A Phase 1, Open-Label, 2-Part, Single Dose, Crossover Study to Examine the Effect of Food and Cobicistat Administration on the Pharmacokinetics and Safety of Plixorafenib in Healthy Participants.
Phase: PHASE1
Conditions: Healthy Participants
Sponsor: Fore Biotherapeutics

TITLE PAGE 
CLINICAL STUDY PROTOCOL 
PROTOCOL NO. F8394-101 
 
 
A PHASE 1, OPEN-LABEL, 2-PART, SINGLE DOSE, CROSSOVER 
STUDY TO EXAMINE THE EFFECT OF FOOD AND COBICISTAT 
ADMINISTRATION ON THE PHARMACOKINETICS AND SAFETY OF 
PLIXORAFENIB IN HEALTHY PARTICIPANTS 
 
 
IND 
115,376 
Sponsor: 
Fore Biotherapeutics 
3675 Market St. 
Suite 200 
Philadelphia, PA 19104 
Sponsor Contact: 
Stacie Peacock Shepherd, MD, PhD 
Chief Medical Officer 
Telephone: 224-226-0158 
Sponsor Medical Monitor: 
Irina Kline, MD, MS 
Fore Biotherapeutics 
Telephone: 908-300-7736 
Email: Irina.Kline@fore.bio 
Safety Reporting: 
ICON Drug Safety 
ICON-Safety-CentralReceipt@iconplc.com 
Fax: +44 (0) 208 100 50057 
Version of Protocol: 
Amendment 1 
Date of Protocol:  
03 October 2024 
 
CONFIDENTIAL 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of Fore Biotherapeutics. 
The study will be conducted according to the International Council for Harmonisation 
Guideline E6(R2): Good Clinical Practice. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 2 
SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Phase 1, Open-Label, 2-Part, Single Dose, Crossover 
Study to Examine the Effect of Food and Cobicistat 
Administration on the Pharmacokinetics and Safety of 
Plixorafenib in Healthy Participants. 
PROTOCOL NUMBER: 
F8394-101 
 
Stacie Peacock Shepherd, MD, PhD 
Chief Medical Officer 
Fore Biotherapeutics 
 
Date 
03-Oct-2024

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 3 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I agree to conduct the study as outlined in the protocol titled “A Phase 1, Open-Label, 2-Part, 
Single Dose, Crossover Study to Examine the Effect of Food and Cobicistat Administration on 
the Pharmacokinetics and Safety of Plixorafenib in Healthy Participants” in accordance with the 
guidelines and all applicable government regulations, including US Title 21 of the Code of 
Federal Regulations Part 54. I have read and understand all sections of the protocol. 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Dr. Kristie Miller, MD 
PPD 
 
 
 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 4 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................................1 
SIGNATURE PAGE ......................................................................................................................2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ............................................................3 
TABLE OF CONTENTS ...............................................................................................................4 
PROTOCOL SYNOPSIS ..............................................................................................................7 
1. 
INTRODUCTION ....................................................................................................17 
1.1 
BACKGROUND ....................................................................................................17 
1.1.1 
Plixorafenib ........................................................................................................17 
1.1.2 
Cobicistat ............................................................................................................19 
1.2 
RATIONALE FOR STUDY ..................................................................................20 
1.3 
RATIONALE FOR DOSE SELECTION...............................................................21 
2. 
STUDY OBJECTIVES .............................................................................................21 
2.1 
PRIMARY OBJECTIVE ........................................................................................21 
2.2 
SECONDARY OBJECTIVES ...............................................................................22 
2.3 
EXPLORATORY OBJECTIVE .............................................................................22 
3. 
STUDY DESIGN .......................................................................................................22 
3.1 
PART A ...................................................................................................................22 
3.2 
PART B ...................................................................................................................24 
3.3 
SCHEDULE OF EVENTS .....................................................................................26 
3.3.1 
Schedule of Events for Study Part A ..................................................................26 
3.3.2 
Schedule of Events for Study Part B ..................................................................28 
4. 
STUDY POPULATION............................................................................................30 
4.1 
INCLUSION CRITERIA .......................................................................................30 
4.2 
EXCLUSION CRITERIA ......................................................................................31 
4.3 
OTHER SCREENING CONSIDERATIONS ........................................................32 
4.3.1 
Lifestyle Restrictions ..........................................................................................32 
4.4 
WITHDRAWAL OF PARTICIPANTS FROM THE STUDY ...............................33 
4.4.1 
Reasons for Withdrawal......................................................................................33 
4.4.2 
Handling of Withdrawals ....................................................................................33 
4.4.3 
Replacements ......................................................................................................33 
5. 
STUDY TREATMENTS ..........................................................................................34 
5.1 
TREATMENTS ADMINISTERED .......................................................................34 
5.2 
STUDY DRUGS ....................................................................................................34 
5.2.1 
Study Drug Packaging and Storage ....................................................................35 
5.2.2 
Study Drug Accountability .................................................................................35 
5.3 
METHOD OF ASSIGNING PARTICIPANTS TO TREATMENT GROUPS .......35 
5.4 
BLINDING .............................................................................................................36 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 5 
5.5 
TREATMENT COMPLIANCE .............................................................................36 
5.5.1 
Prior and Concomitant Medications ...................................................................36 
5.5.1.1 
Prior Medications ............................................................................................36 
5.5.1.2 
Concomitant Medications ...............................................................................36 
6. 
STUDY PROCEDURES ..........................................................................................36 
6.1 
PHARMACOKINETIC AND PHARMACOGENOMICS ASSESSMENTS AND 
ENDPOINTS ..........................................................................................................37 
6.1.1 
Pharmacokinetic Sample Collection ...................................................................39 
6.1.2 
Pharmacokinetic Sample Analysis......................................................................39 
6.1.3 
Pharmacogenomic Sample Analysis ...................................................................39 
6.2 
SAFETY ASSESSMENTS AND ENDPOINTS ....................................................39 
6.2.1 
Sponsor Communication ....................................................................................39 
6.2.2 
Adverse Events ...................................................................................................40 
6.2.2.1 
Adverse Event Definitions ..............................................................................40 
6.2.2.2 
Eliciting and Documenting Adverse Events ...................................................41 
6.2.2.3 
Reporting Adverse Events ..............................................................................41 
6.2.2.4 
Assessment of Severity ...................................................................................42 
6.2.2.5 
Assessment of Causality .................................................................................42 
6.2.2.6 
Adverse Event of Special Interest ...................................................................43 
6.2.2.7 
Follow-up of Adverse Events .........................................................................43 
6.2.3 
Clinical Laboratory Testing ................................................................................43 
6.2.4 
Vital Sign Measurements ....................................................................................44 
6.2.5 
Electrocardiograms .............................................................................................44 
6.2.6 
Physical Examinations ........................................................................................45 
7. 
STATISTICAL ANALYSIS PLANS .......................................................................45 
7.1 
SAMPLE SIZE CALCULATIONS........................................................................45 
7.2 
ANALYSIS SETS ..................................................................................................45 
7.3 
STATISTICAL ANALYSIS ...................................................................................45 
7.3.1 
Pharmacokinetic Analyses ..................................................................................46 
7.3.2 
Safety Analyses ..................................................................................................46 
7.3.3 
Other Analyses ....................................................................................................47 
7.4 
HANDLING OF MISSING DATA ........................................................................47 
7.5 
INTERIM ANALYSES ..........................................................................................47 
8. 
REFERENCE LIST..................................................................................................48 
9. 
APPENDICES ...........................................................................................................49 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS ........................................................49 
9.2 
APPENDIX 2: STUDY GOVERNANCE .............................................................51 
9.2.1 
Data Quality Assurance ......................................................................................51 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 6 
9.2.2 
Investigator Obligations .....................................................................................51 
9.2.2.1 
Confidentiality ................................................................................................51 
9.2.2.2 
Institutional Review ........................................................................................51 
9.2.2.3 
Participant Consent .........................................................................................52 
9.2.2.4 
Study Reporting Requirements .......................................................................52 
9.2.2.5 
Financial Disclosure and Obligations .............................................................52 
9.2.2.6 
Investigator Documentation ............................................................................53 
9.2.2.7 
Study Conduct ................................................................................................53 
9.2.2.8 
Case Report Forms and Source Documents ...................................................53 
9.2.2.9 
Adherence to Protocol ....................................................................................54 
9.2.2.10 
Reporting Adverse Events ..............................................................................54 
9.2.2.11 
Investigator’s Final Report .............................................................................54 
9.2.2.12 
Records Retention ...........................................................................................54 
9.2.2.13 
Publications .....................................................................................................54 
9.2.3 
Study Management .............................................................................................55 
9.2.3.1 
Monitoring ......................................................................................................55 
9.2.3.2 
Management of Protocol Amendments and Deviations .................................55 
9.2.3.3 
Study Termination ...........................................................................................56 
9.2.3.4 
Final Report ....................................................................................................56 
 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 7 
PROTOCOL SYNOPSIS 
PROTOCOL NO.: F8394-101 
TITLE: A Phase 1, Open-Label, 2-Part, Single Dose, Crossover Study to Examine the Effect of 
Food and Cobicistat Administration on the Pharmacokinetics and Safety of Plixorafenib in 
Healthy Participants 
STUDY PHASE: 1 
STUDY SITE: 1 clinical site in the United States 
OBJECTIVES: 
PART A 
The primary objectives for Part A of the study are as follows: 
• To examine the effect of food on the single dose PK of plixorafenib administered with 
cobicistat. 
• To examine the effect of cobicistat administration on the single dose PK of plixorafenib. 
• To determine the safety of plixorafenib administered alone and with cobicistat in a single 
dose regimen in healthy participants. 
The secondary objectives for Part A of the study are as follows: 
• To characterize metabolites of plixorafenib in plasma and urine. 
• To characterize the urinary excretion of plixorafenib. 
The exploratory objective for Part A of the study is as follows: 
• To examine the possible effect of pharmacogenomic variations on the PK of plixorafenib 
and/or the effect of cobicistat, including polymorphisms in P-gp, BCRP, and UGT. 
PART B 
Part A of this study demonstrated that co-administration of plixorafenib and cobicistat with a 
high fat, high caloric meal resulted in about 2-fold increase in average Cmax and about 3-fold 
increase in average AUC0-∞, as compared to the fasted state. Since the target oncology patient 
population may not be able to consume high-fat and/or high-calorie meals, the effect of a low-fat 
meal (400 to 500 calories, with 25% from fat) and a high-fat meal (800 to 1000 calories, with 
≥50% from fat) on the exposure of plixorafenib will be examined in Part B of this study, 
compared to the fasted state. 
The primary objectives for Part B of the study are:  
• To examine the effect of a high-fat and a low-fat meal versus fasted state on the single dose 
PK of plixorafenib administered alone.  
• To examine the effect of a low-fat meal versus fasted state on the single dose PK of 
plixorafenib administered with cobicistat. 
• To determine the safety of plixorafenib administered alone or with cobicistat (low-fat meal 
only) in a single dose regimen.  

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 8 
The exploratory objectives for Part B of the study are as follows: 
• To examine the possible effects of pharmacogenomic variations on the PK of plixorafenib 
and/or the effect of cobicistat, including polymorphisms in P-gp, BCRP, and UGT. 
• The effect of single dose administration of plixorifenib on endogenous biomarkers such as 
coproporphyrin may be evaluated.  
STUDY DESIGN: 
This is a Phase 1, open-label, 2-part, single dose, crossover, single-center study. 
Part A 
Part A is an open-label, randomized, single dose, 3-treatment, 3-period, crossover study designed 
to assess the effect of food and cobicistat administration on the PK and safety of plixorafenib in 
12 healthy adult participants. 
The study will consist of a screening period, 1 check-in, 3 treatment periods (with a 7-day 
washout between dosing in each period), and an EOS visit as illustrated in the table below: 
Treatment Period 
Screening 
Check-in 
Dosing 
Confinement  
1 
Day -28 to -1 
Day -1 
Day 1 
Day -1 to Day 19 
(EOS) 
  
2 
N/A 
N/A 
Day 8 
3 
N/A 
N/A 
Day 15 
N/A, not applicable; EOS, end of study. 
There will be a 7-day washout between dosing in each treatment period. 
EOS visit will be conducted on Day 19. 
 
