definitions of Terms ..........................................................................4 
 
INTRODUCTION ..................................................................................................................5 
 
STUDY OBJECTIVES ..........................................................................................................5 
 
STUDY DESIGN ....................................................................................................................5 
 
HARDWARE AND SOFTWARE ........................................................................................6 
 
DATABASE CLOSURE .......................................................................................................6 
 
SAMPLE SIZE DETERMINATION ...................................................................................7 
 
ANALYSIS POPULATIONS ...............................................................................................7 
 
HANDLING OF MISSING DATA ......................................................................................8 
 
INTERIM ANALYSIS ..........................................................................................................8 
 DATA CONVENTIONS FOR ANALYSIS .........................................................................8 
 General Statistical Principles .........................................................................................8 
 Study Day.......................................................................................................................8 
 Baseline and Change from Baseline ..............................................................................8 
 Analysis Visit Window ..................................................................................................8 
 Multiple Comparisons ....................................................................................................9 
 STATISTICAL EVALUATION ...........................................................................................9 
 Subject Disposition ........................................................................................................9 
 Protocol Deviation .........................................................................................................9 
 Demographic and Baseline Characteristics ...................................................................9 
 Disease History ..............................................................................................................9 
 Prior Therapy ...............................................................................................................10 
 Study Medication Exposure .........................................................................................10 
 Prior and Concomitant Medications ............................................................................10 
 Medical History and Concurrent Procedures ...............................................................11 
 Efficacy Endpoints .......................................................................................................11 
11.9.1 Primary Efficacy Endpoints .............................................................................11 
11.9.2 Other Efficacy Endpoints .................................................................................12 
 Efficacy Analyses ........................................................................................................13 
11.10.1 Primary Efficacy Analyses ..............................................................................13 


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IQVIA Biotech (Confidential) Project # UYA26114 
 
 
11.10.2 Other Efficacy Analyses ..................................................................................13 
11.10.3 Subgroup Analyses ..........................................................................................14 
 Safety Analysis ............................................................................................................14 
11.11.1 Recommended Phase 2 Dose (RP2D)..............................................................14 
11.11.2 Dose Limiting Toxicity (DLT) ........................................................................14 
11.11.3 Adverse Events ................................................................................................15 
11.11.4 Clinical Laboratory Testing .............................................................................16 
11.11.5 Vital Signs ........................................................................................................16 
11.11.6 Electrocardiogram (ECG) ................................................................................16 
11.11.7 Physical Examination.......................................................................................16 
11.11.8 ECOG Performance Status ..............................................................................17 
 CHANGES FROM THE PROTOCOL AND PLANNED ANALYSES .........................17 
 HEADINGS ..........................................................................................................................17 
 ARCHIVING AND RETENTION OF DOCUMENTS ....................................................17 
 


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IQVIA Biotech (Confidential) Project # UYA26114 
 
 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
ADaM 
Analysis data model 
AE 
Adverse event 
ATC 
Anatomical-therapeutic-chemical classification 
BCC 
Basal cell carcinoma 
BID 
Twice daily 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CR  
Complete response 
CRA 
Clinical Research Associate 
CRF  
Case report form, paper or electronic 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTCAE 
Common terminology criteria for adverse events 
DLT 
Dose limiting toxicity 
ECG  
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
Hh 
Hedgehog 
mBCC 
Metastatic basal cell carcinoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
ORR 
Objective response ratio 
PT 
Preferred Term 
RDI 
Relative dose intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase II Dose 
SAE  
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
WHO-DD 
World Health Organization – Drug Dictionary 


