A Phase 2/3 Study to Evaluate the Efficacy and Safety of Unesbulin in Unresectable or Metastatic, Relapsed or Refractory Leiomyosarcoma
Phase: PHASE2
Conditions: Leiomyosarcoma
Sponsor: PTC Therapeutics

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TITLE PAGE 
CLINICAL STUDY PROTOCOL 
Protocol Number: 
PTC596-ONC-008-LMS 
Protocol Title: 
A Phase 2/3 Study to Evaluate the Efficacy and Safety of 
Unesbulin in Unresectable or Metastatic, Relapsed or Refractory 
Leiomyosarcoma 
Name of Study 
Intervention: 
Unesbulin 
Study Phase: 
Phase 2/3 
Approval Date: 
V1.0 
20 December 2021 
V2.0 
31 January 2022 
V3.0 
28 April 2023 
V4.0 
28 November 2023 
IND Number: 
122916 
EudraCT Number: 
2022‐000073‐12 
ClinicalTrials.gov: 
NCT05269355 
Sponsor:  
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, 
New Jersey 07080 
USA 
Notice of Proprietary Information: This document contains confidential information owned by or in the 
possession/control of PTC Therapeutics, Inc. Except as may otherwise be permitted in writing, by accepting or 
reviewing these materials, you agree that this information should not be disclosed to others (except where required by 
applicable law) and should not be used for unauthorized purposes. In the event of an actual or suspected breach of this 
obligation, PTC Therapeutics, Inc. should be notified promptly. 
NCT #: NCT05269355

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PROTOCOL IDENTIFIERS AND STUDY PERSONNEL 
Project Code 
PTC596-ONC 
Therapeutic Area 
Oncology 
PTC Therapeutics Substance Identifier 
PTC596 
International Nonproprietary Name 
Unesbulin 
Protocol Number 
PTC596-ONC-008-LMS 
Protocol Version 
4.0 
Protocol Version Date 
28 November 2023 
Protocol Phase 
2/3 
Protocol Title 
A Phase 2/3 Study to Evaluate the Efficacy and Safety of 
Unesbulin in Unresectable or Metastatic, Relapsed or 
Refractory Leiomyosarcoma 
 
 
PTC Clinical Lead / Medical Monitor 
 
 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
Mobile: 
 
Email: 
 
 
PTC Back-up Medical Monitor 
 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
PTC Telephone (office): 
 
Mobile: 
 
Email:
 
 
PTC Biostatistician 
 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
Telephone (office): 
 
Email: 
 
 
PTC Study Manager 
 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
Mobile: 
  
Email: 
 

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SIGNATURE PAGE 
Sponsor’s Approval 
The protocol has been approved by PTC Therapeutics. 
 
Responsible Medical Officers: 
 
 
 
PTC Therapeutics, Inc. 
 
 
 
 
Date 
 
 
PTC Therapeutics, Inc. 
 
 
 
 
Date 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The eSignature page is located on the last page. 

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INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for unesbulin (PTC596). I have read the 
PTC596-ONC-008-LMS protocol and agree to conduct the study as outlined. I agree to maintain 
the confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 

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SYNOPSIS 
Name of Sponsor/Company: PTC Therapeutics, Inc. 
Name of Investigational Product: Unesbulin (PTC596) 
Name of Active Ingredient: 5-fluoro-2-(6-fluoro-2-methyl-1H-benzo[d]imidazole-1-yl)-N4-
(4-(trifluoromethyl)phenyl)pyrimidine-4,6-diamine 
Protocol Number: PTC596-ONC-008-LMS 
Phase: 2/3 
Country: Global 
Title of Study: A Phase 2/3 Study to Evaluate the Efficacy and Safety of Unesbulin in 
Unresectable or Metastatic, Relapsed or Refractory Leiomyosarcoma 
Studied Period (years): The study period will be approximately 4 years. 
Objectives:  
Primary: 
• Progression-free survival (PFS) of unesbulin plus dacarbazine (DTIC) versus placebo 
plus DTIC 
Secondary: 
Efficacy: 
• Overall survival (OS) of subjects treated with unesbulin plus DTIC versus placebo plus 
DTIC 
• Antitumor activity of unesbulin plus DTIC versus placebo plus DTIC 
Safety: 
• Safety and tolerability of unesbulin plus DTIC versus placebo plus DTIC 
Exploratory: 
Efficacy: 
• Evaluate the antitumor activity of unesbulin plus DTIC versus placebo plus DTIC in 
subjects with at least 4 prior lines of treatment 
Pharmacokinetics (PK): 
• Evaluate the PK of unesbulin in the presence of DTIC in subjects with leiomyosarcoma 
(LMS) 
• Evaluate the PK of DTIC/5-amino-imidazole-4-carboxamide (AIC) alone and in the 
presence of unesbulin in subjects with LMS 
Patient-reported outcomes (PROs): 
• Compare the effect of unesbulin plus DTIC versus placebo plus DTIC on PROs, 
including health-related quality-of-life (HRQoL) assessments 
Biomarkers: 
• Measure genotype of subject tumors, assessed by blood sampling, at baseline and 
posttreatment 
Endpoints: 
Primary: 
• PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by an 
independent central imaging laboratory 
Secondary: 
Efficacy: 
The key secondary endpoint is OS. 
Other secondary efficacy endpoints: 
• Objective response rate (ORR; proportion of subjects with best overall response [BOR] 
of either complete response [CR] or partial response [PR]) 