A screening evaluation will be performed to determine each participant’s eligibility for the study 
approximately 28 to 1 days before the first dose. Participants eligible for participation will report 
to the study facility 1 day before dosing in Treatment Period 1 for check-in. 
On Day 1 of Treatment Period 1, eligible participants will be randomized to 1 of 6 treatment 
sequences: 1:2:3, 2:3:1, 3:2:1, 2:1:3, 3:1:2, 1:3:2. On the first day of each treatment period, each 
participant will receive one of the following treatments according to the sequence in which he or 
she is randomized: 
a) Treatment 1: 900 mg plixorafenib administered after overnight fast (fasted state). 
b) Treatment 2: 900 mg plixorafenib + 150 mg cobicistat administered after overnight fast 
(fasted state). 
c) Treatment 3: 900 mg plixorafenib + 150 mg cobicistat administered following a high fat, 
high caloric meal (fed state). 
For Treatment 2 and Treatment 3, plixorafenib and cobicistat will be co-administered. 
All participants will fast overnight (nothing to eat or drink except water) for at least 10 hours. 
Participants receiving Treatments 1 and 2 (fasted condition) will continue to fast for at least 
4 hours after dosing.  
Participants receiving Treatment 3 will receive a standard high fat (≥50% of the total caloric 
content of the meal), high caloric meal (approximately 800 to 1000 calories) for breakfast before 
dosing and this meal should derive approximately 150, 250, and 500 to 600 calories from 
protein, carbohydrate, and fat, respectively. Participants must consume the entire meal within 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 9 
30 minutes of serving; the percentage of meal consumed will be documented. Dosing must occur 
30 minutes (± 5 minutes) after the start of the meal. Participants receiving Treatment 3 will 
receive their next meal no less than 4 hours after dosing. 
All study drugs will be administered orally with approximately 240 mL of room temperature 
water. Water (except water provided with each dosing) will be restricted 1 hour prior to and 
1 hour after each study drug administration, except for consuming any fluid (ie, water, milk, 
juice) provided with the predose meal (treatment 3 only), but will be allowed ad libitum at all 
other times. Up to an additional 240 mL of water will be allowed, if necessary, to aid in 
swallowing the study drugs when both study drugs are administered simultaneously. 
Participants will remain at the facility from check-in (Day -1) to EOS and would be able to leave 
the facility upon satisfactory safety review. During confinement periods, participants will receive 
standardized meals per the clinic’s standard procedures that are scheduled at the same time in 
each period of the study. Participants will be discharged from the study on Day 19 (Treatment 
Period 3). 
The duration of the study for each participant, excluding screening, will be approximately 
20 days. Including screening, the total study duration for each participant will be 48 days. 
Part B 
Part B is an open-label, randomized, single dose, 4-treatment, 3-period, crossover study designed 
to assess the effect of food (either a high-fat meal or a low-fat meal) on the PK and safety of 
plixorafenib administered alone or with cobicistat (low-fat meal only) in 16 healthy adult 
participants. 
This part will consist of a screening period, 1 check-in, 3 treatment periods (with a 7-day 
washout between dosing in each period), and an EOS visit as illustrated in the table below:  
Treatment Period 
Screening 
Check-in 
Dosing 
Confinement 
1 
Day -28 to -1 
Day -1 
Day 1 
Day -1 to Day 19 (EOS) 
 
2 
N/A 
N/A 
Day 8 
3 
N/A 
N/A 
Day 15 
N/A, not applicable; EOS, end of study.  
There will be a 7-day washout between dosing in each treatment period. EOS visit will be conducted on Day 19.  
A screening evaluation will be performed to determine each participant’s eligibility for the study 
approximately 28 to 1 days before the first dose. Participants eligible for participation will report 
to the study facility 1 day before dosing in Treatment Period 1 for check-in.  
On Day 1 of Treatment Period 1, eligible participants will be randomized to 1 of 4 treatment 
sequences: A:C:D, B:D:A, D:B:C, C:A:B. On the first day of each treatment period, each 
participant will receive one of the following treatments according to the sequence in which he or 
she is randomized:  
a) Treatment A: 900 mg plixorafenib administered after overnight fast (fasted state).  
b) Treatment B: 900 mg plixorafenib administered following a high-fat high caloric meal (fed 
state-high fat meal). 
c) Treatment C: 900 mg plixorafenib administered following a low-fat meal (fed state-low-fat 
meal). 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 10 
d) Treatment D: 900 mg plixorafenib administered with 150 mg cobicistat following a low-fat 
meal (fed state-low-fat meal).   
All participants will fast overnight (nothing to eat or drink except water) for at least 10 hours.  
• Participants receiving Treatment A (fasted condition) will continue to fast for at least 
4 hours after dosing. 
• Participants receiving Treatment B will receive a high fat (≥50% of the total caloric content 
of the meal), high caloric meal (approximately 800 to 1000 calories) for breakfast before 
dosing and this meal should derive approximately 150, 250, and 500 to 600 calories from 
protein, carbohydrate, and fat, respectively.   
• Participants receiving Treatments C and D will receive a low-fat meal (approximately 400 
to 500 total calories, with 25% of the total caloric content of the meal from fat) for 
breakfast before dosing.  
All participants receiving Treatments B, C, or D must consume the entire meal within 30 minutes 
of serving; the percentage of meal consumed will be documented. Dosing must occur 30 minutes 
(± 5 minutes) after the start of the meal. Participants receiving Treatments B, C, and D will 
receive their next meal no less than 4 hours after dosing.  
Plixorafenib will be administered orally with approximately 240 mL of room temperature water. 
Water (except water provided with each dosing) will be restricted 1 hour before and 1 hour after 
each study drug administration, except for consuming any fluid (eg, water, milk, juice) provided 
with the predose meal (Treatments B, C, and D) but will not be limited at other times. Up to an 
additional 240 mL of water will be allowed, if necessary, to aid in swallowing the study drugs 
when administered with cobicistat (Treatment D). 
Participants will remain at the facility from check-in (Day -1) to EOS and would be able to leave 
the facility upon satisfactory safety review by the investigator. During confinement periods, 
participants will receive standardized meals per the clinic’s standard procedures that are 
scheduled at the same time in each period of the study. Participants will be discharged from the 
study on Day 19 (Treatment Period 3).  
The duration of the study for each participant, excluding screening, will be approximately 
20 days. Including screening, the total study duration for each participant will be 48 days.  
STUDY POPULATION: 
Inclusion Criteria: 
Each participant must meet all the following criteria to be enrolled in this study: 
1. The participant is able to provide written informed consent. 
2. Healthy male or non-pregnant, non-lactating female participants aged 18 to 55 years, 
inclusive, with a BMI of 18 kg/m2 or greater, but less than 30 kg/m2. The participant is 
considered by the investigator to be in good general health status as determined by physical 
examination, vital signs, temperature, medical history, no clinically significant abnormalities 
at investigator’s discretion in laboratory and urine analyses, and with normal organ function 
as defined below: 
• Normal renal function: creatinine clearance ≥90 mL/min. 
• Normal liver enzymes and bilirubin (≤ULN). 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 11 
• ECG, with QTcF interval ≤450 msec; at screening. 
3. Healthy female participants must be: 
a) Documented to be surgically sterile (surgical methods inclusive of hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy) or postmenopausal (amenorrhea 
for ≥24 months without an alternative medical cause and FSH ≥30 mIU/mL). 
4. OR 
b) Using contraception, including 1 highly effective nonhormonal methods (eg, intrauterine 
device) in combination with a barrier contraception (eg, male or female condoms, 
diaphragm, spermicide, etc.) from start of plixorafenib administration until 30 days after 
the last plixorafenib administration, and having a negative serum or urine β-hCG 
pregnancy test (with a sensitivity of at least 25 mIU/mL) at screening and check-in. 
5. Male participants with female partners of childbearing potential must be sterile (confirmed 
by documented azoospermia 90 days after the procedure) or agree to use (from check-in until 
90 days after discharge) one of the following approved methods of contraception: male 
condom with spermicide; sterile sexual partner (males must still agree to use condom with 
their surgically sterile female partner if unable to provide documentation of partner’s 
sterility); or practice abstinence (abstinence is acceptable only as true abstinence when this is 
in line with the preferred and usual lifestyle of the participant, periodic abstinence won’t be 
allowed); or use of an intrauterine device with spermicide by female sexual partner; a female 
condom with spermicide; a contraceptive sponge with spermicide; an intravaginal system; a 
diaphragm with spermicide; a cervical cap with spermicide; or oral, implantable, transdermal, 
or injectable contraceptives. 
6. Male participants must refrain from sperm donation and female participants must refrain 
from egg donation from check-in until 90 days after discharge from the study. 
7. The participant agrees to comply with all protocol requirements for the duration of the study. 
Exclusion Criteria: 
Participants meeting any of the following criteria will be excluded from the study: 
1. The participant has a history of clinically significant drug allergy or anaphylaxis, including 
known hypersensitivity to any components of plixorafenib or cobicistat. 
2. The participant has a history of any condition(s) or gastrointestinal surgeries, including 
gallbladder procedures, which might affect drug absorption, metabolism, or excretion. 
3. The participant has clinical evidence or a history of clinically significant cardiovascular, 
respiratory, renal, hepatic, gastrointestinal, hematological, neurologic, or other chronic 
disease as judged by the investigator. 
4. The participant has a history of psychiatric disease, a suicidal attempt, hospitalization for 
psychiatric disease, a period of disability due to a psychiatric disease, or administers 
treatment to control the condition. Psychiatric disease includes major depression, bipolar 
disorder, or psychosis for ≥3 months. 
5. The participant has a history or other evidence of illness, test abnormalities, or any other 
conditions which would make the participant, in the opinion of the investigator, unsuitable 
for the study. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 12 
6. The participant has any history of alcoholism or drug abuse, or excessive alcohol 
consumption (regular alcohol intake >21 units per week for male participants and >14 units 
of alcohol per week for female participants) (1 unit is equal to approximately ½ pint 
[200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure [25 mL] of spirits) within 
3 months before screening. 
7. The participant has positive results on screen for drugs of abuse or alcohol (Section 6.2.3 
[Other analyses]) at screening visit or Day -1. 
8. The participant is a smoker or has used nicotine or nicotine-containing products (eg, snuff, 
nicotine pouch (eg, ZYN), nicotine patch, nicotine chewing gum, mock cigarettes, vape 
cigarette alternatives, or inhalers), marijuana, and cannabinoids within 1 year before the first 
dose of study drug. 
9. The participant has donated blood in the past 90 days prior to screening or has poor 
peripheral venous access. 
10. The participant has a diagnosis of chronic or acute liver disease, for example, auto-immune, 
alcoholic, or neoplastic liver disease. 
11. The participant has positive serostatus for HIV, HCV, or HBV. 
12. Male partners of females who are pregnant. 
13. Female participant of childbearing potential who is pregnant, lactating, or planning to 
become pregnant within 90 days after the last dose of study drug. 
14. The participant has received an investigational drug, biologic, or device within 3 months or 
5 half-lives of the investigational drug (whichever is longer), before receiving study drug. 
15. The participant has used any systemic medications, including vitamins and over-the-counter 
items, during the 14 days (or 5 times the elimination half-life of the medication, whichever is 
longer) before receiving study drug or will require their use during the study. Inducers and 
inhibitors of metabolic enzymes and/or transporters (in particular CYP3A inhibitors or 
inducers, P-gp, and BCRP), and herbal preparations, nutritional supplements (eg, St. John’s 
Wort), or foods, including grapefruit juice, grapefruit/grapefruit-related citrus fruits 
(eg, Seville oranges, pomelos), which have been shown to produce metabolic enzyme or 
transporter induction or inhibition, are prohibited before 5 half-lives of the investigational 
drug prior to check-in (Day -1). Paracetamol ≤3000 mg/day will be allowed up to 
2 consecutive days before dosing and during the outpatient phase of the study, as needed. 
16. The participant has been on a diet incompatible with the on-study diet, in the opinion of the 
investigator or designee, within 30 days prior to the first dosing and throughout the study. 
17. The participant is part of the clinical staff personnel or a family member of the clinical site 
staff. 
STUDY TREATMENTS: 
Part A 
Each participant will receive the following study treatments in a crossover design:  
• Treatment 1: 900 mg plixorafenib (6 × 150 mg tablets) administered after overnight fast 
(fasted state). 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 13 
• Treatment 2: 900 mg plixorafenib (6 × 150 mg tablets) + cobicistat (1 × 150 mg tablet) 
administered after overnight fast (fasted state). 
• Treatment 3: 900 mg plixorafenib (6 × 150 mg tablets) + cobicistat (1 × 150 mg tablet) 
administered following a high fat, high caloric meal (fed state). 
Part B 
Each participant will receive three of the following study treatments per randomization in a 
crossover design:   
• Treatment A: 900 mg plixorafenib (6 × 150 mg tablets) administered after overnight fast 
(fasted state).  
• Treatment B: 900 mg plixorafenib (6 × 150 mg tablets) administered following a high fat, 
high caloric meal (fed state-high fat meal).  
• Treatment C: 900 mg plixorafenib (6 × 150 mg tablets) administered following a low-fat 
meal (fed state-low-fat meal). 
• Treatment D: 900 mg plixorafenib (6 × 150 mg tablets) administered with 150 mg 
cobicistat (1 × 150 mg tablet) following a low-fat meal (fed state-low-fat meal). 
STUDY PROCEDURES: 
Pharmacokinetic Assessments and Endpoints: 
Following administration of the study treatments, participants will have serial blood drawn 
(Part A and Part B) and urine (for Part A only) samples collected for determination of blood and 
urine concentration of plixorafenib.  
Blood PK sample collection timepoints are as follows: 
Study Days 
Timepoints 
D1, D8, D15 
(Dosing) 
D2, D9, D16 
D3, D10, D17 
D4, D11, D18 
D5, D12, D19 
0 hour (0800)* 
✓ (Predose)** 
✓ (24 h) 
✓ (48 h) 
✓ (72 h) 
✓ (96 h) 
0.5 hour (0830) 
✓ 
 
 
 
 
1 hour (0900) 
✓ 
 
 
 
 
2 hour (1000) 
✓ 
 
 
 
 
3 hour (1100) 
✓ 
 
 
 
 
4 hour (1200) 
✓ 
 
 
 
 
6 hour (1400) 
✓ 
 
 
 
 
8 hour (1600) 
✓ 
✓ (32 h) 
 
 
 
10 hour (1800) 
✓ 
 
 
 
 
12 hour (2000) 
✓ 
 
 
 
 
D, day; h, hours. 
*Nominal clock time.  
**Predose sample will be collected within 15 minutes prior to the dosing. 0 hour means dosing of study drug. 
 
For Part A only: Prior to the predose sample, each participant will be instructed as to urine 
collection methods. Urine samples for the determination of plixorafenib concentrations will be 
collected at selected time intervals, as specified in the table below. All participants will be asked 
to void their bladder within 45 minutes prior to dosing. After administration of plixorafenib, all 
urine will be collected completely per each collection interval. Urine portions will be pooled per 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 14 
participant within this collection interval. Just prior to the end of the sampling interval, 
participants will be encouraged to void their bladder again to complete the collection. The start 
and end times of the urine collection will be recorded. Three aliquot (5 mL each) will be obtained 
from each pooled urine sample: 1 for the quantification of plixorafenib, 1 for the metabolite 
analysis, and 1 as a back-up. Instructions for sample preparation and storage can be found in the 
study lab manual. 
Urine samples for the quantitation of plixorafenib, collection timepoints are as follows: 
Study Days 
Timepoints 
D1, D8, D15 
(Dosing Day) 
D2, D9, D16 
Predose* 
✓ 
 
0-4 hours 
✓ 
 
4-8 hours 
✓ 
 
8-12 hours 
✓ 
 
12-24 hours 
 
✓ 
24-48 hours 
 
✓ 
D, days. 
*45 minutes prior to dosing. 
 