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 INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the study Protocol version 6.0 dated 06 April 
2022.   
This document provides additional details concerning the statistical analyses outlined in the 
protocol and reflects any changes to the protocol from any amendments. This plan will not repeat 
all the definitions given in the protocol but will provide further details of the summaries and 
analyses planned therein. Any deviations from the analysis plan, including any after the time of 
database lock, will be documented as such in the study report.    
 STUDY OBJECTIVES 
Primary Objective:  The primary objective of this study is to determine the recommended phase 
II dose (RP2D) and schedule of CX-4945 when administered orally twice daily for 28 consecutive 
days, in a 4-week (28 days) cycle, in patients with locally advanced or metastatic basal cell 
carcinoma (BCC). 
Secondary Objectives: 
• To establish the safety and tolerability of CX-4945 in this patient population.  
• To assess preliminary evidence of antitumor effects in this patient population by 
documentation of objective responses using standardized criteria.  
• To evaluate the effect of CX-4945 treatment on the Hedgehog (Hh) signaling pathway 
using qRT-PCR in tissue from patients with locally advanced BCC obtained at baseline 
and following CX-4945 treatment.  
 STUDY DESIGN 
This is an open-label, multicenter, treatment-duration-increment Phase I run-in study followed by 
two expansion cohorts in patients with advanced basal cell carcinoma, to evaluate the safety, 
pharmacodynamic and preliminary antitumor activity of CX-4945. All patients will receive CX-
4945 until evidence of progression, intolerable toxicities most probably attributable to CX-4945, 
or withdrawal from the study.  
This study population will consist of patients ≥ 18 years old with a histologically confirmed 
diagnosis of advanced BCC (metastatic BCC [mBCC] or locally advanced BCC defined as 
follows) which has progressed on smoothened inhibitor or that are intolerant to smoothened 
inhibitor.  Patients with mBCC are required to have histologic confirmation of a distant BCC 
metastasis (e.g., lung, liver, lymph nodes, or bone).  Patients with locally advanced BCC are 
required to have disease that is considered inoperable or to have a medical contraindication to 
surgery.  Patients with nevoid BCC syndrome (Gorlin syndrome) may enroll in this study but must 
meet the criteria for locally advanced or metastatic disease listed above.  


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In the phase I treatment-duration-increment part of the study, the 28-day continuous dosing of CX-
4945 [1000 mg twice daily] will be explored. Dose cohort will initially include a minimum of 3 
patients. A standard 3+3 design will be used.  
• If no DLTs are seen in the 3 patients, the treatment-duration-increment part will be closed 
and the expansion cohorts will be opened.  
• If 1 patient out of 3 experiences a DLT, up to 3 additional patients will be recruited (for a 
maximum of 6). If there are < 2/6 patients with DLT, this will be declared the dose for the 
Recommended Phase II Dose (RP2D), Phase I will be closed and the expansion cohorts 
will be opened.  
• If 2 out of 3, or 2 out of 6, patients experience DLT, the previous Phase I oral dosing 
regimen of 1000 mg BID (total daily dose 2000 mg) for 21 days followed by 7 days of rest 
will be selected for the expansion cohorts.  
The expansion cohorts will include 10 patients with locally advanced BCC and 10 patients with 
metastatic BCC.  
During the treatment-duration-increment part, the first patient enrolled at the 28-day continuous 
dosing schedule must receive ≥ 75% planned doses with no observed DLTs before a second patient 
and a third patient are treated one week apart in that cohort. If no patient in the cohort experiences 
a DLT after the completion of Day 28 of the final patient in the cohort, then the Expansion Cohorts 
may proceed with the 28-day continuous dosing schedule.  
Patients that have experienced a DLT may be offered the option to continue at the previous Phase 
I oral dosing regimen of 1000 mg bid (total daily dose of 2000 mg) for 21-day followed by 7 days 
of rest if this is considered safe by the Investigator and the Sponsor. 
 HARDWARE AND SOFTWARE 
Statistical analysis will be performed following IQVIA Biotech standard operating procedures and 
on the IQVIA Biotech computer network. All statistical analysis will be performed using SAS 
Version 9.4 or later with program code prepared specifically for the project by qualified IQVIA 
Biotech statisticians and SAS programmers. 
The SAS programs will generate rich-text-formatted (RTF) output with the “RTF” extension using 
the SAS Output Delivery System (ODS). Datasets will be created and taken as input to validated 
SAS programs to generate report-ready tables, listings, and figures. Each output display will show 
the names of the data sets and SAS program used to produce it.   
 DATABASE CLOSURE 
After completion of all data review procedures, validation of the project database, and approval of 
the data review document by the study sponsor, the clinical database will be closed. Any change 
to the clinical database after this time will require written authorization, with explanation, by the 
Sponsor and the IQVIA Biotech Biostatistician.   