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• Disease control rate (DCR) or clinical benefit rate (CBR), defined as the proportion of 
subjects with BOR of CR, PR, or at least 3 months of stable disease (SD) 
• Duration of response (DoR) 
Safety: 
• Vital signs, physical examination, electrocardiograms (ECG), laboratory abnormalities, 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores, and 
adverse events (AEs) 
Exploratory: 
Efficacy: 
• PFS, OS, ORR, DCR, and DoR in subjects with at least 4 prior lines of treatment 
PK: 
• PK parameters of unesbulin in subjects who receive unesbulin plus DTIC: Cmax, Tmax, 
and area under the concentration versus time curve from time zero to the last sampled 
time or the last non-zero concentration (AUC0-t) 
• PK parameters of DTIC and its inactive metabolite AIC in subjects who receive 
unesbulin plus DTIC and placebo plus DTIC: Cmax, Tmax, and AUC0-t 
PROs: 
• 30-item score European Organisation for the Research and Treatment of Cancer 
Quality-of-Life Questionnaire (EORTC QLQ-C30) 
• EuroQol 5-level EQ-5D version (EQ-5D-5L) 
Biomarkers: 
• Genetic evaluation of the tumors by analyzing circulating cell-free tumor DNA 
(ccfDNA)  
Study Design and Methodology: 
This is an international, multicenter, randomized, double-blind, placebo-controlled, Phase 2/3 
study to compare the safety and efficacy of unesbulin plus DTIC versus placebo plus DTIC in 
subjects with unresectable or metastatic, relapsed or refractory LMS who have received at 
least 1 prior line of systemic therapy. 
Eligible subjects will be randomized 2:1 (unesbulin plus DTIC: placebo plus DTIC) to one of 
the following treatment groups: 
• Unesbulin plus DTIC: Unesbulin 300 mg will be administered PO twice weekly 
(BIW) in each 3-week treatment cycle. DTIC 1000 mg/m2 will be administered IV once 
every 21 days (Q21D). 
• Placebo plus DTIC: Matching placebo will be administered PO BIW in each 3-week 
treatment cycle. DTIC 1000 mg/m2 will be administered IV Q21D. 
For approximately 300 subjects with 1 to 3 prior lines of treatment, randomization will be 
stratified as follows: 
• Number of prior systemic therapies (1 or >1) 
• ECOG PS score (0 or 1) 
• Histological tumor type (uterine versus nonuterine LMS) 
Forty-five subjects with at least 4 prior lines of treatment will be randomized and stratified as 
follows: 
• ECOG PS score (0 or 1) 
• Histological tumor type (uterine versus nonuterine LMS) 

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One treatment cycle will constitute 21 days. DTIC will be administered on Day 1 of each 
3-week treatment cycle. Unesbulin/placebo tablets will be administered on Days 2 and 5 of 
Week 1 and Days 1 and 4 of Weeks 2 and 3 of each 3-week treatment cycle (Note: the 
preferable duration between 2 doses of unesbulin/placebo is approximately 72 hours). 
Approximately 12 randomized subjects will be assessed for PK of unesbulin, DTIC, and AIC 
(an inactive metabolite of DTIC). For Cycles 1 and 3, rich PK sampling will occur on Day 1 
for DTIC and AIC, and on Day 2 for unesbulin. The target is for approximately 7 PK 
evaluable subjects in the unesbulin group to complete Cycle 3. For Cycles 2 and 4, sparse PK 
sampling will occur on Day 1 for DTIC and AIC. 
All subjects will receive treatment until evidence of disease progression, unacceptable toxicity, 
or other withdrawal criteria are met. No crossover will be permitted. 
An independent Data Monitoring Committee (DMC) has been established and will review 
safety data as per the DMC charter. In addition, one interim efficacy analysis will be 
performed (by an external vendor) and reviewed by the DMC. Based on the results of this 
interim analysis, the DMC will make recommendations to either continue or stop the study. 
The DMC Charter (a separate document) and the DMC Statistical Analysis Plan (SAP) will 
provide detailed guidance for the conduct of this interim analysis. 
Dose modifications/stopping criteria: 
If treatment-related toxicities are observed, a stepped reduction in the dose of DTIC is 
permitted beginning with the starting dose of 1000 to 850 mg/m2, followed by 700, 600, and 
500 mg/m2. The following guidelines should be observed: 
• If a subject requires a dose reduction of DTIC to less than 500 mg/m2, then DTIC should 
be discontinued. 
• Subjects should receive all necessary supportive care including blood products, platelet 
transfusions, antiemetics, and antibiotics while being treated on this study. 
• The use of granulocyte colony-stimulating factor (eg, pegfilgrastim) and erythropoietin or 
thrombopoietin-stimulating agents is permitted per institutional practice. 
No dose reduction of unesbulin/placebo is permitted. Guidelines for unesbulin/placebo dosing 
when treatment-related toxicities continue beyond the stepwise dose reduction of DTIC is 
detailed in this protocol.  
Sample Size Justification: 
The sample size was computed based on the comparison of PFS between subjects randomized 
to unesbulin plus DTIC and subjects randomized to placebo plus DTIC. 
The median PFS was assumed to be approximately 1.5 to 2.5 months for the placebo plus 
DTIC group and more than 4 months for the unesbulin plus DTIC group. With an overall 
one-sided alpha level of 0.025, a total of 245 events are required to achieve at least 90% power 
at a hazard ratio of 0.5. Assuming 19 months of enrollment time, a minimum follow-up period 
of 6 months for the primary endpoint, and approximately 11.5% uniform dropout rate, a total 
of 300 subjects are planned to be randomized. 
One interim analysis will be performed when approximately 36% of the PFS events occur 
(approximately 88 events). The study may stop for both efficacy and futility. The study may 
stop for efficacy if the observed hazard ratio is less than 0.447, and the study may stop for 
futility if the observed hazard ratio is more than 0.67. 
The alpha allocation will be controlled separately at the interim and the final analysis 
timepoints by using the Lan-DeMets spending function that approximates the 