The following PK parameters will be calculated using model-independent approaches (NCA) 
from plixorafenib individual plasma concentrations, whenever practical. 
Plasma Parameters (Part A and Part B) 
• Area under the plasma concentration versus time curve (AUC) from time 0 to the last 
quantifiable concentration (AUC0-t). 
• AUC from time 0 extrapolated to infinity (AUC0-inf). 
• Maximum observed plasma concentration (Cmax). 
• Time to maximum observed plasma concentration (Tmax). 
• Terminal elimination rate constant (Kel). 
• Terminal phase half-life (t1/2). 
• Apparent oral clearance (CL/F). 
• Apparent volume of distribution (Vd/F). 
• Terminal rate constant calculated from the terminal slope of the log-linear regression of 
concentration with time (z). 
• Calculated lag time: time taken for the drug to appear in the systemic circulation following 
administration, when applicable (Tlag). 
Urine Parameters (Part A Only) 
• Cumulative amount of plixorafenib excreted in urine, calculated as the sum of the product 
of urine concentration and urine volume (Ae). 
• Percent of dose excreted in urine in 48 hours calculated as 100*Ae/Dose. 
Blood and urine samples may be used to evaluate the metabolic profile of plixorafenib and the 
results will be described separately. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 15 
Blood and/or plasma samples may be used to measure endogenous biomarkers, such as 
coproporphyrin I, to assess possible transporters inhibition. 
Pharmacogenomics:  
A blood sample for pharmacogenomic evaluation will be collected at screening. Possible effects 
of pharmacogenomic variations on the PK of plixorafenib and/or the effect of cobicistat, 
including but not limited to polymorphisms in P-gp, BCRP, and UGT, will be examined, if 
feasible. 
Safety Assessments and Endpoints: 
Safety will be assessed by the following: monitoring and recording of AEs; clinical laboratory 
test results (hematology, serum chemistry, and urinalysis), vital sign measurements, 12-lead ECG 
results, and physical examination findings. 
STATISTICAL ANALYSIS PLANS: 
Sample Size: 
The number of participants is based on clinical and practical considerations and not on a formal 
statistical power calculation. The total sample size of 12 participants in Part A and 16 participants 
in Part B is considered sufficient for the objectives of the study. 
Analysis Sets: 
The PK population will include participants who receive at least 1 dose of plixorafenib with or 
without cobicistat and have sufficient concentration data to support accurate estimation of at least 
1 PK parameter. Participants who experience vomiting within 2 times the median Tmax after study 
drug dosing will be excluded from the PK analysis. 
The safety population will include all participants who receive at least 1 dose of plixorafenib 
with or without cobicistat. 
Pharmacokinetic Analyses: 
Individual plasma concentration and time deviation data will be presented in a data listing. 
Plasma concentration data will be summarized by time point for each treatment (plixorafenib 
alone in fasted state, plixorafenib + cobicistat in fasted state or plixorafenib + cobicistat in fed 
state) using the following descriptive statistics: number of participants, arithmetic mean, SD, CV, 
geometric mean, geometric CV, median, minimum, and maximum. Individual and mean plasma 
concentration versus scheduled time profiles will be presented in figures on both linear and 
semilogarithmic scales. 
The PK parameters of plixorafenib will be determined using noncompartmental methods based 
on the actual sampling times. All parameters will be calculated using Phoenix® WinNonlin® 
(Certara USA Inc., Princeton, New Jersey) Version 8.3 or higher. The individual PK parameters 
will be presented in data listings and summarized by treatment using the following descriptive 
statistics: number of participants, mean, SD, CV, median, minimum, and maximum. Geometric 
means will be included for AUC0-t, AUC0-inf, and Cmax. 
If warranted, a linear mixed model with treatment as a fixed effect and participant as a random 
effect will be performed on the natural log-transformed values of AUC0-t, AUC0-inf, and Cmax to 
assess the effect of cobicistat and/or food on the PK of plixorafenib. The geometric least squares 
means and corresponding 90% CIs will be computed for AUC0-t, AUC0-inf, and Cmax of 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 16 
plixorafenib administered alone (Reference Treatment) versus plixorafenib with cobicistat and/or 
food (Test Treatments) by taking the antilog of the least squares means from the linear 
mixed-effect model on the natural logarithms of the corresponding PK parameters. A 90% CI for 
the ratio will be constructed as the antilog of the confidence limits of the mean difference. 
It will be concluded that there is no relevant interaction of cobicistat or food on plixorafenib if 
the 90% CIs for AUC0-t, AUC0-inf, and Cmax ratios of the Reference Treatment to the Test 
Treatments are completely contained within the (80%, 125%) interval. 
Safety Analyses: 
Adverse events will be coded by preferred term and system organ class using the latest version of 
MedDRA. All AE data will be presented in a data listing. TEAEs will be summarized by 
treatment and overall, as well as by severity, seriousness, and relationship to study drug. SAEs 
and AEs leading to discontinuation of study drug will also be presented in the data listings and 
summarized by treatment and overall. 
Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized by treatment at each time point 
using descriptive statistics (number of participants, mean, SD, median, minimum, and maximum. 
Physical examination findings will be presented in a data listing. 
Other Analyses: Evaluation of the metabolic profile of plixorafenib in plasma (Parts A and B) 
and urine (Part A only) will be conducted and the results will be reported separately. 
Possible effects of pharmacogenomic variations on the PK of plixorafenib and/or the effect of 
cobicistat, including but not limited to polymorphisms in P-gp, BCRP, and UGT, will be 
examined, if feasible. 
DATE OF PROTOCOL: Amendment 1, 03 October 2024 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 17 
1. 
INTRODUCTION 
1.1 
BACKGROUND 
1.1.1 
Plixorafenib 
Plixorafenib (also known as FORE8394 and formerly known as PLX8394) is a first-in-class 
selective RAF murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor that blocks mutant 
BRAF in tumor cells without activating the MAPK pathway. Plixorafenib has nonclinical and 
clinical activity against both monomeric V600 mutations and dimeric non-V600 BRAF 
alterations, including BRAF fusions and deletion mutations. 
Plixorafenib is a next-generation, orally available, small-molecule, selective potent inhibitor of 
activated BRAF (Class 1 and 2, including fusions). Unlike first-generation RAF inhibitors, 
plixorafenib specifically disrupts BRAF-containing dimers and does not appear to induce 
paradoxical activation of the MAPK pathway. Therefore, plixorafenib as a “paradox breaker” 
may provide both improved safety and more durable efficacy than first- and second-generation 
RAF inhibitors. Preclinical and clinical findings support that plixorafenib does not have the 
tumor activating potential observed with the first- and second-generation compounds. 
Plixorafenib as a BRAF inhibitor presents a notable differential regulation of major pathways, 
including MAPK signaling, apoptosis, cell cycle, or developmental signaling pathways. 
Combinatorial treatments of plixorafenib with MCL-1 and Notch modulators show a better effect 
than single agent treatments, suggesting additional pathways could be further exploited in novel 
efficient combinatorial treatment protocols with plixorafenib (Koumaki 2021). 
Plixorafenib overcomes several known mechanisms of resistance to first-generation BRAF 
inhibitors when tested in relevant vemurafenib resistant cell models. The in vivo anti-tumor 
activity of plixorafenib and PK-PD relationship have been characterized in several 
BRAF-V600E xenograft models. To date, no specific concerns about safety have emerged from 
safety pharmacology evaluations of plixorafenib. 
Nonclinical Summary:  
Pharmacology: Plixorafenib inhibits the mutated BRAF kinases including Class 1 BRAF-V600E 
and V600K and Class 2 BRAF K601E, T599I, and G469A with single-digit nM IC50 values and 
to a lesser extent wild type BRAF and CRAF, while having minimal effects on the activities of 
>260 other kinases. Unlike all first-generation BRAF inhibitors, plixorafenib does not induce 
RAF dimer formation. In nonclinical squamous cell tumor models, the first-generation- RAF 
inhibitor vemurafenib stimulated in vitro and in vivo growth and induced the expression of both 
downstream MAPK pathway response genes and upstream EGFR ligands. In contrast, 
plixorafenib had no effect. By dissociating MAPK pathway inhibition from pathway activation, 
plixorafenib may provide improved clinical outcomes with fewer side effects or the need for co-
administration of a MEK inhibitor related to unwanted activation. No specific concerns have 
emerged from safety pharmacology evaluations of plixorafenib. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 18 
Pharmacokinetics: Plixorafenib is a metabolically stable drug that displays low aqueous 
solubility, high permeability, and extensive plasma protein binding. In vivo testing in multiple 
species has shown that plixorafenib is absorbed within 3 to 5 hours following oral 
administration. Following a single oral dose of plixorafenib in Sprague Dawley rats, wide tissue 
distribution was observed, with low CNS to plasma ratio. 
In vitro data suggest that the metabolism of plixorafenib is mediated primarily by the cytochrome 
P450 (CYP)3A isoenzyme. Based on in vitro transporter substrate and inhibition studies, 
plixorafenib is a substrate of P-gp, and BCRP, and an inhibitor of P-gp, BCRP, BSEP, OAT1, 
OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2K, MRP3, and MRP4. Cobicistat 
is an inhibitor of CYP3A and CYP2D6, and inhibits the following transporters: P-gp, BCRP, 
OATP1B1, and OATP1B3. In an in-vitro experiment in human liver cells, the addition of 
cobicistat completely blocked the metabolism of plixorafenib. Plixorafenib neither inhibits 
(direct or time-dependent) nor induces CYP enzymes in vitro. 
Toxicology: In the GLP repeat-dose 28-day toxicology studies in Sprague Dawley rats and 
beagle dogs, the NOAELs were determined to be 450 mg/kg/day and 300 mg/kg/day, 
respectively. No adverse effects thought to be related to plixorafenib treatment were identified. A 
non-adverse slight increase in the severity of renal hyaline droplets in the kidneys was observed 
in male rats at ≥150 mg/kg/day; however, this kidney change was not relevant to humans. 
Non-adverse plixorafenib-related microscopic observations were noted in the bone marrow 
(minimal to mild coagulative necrosis) and liver (minimal single cell necrosis) of male dogs at 
300 mg/kg/day. Exacerbation of spontaneous polyarteritis, not considered a plixorafenib-related 
effect, was also observed in dogs at ≥100 mg/kg/day. Importantly, no ophthalmologic findings 
were identified in either species. In genotoxicity studies performed under GLP conditions, 
plixorafenib was found to be non-mutagenic and non-clastogenic (Fore Biotherapeutics 2023). 
Clinical Summary:  
As of 29 January 2024, a total of 174 participants have been exposed to study drug in clinical 
trials. Two studies have been completed, Study PLX120-01 and Study PLX120-04. One study 
(PLX120-03) is ongoing with the enrollment complete, and 1 study (F8394-201) is actively 
enrolling. 
Study PLX120-04 was a Phase 1, open-label, 2-part study to evaluate the PK and safety of single 
ascending doses of plixorafenib (previous HME formulation) and to assess the effect of 
cobicistat (a pharmacoenhancer) on the PK of plixorafenib in healthy participants. In Study 
PLX120-04, plixorafenib showed linear PK when administered as single ascending doses under 
fasted conditions over the studied dose range of 150 to 900 mg. Cobicistat co-administration 
increased plixorafenib exposure. Compared with plixorafenib administered alone, the mean AUC 
from AUC0-t and AUC0-inf increased 2.6-fold (300 mg level) and 3.8-fold (900 mg level), and the 
mean Cmax increased 1.8-fold (300 mg level) and 2.7-fold (900 mg level). Single doses of 
plixorafenib were well tolerated when administered either alone or in combination with 
cobicistat. 
Study PLX120-03 is an ongoing, Phase 1/2a, open-label, single-arm clinical trial designed to 
evaluate the safety, PK, pharmacodynamics, and preliminary efficacy of plixorafenib in adult and 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 19 
pediatric participants with advanced unresectable solid or CNS tumors harboring BRAF 
alterations. Preliminary PK data are available from 84 adult participants through 
31 October 2022. When plixorafenib was administered alone, a modest increase in exposure was 
observed between the 450 mg BID and the 900 mg BID dose groups. In addition, slight 
accumulation was observed upon BID dosing for at least 15 days. Administration of plixorafenib 
with cobicistat resulted in approximately 2- to 3-fold increase in systemic exposure compared to 
plixorafenib alone. Increases in dose resulted in increases in plixorafenib exposure up to 900 mg 
BID with no additional increase in exposure observed at the 1350 mg and 1800 mg BID dose. 
Exposure parameters for the SDD formulation suggest comparable exposure for the HME and 
the SDD formulations. Overall, the high variability in the data, along with the small number of 
participants and limited sampling scheme, may have impacted the PK assessments. Plixorafenib 
has demonstrated an acceptable safety profile. Cutaneous events with potential to develop into 
treatment-emergent malignancies in the skin and other epithelial tissues, that have been observed 
with other first-generation inhibitors, have not been observed with plixorafenib, supporting the 
lack of paradoxical activation. Preliminary efficacy from the ongoing PLX120-03 Phase 1/2a 
study supports long term tolerability and a promising signal of clinical benefit with 
10 participants receiving study treatment for ≥2 years (range: 2.4 to 7.6 years) and responses 
observed across advanced solid tumors harboring V600 or non-V600 BRAF alterations. 
The F8394-201 study is a Phase 2 global multicenter master protocol to assess the efficacy and 
safety of plixorafenib in participants 10 years of age or older with advanced cancer harboring 
eligible BRAF alterations. The potential benefits of plixorafenib treatment include durable 
single-agent anti-tumor effects against BRAF-altered tumors in both adults and children with 
advanced malignancies or LCH and a reduced risk of paradoxical MAPK pathway activation. 
Cobicistat is a PK booster administered with plixorafenib. In clinical studies, cobicistat resulted 
in about a 2- to 3-fold increase in systemic exposure of plixorafenib compared to plixorafenib 
alone. Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion 
of creatinine without affecting actual renal glomerular function. Cobicistat may have possible or 
significant known interactions with concomitant medications, foods, or herbal remedies. The 
potential for interactions should be considered when cobicistat is administered and steps taken to 
prevent or manage these possible and known significant drug interactions. Refer to the 
prescribing information of cobicistat for further information. 
Further information on the study drug can be found in the Investigator’s Brochure (Fore 
Biotherapeutics 2023). 
1.1.2 
Cobicistat 
Cobicistat is a mechanism-based inhibitor of the CYP3A isoenzyme family that is approved and 
marketed as a PK enhancer of HIV-1 protease inhibitors in adults (Tybost® 2021). Cobicistat is 
also an inhibitor of several transporters that include P-gp, BCRP, OATP1B1, and OATP1B3. The 
most common Grade ≥2 ADRs observed with cobicistat (in combination with atazanavir) are 
jaundice and rash. Cobicistat is contraindicated with certain drugs for which altered plasma 
concentrations are associated with serious and/or life-threatening events or loss of therapeutic 
effect. The plasma concentration of drugs that are primarily metabolized by CYP3A or CYP2D6, 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 20 
or are substrates of P-gp, BCRP, OATP1B1, or OATP1B3, may be increased if those drugs are 
coadministered with cobicistat. 
As plixorafenib is a substrate of P-gp and in vitro data suggest that the metabolism of 
plixorafenib is mediated primarily by CYP3A, cobicistat was evaluated as a possible booster of 
plixorafenib exposure. In an in vitro study, the addition of cobicistat completely blocked the 
metabolism of plixorafenib by CYP3A4. In an in vitro blood-brain barrier model, cobicistat 
5 μM increased the apical to basolateral permeability coefficient value (Papp) of plixorafenib 
13-fold. In clinical studies in participants with advanced cancer (PLX120-03), administration of 
plixorafenib with cobicistat resulted in about 2- to 3-fold increase in systemic exposure 
compared to plixorafenib alone.  
Cobicistat exposures were not affected by food. (Prezcobix® 2023). 
1.2 
RATIONALE FOR STUDY 
This study will assess the effect of food on the single dose PK of plixorafenib administered with 
cobicistat in accordance with the FDA guidance for industry on assessing the effects of food on 
drugs in INDs and NDAs — Clinical Pharmacology Considerations (DHHS 2022). 
This study is designed in accordance with the US FDA Guidance for Industry, Clinical Drug 
Interaction Studies—Study Design, Data Analysis, and Clinical Implications (DHHS 2017) to 
assess the effects of cobicistat administration on the single dose PK of plixorafenib. 
For Part A, the effect of food on the single dose PK of plixorafenib (900 mg) administered 
concomitantly with cobicistat, will be evaluated as participants in other current studies 
evaluating plixorafenib are instructed to take their study treatment on an empty stomach (fasting 
for 2 hours before and one hour after dosing) as the effect of food on the PK of plixorafenib has 
not been formally evaluated yet. Characterizing the food effect may allow more flexibility in 
plixorafenib dosing. This study will investigate the effect of cobicistat on the PK and safety of 
plixorafenib using the SDD formulation. 
Metabolism and urinary excretion will also be evaluated in this study to assess the urinary 
excretion of plixorafenib and examine its metabolic fate. 
Plixorafenib is being administered with cobicistat in this study as in vitro data suggest that the 
metabolism of plixorafenib is mediated primarily by the CYP3A isoenzyme. In a clinical study 
(Study PLX120-04), cobicistat co-administration increased plixorafenib exposure. Compared 
with plixorafenib administered alone as the HME formulation, the mean AUC from AUC0-t and 
AUC0-inf increased 2.6-fold (300 mg level) and 3.8-fold (900 mg level), and the mean Cmax 
increased 1.8-fold (300 mg level) and 2.7-fold (900 mg level). Single doses of plixorafenib were 
well tolerated when administered either alone or in combination with cobicistat. 
Part A of this study demonstrated that co-administration of plixorafenib and cobicistat with a 
high fat, high caloric meal resulted in about 2-fold increase in average Cmax and about 3-fold 
increase in average AUC0-∞, as compared to the fasted state. Since the target oncology patient 
population may not be able to consume high-fat and/or high-calorie meals, the effect of a low-fat 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 21 
meal (400 to 500 calories, with 25% from fat) and a high-fat meal (800 to 1000 calories, with 
≥50% from fat) on the exposure of plixorafenib will be examined in Part B of this study, 
compared to the fasted state. 
1.3 
RATIONALE FOR DOSE SELECTION 
Nonclinical and clinical data to date indicate that plixorafenib has an acceptable safety profile. 
In the PLX120-03 Phase 1/2a study evaluating multiple dosing (ranging from plixorafenib 
900-3600 mg/day with and without cobicistat; N=113) administered until disease progression in 
participants with advanced cancers, plixorafenib 900 mg QD with cobicistat 150 mg QD was 
selected as the RP2D based upon the overall safety, PK, PD, and efficacy in BRAF-altered 
tumors. DLTs consisted of transient Grade 3 laboratory abnormalities in transaminases and/or 
bilirubin and occurred in 6 participants (none meeting Hy’s law). No DLTs were observed with 
plixorafenib ≤1200 mg/day, with or without cobicistat, including at the RP2D of plixorafenib 
900 mg QD co-administered with cobicistat 150 mg QD. 
Transient increases in ALT, AST, and bilirubin have been observed in participants with advanced 
malignancies receiving plixorafenib until disease progression. These changes can be monitored 
with routine laboratory studies and are manageable with dose interruptions and reductions. 
Participants have continued to tolerate treatment following these events, and no cases of hepatic 
failure have been reported. To mitigate this risk, liver chemistry assessments are closely 
monitored in all clinical studies (Fore Biotherapeutics 2023). The single dose of plixorafenib 
with or without cobicistat utilized in this Phase 1 study are in line with those evaluated in the 
PLX120-04 Phase 1 study in healthy participants (plixorafenib 150 to 900 mg; including 
assessing the effect of cobicistat) that encompassed a clinically relevant exposure and 
demonstrated an acceptable safety profile. 
2. 
STUDY OBJECTIVES 
The objectives of Part A and Part B are provided below.  
2.1 
PRIMARY OBJECTIVE 
The primary objectives for Part A of the study are as follows: 
• To examine the effect of food on the single dose PK of plixorafenib administered with 
cobicistat. 
• To examine the effect of cobicistat administration on the single dose PK of plixorafenib. 
• To determine the safety of plixorafenib administered alone and with cobicistat in a single 
dose regimen in healthy participants. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 22 
The primary objectives for Part B of the study are:  
• To examine the effect of a high-fat and a low-fat meal versus fasted state on the single dose 
PK of plixorafenib administered alone.  
• To examine the effect of a low-fat meal versus fasted state on the single dose PK of 
plixorafenib administered with cobicistat. 
• To determine the safety of plixorafenib administered alone or with cobicistat (low-fat meal 
only) in a single dose regimen. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives for Part A of the study are as follows: 
• To characterize metabolites of plixorafenib in plasma and urine. 
• To characterize the urinary excretion of plixorafenib. 
There are no secondary objectives for Part B of the study. 
2.3 
EXPLORATORY OBJECTIVE 
The exploratory objective for Part A and Part B of the study is as follows: 
• To examine the possible effect of pharmacogenomic variations on the PK of plixorafenib 
and/or the effect of cobicistat, including polymorphisms in P-gp, BCRP, and UGT. 
The exploratory objective for Part B of the study is as follows: 
• The effect of single dose administration of plixorifenib on endogenous biomarkers such as 
coproporphyrin may be evaluated. 
3. 
STUDY DESIGN 
This is a Phase 1, open-label, 2-part, single dose, crossover, single-center study. 
3.1 
PART A 
Part A is an open-label, randomized, single dose, 3-treatment, 3-period, crossover study designed 
to assess the effect of food and cobicistat administration on the PK and safety of plixorafenib in 
12 healthy adult participants. 
The study will consist of a screening period, 1 check-in, 3 treatment periods (with a 7-day 
washout between dosing in each period), and an EOS visit as illustrated in Table 3-1: 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 23 
Table 3-1 
Study Description for Part A 
Treatment Period 
Screening 
Check-in 
Dosing 
Confinement  
1 
Day -28 to -1 
Day -1 
Day 1 
Day -1 to Day 19 
(EOS) 
  