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 SAMPLE SIZE DETERMINATION 
In the treatment-duration-increment part of the study, a 3+3 study design will be utilized, therefore 
approximately 3-6 patients will be enrolled to define the RP2D.  
In the expansion part of the study, a total sample size of 20 patients is proposed; 10 patients with 
local advanced BCC and 10 patients with metastatic BCC. Assume that CX-4945 is of no interest 
if its true response is 5% or lower, the proposed sample size for each sub-population will provide 
an 80% confidence interval of (5.5%, 45.0%) given that there are 2 responses out of the 10 patients. 
This would provide adequate evidence to suggest that additional studies with this agent may be 
warranted. 
10 patients with metastatic BCC were planned in the expansion part of the study, but only 2 were 
enrolled due to early termination.    
 ANALYSIS POPULATIONS 
The following analysis sets/populations will be used in this trial: 
• Safety population: All enrolled patients who receive any amount of study drug. Unless 
otherwise noted, all safety analyses will be performed using Safety population. 
• Dose determining population: All patients treated in the Phase 1 treatment-duration-
increment part of the study. The dose determining population will be used to determine the 
primary outcome of the study, the RP2D dose.    
• Efficacy population: All patients who are treated in the treatment-duration-increment 
cohort or the expansion cohort and whose pathologist’s interpretation of baseline biopsy is 
consistent with BCC. Patients without interpretable baseline tissue, as determined by the 
pathologist, or by pathology report from the study site documenting a pathologist’s 
determination of BCC will be excluded from the Efficacy population. Such patients’ 
efficacy data will be presented in by-subject listings but excluded from all summary 
analyses. Objective response will be assessed separately for patients with mBCC vs. locally 
advanced BCC.  
• Relative Dose Intensity (RDI) population: All patients treated in the expansion cohort 
including those who complete the protocol-defined treatment or discontinue treatment due 
to adverse events or for disease progression. Patients who are discontinued for any reason 
other than for adverse events or for disease progression will not be included in the relative 
dose intensity assessment. The RDI population will be used for the assessment of relative 
dose intensity defined for each cycle.  
For some objectives (pharmacodynamics, biomarker parameters) a subgroup of patients of the 
efficacy population with respective baseline and post-baseline measurements will be used as 
described in section 11.9.1 below. 


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 HANDLING OF MISSING DATA  
Missing data will not be replaced with imputed values.  
 INTERIM ANALYSIS 
No interim analysis is planned for this study. 
 DATA CONVENTIONS FOR ANALYSIS 
 General Statistical Principles 
All statistical processing will be performed using SAS® unless otherwise stated. Any statistical 
tests will be two-tailed at significance level of 0.05 unless otherwise specified.  
All observed and derived variables (e.g., change from baseline, percentage change from baseline, 
and response status) used in the summaries of analyses will be presented in by-subject listings. 
Unless otherwise noted, the data will be sorted first by treatment assignment, then by subject 
number and then by date within subject number.  
Efficacy and safety results will be summarized descriptively. Categorical parameters will be 
summarized by the number and percentage of subjects in each category. Denominators for 
percentages will be appropriate to the purpose of the analysis. Percentages will typically be 
presented to one decimal (Note: 0% and 100% will be in integer format). Continuous parameters 
will be summarized as number of subjects, mean, standard deviation (SD), median, minimum, and 
maximum. 
 Study Day 
Day 1 is defined as the date of first study drug administration. Study day is calculated relative to 
the date of Day 1. For subjects who did not have a recorded date of first study drug administration, 
study day will not be calculated.  
 Baseline and Change from Baseline 
Baseline is defined as the last non-missing assessment prior to the first administration of study 
drug. Change from baseline is defined as post-baseline value minus baseline value unless 
otherwise specified. Percent change from baseline is (Change from baseline / Baseline) * 100%. 
 Analysis Visit Window 
Results will be summarized according to the visit as recorded in the eCRF.  No visit windows will 
be applied. 