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O’Brien-Fleming approach. The family-wise significance level is 0.025, with 0.000184 
allocated at the interim analysis and 0.024816 allocated at the final analysis. 
For the key secondary endpoint OS, sample size is based on detecting a hazard ratio of 0.625 
(median OS of 10 months versus 16 months, for placebo plus DTIC vs unesbulin plus DTIC, 
respectively) and a minimum 15-month follow-up. With 184 events (among 265 subjects) a 
1-sided 0.025 level log-rank test will have approximately 84% power. A separate group 
sequential design and monitoring will be performed for OS, with one interim analysis 
performed when at least 60% of the OS events occur and a final OS analysis when 184 events 
occur. The alpha allocation will be controlled by using the Lan-DeMets spending function that 
approximates the O’Brien-Fleming approach.  
Data from the additional 45 subjects enrolled with at least 4 prior lines of therapy will not be 
included in the primary analysis; rather, the efficacy analysis of data from these subjects will 
be considered exploratory and included as a sensitivity analysis only. 
Number of Subjects (Planned): 
Randomized: Approximately 345 (300 subjects with 1 to 3 prior lines of systemic therapy for 
the primary analysis and 45 subjects with at least 4 prior lines of systemic therapy for the 
exploratory analysis) 
Inclusion Criteria: 
1. Subject is willing and able to provide informed consent 
2. Willingness and ability to comply with scheduled visits, drug administration plan, 
laboratory tests, other study procedures, and study restrictions 
3. Disease status including: 
a. Histological or cytological confirmation of LMS arising at any anatomic site except 
bone sarcoma 
b. Unresectable or metastatic, relapsed or refractory disease 
c. Measurable disease per RECIST 1.1 criteria 
d. Disease progression on previous treatment before screening or intolerability to other 
oncology treatments 
Demographics: 
4. Age ≥18 years 
5. Male or female 
Performance status: 
6. ECOG PS score of 0 or 1 
Hematopoietic: 
7. Absolute neutrophil count ≥1500/mm3 without the use of growth factors in the past 7 days 
8. Platelet count ≥100000/mm3 without platelet transfusion in the past 14 days 
9. Hemoglobin ≥9 g/dL (packed red blood cell transfusion is not allowed within 7 days) 
Hepatic: 
10. Bilirubin ≤ upper limit of normal (ULN) except for those patients with Gilbert’s 
syndrome 
11. Aspartate aminotransferase and alanine aminotransferase <3 times the ULN 
12. Subjects with liver metastases may be enrolled 
Pulmonary: 
13. Subjects with well-controlled asthma (eg, use of rescue medications <2 times per week 
over the last 12 months) or chronic obstructive pulmonary disease (eg, no exacerbations 
over the prior 3 months) may be enrolled. 

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Renal: 
14. Creatinine <1.5 times normal OR creatinine clearance ≥ 60 mL/min 
Prior therapeutics: 
15. Toxicity from prior therapies recovered to Grade ≤1 or subject’s baseline, except for 
alopecia. In addition, endocrinopathies associated with prior immunotherapy-based 
treatments that are well controlled on replacement medication are not exclusionary. 
Chemotherapy and targeted therapy: 
16. At least 1 prior systemic cytotoxic or targeted therapy regimen for LMS, which may 
include but is not limited to single-agent doxorubicin or other anthracycline, doxorubicin 
plus ifosfamide, trabectedin, pazopanib, or gemcitabine with or without docetaxel  
Surgery: 
17. At least 4 weeks since prior surgery and recovered in the opinion of investigator 
Other: 
18. Capable of swallowing oral medication 
19. Women of childbearing potential (WOCBP; as defined by the Clinical Trials 
Facilitation and Coordination Group [CTFG]) must have a negative serum pregnancy test 
at screening and agree to abstinence or the use at least one of the following highly 
effective forms of contraception (with a failure rate of <1% per year when used 
consistently and correctly) (Clinical Trials Facilitation and Coordination Group 2020). 
Contraception or abstinence must be continued for the duration of the study and for at 
least 6 months after the last dose of study drug: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 
− Injectable 
− Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner with confirmed azoospermia 
All females will be considered of childbearing potential unless they are postmenopausal (at 
least 12 months consecutive amenorrhea in the appropriate age group without other known 
or suspected cause) or have been sterilized surgically (eg, bilateral salpingectomy, 
hysterectomy, bilateral oophorectomy). 
20. Lactating females are not eligible unless they have agreed not to breastfeed their 
infants during treatment and for a period of 1 month following completion of treatment. 
21. Males who are sexually active with WOCBP who have not had a vasectomy must 
agree to use a barrier method of birth control from the start of study drug administration 
through at least 6 months after the last dose of study drug. Males should not donate sperm 
from the start of study treatment through at least 6 months after the last dose of study 
drug). 