2 
N/A 
N/A 
Day 8 
3 
N/A 
N/A 
Day 15 
N/A, not applicable; EOS, end of study 
There will be a 7-day washout between dosing in each treatment period. 
EOS visit will be conducted on Day 19. 
 
A screening evaluation will be performed to determine each participant’s eligibility for the study 
approximately 28 to 1 days before the first dose. Participants eligible for participation will report 
to the study facility 1 day before dosing in Treatment Period 1 for check-in. 
On Day 1 of Treatment Period 1, eligible participants will be randomized to 1 of 6 treatment 
sequences: 1:2:3, 2:3:1, 3:2:1, 2:1:3, 3:1:2, 1:3:2. On the first day of each treatment period, each 
participant will receive one of the following treatments according to the sequence in which he or 
she is randomized: 
• Treatment 1: 900 mg plixorafenib administered after overnight fast (fasted state). 
• Treatment 2: 900 mg plixorafenib + 150 mg cobicistat administered after overnight fast 
(fasted state). 
• Treatment 3: 900 mg plixorafenib + 150 mg cobicistat administered following a high fat, 
high caloric meal (fed state). 
For Treatment 2 and Treatment 3, plixorafenib and cobicistat will be co-administered. 
All participants will fast overnight (nothing to eat or drink except water) for at least 10 hours. 
Participants receiving Treatments 1 and 2 (fasted condition) will continue to fast for at least 
4 hours after dosing. 
Participants receiving Treatment 3 will receive a standard high fat (≥50% of the total caloric 
content of the meal), high caloric meal (approximately 800 to 1000 calories) for breakfast before 
dosing and this meal should derive approximately 150, 250, and 500 to 600 calories from 
protein, carbohydrate, and fat, respectively (DHHS 2022). Participants must consume the entire 
meal within 30 minutes of serving; the percentage of meal consumed will be documented. 
Dosing must occur 30 minutes (± 5 minutes) after the start of the meal. Participants receiving 
Treatment 3 will receive their next meal no less than 4 hours after dosing. 
All study drugs will be administered orally with approximately 240 mL of room temperature 
water. Water (except water provided with each dosing) will be restricted 1 hour prior to and 
1 hour after each study drug administration, except for any fluid (ie, water, milk, juice) provided 
with the predose meal (Treatment 3 only), but will be allowed ad libitum at all other times. Up to 
an additional 240 mL of water will be allowed, if necessary, to aid in swallowing the study drugs 
when both study drugs are administered simultaneously. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 24 
Participants will remain at the facility from check-in (Day -1) to EOS and would be able to leave 
the facility upon satisfactory safety review. During confinement, participants will receive 
standardized meals per the clinic’s standard procedures that are scheduled at the same time in 
each period of the study. Participants will be discharged from the study on Day 19 (Treatment 
Period 3). 
The duration of the study for each participant, excluding screening period, will be approximately 
20 days. Including screening period, the total study duration for each participant will be 48 days. 
3.2 
PART B 
Part B is an open-label, randomized, single dose, 4-treatment, 3-period, crossover study designed 
to assess the effect of food (either a high-fat meal or a low-fat meal) on the PK and safety of 
plixorafenib administered alone or with cobicistat (low-fat meal only) in 16 healthy adult 
participants. 
This part will consist of a screening period, 1 check-in, 3 treatment periods (with a 7-day 
washout between dosing in each period), and an EOS visit as illustrated in Table 3-2:  
Table 3-2 
Study Description for Part B 
Treatment Period 
Screening 
Check-in 
Dosing 
Confinement 
1 
Day -28 to -1 
Day -1 
Day 1 
Day -1 to Day 19 (EOS) 
 
2 
N/A 
N/A 
Day 8 
3 
N/A 
N/A 
Day 15 
N/A, not applicable; EOS, end of study.  
There will be a 7-day washout between dosing in each treatment period. EOS visit will be conducted on Day 19.  
A screening evaluation will be performed to determine each participant’s eligibility for the study 
approximately 28 to 1 days before the first dose. Participants eligible for participation will report 
to the study facility 1 day before dosing in Treatment Period 1 for check-in.  
On Day 1 of Treatment Period 1, eligible participants will be randomized to 1 of 4 treatment 
sequences: A:C:D, B:D:A, D:B:C, C:A:B. On the first day of each treatment period, each 
participant will receive one of the following treatments according to the sequence in which he or 
she is randomized:  
a) Treatment A: 900 mg plixorafenib administered after overnight fast (fasted state).  
b) Treatment B: 900 mg plixorafenib administered following a high-fat high caloric meal (fed 
state-high fat meal). 
c) Treatment C: 900 mg plixorafenib administered following a low-fat meal (fed state-low-fat 
meal). 
d) Treatment D: 900 mg plixorafenib administered with 150 mg cobicistat following a low-fat 
meal (fed state-low-fat meal).   

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 25 
All participants will fast overnight (nothing to eat or drink except water) for at least 10 hours.  
• Participants receiving Treatment A (fasted condition) will continue to fast for at least 4 hours 
after dosing. 
• Participants receiving Treatment B will receive a high fat (≥50% of the total caloric content 
of the meal), high caloric meal (approximately 800 to 1000 calories) for breakfast before 
dosing and this meal should derive approximately 150, 250, and 500 to 600 calories from 
protein, carbohydrate, and fat, respectively.   
• Participants receiving Treatments C and D will receive a low-fat meal (approximately 400 to 
500 total calories, with 25% of the total caloric content of the meal from fat) for breakfast 
before dosing.  
All participants receiving Treatments B, C, or D must consume the entire meal within 30 minutes 
of serving; the percentage of meal consumed will be documented. Dosing must occur 30 minutes 
(± 5 minutes) after the start of the meal. Participants receiving Treatments B, C, and D will 
receive their next meal no less than 4 hours after dosing.  
Plixorafenib will be administered orally with approximately 240 mL of room temperature water. 
Water (except water provided with each dosing) will be restricted 1 hour before and 1 hour after 
each study drug administration, except for consuming any fluid (eg, water, milk, juice) provided 
with the predose meal (Treatments B, C, and D) but will not be limited at other times. Up to an 
additional 240 mL of water will be allowed, if necessary, to aid in swallowing the study drugs 
when administered with cobicistat (Treatment D). 
Participants will remain at the facility from check-in (Day -1) to EOS and would be able to leave 
the facility upon satisfactory safety review by the investigator. During confinement periods, 
participants will receive standardized meals per the clinic’s standard procedures that are 
scheduled at the same time in each period of the study. Participants will be discharged from the 
study on Day 19 (Treatment Period 3).  
The duration of the study for each participant, excluding screening, will be approximately 
20 days. Including screening, the total study duration for each participant will be 48 days.  