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 Multiple Comparisons 
Not applicable. There will be no formal hypothesis testing.  
 STATISTICAL EVALUATION 
 Subject Disposition 
The number and percentage of subjects screened, enrolled, included in key analysis populations, 
completing the study, and withdrawing from the study (together with the reasons for withdrawal) 
will be summarized using frequencies and percentages, overall and by cohort (treatment-duration-
increment, expansion).  
A by-subject listing will show all subjects enrolled and their disposition. 
The number of days in the study (date of study completion / discontinuation minus date of Day 1 
plus 1) will be summarized descriptively, overall and by cohort (treatment-duration-increment, 
expansion). 
 Protocol Deviation 
Protocol deviations will be logged throughout the study and classified as minor or major. Major 
protocol deviations will be summarized for all enrolled patients. 
All protocol deviations will also be listed by subject. 
 Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized separately in mBCC and locally 
advanced BCC groups as well as overall for the Safety and Efficacy populations. The following 
demographic and baseline variables will be included: 
• Age (years) 
• Gender  
• Race 
• Ethnicity 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
• ECOG performance status 
 Disease History 
For the summary of BCC history, the following will be summarized separately in mBCC and 
locally advanced BCC groups and listed: 


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• Time since diagnosis (calculated as year of informed consent – year of initial diagnosis) 
• BCC variant (nodular, superficial, infiltrative, basosquamous, other) 
• Gorlin’s syndrome (Y, N) 
 Prior Therapy 
Prior BCC therapy will be listed in three separate listings: (i) radiotherapy, (ii) systemic therapy, 
and (iii) anti-cancer surgery. 
The summary of prior radiotherapy will include a summary of radiotherapy locations, including 
all locations recorded for each subject.  
The summary of prior systemic therapy will include the total number of systemic therapies, the 
therapy type(s), and the time between end of last treatment to start of study treatment, and the best 
response after each treatment up to and including the last recorded. 
The summary of prior anti-cancer surgery will include the time between the last surgery to start 
of study treatment and reason for surgery.  
All summaries will be provided separately in mBCC and locally advanced BCC patients as well 
as overall. 
 Study Medication Exposure  
The following parameters of study drug exposure will be summarized for the RDI population: 
• Cumulative dose (g), calculated as total number of capsules taken per subject diary* 0.2g, 
for each cycle and overall. 
• Dose intensity (g/day, calculated as [cumulative dose (g) / duration of dosing (days)]), 
defined for each cycle  
• Planned dose intensity (g/day, 1000mg BID=2g/day), defined for each cycle 
• Relative dose intensity (% of planned, calculated as [dose intensity / planned dose 
intensity] *100), defined for each cycle 
Cumulative dose will also be summarized for the Safety population. 
 Prior and Concomitant Medications 
Prior (within the previous 7 days and with stop dates prior to first dose of study drug) and 
concomitant (ongoing or with stop dates on or after first dose of study drug) medications will be 
presented for the safety population in a by-subject listing. If the medication is ongoing or the stop 
year is missing, the medication will be considered as received for the entire duration of the study. 
Medications will be coded using WHO-DD terminology.  
For the determination of prior vs concomitant medications, the following rules regarding the stop 
date will be applied:  


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• If only year was recorded, and it is before Baseline, it is a prior medication; if year is same 
or after Baseline, it is assumed to be a concomitant medication.  
• If day is missing, but month and year are before Baseline, it is a prior medication; if month 
and year are the same as Baseline, it is assumed to be a concomitant medication; if month 
and year are after Baseline, it is a concomitant medication.  
• If start date is after Baseline, it is a concomitant medication regardless.  
Concomitant medications will be summarized by WHO-DD Anatomical-Therapeutic-Chemical 
(ATC) classification level 4 or highest level available and preferred term (PT). 
Use of dispensed anti-emetics and use of dispensed loperamide will be listed in separate listings. 
 Medical History and Concurrent Procedures 
Medical history (including previous and ongoing medical conditions) will be coded using 
MedDRA (version 23.0) and summarized by System Organ Class (SOC) and preferred term (PT).  
 Efficacy Endpoints 
11.9.1 Primary Efficacy Endpoints 
The efficacy endpoints include the following: 
• Best Overall Response: Assessed separately for patients with mBCC and with locally 
advanced BCC as a function of radiographic, photographic, and pathologic review 
(Appendices B, C, G and H of the protocol) as described below.  
For patients with mBCC: Overall Response will be assessed using the Response Evaluation 
Criteria in Solid Tumors (RECIST). 
For patients with locally advanced BCC: Overall response will be assessed using a 
composite response endpoint that incorporates externally visible tumor dimension and 
tumor ulceration, as well as RECIST for lesions with a RECIST-measurable component. 
Patients will be categorized as Complete Response (CR), Partial Response (PR), Stable 
Disease (SD), Progressive Disease (PD), and Not Evaluable (NE) in Overall Response at 
each assessment. 
• Objective Response: Defined as a Complete Response (CR) or Partial Response (PR) in 
Overall Response determined on two consecutive assessments ≥ 4 weeks apart.  
In patients with locally advanced BCC achieving a CR or PR, tumor biopsies will be used 
in the final determination of CR. CR is defined as absence of residual BCC on biopsy; PR 
is defined as presence of residual BCC on biopsy.  