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Exclusion Criteria: 
1. Received temozolomide or DTIC at any time 
2. Any other systemic anticancer therapy including investigational agents ≤3 weeks 
before initiation of study treatment. Additionally, subjects may not have received 
radiation ≤3 weeks before initiation of study treatment. 
3. Known intolerance to DTIC or one or more of the excipients in unesbulin. 
4. Co-existing active infection or any co-existing medical condition likely to interfere 
with study procedures, including: 
a. Significant cardiovascular disease (New York Heart Association Class III or IV 
cardiac disease), myocardial infarction within the past 6 months, unstable 
angina, congestive heart failure requiring therapy, unstable arrhythmia or a 
need for antiarrhythmic therapy, or evidence of ischemia on ECG, marked 
baseline prolongation of QT/QTc (corrected QT) interval, eg, repeated 
demonstration of a QTc interval >500 msec (Long QT Syndrome [congenital]) 
5. Human immunodeficiency virus, hepatitis B virus, or hepatitis C virus positivity 
6. History of solid organ transplantation 
Therapeutics: 
7. Known or suspected allergy or immediate or delayed hypersensitivity to unesbulin or 
DTIC, their excipients, or any agent given in this study 
Gastrointestinal: 
8. Bowel obstruction, malabsorption, or other contraindication to oral medication 
9. Gastrointestinal disease or other conditions that could affect absorption. Active peptic 
ulcer disease, active gastritis, or previous history of gastric perforation within the last 
2 years 
10. Inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), 
diverticulitis, cholecystitis, symptomatic cholangitis, or appendicitis 
Wounds/surgery: 
11. Serious non-healing wound, ulcer, or bone fractures 
12. Major surgery, open biopsy, or significant traumatic injury that has not recovered, in 
the opinion of the investigator, within 28 days of baseline 
13. Mucosal or internal bleeding 
Concomitant medications: 
14. Concomitant strong CYP1A2 inhibitors (such as fluoroquinolones [broad spectrum 
quinolone antibiotics, including enoxacin and ciprofloxacin] and selective serotonin 
reuptake inhibitor [SSRI] agents fluvoxamine and fluoxetine) should be avoided on the 
same day that DTIC or unesbulin/placebo is administered. CYP1A2 inhibitors may 
inhibit the conversion of DTIC to its active metabolite and may increase the exposure 
of unesbulin. 
15. Concomitant use of moderate CYP1A2 inducers (such as phenytoin, rifampin, 
ritonavir, teriflunomide, and barbiturates). Chronic use of marijuana should be avoided, 
but irregular recreational use may be permitted at the discretion of the treating 
investigator. CYP1A2 inducers may increase the conversion of DTIC to its active 
metabolites. 
16. Coadministration of acid-reducing agents should be avoided approximately 4 hours 
before and after unesbulin/placebo administration. 

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17. Immunization with a live vaccine within 30 days before starting study drug due to the 
risk of serious and life-threatening infections. 
Other: 
18. Prior malignancies, other than LMS, that required treatment or have shown evidence of 
recurrence (except for non-melanoma skin cancer, adequately treated cervical 
carcinoma in situ, prostate cancer in situ or any other low risk malignancy that is 
approved by the medical monitor) during the 5 years before initiation. Cancer treated 
with curative intent more than 5 years previously and without evidence of recurrence is 
not an exclusion. 
19. Known coagulopathy or bleeding diathesis. Subjects on anticoagulation should be 
monitored closely and International Normalized Ratio and/or activated partial 
thromboplastin time (APTT)/prothrombin time (PT) should be within the required 
range where applicable. 
20. Prior or ongoing clinically significant illness, medical or psychiatric condition, medical 
history, physical findings, ECG findings, or laboratory abnormality that, in the 
investigator’s opinion, could affect the safety of the subject, or alter the absorption, 
distribution, metabolism, or excretion of the study drugs, or could impair the 
assessment of study results. 
21. History of brain metastases or leptomeningeal disease at any time in subject’s history, 
including treated central nervous system (CNS) disease  
Investigational product, dosage, and mode of administration: 
Unesbulin tablets for oral administration will be provided in strengths of 50 and 200 mg. 
Subjects will be treated with unesbulin 300 mg PO BIW in combination with DTIC 
administered IV Q21D. One treatment cycle will constitute 21 days. Unesbulin is to be 
administered on Days 2 and 5 of Week 1 and on Days 1 and 4 of Weeks 2 and 3. 
Matching placebo tablets will be provided and should be administered on the same schedule as 
unesbulin. 
Based on the results from a food effect assessment in the ongoing Phase 1b 
Study PTC596-ONC-007-LMS, it is recommended that unesbulin/placebo be taken with food. 
Duration of treatment: 
Treatment will continue for each subject until evidence of disease progression, unacceptable 
toxicity, or any of the following reasons: withdrawal of consent by subject, pregnancy, 
significant noncompliance, withdrawal by investigator, or study discontinuation by PTC or 
regulatory authority. 