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 26 
3.3 
SCHEDULE OF EVENTS 
3.3.1 
Schedule of Events for Study Part A 
 
Phase 
Screening Check-in 
Treatment Period 1 
Treatment Period 2 
Treatment Period 3 
Procedure(a) 
Day/Treatment 
D–28 to 
 –1 
Day 
-1 
D1 D2 D3 D4 D5 
D8 
D9 
D10 
D11 
D12 
D15 
D16 D17 D18 D19/EOS 
Admission to clinic 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from the clinic/study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology(b) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH(c) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight, and BMI(d) 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Physical examination(e) 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Vital sign measurements(f) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG(g) 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Clinical laboratory testing(h) 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
Urinalysis(h) 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
Urine drug/alcohol/cotinine 
screen(i) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test(j)  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Sample for pharmacogenomics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration(k) 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
PK sample collection(l) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine PK sample collection(m) 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
Adverse events(n) 
X 
Prior/concomitant medications (o) 
X 
Abbreviations: AEs, adverse events; BCRP, breast cancer resistance protein; BMI, body mass index; D, day; ECG, electrocardiogram; EOS, end of study; FSH, 
follicle-stimulating hormone; PD, pharmacodynamic; P-gp, P-glycoprotein; PK, pharmacokinetic; QTcF, QT interval corrected for heart rate using Fridericia’s 
formula  
Notes:  
a) When procedures are scheduled for the same timepoint ECG should be performed first, followed by vital sign assessment, urine collection, meal, blood 
collection, and dose (in that order). 
b) A complete list of serology assessments is provided in Section 6.2.3. 
c) Females only. Further details are provided in Section 6.2.3. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 27 
d) Height and weight will be measured, and BMI calculated at screening only. Only weight will be measured at check-in, dosing, and EOS. 
e) A full physical examination will be performed at screening and check-in. A symptom-driven physical examination may be performed at other times, at 
the investigator’s or designee’s discretion. Further details are provided in Section 6.2.6. 
f) 
Further details on vital signs (respiratory rate, body temperature, pulse rate, and blood pressure) measurements are provided in Section 6.2.4. 
g) ECG should be recorded at screening, predose within 2 hours on each dosing day, and at EOS. Further details on ECG recordings are provided in 
Section 6.2.5. 
h) Clinical laboratory testing will occur at screening, check-in, 3 days from dosing (Day 4, 11, 18), and at EOS. If any concerning trends are seen during 
study, the investigator can order additional testing for safety on PRN basis. Further details on clinical laboratory assessments, including a complete list 
of assessments, are provided in Section 6.2.3. 
i) 
Further details are provided in Section 6.2.3.  
j) 
Urine pregnancy test to be done at screening. Serum pregnancy test to be done at check-in, and at EOS. 
k) Further details on dosing of study treatments are provided in Section 5.1. 
l) 
Further details on the collection of blood samples for PK analysis are provided in Section 6.1 and in Table 6-1. 
m) Further details on the collection of urine samples for PK analysis are provided in Section 6.1 and in Table 6-2. 
n) Further details on collection and reporting of AEs are provided in Section 6.2. 
o) Information regarding prior medications taken by the participant within the 30 days before signing the ICF will be recorded in the participant’s eCRF. 
Details regarding prior and concomitant medications are provided in Section 5.5.1. 
 
 
 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 28 
3.3.2 
Schedule of Events for Study Part B 
 
Phase 
Screening Check-in 
Treatment Period 1 
Treatment Period 2 
Treatment Period 3 
Procedure(a) 
Day/Treatment 
D–28 to 
 –1 
Day 
-1 
D1 D2 D3 D4 D5 
D8 
D9 
D10 
D11 
D12 
D15 
D16 D17 D18 D19/EOS 
Admission to clinic 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from the clinic/study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology(b) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH(c) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight, and BMI(d) 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Physical examination(e) 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Vital sign measurements(f) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG(g) 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Clinical laboratory testing(h) 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
X 
Urinalysis(h) 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
X 
Urine drug/alcohol/cotinine 
screen(i) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test(j)  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Sample for pharmacogenomics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration(k) 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
PK sample collection(l) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events(m) 
X 
Prior/concomitant medications (n) 
X 
Abbreviations: AEs, adverse events; BCRP, breast cancer resistance protein; BMI, body mass index; D, day; ECG, electrocardiogram; EOS, end of study; FSH, 
follicle-stimulating hormone; PD, pharmacodynamic; P-gp, P-glycoprotein; PK, pharmacokinetic; QTcF, QT interval corrected for heart rate using Fridericia’s 
formula  
Notes:  
a) When procedures are scheduled for the same timepoint ECG should be performed first, followed by vital sign assessment, urine collection, meal, blood 
collection, and dose (in that order). 
b) A complete list of serology assessments is provided in Section 6.2.3. 
c) Females only. Further details are provided in Section 6.2.3. 
d) Height and weight will be measured, and BMI calculated at screening only. Only weight will be measured at check-in, dosing, and EOS. 
e) A full physical examination will be performed at screening and check-in. A symptom-driven physical examination may be performed at other times, at 
the investigator’s or designee’s discretion. Further details are provided in Section 6.2.6. 
f) 
Further details on vital signs (respiratory rate, body temperature, pulse rate, and blood pressure) measurements are provided in Section 6.2.4. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 29 
g) ECG should be recorded at screening, predose within 2 hours on each dosing day, and at EOS. Further details on ECG recordings are provided in 
Section 6.2.5. 
h) Clinical laboratory testing will occur at screening, check-in, predose within 2 hours on each dosing day, 3 days from dosing (Day 4, 11, 18), and at EOS. 
If any concerning trends are seen during study, the investigator can order additional testing for safety on PRN basis. Further details on clinical laboratory 
assessments, including a complete list of assessments, are provided in Section 6.2.3. 
i) 
Further details are provided in Section 6.2.3.  
j) 
Urine pregnancy test to be done at screening. Serum pregnancy test to be done at check-in, and at EOS. 
k) Further details on dosing of study treatments are provided in Section 5.1. 
l) 
Further details on the collection of blood samples for PK analysis are provided in Section 6.1 and in Table 6-1. 
m) Further details on collection and reporting of AEs are provided in Section 6.2. 
n) Information regarding prior medications taken by the participant within the 30 days before signing the ICF will be recorded in the participant’s eCRF. 
Details regarding prior and concomitant medications are provided in Section 5.5.1. 
 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 30 
4. 
STUDY POPULATION 
Approximately 12 participants in Part A and 16 participants in Part B will be enrolled at a single 
center in the United States. 
4.1 
INCLUSION CRITERIA 
Each participant must meet all the following criteria to be enrolled in this study: 
 The participant is able to provide written informed consent. 
 Healthy male or non-pregnant, non-lactating female participants aged 18 to 55 years, 
inclusive, with a BMI of 18 kg/m2 or greater, but less than 30 kg/m2. The participant is 
considered by the investigator to be in good general health status as determined by physical 
examination, vital signs, temperature, medical history, no clinically significant abnormalities 
at investigator’s discretion in laboratory and urine analyses and with normal organ function 
as defined below: 
• Normal renal function: creatinine clearance ≥90 mL/min 
• Normal liver enzymes and bilirubin (≤ULN) 
• ECG, with QTcF interval ≤450 msec; at screening. 
 Healthy female participants must be: 
a) Documented to be surgically sterile (surgical methods inclusive of hysterectomy, bilateral 
salpingectomy, and/or bilateral oophorectomy) or postmenopausal (amenorrhea for 
≥24 months without an alternative medical cause and FSH ≥30 mIU/mL). 
OR 
b) Using contraception, including 1 highly effective nonhormonal methods (eg, intrauterine 
device) in combination with a barrier contraception (eg, male or female condoms, 
diaphragm, spermicide, etc.) from start of plixorafenib administration until 30 days after 
the last plixorafenib administration, and having a negative serum or urine β-hCG 
pregnancy test (with a sensitivity of at least 25 mIU/mL) at screening and check-in. 
 Male participants with female partners of childbearing potential must be sterile (confirmed 
by documented azoospermia 90 days after the procedure) or agree to use (from check-in until 
90 days after discharge) one of the following approved methods of contraception: male 
condom with spermicide; sterile sexual partner (males must still agree to use condom with 
their surgically sterile female partner if unable to provide documentation of partner’s 
sterility); or practice abstinence (abstinence is acceptable only as true abstinence when this is 
in line with the preferred and usual lifestyle of the participant, periodic abstinence won’t be 
allowed); or use of an intrauterine device with spermicide by female sexual partner; a female 
condom with spermicide; a contraceptive sponge with spermicide; an intravaginal system; a 
diaphragm with spermicide; a cervical cap with spermicide; or oral, implantable, transdermal, 
or injectable contraceptives. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 31 
 Male participants must refrain from sperm donation and female participants must refrain 
from egg donation from check-in until 90 days after discharge from the study. 
 The participant agrees to comply with all protocol requirements for the duration of the study. 
4.2 
EXCLUSION CRITERIA 
Participants meeting any of the following criteria will be excluded from the study: 
 The participant has a history of clinically significant drug allergy or anaphylaxis, including 
known hypersensitivity to any components of plixorafenib or cobicistat. 
 The participant has a history of any condition(s) or gastrointestinal surgeries, including 
gallbladder procedures, which might affect drug absorption, metabolism, or excretion. 
 The participant has clinical evidence or a history of clinically significant cardiovascular, 
respiratory, renal, hepatic, gastrointestinal, hematological, neurologic, or other chronic 
disease as judged by the investigator. 
 The participant has a history of psychiatric disease, a suicidal attempt, hospitalization for 
psychiatric disease, a period of disability due to a psychiatric disease, or administers 
treatment to control the condition. Psychiatric disease includes major depression, bipolar 
disorder, or psychosis for ≥3 months. 
 The participant has a history or other evidence of illness, test abnormalities, or any other 
conditions which would make the participant, in the opinion of the investigator, unsuitable 
for the study. 
 The participant has any history of alcoholism or drug abuse, or excessive alcohol 
consumption (regular alcohol intake >21 units per week for male participants and >14 units 
of alcohol per week for female participants) (1 unit is equal to approximately ½ pint 
[200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure [25 mL] of spirits) within 
3 months before screening. 
 The participant has positive results on screen for drugs of abuse or alcohol (Section 6.2.3 
[Other analyses]) at screening visit or Day -1. 
 The participant is a smoker or has used nicotine or nicotine-containing products (eg, snuff, 
nicotine pouch (eg, ZYN), nicotine patch, nicotine chewing gum, mock cigarettes, or vape 
cigarette alternatives, inhalers), marijuana, and cannabinoids within 1 year before the first 
dose of study drug. 
 The participant has donated blood in the past 90 days prior to screening or has poor 
peripheral venous access. 
 The participant has a diagnosis of chronic or acute liver disease, for example, auto-immune, 
alcoholic, or neoplastic liver disease. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 32 
 The participant has positive serostatus for HIV, HCV, or HBV. 
 Male partners of females who are pregnant. 
 Female participant of childbearing potential who is pregnant, lactating, or planning to 
become pregnant within 90 days after the last dose of study drug. 
 The participant has received an investigational drug, biologic, or device within 3 months or 
5 half-lives of the investigational drug (whichever is longer), before receiving study drug. 
 The participant has used any systemic medications, including vitamins and over-the-counter 
items, during the 14 days (or 5 times the elimination half-life of the medication, whichever is 
longer) before receiving study drug or will require their use during the study. Inducers and 
inhibitors of metabolic enzymes and/or transporters (in particular CYP3A inhibitors or 
inducers, P-gp, and BCRP), and herbal preparations, nutritional supplements (eg, St. John’s 
Wort), or foods, including grapefruit juice, grapefruit/grapefruit-related citrus fruits 
(eg, Seville oranges, pomelos), which have been shown to produce metabolic enzyme or 
transporter induction or inhibition, are prohibited before 5 half-lives of the investigational 
drug prior to check-in (Day -1). Paracetamol ≤3000 mg/day will be allowed up to 
2 consecutive days before dosing and during the outpatient phase of the study, as needed. 
 The participant has been on a diet incompatible with the on-study diet, in the opinion of the 
investigator or designee, within 30 days prior to the first dosing and throughout the study.  
 The participant is part of the clinical staff personnel or a family member of the clinical site 
staff. 
4.3 
OTHER SCREENING CONSIDERATIONS 
For coronavirus disease of 2019 screening, Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2) testing will be conducted as per clinical research unit’s policy at the time of 
conduction. 
4.3.1 
Lifestyle Restrictions 
The following lifestyle restrictions will be followed by the participants throughout the study until 
EOS: 
 Participants will abstain from alcohol for 48 hours prior to study drug administration and 
until the last set of laboratory evaluations at EOS. 
 Participants will abstain from smoking and drug use for the duration of the study. List of 
drugs that will be screened at screening and check-in are provided in Section 6.2.3 (Other 
analyses). 
 Foods or herbal preparations, including grapefruit juice, grapefruit/grapefruit-related citrus 
fruits (eg, Seville oranges, pomelos), are prohibited for the duration of the study. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 33 
4.4 
WITHDRAWAL OF PARTICIPANTS FROM THE STUDY 
4.4.1 
Reasons for Withdrawal 
Participants can withdraw consent and discontinue from the study at any time, for any reason, 
without prejudice to further treatment. 
The investigator may withdraw a participant from the study if the participant: 
1. Is non-compliant with the protocol; 
2. Experiences a SAE or intolerable AE(s) that in the investigator’s opinion requires withdrawal 
from the study; 
3. Has laboratory safety assessments that reveal clinically significant hematological or 
biochemical changes from baseline values; 
4. Develops, during the course of the study, symptoms or conditions listed in the exclusion 
criteria; 
5. Requires a medication prohibited by the protocol; or 
6. Requests an early discontinuation for any reason. 
The investigator can also withdraw a participant upon the request of the sponsor, or if the 
sponsor terminates the study. Upon occurrence of an SAE or intolerable AE, the investigator will 
confer with the sponsor. If a participant is discontinued because of an AE, the event will be 
followed until it is resolved, stable, or judged by the investigator to be not clinically significant. 
4.4.2 
Handling of Withdrawals 
Participants are free to withdraw from the study at any time upon request. Participant’s 
participation in the study may be stopped at any time at the discretion of the investigator or at the 
request of the sponsor. 
When a participant withdraws from the study, the reason(s) for withdrawal shall be recorded by 
the investigator on the relevant page of the eCRF. Whenever possible, any participant who 
withdraws from the study prematurely will undergo all EOS assessments. Any participant who 
fails to return for final assessments will be contacted by the site in an attempt to have them 
comply with the protocol. The status of participants who fail to complete final assessments will 
be documented in the eCRF. 
4.4.3 
Replacements 
Any participant who is withdrawn or discontinued from the study may be replaced. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 34 
5. 
STUDY TREATMENTS 
5.1 
TREATMENTS ADMINISTERED 
For Part A, each participant will be randomly assigned to 1 of 6 treatment sequences; the 
sequences will dictate the order in which each participant receives each of the planned 
treatments. Refer to Section 3 for a description of the treatment sequences.  
For Part A, each participant will receive the following study treatments in a crossover design:  
• Treatment 1: 900 mg plixorafenib (6 × 150 mg tablets) administered after overnight fast 
(fasted state). 
• Treatment 2: 900 mg plixorafenib (6 × 150 mg tablets) + cobicistat (1 × 150 mg tablet) 
administered after overnight fast (fasted state). 
• Treatment 3: 900 mg plixorafenib (6 × 150 mg tablets) + cobicistat (1 × 150 mg tablet) 
administered following a high fat, high caloric meal (fed state). 
For Part B, each participant will be randomly assigned to 1 of 4 treatment sequences; the 
sequences will dictate the order in which each participant receives each of the planned 
treatments. Refer to Section 3 for a description of the treatment sequences.  
For Part B, each participant will receive three of the following study treatments per 
randomization in a crossover design:   
• Treatment A: 900 mg plixorafenib (6 × 150 mg tablets) administered after overnight fast 
(fasted state).  
• Treatment B: 900 mg plixorafenib (6 × 150 mg tablets) administered following a high fat, 
high caloric meal (fed state-high fat meal).  
• Treatment C: 900 mg plixorafenib (6 × 150 mg tablets) administered following a low-fat 
meal (fed state-low-fat meal). 
• Treatment D: 900 mg plixorafenib (6 × 150 mg tablets) administered with 150 mg cobicistat 
(1 × 150 mg tablet) following a low-fat meal (fed state-low-fat meal). 
There will be a washout of at least 7 days between dosing in each treatment period. 
5.2 
STUDY DRUGS 
The study drugs that will be used are as follows: 
Product 
Supplied Formulation 
Plixorafenib 
150 mg tablet 
Cobicistat 
150 mg tablet 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 35 
 