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• Analysis of the changes in Gli1 expression will be conducted by the OncoCyte Corporation 
(formerly Insight Genetics) and a separate report will be prepared. Thus detailed analysis 
is not included in this SAP.  
11.9.2 Other Efficacy Endpoints 
• Progression Free Survival (PFS): Defined as the time from the date of the first dose of 
study drug until the date of progressive disease or death from any cause, whichever occurs 
first. PFS will be censored as follows: 
- 
Patients who had no event (i.e., they did not die or have PD) will be censored at the 
date of their last tumor assessment.   
- 
Patients with no baseline assessment will be censored at the date of the first dose. 
- 
Patients who started a new anti-cancer therapy prior to documented PD or death 
will be censored at the last tumor assessment prior to initiation of new anti-cancer 
therapy.   
 
• Duration of Response (DOR): Defined as the time from the date of first documented 
response (CR or PR) until the date of progressive disease or death from any cause, 
whichever occurs first, after achieving response. DOR will be censored as follows: 
- 
Patients who had no event (i.e., they did not die or have PD) will be censored at the 
date of their last tumor assessment.   
- 
Patients who started a new anti-cancer therapy prior to documented PD or death 
will be censored at the last tumor assessment prior to initiation of new anti-cancer 
therapy.   
 
• Duration of Stable Disease (DSD): Defined as the time from the date of first documented 
Stable Disease (SD) response until the date of progressive disease or death from any cause, 
whichever occurs first, after achieving SD response. DSD will be censored as follows: 
- 
Patients who had no event (i.e., they did not die or have PD) will be censored at the 
date of their last tumor assessment.   
- 
Patients who started a new anti-cancer therapy prior to documented PD or death 
will be censored at the last tumor assessment prior to initiation of new anti-cancer 
therapy.   
• Disease Control Rate (DCR): Defined as the percentage of patients who have achieved 
CR, PR, or SD lasting at least 6 months. 
• Duration of Disease Control (DDC): Defined as the time from the date of first 
documented response (CR or PR) or Stable Disease (SD) until the date of progressive 
disease or death from any cause, whichever occurs first, for patients with CR, PR or SD 
lasting at least 6 months. DDC will be censored as follows: 
- 
Patients who had no event (i.e., they did not die or have PD) will be censored at the 
date of their last tumor assessment.   


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- 
Patients who started a new anti-cancer therapy prior to documented PD or death 
will be censored at the last tumor assessment prior to initiation of new anti-cancer 
therapy.   
• Rate of patients with CR+PR+SD (regardless of duration): Defined as the percentage 
of patients who have achieved CR, PR, or SD. 
• Duration of CR+PR+SD: Defined as the time from the date of first documented response 
(CR or PR) or Stable Disease (SD) until the date of progressive disease or death from any 
cause, whichever occurs first, for patients with CR, PR or SD. The duration will be 
censored as follows: 
- 
Patients who had no event (i.e., they did not die or have PD) will be censored at the 
date of their last tumor assessment.   
- 
Patients who started a new anti-cancer therapy prior to documented PD or death 
will be censored at the last tumor assessment prior to initiation of new anti-cancer 
therapy.   
 Efficacy Analyses 
11.10.1Primary Efficacy Analyses 
The primary endpoints will be assessed in the Efficacy population, overall and separately for 
patients with mBCC and patients with locally advanced BCC.  
The objective response rate (ORR) will be calculated as the number of patients satisfying the OR 
criteria divided by the number of subjects in the Efficacy population. Patients without at least one 
post-baseline response assessment will be treated as non-responders. Further, patients who 
experience progressive disease but continue treatment under the protocol and experience partial or 
complete response in a subsequent tumor assessment, will be considered partial or complete 
responders. A continuity-corrected 95% confidence interval based on the normal approximation 
will accompany each ORR. 
Complete response rates (CRR) will be summarized in parallel fashion to ORR. 
11.10.2Other Efficacy Analyses 
PFS will be analyzed using the Kaplan-Meier method in the Efficacy population, separately for 
patients with mBCC and patients with locally advanced BCC. 
Summary statistics from the Kaplan-Meier distribution will be determined, including the median 
and estimates at 3, 6, 9, 12 months. These statistics will be provided as point estimates with 95% 
confidence intervals. 
DOR summary will include at least median (in months), range and patients (n, %) with observed 
DOR for at least 6 months.  