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Reference therapy, dosage, and mode of administration: 
DTIC for injection will be provided (by the site or by the sponsor) and will be reconstituted 
with Sterile Water for Injection, USP. The resulting solution contains 10 mg/mL of DTIC 
having a pH of 3.0 to 4.0. The reconstitution step may be modified based on institutional 
policy and or the availability of a specific strength of the DTIC vial to obtain a resulting DTIC 
solution of 10 mg/mL. The calculated dose of the resulting solution is drawn into a syringe. 
The reconstituted solution is further diluted with 5% Dextrose Injection, USP or 0.9% Sodium 
Chloride injection and administered as an IV infusion over 1 hour ±30 minutes. Within 
30 minutes before DTIC administration, the following premedication regimen is 
recommended: fosaprepitant 150 mg IV once, dexamethasone 20 mg PO once, and 
ondansetron 16 mg PO once. The premedication regimen as per institutional practice is 
allowed. 
Placebo tablets will be supplied and administered in a blinded manner to subjects BIW in 
combination with DTIC per the same dosing schedule as for unesbulin. 
Criteria for Evaluation: 
Efficacy: Response assessments will be performed by radiological imaging using RECIST 1.1 
criteria every 6 weeks (±7 days) until disease progression. After Cycle 8, scans may be 
performed every 9 weeks. If any subject responds with a CR or PR at any assessment, then the 
subsequent confirmatory scan should be performed 4 weeks (+5 days) after the previous scan 
where the objective response was first evidenced. Assessment of response and the primary 
endpoint, PFS, will be performed by an independent central reader who will be blinded to 
treatment assignment. 
Subjects should be followed with the same imaging procedure throughout the study. 
Computed tomography scans or magnetic resonance imaging may be used as clinically 
indicated. If the subject withdraws for reasons other than tumor progression, an end-of-
treatment (EOT) scan should be performed if the last scan was ≥3 weeks earlier. 
Survival follow-up will continue every 3 months until the later of 184 events or 2 years after 
the last subject is randomized. 
PRO: HRQoL will be assessed using the EORTC QLQ-C30 and the EQ-5D-5L. 
PK: For the subset of subjects who provide consent, blood samples per PK sample interval 
will be collected for the determination of DTIC, AIC, and unesbulin. PK sample collection, 
processing, storage, and shipment will be performed according to instructions outlined in the 
laboratory manual separate from this protocol. The collected PK samples may also be used for 
further exploratory analysis of unesbulin and DTIC metabolism. 
Safety: Subjects will be monitored closely for AEs and laboratory abnormalities during the 
study. Safety assessments will include vital signs, physical examination, electrocardiograms, 
laboratory values, ECOG PS scores, and AEs. 
Biomarkers: Blood samples (10 mL) will be collected at screening (predose) and prior to 
dosing on Day 1 of Cycle 3 and at the time of disease progression or EOT for all subjects and 
analyzed for exploratory circulating soluble biomarkers, and genetic evaluation of tumors will 
be performed. 

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Statistical Methods: 
The primary objective of this study is to compare PFS of unesbulin plus DTIC versus placebo 
plus DTIC per RECIST 1.1. 
Efficacy: All hypothesis testing will be one-sided based on a significance level of 0.025. 
For subjects with 1 to 3 prior lines of treatment, the distribution of PFS will be compared in 
the 2 randomized groups via log-rank test stratified by prior lines of therapy (1 versus >1), 
ECOG PS score (0 versus 1), and LMS origin (uterine versus nonuterine). The hazard ratio 
and the corresponding 95% CI will be estimated in a stratified Cox proportional hazards model 
using randomized group as the single covariate. The PFS curves for each randomized group 
will be estimated using the Kaplan-Meier (KM) product-limit method. Two-sided, 95% CIs for 
median PFS will be computed by Brookmeyer and Crowley method (using log-log 
transformation). PFS rates at 3, 6, 12, 18, 24, and 30 months will also be estimated using KM 
estimates on the PFS curve for each randomized group. Associated two-sided 95% CIs will be 
calculated using the Greenwood formula. 
OS will be compared between the 2 treatment groups. Two analyses are planned for OS: the 
first (interim) at the time of the final analysis for PFS (provided PFS is significant), at which 
point the information fraction for OS will be at least 60% and a second (final) analysis when 
184 events have accumulated. The same statistical models applied to the analysis of PFS will 
be applied to the analysis of OS. 
BOR will be summarized by response category for each treatment group. ORR will be 
computed in each treatment group along with the exact 95% CI using Clopper-Pearson 
method. An estimate of the difference in ORRs and corresponding 95% CI will be calculated 
using Cochran-Mantel-Haenszel methodology and adjusted by the same stratification factors 
as in primary analysis of PFS. 
For subjects with at least 4 prior lines of treatment, a sensitivity analysis will be performed to 
explore the efficacy for this population. 
PK: PK of unesbulin, DTIC, and AIC will be analyzed using standard compartmental or 
noncompartmental analysis methods, as appropriate for the data. The impact of unesbulin on 
the PK of DTIC and AIC will be investigated. 
Safety: The safety analysis will be performed for all treated subjects. Descriptive statistics of 
safety will be presented using National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events Version 5.0 (CTCAE V5.0) by treatment group. All treatment-emergent 
AEs will be tabulated by system organ class and Medical Dictionary for Regulatory Affairs 
(MedDRA) preferred term. Laboratory abnormalities, including hematology and chemistry, 
will be summarized using worst grade per NCI CTCAE V5.0 criteria. 