Plixorafenib is available as white to off-white oval tablet (uncoated or film-coated tablets) and 
contains the following inactive excipients: HPMCAS, sodium lauryl sulfate, microcrystalline 
cellulose, mannitol, croscarmellose sodium, silicon dioxide, and sodium stearyl fumarate. 
Film-coated tablets also contain titanium dioxide, polyvinyl alcohol, macrogol, and talc. 
Further information on the study drug can be found in the Investigator’s Brochure (Fore 
Biotherapeutics 2023). 
Cobicistat (150 mg) tablet is commercially available and will be supplied or obtained by the 
clinical unit according to the study agreement and in accordance with local guidelines. Refer to 
the prescribing of cobicistat for more details on the formulation, preparation, storage conditions, 
the approved indications, known precautions, warnings, and adverse reactions. Cobicistat will be 
dispensed by the pharmacy staff at the clinical study site. 
5.2.1 
Study Drug Packaging and Storage 
Fore Biotherapeutics will provide the investigator and clinical unit with adequate quantities of 
plixorafenib. Cobicistat will be provided by clinical unit. Detailed instructions for the preparation 
of study treatments will be provided in a separate pharmacy manual. 
All study drugs must be stored according to the labeled instructions in a secure cabinet or room 
with access restricted to necessary clinic personnel. A temperature log to record compliance with 
storage conditions will be required to be maintained at the site. 
Instructions regarding storage and handling of plixorafenib is provided in the pharmacy manual. 
5.2.2 
Study Drug Accountability 
The investigator will maintain accurate records of receipt of all study drugs, including dates of 
receipt. Accurate records will be kept regarding when and how much study drug is dispensed and 
used by each participant in the study. Reasons for departure from the expected dispensing 
regimen must also be recorded. At the completion of the study, and to satisfy regulatory 
requirements regarding drug accountability, all study drugs will be reconciled and retained or 
destroyed according to applicable regulations. 
5.3 
METHOD OF ASSIGNING PARTICIPANTS TO TREATMENT 
GROUPS 
The Contract Research Organization will generate the randomization schedule. Participants who 
meet all inclusion and none of the exclusion criteria will be randomly assigned to one of the 6 
treatment sequences for Part A and one of the 4 treatment sequences for Part B as described in 
Section 3. Randomization numbers (in sequential order) will be assigned before the first dose of 
study drug is administered. There will be no stratification. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 36 
5.4 
BLINDING 
This is an open-label study.  
5.5 
TREATMENT COMPLIANCE 
All doses of the study drug will be administered in the clinical unit under direct observation of 
clinic personnel and recorded in the eCRF. Clinic personnel will confirm that the participant has 
received the entire dose of study drug. 
The date and time of study drug dosing will be recorded on the appropriate page of the eCRF. If 
a participant is not administered study drug, the reason for the missed dose will be recorded. 
5.5.1 
Prior and Concomitant Medications 
Prohibited and/or restricted prior and concomitant medications and therapies are provided in 
Sections 4.2 and 5.5.1.2.1. Prior and concomitant medications and therapies will be coded using 
the latest version of the World Health Organization Drug Dictionary. 
5.5.1.1 
Prior Medications 
Information regarding prior medications taken by the participant within the 30 days before 
signing the ICF will be recorded in the participant’s eCRF. 
5.5.1.2 
Concomitant Medications 
During the study, any concomitant medication deemed necessary for the welfare of the 
participant may be given at the discretion of the investigator. If a concomitant medication is 
taken, except for those specified in the protocol, a joint decision will be made by the investigator 
and the sponsor to continue or discontinue the participant based on the time the medication was 
administered, its pharmacology and PK, the potential for drug interactions, and whether the use 
of the medication will compromise the safety of the participant or the interpretation of the data. 
The investigator is responsible for ensuring that details regarding the medication are adequately 
recorded in the eCRF. 
5.5.1.2.1 
Prohibited Medications 
Agents that are known strong inducers or inhibitors of CYP3A4 are prohibited throughout the 
study. Herbal medications including St. John’s Wort, are prohibited, throughout the study. Agents 
that are contraindicated with cobicistat are prohibited throughout the study. 
6. 
STUDY PROCEDURES 
Before performing any study procedures, all potential participants will sign an ICF as outlined in 
Section 9.2.2.3. Participants will undergo study procedures at the time points specified in the 
SOE (Section 3.3). 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 37 
The total amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 500 mL. 
6.1 
PHARMACOKINETIC AND PHARMACOGENOMICS 
ASSESSMENTS AND ENDPOINTS 
Following administration of the study treatments, participants will have serial blood drawn 
(Part A and Part B) and urine (for Part A only) samples collected for determination of blood and 
urine concentration of plixorafenib. 
Blood PK sample collection timepoints are provided in Table 6-1. 
Table 6-1 
Blood PK Sampling Timepoints 
Study Days 
Timepoints 
D1, D8, D15 
(Dosing) 
D2, D9, D16 
D3, D10, D17 
D4, D11, D18 
D5, D12, D19 
0 hour (0800)* 
✓ (Predose)** 
✓ (24 h) 
✓ (48 h) 
✓ (72 h) 
✓ (96 h) 
0.5 hour (0830) 
✓ 
 
 
 
 
1 hour (0900) 
✓ 
 
 
 
 
2 hour (1000) 
✓ 
 
 
 
 
3 hour (1100) 
✓ 
 
 
 
 
4 hour (1200) 
✓ 
 
 
 
 
6 hour (1400) 
✓ 
 
 
 
 
8 hour (1600) 
✓ 
✓ (32 h) 
 
 
 
10 hour (1800) 
✓ 
 
 
 
 
12 hour (2000) 
✓ 
 
 
 
 
D, day; h, hours  
*Nominal clock time.  
**Predose sample will be collected within 15 minutes prior to the dosing. 0 hour means dosing of study drug. 
 
For Part A only: Prior to the predose sample, each participant will be instructed as to urine 
collection methods. Urine samples for the determination of plixorafenib concentrations and its 
metabolites will be collected at selected time intervals, as specified in the table below. All 
participants will be asked to void their bladder within 45 minutes prior to dosing. After 
administration of plixorafenib, all urine will be collected completely per each collection interval. 
Urine portions will be pooled per participant within this collection interval. Just prior to the end 
of the sampling interval, participants will be encouraged to void their bladder again to complete 
the collection. The start and end times of the urine collection will be recorded. Three aliquot 
(5 mL each) will be obtained from each pooled urine sample: 1 for the quantification of 
plixorafenib, 1 for the metabolite analysis, and 1 as a back-up. Instructions for sample 
preparation and storage can be found in the study lab manual. 
Urine samples for the quantitation of plixorafenib, collection timepoints are in Table 6-2. 
Table 6-2 
Urine Sample Collection Timepoints 
Study Days 
Timepoints 
D1, D8, D15 
(Dosing Day) 
D2, D9, D16 
Predose* 
✓ 
 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 38 
Study Days 
Timepoints 
D1, D8, D15 
(Dosing Day) 
D2, D9, D16 
0-4 hours 
✓ 
 
4-8 hours 
✓ 
 
8-12 hours 
✓ 
 
12-24 hours 
 
✓ 
24-48 hours 
 
✓ 
D, days.  
*45 minutes prior to dosing. 
 