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DSD summary will include at least median, range, min, max and patients (n, %) with observed SD 
for at least 6 months. 
DCR summary will include at least median, range, min, max and patients (n, %) with observed 
DCR for at least 6 months. 
Summary of patients with CR+PR+SD (regardless of duration) will include at least median, range, 
min, max and patients (n, %) with observed CR+PR+SD. 
11.10.3Subgroup Analyses 
Not applicable.  
 Safety Analysis 
Safety will be summarized over the Safety population unless indicated otherwise. 
11.11.1Recommended Phase 2 Dose (RP2D) 
The primary endpoint for this study is the determination of RP2D in the 28-day continuous dosing 
of CX-4945 [1000 mg twice daily] of the phase I treatment-duration-increment part of the study, 
as following: 
• If no DLTs are seen in the 3 patients, the treatment-duration-increment part will be closed 
and the expansion cohorts will be opened. This will be declared the dose for the RP2D. 
• If 1 patient out of 3 experiences a DLT, up to 3 additional patients will be recruited (for a 
maximum of 6). If there are < 2/6 patients with DLT, this will be declared the dose for the 
RP2D, Phase I will be closed and two expansion cohorts will be opened.  
• If 2 out of 3, or 2 out of 6, patients experience DLT, the previous Phase I oral dosing 
regimen of 1000 mg BID (total daily dose 2000 mg) for 21 days followed by 7 days of rest 
will be selected for the expansion cohorts.  
The procedures and rules to determine the RP2D are given in Section 9.1 of the protocol and as 
described above. Because of the small number of patients involved in this endpoint, no summaries 
will be generated. The determination of the RP2D in the RP2D population (see Section 7) will be 
described textually. 
11.11.2Dose Limiting Toxicity (DLT) 
Dose limiting toxicity (DLT) will be defined as any of the following drug related adverse events 
occurring during Cycle 1 (first 28 days of dosing):  
• Grade 3 or 4 non-hematologic toxicity (excluding inadequately managed nausea and 
vomiting, alopecia or grade 3 fatigue lasting < 7 days),  
• Grade 4 myelosuppression ≥ 7 days, febrile neutropenia or ≥ grade 3 thrombocytopenic 
bleeding,  