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SCHEDULE OF ASSESSMENTS 
Table 1: 
Schedule of Study Assessments and Procedures 
Assessment 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 + 
EOTa 
FUPa 
sFUPa 
Study Week 
 
1 
2 
3 
1 
2 
3 
1 
2 
3 
Cycle Day 
-28 to -1 
1 
2 
5 
8 
11 
15 
18 
1 
2 
5 
8 
11 
15 
18 
1 
2 
5 
8 
11 
15 
18 
 
 
 
Time Windowb 
- 
2 
1 
1 
2 
1 
2 
1 
2 
1 
1 
2 
1 
2 
1 
2 
1 
1 
2 
1 
2 
1 
1 
3 
3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con. medsc 
X 
Throughout study 
X 
 
Pathology reviewd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exame 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weightf 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Vital signs 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
ECOG PS 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Adverse events 
X 
Throughout study 
X 
 
Laboratory testsg 
X 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
HIV, hepatitis 
serologies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine/serum 
pregnancy testh  
X 
Xh 
 
 
 
 
 
 
Xh 
 
 
 
 
 
 
Xh 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ECG (single) for 
subjects not in the 
PK assessment i  
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
ECG (single) for 
subjects in the PK 
assessment j 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
Tumor imagingK 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Survival 
 
Throughout study 
X 
PROsl 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Biomarker 
samplingm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Blood for PKn 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
Dispense 
unesbulin/placebo 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Study drug 
accountabilityo 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
DTIC (IV)p 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 

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Assessment 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 + 
EOTa 
FUPa 
sFUPa 
Study Week 
 
1 
2 
3 
1 
2 
3 
1 
2 
3 
Cycle Day 
-28 to -1 
1 
2 
5 
8 
11 
15 
18 
1 
2 
5 
8 
11 
15 
18 
1 
2 
5 
8 
11 
15 
18 
 
 
 
Time Windowb 
- 
2 
1 
1 
2 
1 
2 
1 
2 
1 
1 
2 
1 
2 
1 
2 
1 
1 
2 
1 
2 
1 
1 
3 
3 
Unesbulin or 
placebo (PO) in 
clinic or homeq 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Abbreviations: AE, adverse events; AIC, 5-amino-imidazole-4-carboxamide; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete 
blood count; CMP, complete metabolic panel; Con., concomitant; DTIC, dacarbazine; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOI, 
end of infusion; EORTC QLQ-C30, 30-item score European Organisation for the Research and Treatment of Cancer Quality-of-Life Questionnaire; EOT, end-of-
treatment; EQ-5D-5L,  EuroQol 5-level EQ-5D version; FUP, follow-up; OS, overall survival; PK, pharmacokinetics; PROs, patient-reported outcomes; PS, 
performance status; RBC, red blood cell; SAE, serious adverse event; sFUP, survival follow-up; SOI, start of infusion; WBC, white blood count 
a The EOT visit should be performed within 30 days after the end of treatment or until recovery from or stabilization of the AE, whichever occurs latest. The EOT 
imaging should be performed if the last scan was ≥3 weeks earlier. For subjects requiring immediate initiation of a new treatment option, the EOT visit may be 
completed earlier. A safety FUP assessment should be performed by phone at 30 days (±3 days) after the EOT to assess AEs and concomitant medications. 
sFUP assessments should be performed by phone every 3 months (±7 days) after the EOT until the later of 184 events or 2 years after the last subject has been 
randomized. 
b Specified time window is ± days. Unesbulin/placebo should not be dosed on consecutive days, and preferably at least 3 days (72 hours) between each 
unesbulin/placebo dose. The window for completion of the activities associated with Cycle 1 Day 1 and Cycle 2 Day 1 may be divided between a 2-day span. 
c Concomitant medications involve a complete medication reconciliation, including medications used for tolerability (eg, antiemetics and antidiarrheals). 
d Pathology review to confirm the histologic diagnosis of leiomyosarcoma is required. An outside pathology report documenting leiomyosarcoma is acceptable. 
e Full physical examination should be done at screening and EOT visits. Symptom-directed physical examination can be done at all other timepoints. 
f Assess weight on the day of DTIC administration; modify dose of DTIC if >10% change from baseline (or the last time the dose was changed). 
g Local laboratory testing is acceptable. Screening laboratory assessments and urinalysis must be collected within 3 weeks of Cycle 1 Day 1. Cycle 1 Day 1 
laboratory assessments may be collected up to 24 hours before the first dose, but this window may be extended up to 72 hours for sites if it is impacted by 
laboratory working hours. For subsequent cycles, laboratory assessments may be collected up to 48 hours before dosing. On Day 1 Week 1 of each cycle, all 
laboratory assessments should be performed. On Day 1 of Weeks 2 and 3 of Cycles 1, 2, and 3, a CBC and CMP should be assessed for each subject. After 
Cycle 3, clinical laboratory assessments are required only once every cycle instead of on a weekly basis. If DTIC is held due to toxicity (see Section 3.3), then 
laboratory assessments should be completed while dosing with unesbulin/placebo continues. If DTIC is interrupted or held, then laboratory assessments should be 
done within 24 hours of resuming dosing with DTIC and continue on a weekly basis for the first 3 weeks after DTIC reintroduction. For subsequent cycles, the 
clinical laboratory assessments may be performed at a minimum of once per cycle or more frequently per the investigator’s discretion to ensure that the subject 
meets the protocol-defined safety criteria in Section 3.3.  
Laboratory tests include: (1) CBC (hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration), WBC count, WBC differential (may be automated or manual as per institutional standards), RBC count, lymphocytes, monocytes, neutrophils, band 
neutrophils (if reported), eosinophils, basophils, platelets; and (2) CMP: albumin, alkaline phosphatase, total bilirubin, bicarbonate, blood urea nitrogen, calcium, 
chloride, creatinine, glucose, potassium, total protein, AST, ALT, and sodium. 
h For women of childbearing potential, a serum pregnancy test should be performed at screening (with a window of 7 days) and a urine pregnancy test 
should be performed within 24 hours of Day 1 of Cycle 1. A urine or serum pregnancy test should be performed within 24 hours prior to dosing on 
Day 1 of Cycle 2 and continuing every 2 cycles beginning at Cycle 4.  
i For subjects not participating in the PK assessment, a single ECG should be collected on Day 1 of the first 3 treatment cycles only, approximately 2 hours 
after DTIC infusion. If DTIC is interrupted, then the single ECG should be collected approximately 2 hours after DTIC infusion and recorded on an unscheduled 
case report form page. 
j For subjects participating in the PK assessment, a single ECG should be taken as follows: 
• 
Predose and 1.5, 4, and 8 hours postdose on Day 1 of Cycles 1 and 3 concurrent with intensive PK sampling for DTIC/AIC.  