The following PK parameters will be calculated using model-independent approaches (NCA) 
from plixorafenib individual plasma concentrations, whenever practical. 
Plasma Parameters (Part A and B) 
• Area under the plasma concentration versus time curve (AUC) from time 0 to the last 
quantifiable concentration (AUC0-t). 
• AUC from time 0 extrapolated to infinity (AUC0-inf). 
• Maximum observed plasma concentration (Cmax). 
• Time to maximum observed plasma concentration (Tmax). 
• Terminal elimination rate constant (Kel). 
• Terminal phase half-life (t1/2). 
• Apparent oral clearance (CL/F). 
• Apparent volume of distribution (Vd/F). 
• Terminal rate constant calculated from the terminal slope of the log-linear regression of 
concentration with time (z). 
• Calculated lag time: time taken for the drug to appear in the systemic circulation following 
administration, when applicable (Tlag). 
Urine Parameters (Part A Only) 
• Cumulative amount of plixorafenib excreted in urine, calculated as the sum of the product of 
urine concentration and urine volume (Ae) 
• Percent of dose excreted in urine in 48 hours calculated as 100*Ae/Dose 
Blood and urine samples may be used to evaluate the metabolic profile of plixorafenib and the 
results will be described separately. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 39 
Blood and/or plasma samples may be used to measure endogenous biomarkers, such as 
coproporphyrin I, to assess possible transporters inhibition. 
6.1.1 
Pharmacokinetic Sample Collection 
Details for the collection, processing, storage, and shipping of PK samples will be provided to 
the clinical unit separately. 
6.1.2 
Pharmacokinetic Sample Analysis 
Plasma samples for the quantitation of plixorafenib will be analyzed using a validated liquid 
chromatography coupled with tandem mass spectrometry assay (LC/MS/MS method) for 
plixorafenib in human plasma. Assay results and validation details will be provided in a separate 
bioanalytical report. A qualified assay will be used to quantitate plixorafenib urine 
concentrations. An exploratory assay will be used for metabolite identification in plasma and 
urine.  
6.1.3 
Pharmacogenomic Sample Analysis 
A blood sample for pharmacogenomic evaluation will be collected at screening. Possible effect 
of pharmacogenomic variations on the PK of plixorafenib and/or the effect of cobicistat, 
including but not limited to polymorphisms in P-gp, BCRP, and UGT, will be examined, if 
feasible.  
6.2 
SAFETY ASSESSMENTS AND ENDPOINTS 
Safety will be assessed by the following: monitoring and recording of AEs, clinical laboratory 
test results (hematology, serum chemistry, and urinalysis), vital sign measurements, 12-lead ECG 
results, and physical examination findings. 
For all safety assessments, the investigator will determine whether results are clinically 
significant, which is defined as any variation in a result that has medical relevance or may result 
in an alteration in medical care (eg, active observation, diagnostic measures, or therapeutic 
measures). If clinical significance is noted, the result and reason for significance will be 
documented and an AE reported on the AE page of the participant’s eCRF. The investigator will 
monitor the participant until the result has reached the reference range or the result at screening, 
or until the investigator determines that follow-up is no longer medically necessary. 
6.2.1 
Sponsor Communication 
The sponsor Medical Monitor will be contacted as quickly as possible for Grade 2 or above 
changes in blood AST, ALT, GGT, bilirubin (total or fractionated), or creatinine, or ≥ Grade 3 
laboratory abnormalities or adverse events. Communication with the sponsor Medical Monitor 
should not delay immediate management of the participant. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 40 
6.2.2 
Adverse Events 
Adverse events will be assessed from the time the participant signs the ICF until EOS and should 
be followed until they are resolved, stable, or judged by the investigator to be not clinically 
significant. 
The investigator is responsible for ensuring that all AEs and SAEs are recorded in the eCRF and 
reported to the sponsor, regardless of their relationship to study drug or clinical significance. If 
there is any doubt as to whether a clinical observation is an AE, the event should be reported. 
6.2.2.1 
Adverse Event Definitions 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. Participants will be instructed to contact the 
investigator at any time after randomization if any symptoms develop. 
A TEAE is defined as any event not present before exposure to study drug or any event already 
present that worsens in intensity or frequency after exposure. TEAE will be assessed from first 
dose of study drug until EOS and should be followed until they are resolved, stable, or judged by 
the investigator to be not clinically significant. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the study 
drug caused the AE. For the purposes of investigational new drug safety reporting, “reasonable 
possibility” means that there is evidence to suggest a causal relationship between the study drug 
and the AE. A suspected adverse reaction implies a lesser degree of certainty about causality than 
an adverse reaction. 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or if it occurs with specificity or severity that has not been previously 
observed with the study drug being tested; or, if an investigator brochure is not required or 
available, the AE or suspected adverse reaction is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. For 
example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the investigator brochure referred only to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the investigator brochure listed only cerebral vascular accidents. 
“Unexpected,” as used in this definition, also refers to AEs or suspected adverse reactions that 
are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug but are not specifically mentioned as occurring 
with the particular drug under investigation. 
An AE is considered an SAE/suspected unexpected serious adverse reaction if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: 
• Death 
• Life-threatening AE 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 41 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• Congenital anomaly or birth defect 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
An AE or suspected adverse reaction is considered “life threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the participant at immediate risk of death. It does 
not include an AE or suspected adverse reaction that might have caused death if it had been more 
severe. 
6.2.2.2 
Eliciting and Documenting Adverse Events 
Participants will be asked a standard question to elicit any medically related changes in their 
well-being. They will also be asked if they have been hospitalized, had any accidents, used any 
new medications, or changed concomitant medication regimens (both prescription and over-the-
counter medications). 
In addition to participant’s observations, AEs will be documented from any data collected on the 
AE page of the eCRF (eg, laboratory values, physical examination findings, and ECG changes) 
or other documents that are relevant to participant safety. 
6.2.2.3 
Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page of the eCRF. 
Information to be collected includes drug treatment, type of event, time of onset, dosage, 
investigator-specified assessment of severity, seriousness, and relationship to study drug, time of 
resolution of the event, seriousness, any required treatment or evaluations, and outcome. Any 
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must also be reported. All AEs will be followed 
until they are resolved, stable, or judged by the investigator to be not clinically significant. The 
Medical Dictionary of Regulatory Activities will be used to code all AEs. 
Any medical condition that is present at the time that the participant is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 42 
Any AE that is considered serious by the investigator or which meets SAE criteria 
(Section 6.2.2.1) must be reported to the sponsor immediately (after the investigator has 
confirmed the occurrence of the SAE). The investigator will assess whether there is a reasonable 
possibility that the study drug caused the SAE. The sponsor will be responsible for notifying the 
relevant regulatory authorities of any SAE as outlined in US Title 21 CFR Parts 312 and 320. 
The investigator is responsible for notifying the IRB directly. 
For this study, the following contact information will be used for SAE reporting: 
ICON Drug Safety 
ICON-Safety-CentralReceipt@iconplc.com 
Fax: +44 (0) 208 100 5005 
6.2.2.4 
Assessment of Severity 
Seriousness (Section 6.2.2.1) and severity of an event are not synonymous. The severity (or 
intensity) of an AE refers to the extent to which it affects the participant’s daily activities and will 
be classified as mild, moderate, or severe using the following criteria: 
• Mild: These events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
• Moderate: These events result in a low level of inconvenience or require minor therapeutic 
measures. Moderate events may cause some interference with normal functioning. 
• Severe: These events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 
Changes in the severity of an AE should be documented to allow the duration of the event at each 
level of intensity to be assessed. An AE characterized as intermittent does not require 
documentation of the onset and duration of each episode.  
The Common Toxicity Criteria for Adverse Events (CTCAE) V5.0 grading criteria will also be 
used for assessment of severity of AEs. 
6.2.2.5 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the documentation 
process but is not a factor in determining what is or is not reported in the study. 
The investigator will assess causality (ie, whether there is a reasonable possibility that the study 
drug caused the event) for all AEs and SAEs. The relationship will be classified as follows: 
• Not related: The adverse event is considered unrelated to the study drug. 
o Another cause of the event is most plausible, or 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 43 
o Clinically plausible temporal sequence is inconsistent with the onset of the event and 
the study treatment administration 
o A causal relationship is considered biologically implausible 
• Possibly related: Based on evidence suggesting a causal relationship between the study drug 
and the AE, there is a reasonable possibility that the drug caused the event. The event follows 
a reasonable temporal sequence from the time of drug administration or follows a known 
response pattern to the study drug, but could also have been produced by other factors. 
• Probably related: A reasonable temporal sequence of the event with drug administration 
exists and, based upon the known pharmacological action of the drug, known or previously 
reported adverse reactions to the drug or class of drugs, or judgment based on the 
investigator’s clinical experience, association of the event with the study drug seems likely. 
6.2.2.6 
Adverse Event of Special Interest 
The following are AESIs for this study: 
• Grade ≥2 increased bilirubin 
• Grade ≥2 increased ALT 
• Grade ≥2 increased AST 
The sponsor Medical Monitor will be notified promptly of AESIs. AESIs will be reported using 
the same process as for AEs. 
6.2.2.7 
Follow-up of Adverse Events 
All AEs must be reported in detail on the appropriate page of the eCRF and followed until they 
are resolved, stable, or judged by the investigator to be not clinically significant. 
6.2.3 
Clinical Laboratory Testing 
Clinical laboratory testing will occur at screening, check-in, predose within 2 hours on each 
dosing day (Days 1, 8, and 15) (for Part B only), 3 days from dosing (Day 4, 11, 18), and at EOS. 
Clinical laboratory tests will be performed by the PPD Central Laboratory. Blood and urine 
samples will be collected under fasting conditions and will be prepared using standard 
procedures. If any concerning trends are seen during study, investigator can order additional 
testing for safety on PRN basis. 
Repeat clinical laboratory tests may be performed at the discretion of the investigator, if 
necessary, to evaluate inclusion and exclusion criteria or clinical laboratory abnormalities. The 
clinical laboratory that will perform the tests will provide the reference ranges for all clinical 
laboratory parameters. Abnormal clinical laboratory values will be flagged as either high or low 
(or normal or abnormal) based on the reference ranges for each laboratory parameter. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 44 
The following clinical laboratory assessments will be performed: 
Hematology 
Absolute neutrophil count and differential, hematocrit, hemoglobin, 
mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, leukocytes-absolute counts and percentages (basophils, 
eosinophils, lymphocytes, monocytes, neutrophils), mean corpuscular 
volume, platelet count, red blood cell count, and red cell distribution 
width 
Serum Chemistry 
Alanine aminotransferase, albumin, alkaline phosphatase, aspartate 
aminotransferase, bilirubin (total + indirect and direct fractions), blood 
urea nitrogen, calcium, carbon dioxide, chloride, creatinine, 
gamma-glutamyltransferase, globulin, glucose, lactate dehydrogenase, 
phosphorus, potassium, sodium, total protein, uric acid, and creatine 
kinase 
Urinalysis 
Appearance, bilirubin, color, glucose, ketones, leukocytes, reflex 
microscopy (performed if dipstick is positive for protein or the blood 
value is 1+ or greater; and includes bacteria, casts, crystals, epithelial 
cells, red blood cells, and white blood cells), nitrites, occult blood, pH, 
protein, specific gravity, turbidity, and urobilinogen 
Serology 
Hepatitis B surface antigen, hepatitis C virus antibody, and human 
immunodeficiency virus antibody types 1 and 2 (screening only) 
Other analyses 
All participants: Urine drug screen (alcohol, amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine metabolites, 
cotinine, methamphetamines, methylenedioxymethamphetamine, and 
opiates [including heroin, codeine, and oxycodone]) 
Female participants: Follicle-stimulating hormone, urine pregnancy 
test/ serum pregnancy test (human chorionic gonadotropin)  
 