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• Other toxicity of concern to the investigators including toxicities requiring delays ≥ 14 
days.  
All DLTs will be listed and summarized by cohort (treatment-duration-increment, expansion) and 
overall for the Safety population. 
11.11.3Adverse Events 
Adverse event terms will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. A treatment-emergent AE (TEAE) is defined as an AE that starts or worsen on or after 
the date of the first dose of study medication. Adverse events that have missing onset dates will be 
considered to be treatment emergent, unless the stop date is known to be prior to the first 
administration of the study medication. If the AE onset date is partial, the date will be compared 
as far as possible with the date of first dose of study medication. Adverse events will be assumed 
to be treatment-emergent, unless there is clear evidence (through comparison of partial dates) to 
suggest that the AE started prior to the first dose of study medication. All TEAE swill be mapped 
to thesaurus terms and graded according to the NCI CTCAE, version 5.0.   
All AEs will be listed by subject, detailing the verbatim term given by the investigator, the 
preferred term (PT), system organ class (SOC), onset date, end date, CTCAE Grade, outcome, 
relationship to study drug, action taken with study drug, other action taken, seriousness and criteria 
for seriousness. Serious AEs (SAEs) and TEAEs leading to study discontinuation will also be 
listed separately.  
The following TEAE summaries will be produced by cohort (treatment-duration-increment, 
expansion) and overall: 
• An overall summary of safety will summarize the numbers (and percentages) of patients 
with the following:    
- 
Any TEAEs and serious adverse event (SAE) 
- 
AEs related to study drug 
- 
SAEs related to study drug 
- 
AEs of Clinical Interest  
- 
DLTs 
- 
Who discontinued study drug due to at least one AE (regardless of causality, and 
related to each study drug) 
- 
AEs leading to death 
• Separate summaries of TEAEs by SOC and PT, subset as follows: 
- 
All AEs 
- 
AEs related to study drug. Related AEs will include AEs with a drug relationship 
of “Related” recorded on CRF.     
- 
All SAEs 
- 
SAEs related to study drug 
- 
All Grade 3 or above AEs 


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- 
Grade 3 or above AEs related to study drug 
- 
All AEs in at least 10% of subjects 
- 
AEs in at least 10% of subjects related to study drug 
- 
All AEs leading to discontinuation of study drug 
- 
All AEs leading to dose interruptions 
- 
All AEs leading to dose modifications 
- 
All AEs leading to death, overall, while on study and during the 3-month follow-
up period  
• All AEs by SOC, PT and CTCAE toxicity grade 
• All AEs by SOC, PT and action taken with study drug 
• All AEs by PT 
If a patient has multiple occurrences of an AE, the strongest level of relationship to study drug and 
the worst toxicity grade a patient experiences for a given AE will be used in these tables. Further, 
if the toxicity grade is missing, the event will be reported as ‘unknown’ in the summary tables. 
Likewise, if causality data is missing, ‘unknown’ will be reported.  
11.11.4Clinical Laboratory Testing 
Clinical laboratory values will be reported as complete listings of individual subject data. All 
laboratory values will be classified as normal, low, or high based on normal ranges supplied by 
the laboratory. Clinical laboratory values outside of normal range will be listed in a separate by-
subject listing.  
Absolute values and changes from baseline of clinical laboratory data (hematology, chemistry, and 
continuous urinalysis parameter) will be summarized descriptively. Changes in out-of-range 
reference flags from Baseline to post-baseline visits in clinical laboratory data will also be 
summarized using shift tables.  
Vitamin D assessments, pregnancy test results will be presented in separate by-subject listings. 
11.11.5Vital Signs 
Vital signs including body weight, blood pressure (systolic and diastolic), pulse rate, respiratory 
rate, and body temperature will be presented in a by-subject listing by visit. Absolute values and 
change from baseline value will be summarized by treatment group using descriptive statistics. 
11.11.6Electrocardiogram (ECG) 
ECG data measured at Screening will be presented in a by-subject listing.  
11.11.7Physical Examination 
Physical examination results will be captured on eCRF but will not be presented in tables or 
listings.  


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11.11.8ECOG Performance Status  
The Eastern Cooperative Oncology Group (ECOG) status of patients will be listed and summarized 
using frequency counts and percentages by visit.  
 CHANGES FROM THE PROTOCOL AND PLANNED ANALYSES 
This SAP reflects the analysis plan outlined in the study protocol without significant change. Any 
analysis changes or additional analysis not specified in this SAP will have the status of unblinded 
and exploratory investigations. 
 HEADINGS 
Each page of the analysis will show the sponsor’s name, the investigational product, and the 
protocol number. Report tables will be embedded in the MS Word report document from SAS 
program output without change. The footer of each table will show the name of the SAS program 
module which generated it, the names of all data sets providing input data in the program and the 
date and time the table was generated. 
 ARCHIVING AND RETENTION OF DOCUMENTS 
After finalization of the analysis, the following will be archived at IQVIA Biotech and/or with the 
study sponsor: 
• SAP and any amendments 
• All SAS code used in the project for statistical analysis, report tables generation, and 
analysis data set creation 
• Tables, listings and figures as included in the clinical study report 
• SAS study data tabulation model (SDTM) and analysis datasets