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• 
Predose and 2, 4, 6, and 8 hours postdose on Day 2 of Cycles 1 and 3 concurrent with intensive PK sampling for unesbulin.  
• 
Approximately 2 hours after DTIC infusion on Cycle 2. 
k Pretreatment, baseline imaging should be performed ≤14 days before Cycle 1 Day 1. On-treatment imaging should be performed every 6 weeks (±7 days). After 
Cycle 8, scans may be performed every 9 weeks. If any subject responds with a CR or PR at any assessment, then the subsequent confirmatory scan should be 
performed 4 weeks (+5 days) after the previous scan where the objective response was first evidenced. If the subject withdraws from the study for reasons other 
than progression of disease, EOT imaging should be performed if the last scan was ≥3 weeks earlier. Subjects should be followed with the same imaging 
procedure throughout the study. Computed tomography scans or magnetic resonance imaging may be used as clinically indicated. 
l PROs include EORTC QLQ-C30 and EQ-5D-5L. 
m Blood samples (10 mL) to assess circulating biomarkers will be collected at screening (predose) and prior to dosing on Day 1 of Cycle 3 and at the time of 
disease progression or EOT. Samples will be processed, stored, and shipped according to instructions in the laboratory manual. 
n For subjects participating in the PK assessments: 
• 
PK for DTIC/AIC: On Day 1 of Cycles 1 and 3, blood samples will be collected at predose, 0.5, 1.0 (within 10 minutes before EOI), 1.25 (approximately 
15 minutes post EOI), 1.5, 2, 4, 8, 10, and 24 hours postdose (SOI). On Day 1 of Cycles 2 and 4, sparse blood samples will be collected at predose, 1.25, 
and 4 hours postdose (SOI). If DTIC is interrupted or held in Cycle 3, then the same intensive PK sampling schedule for DTIC should be followed on the 
day that DTIC resumes in the subsequent cycle. For PK assessments, DTIC must be administered the day before unesbulin/placebo dosing. DTIC should 
not be administered on the same day as unesbulin/placebo. 
• 
PK for unesbulin: On Day 2 of Cycles 1 and 3, blood samples will be collected at predose, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose. PK sample 
collection, processing, storage, and shipment will be performed according to instructions outlined in the laboratory manual separate from this protocol. If 
DTIC is interrupted or held in Cycle 3, then the same intensive PK sampling schedule for unesbulin/placebo should be followed on the day after DTIC 
resumes in the subsequent cycle. For PK assessments, DTIC must be administered the day before unesbulin/placebo dosing. DTIC should not be 
administered on the same day as unesbulin/placebo. 
• 
The collected PK samples may also be used for further exploratory analysis of unesbulin and DTIC metabolism. 
o Subject medication diary is given to subjects to record unesbulin/placebo dosing at home and will be provided at Day 1 of each cycle or at other visits, as needed, 
to ensure compliance. Subject should bring the diary back at all scheduled visits for review with the research staff to assess treatment compliance. 
p Within 30 minutes before DTIC administration, the following premedication regimen is recommended: fosaprepitant 150 mg IV once, dexamethasone 20 mg PO 
once, and ondansetron 16 mg PO once. The premedication regimen as per institutional practice is allowed. Please refer to Section 3.3 for instructions on DTIC 
interruptions and dose modifications due to toxicity. 
q For subjects participating in the PK assessment, unesbulin/placebo will be administered at the clinic on the day of intensive PK sampling (Day 2 of Cycle 1 and 
Cycle 3 except in cases of DTIC interruption) and at home on other scheduled unesbulin/placebo dosing days. For all other subjects (ie, those not in the PK 
assessment), unesbulin/placebo should be taken by the subject at home. 
Note: Treatment cycles will repeat until the subject meets the criteria for withdrawal from the study. All windows refer to business days (exclude weekends and 
holidays). Activities designed to be completed in a single day, such as PK sampling from before dosing to hour 8 postdose, may not be split up between the 2 days 
of a window. 
If DTIC is interrupted and toxicity resolves as per criteria in Section 3.3, then clinical laboratory (ie, CBC and CMP) and body weight assessments must be 
performed within 24 hours prior to DTIC reintroduction. A single ECG must also be performed approximately 2 hours after reintroduction of DTIC if the interruption 
occurs within the first 3 treatment cycles. If DTIC is interrupted or held in Cycle 3, then the same intensive PK sampling schedule should be followed upon 
reintroduction of DTIC as described in footnote “n”.