 
6.2.4 
Vital Sign Measurements 
Vital signs will be measured at screening and check-in; within 60 to 90 minutes prior to 
plixorafenib dosing in each period; on each study day; and at EOS after the participant has been 
in the seated position for at least 5 minutes.  
Vital signs will include systolic and diastolic blood pressure, pulse rate, respiratory rate, and 
body temperature. 
6.2.5 
Electrocardiograms 
Single 12-lead ECG recordings will be made at screening, each dosing day (Days 1, 8, and 15)-
predose within 2 hours, and at EOS after the participant has been in the supine position for at 
least 5 minutes. A single repeat measurement is permitted at screening for eligibility 
determination.  
ECG assessments will include comments on whether the tracings are normal or abnormal, 
rhythm, presence of arrhythmia or conduction defects, morphology, any evidence of myocardial 
infarction, or ST-segment, T-Wave, and U-Wave abnormalities. In addition, measurements of the 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 45 
following intervals will be measured and reported: RR interval, PR interval, QRS width, QT 
interval, and QT interval corrected for heart rate using Fridericia’s formula. 
6.2.6 
Physical Examinations 
Physical examinations will be performed at screening, check-in, at each dosing day (Days 1, 8, 
15), and at EOS (Day 19). 
A full physical examination will be performed at screening and check-in. A symptom-driven 
physical examination may be performed at other times, at the investigator’s or designee’s 
discretion. 
A full physical examination will include, at minimum, assessment of skin, head, ears, eyes, nose, 
throat, neck, thyroid, lungs, heart, cardiovascular, abdomen, lymph nodes, and musculoskeletal 
system/extremities. A brief physical examination will include, at minimum, assessment of skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). Interim physical examinations 
may be performed at the discretion of the investigator, if necessary, to evaluate AEs or clinical 
laboratory abnormalities. 
7. 
STATISTICAL ANALYSIS PLANS 
7.1 
SAMPLE SIZE CALCULATIONS 
The number of participants is based on clinical and practical considerations and not on a formal 
statistical power calculation. The total sample size of 12 participants in Part A and 16 participants 
in Part B is considered sufficient for the objectives of the study. 
7.2 
ANALYSIS SETS 
The analysis populations are as follows: 
• The PK population will include participants who receive at least 1 dose of plixorafenib with 
or without cobicistat and have sufficient concentration data to support accurate estimation of 
at least 1 PK parameter. Participants who experience vomiting within 2 times the median 
Tmax after study drug dosing will be excluded from the PK analysis. 
• The safety population will include all participants who receive at least 1 dose plixorafenib 
with or without cobicistat. 
7.3 
STATISTICAL ANALYSIS 
Details of all statistical analyses will be described in a statistical analysis plan. All data collected 
will be presented in data listings. Data from participants excluded from an analysis population 
will be presented in the data listings, but not included in the calculation of summary statistics. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 46 
For categorical variables, frequencies and percentages will be presented. Continuous variables 
will be summarized using descriptive statistics (number of participants, mean, median, SD, 
minimum, and maximum). 
Baseline demographic and background variables will be summarized overall for all participants. 
The number of participants who enroll in the study and the number and percentage of 
participants who complete the study will be presented. Frequency and percentage of participants 
who withdraw or discontinue from the study, and the reason for withdrawal or discontinuation, 
will also be summarized. 
7.3.1 
Pharmacokinetic Analyses 
Individual plasma concentration and time deviation data will be presented in a data listing. 
Plasma concentration data will be summarized by time point for each treatment (plixorafenib 
alone in fasted state, plixorafenib + cobicistat in fasted state or plixorafenib + cobicistat in fed 
state) using the following descriptive statistics: number of participants, arithmetic mean, SD, CV, 
geometric mean, geometric CV, median, minimum, and maximum. Individual and mean plasma 
concentration versus scheduled time profiles will be presented in figures on both linear and 
semilogarithmic scales. 
The PK parameters of plixorafenib will be determined using noncompartmental methods based 
on the actual sampling times. All parameters will be calculated using Phoenix® WinNonlin® 
(Certara USA Inc., Princeton, New Jersey) Version 8.3 or higher. The individual PK parameters 
will be presented in data listings and summarized by treatment using the following descriptive 
statistics: number of participants, mean, SD, CV, median, minimum, and maximum. Geometric 
means will be included for AUC0-t, AUC0-inf, and Cmax. 
If warranted, a linear mixed model with treatment as a fixed effect and participant as a random 
effect will be performed on the natural log-transformed values of AUC0-t, AUC0-inf, and Cmax to 
assess the effect of cobicistat and/or food on the PK of plixorafenib. The geometric least squares 
means and corresponding 90% CIs will be computed for AUC0-t, AUC0-inf, and Cmax of 
plixorafenib administered alone (Reference Treatment) versus plixorafenib with cobicistat and/or 
food (Test Treatments) by taking the antilog of the least squares means from the linear mixed-
effect model on the natural logarithms of the corresponding PK parameters. A 90% CI for the 
ratio will be constructed as the antilog of the confidence limits of the mean difference.  
It will be concluded that there is no relevant interaction of cobicistat or food on plixorafenib if 
the 90% CIs for AUC0-t, AUC0-inf, and Cmax ratios of the Reference Treatment to the Test 
Treatments are completely contained within the (80%, 125%) interval. 
The statistical analysis plan will include a more detailed description of these analyses. 
7.3.2 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class using the latest version of 
MedDRA. All AE data will be presented in a data listing. TEAEs will be summarized by 
treatment and overall, as well as by severity, seriousness, and relationship to study drug. Serious 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 47 
AEs and AEs leading to discontinuation of study drug will also be presented in the data listings 
and summarized by treatment and overall. 
Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized by treatment at each time point 
using descriptive statistics (number of participants, mean, SD, median, minimum, and 
maximum). Physical examination findings will be presented in a data listing. 
For safety analysis, unless stated otherwise, baseline will be defined as the last nonmissing 
assessment (including repeat and unscheduled assessments) predose for each period. An overall 
baseline for by-sequence analysis will be defined as the last value prior to Day 1 dose. 
7.3.3 
Other Analyses 
Evaluation of the metabolic profile of plixorafenib in plasma (Parts A and B) and urine (Part A 
only) will be conducted and the results will be reported separately. 
For Part A and Part B, possible effect of pharmacogenomic variations on the PK of plixorafenib 
and/or the effect of cobicistat, including, but not limited to, polymorphisms in P-gp, BCRP, and 
UGT, will be examined, if feasible. 
7.4 
HANDLING OF MISSING DATA 
Missing data will not be interpolated or extrapolated. 
7.5 
INTERIM ANALYSES 
No formal interim analyses will be performed in this study. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 48 
8. 
REFERENCE LIST 
Department of Health and Human Services, Food and Drug Administration (DHHS), Center for 
Drug Evaluation and Research (US). Guidance for industry: Assessing the effects of food on 
drugs in INDs and NDAs — clinical pharmacology considerations. June 2022. [cited 2024 Jan 
25] [12 screens] Available from: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/assessing-effects-food-drugs-inds-and-ndas-clinical-pharmacology-
considerations 
Department of Health and Human Services (DHHS), Food and Drug Administration, Center for 
Drug Evaluation and Research, Center for Biologics Evaluation and Research (US). Guidance 
for Industry: Clinical Drug Interaction Studies—Study Design, Data Analysis, and Clinical 
Implications.  October 2017 [cited 25 Jan 2018] [29 screens]. Available from: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM292362.pdf 
Fore Biotherapeutics. Plixorafenib. Investigator’s Brochure. 8th Ed, 2024. 
Koumaki K, Kontogianni G, Kosmidou V, et al. BRAF paradox breakers PLX8394, PLX7904 
are more effective against BRAFV600Ε CRC cells compared with the BRAF inhibitor PLX4720 
and shown by detailed pathway analysis. Biochim Biophys Acta Mol Basis Dis. 
2021;1867(4):166061. doi: 10.1016/j.bbadis.2020.166061. 
Prezcobix® (darunavir and cobicistat) tablets. Prescribing information. Janssen Pharmaceutical 
Companies; 2023.  
Tybost® (cobicistat). Package insert. Gilead Sciences; 2021. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 49 
9. 
APPENDICES 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS 
Abbreviation 
Term 
z 
terminal rate constant calculated from the terminal slope of the log-
linear regression of concentration with time 
e 
cumulative amount of plixorafenib excreted in urine 
ADR 
adverse drug interactions 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC0-inf 
area under the plasma concentration versus time curve from time 0 
extrapolated to infinity 
AUC0-t 
area under the plasma concentration versus time curve from time 0 to 
the last quantifiable concentration 
BCRP 
Breast cancer resistance protein 
β-hCG 
beta-subunit human gonadotropin 
BMI 
body mass index 
BSEP 
bile salt export pump 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL/F 
apparent oral clearance 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DLT 
dose limiting toxicity 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
EOS 
end of study 
ERK 
extracellular signal-regulated kinase 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GLP 
good laboratory practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HME 
hot-melt extrusion 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 50 
Abbreviation 
Term 
ICH 
International Council for Harmonisation 
IRB 
institutional review board 
LCH 
Langerhans cell histiocytosis 
MAPK 
mitogen-activated protein kinase 
MATE 
multidrug and toxin extrusion transporter 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
MAPK/ERK kinase 
MRP 
multidrug resistance associated protein 
NCA 
Noncompartmental analysis  
NOAEL 
no-observed-adverse-effect levels 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptide 
OCT 
organic cation transporter 
PK 
pharmacokinetic(s) 
P-gp 
P-glycoprotein 
PRN 
as needed 
QTcF 
QT correction (Fridericia) 
RAF 
rapidly accelerated fibrosarcoma 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SDD 
spray-dried dispersion 
SOE 
schedule of events 
t1/2 
terminal phase half-life 
TEAE 
treatment-emergent adverse events 
Tmax 
time to maximum observed plasma concentration 
UGT 
uridine diphosphate (UDP)-glucuronosyltransferases 
ULN 
upper limit of normal 
Vd/F 
apparent volume of distribution 
 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 51 
9.2 
APPENDIX 2: STUDY GOVERNANCE 
9.2.1 
Data Quality Assurance 
This study will be conducted using the quality processes described in applicable procedural 
documents. The quality management approach to be implemented will be documented and will 
comply with current ICH guidance on quality and risk management. All aspects of the study will 
be monitored for compliance with applicable government regulatory requirements, current Good 
Clinical Practice, the protocol, and standard operating procedures. The monitor will maintain 
current personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the investigator and staff. 
Electronic CRFs and electronic data capture will be utilized. The electronic data capture system 
is validated and compliant with US Title 21 CFR Part 11. Each person involved with the study 
will have an individual identification code and password that allows for record traceability. 
Important protocol deviations, should they occur during the study, will be presented in Section 
10.2 of the clinical study report. 
9.2.2 
Investigator Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study and may be participant to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB but 
will not result in protocol amendments. 
9.2.2.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participant confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the participant, except as necessary for monitoring and auditing by the sponsor, its 
designee, the FDA, or the IRB. 
The investigator and all employees and coworkers involved with this study may not disclose or 
use for any purpose other than performance of the study, any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from the sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties. 
9.2.2.2 
Institutional Review 
Federal regulations and ICH guidelines require that approval be obtained from an IRB before 
participation of human participants in research studies. Before study onset, the protocol, ICF, 
advertisements to be used for the recruitment of study participants, and any other written 
information regarding this study that is to be provided to the participants must be approved by 
the IRB. Documentation of all IRB approvals and of the IRB compliance with the ICH 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 52 
harmonised tripartite guideline E6(R2): Good Clinical Practice will be maintained by the site and 
will be available for review by the sponsor or its designee. 
All IRB approvals should be signed by the IRB chairman or designee and must identify the IRB 
name and address, the clinical protocol by title or protocol number or both, and the date approval 
or a favorable opinion was granted. 
9.2.2.3 
Participant Consent 
Written informed consent in compliance with US Title 21 CFR Part 50 shall be obtained from 
each participant before he or she enters the study or before performing any unusual or nonroutine 
procedure that involves risk to the participant. If any institution-specific modifications to 
study-related procedures are proposed or made by the site, the consent should be reviewed by the 
sponsor or its designee or both before IRB submission. Once reviewed, the investigator will 
submit the ICF to the IRB for review and approval before the start of the study. If the ICF is 
revised during the course of the study, all active participating participants must sign the revised 
form. 
Before recruitment and enrollment, each prospective participant will be given a full explanation 
of the study and will be allowed to read the approved ICF. Once the investigator is assured that 
the participant understands the implications of participating in the study, the participant will be 
asked to give his or her consent to participate in the study by signing the ICF. A copy of the ICF 
will be provided to the participant. 
9.2.2.4 
Study Reporting Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs according to the 
time line and method outlined in this protocol. In addition, the investigator agrees to submit 
annual reports to his or her IRB as appropriate. 
9.2.2.5 
Financial Disclosure and Obligations 
The investigator is required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under US Title 
21 CFR Part 54. In addition, the investigator must provide to the sponsor a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the sponsor nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the absence 
of specific arrangements, neither the sponsor nor PPD is financially responsible for further 
treatment of the disease under study. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 53 
9.2.2.6 
Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R2) Section 
8.2 and US Title 21 of the CFR by providing essential documents, including but not limited to, 
the following: 
• IRB approval 
• An original investigator-signed investigator agreement page of the protocol, 
• Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 1572 
• Curriculum vitae for the principal investigator and each subinvestigator listed on Form 
FDA 1572. Current licensure must be noted on the curriculum vitae. Curriculum vitae will be 
signed and dated by the principal investigators and subinvestigators at study start-up, 
indicating that they are accurate and current. 
• Financial disclosure information for the principal investigator and each subinvestigator listed 
on Form FDA 1572 to allow the sponsor to submit complete and accurate certification or 
disclosure statements required under US Title 21 CFR Part 54. In addition, the investigators 
must provide to the sponsor a commitment to promptly update this information if any 
relevant changes occur during the course of the investigation and for 1 year after the 
completion of the study. 
• An IRB-approved ICF, samples of site advertisements for recruitment for this study, and any 
other written information about this study that is to be provided to the participant 
• Laboratory certifications and reference ranges for any local laboratories used by the site, in 
accordance with US Title 42 CFR Part 493 
9.2.2.7 
Study Conduct 
The investigator agrees to perform all aspects of this study in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, ICH E6(R2): Good Clinical 
Practice; the protocol; and all national, state, and local laws or regulations. 
9.2.2.8 
Case Report Forms and Source Documents 
Site personnel will maintain source documentation, enter participant data into the eCRF as 
accurately as possible, and will rapidly respond to any reported discrepancies. 
Electronic CRFs and electronic data capture will be utilized. The electronic data capture system 
is validated and compliant with US Title 21 CFR Part 11. Each person involved with the study 
will have an individual identification code and password that allows for record traceability. Thus, 
the system, and any subsequent investigative reviews, can identify coordinators, investigators, 
and individuals who have entered or modified records, as well as the time and date of any 
modifications. There may be an internal quality review audit of the data and additional reviews 
by the clinical monitor. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 54 
Each eCRF is presented as an electronic copy, allowing data entry by site personnel, who can add 
and edit data, add new participants, identify and resolve discrepancies, and view records. This 
system provides immediate direct data transfer to the database, as well as immediate detection of 
discrepancies, enabling site coordinators to resolve and manage discrepancies in a timely 
manner. 
Paper copies of the eCRFs and other database reports may be printed and signed by the 
investigator. This system provides site personnel, monitors, and reviewers with access to 
hardcopy audits, discrepancy reviews, and investigator comment information. 
9.2.2.9 
Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol, in accordance with ICH 
E6(R2) and all applicable guidelines and regulations. 
9.2.2.10 
Reporting Adverse Events 
By participating in this study, the investigator agrees to submit reports of SAEs according to the 
timeline and method outlined in this protocol. In addition, the investigator agrees to submit 
annual reports to his or her IRB as appropriate. The investigator also agrees to provide the 
sponsor with an adequate report, if applicable, shortly after completion of the investigator’s 
participation in the study. 
9.2.2.11 
Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the institution; 
the investigator/institution should provide the IRB with a summary of the study’s outcome and 
the sponsor and regulatory authorities with any reports required. 
9.2.2.12 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug. These documents should be retained 
for a longer period, however, if required by applicable regulatory requirements or by an 
agreement with the sponsor. The sponsor is responsible for informing the investigator/institution 
when these documents no longer need to be retained. 
9.2.2.13 
Publications 
After completion of the study, the data may be considered for reporting at a scientific meeting or 
for publication in a scientific journal. In these cases, the sponsor will be responsible for these 
activities and will work with the investigators to determine how the manuscript is written and 
edited, the number and order of authors, the publication to which it will be submitted, and any 
other related issues. The sponsor has final approval authority over all such issues. 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 55 
Data are the property of the sponsor and cannot be published without their prior authorization, 
but data and any publication thereof will not be unduly withheld. 
9.2.3 
Study Management 
9.2.3.1 
Monitoring 
9.2.3.1.1 
Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, is obligated to follow the study closely. 
In doing so, the monitor will visit the investigator and study site at periodic intervals in addition 
to maintaining necessary telephone and email contact. The monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the investigator and staff. 
All aspects of the study will be carefully monitored by the sponsor or its designee for compliance 
with applicable government regulation with respect to current ICH E6(R2) guidelines and 
standard operating procedures. 
9.2.3.1.2 
Inspection of Records 
The investigator and institution involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. In 
the event of an audit, the investigator agrees to allow the sponsor, their representatives, the FDA, 
or other regulatory agencies access to all study records. 
The investigator should promptly notify the sponsor and study site(s) of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
9.2.3.2 
Management of Protocol Amendments and Deviations 
9.2.3.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent immediate 
hazard to the participant, must be reviewed and approved by the sponsor or designee. 
Amendments to the protocol must be submitted in writing to the investigator’s IRB for approval 
before participants are enrolled into an amended protocol. 
9.2.3.2.2 
Protocol Deviations 
The investigator or designee must document and explain in the participant’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change to, the protocol to eliminate an immediate hazard to study 
participants without prior IRB approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 

Fore Biotherapeutics 
Plixorafenib 
Protocol No. F8394-101 
Protocol Amendment 1, 03Oct2024 
 
CONFIDENTIAL 
Page 56 
should be submitted to the IRB for review and approval, to the sponsor for agreement, and to the 
regulatory authorities, if required. 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol. An important deviation (sometimes referred to as a major or significant 
deviation) is a subset of protocol deviations that leads to a participant being discontinued from 
the study, or significantly affects the participant’s rights, safety, or well-being and/or the 
completeness, accuracy, and reliability of the study data. An important deviation can include 
nonadherence to inclusion or exclusion criteria or nonadherence to FDA regulations or ICH 
E6(R2) guidelines. 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. The investigator will be notified in writing by the monitor of deviations. The 
IRB should be notified of all protocol deviations, if appropriate, in a timely manner. 
9.2.3.3 
Study Termination 
Although the sponsor has every intention of completing the study, they reserve the right to 
discontinue it at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last participant completes the last visit 
(including the EOS visit and any additional long-term follow-up). Any additional long-term 
follow-up that is required for monitoring of the resolution of an AE or finding may be appended 
to the clinical study report. 
9.2.3.4 
Final Report 
Regardless of whether the study is completed or prematurely terminated, the sponsor will ensure 
that clinical study reports are prepared and provided to regulatory agency(ies) as required by the 
applicable regulatory requirement(s). The sponsor will also ensure that clinical study reports in 
marketing applications meet the standards of the ICH harmonised tripartite guideline E3: 
Structure and content of clinical study reports. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the opportunity 
to review complete study results. 
Upon completion of the clinical study report, the investigator(s) will be provided with the final 
approved clinical study report, as appropriate.