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TABLE OF CONTENTS 
PROTOCOL IDENTIFIERS AND STUDY PERSONNEL ...........................................................2 
SIGNATURE PAGE .......................................................................................................................3 
INVESTIGATOR’S AGREEMENT ...............................................................................................4 
SYNOPSIS  ......................................................................................................................................5 
SCHEDULE OF ASSESSMENTS ................................................................................................14 
TABLE OF CONTENTS ...............................................................................................................17 
LIST OF TABLES .........................................................................................................................20 
LIST OF FIGURES .......................................................................................................................21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................22 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Disease Background ...................................................................................................24 
1.2. 
Study Rationale ...........................................................................................................25 
1.3. 
Risk/Benefit Assessment ............................................................................................27 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................28 
2.1. 
Primary Objective .......................................................................................................28 
2.2. 
Secondary Objectives .................................................................................................28 
2.3. 
Exploratory Objectives ...............................................................................................28 
2.4. 
Primary Endpoint ........................................................................................................28 
2.5. 
Secondary Endpoints ..................................................................................................28 
2.6. 
Exploratory Endpoints ................................................................................................29 
3. 
INVESTIGATIONAL PLAN .....................................................................................30 
3.1. 
Overall Study Design ..................................................................................................30 
3.2. 
Number of Subjects ....................................................................................................32 
3.3. 
Dose Adjustment and Stopping Criteria .....................................................................32 
3.4. 
End of Study Definition ..............................................................................................33 
3.5. 
Criteria for Study Termination ...................................................................................33 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................34 
4.1. 
Subject Inclusion Criteria ...........................................................................................34 
4.2. 
Subject Exclusion Criteria ..........................................................................................36 
4.3. 
Screen Failures ............................................................................................................38 
5. 
STUDY INTERVENTION MATERIALS AND MANAGEMENT .........................39 

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5.1. 
Description of Study Drug ..........................................................................................39 
5.2. 
Study Intervention Preparation and Administration ...................................................39 
5.3. 
Storage, Handling, and Accountability .......................................................................40 
5.3.1. 
Storage ........................................................................................................................40 
5.3.2. 
Handling and Accountability ......................................................................................40 
5.4. 
Study Intervention and Compliance ...........................................................................40 
5.5. 
Concomitant Medications ...........................................................................................40 
5.6. 
Randomization and Blinding ......................................................................................42 
5.6.1. 
Emergency Procedure for Unblinding ........................................................................42 
6. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................43 
6.1.1. 
Discontinuation of Study Intervention ........................................................................43 
6.1.2. 
Participant Discontinuation/Withdrawal from the Study Drug or Study ....................43 
6.1.3. 
Lost to Follow-up .......................................................................................................44 
7. 
STUDY ASSESSMENT AND PROCEDURES ........................................................45 
7.1. 
Assessment of Efficacy ...............................................................................................45 
7.2. 
Assessment of Safety ..................................................................................................45 
7.2.1. 
Safety Parameters .......................................................................................................45 
7.3. 
Adverse Events and Serious Adverse Events .............................................................46 
7.3.1. 
Definition of Adverse Event .......................................................................................46 
7.3.2. 
Definition of Serious Adverse Events ........................................................................47 
7.3.2.1. 
Disease Progression ....................................................................................................48 
7.3.3. 
Unexpected Adverse Events .......................................................................................48 
7.3.4. 
Eliciting Adverse Event Information ..........................................................................48 
7.3.5. 
Recording Nonserious Adverse Events ......................................................................48 
7.3.6. 
Describing Adverse Event Relationship to Study Drug .............................................49 
7.3.7. 
Grading of Severity of Adverse Event ........................................................................49 
7.3.8. 
Reporting Adverse Events ..........................................................................................50 
7.3.9. 
Serious Adverse Events Reporting .............................................................................50 
7.3.10. 
Contraception ..............................................................................................................51 
7.3.11. 
Reporting Pregnancy ..................................................................................................51 
7.3.12. 
PTC Safety Reporting Requirement ...........................................................................52 
7.4. 
Pharmacokinetics ........................................................................................................52 

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7.5. 
Patient-Reported Outcomes ........................................................................................52 
7.6. 
Biomarkers ..................................................................................................................53 
8. 
STATISTICS ..............................................................................................................54 
8.1. 
Statistical Hypotheses .................................................................................................54 
8.2. 
Sample Size Determination ........................................................................................54 
8.3. 
Analysis Populations ..................................................................................................55 
8.4. 
Statistical Analyses .....................................................................................................55 
8.4.1. 
General Approach .......................................................................................................55 
8.4.2. 
Analysis of Primary Efficacy Endpoints ....................................................................55 
8.4.3. 
Analysis of Key Secondary Efficacy Endpoint ..........................................................56 
8.4.4. 
Analysis of Other Secondary Efficacy Endpoints ......................................................56 
8.4.5. 
Safety Analyses ..........................................................................................................57 
8.4.5.1. 
Adverse Events ...........................................................................................................57 
8.4.5.2. 
Laboratory Abnormalities ...........................................................................................57 
8.4.5.3. 
Other Safety Assessments ...........................................................................................57 
8.4.6. 
Baseline Descriptive Statistics ....................................................................................58 
8.4.6.1. 
Disposition ..................................................................................................................58 
8.4.6.2. 
Demographics and Baseline Characteristics ...............................................................58 
8.4.6.3. 
Medical History and Prior Medication .......................................................................58 
8.4.7. 
Extent of Exposure, Treatment Compliance, and Concomitant Medications ............58 
8.4.8. 
Exploratory Analyses ..................................................................................................58 
8.4.8.1. 
Pharmacokinetics ........................................................................................................58 
8.4.8.2. 
Patient-Reported Outcomes ........................................................................................58 
8.4.8.3. 
Biomarkers ..................................................................................................................58 
8.4.9. 
Planned Interim Analysis ............................................................................................59 
8.4.10. 
Subgroup Analyses .....................................................................................................59 
9. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................60 
9.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................60 
9.1.1. 
Ethics ..........................................................................................................................60 
9.1.1.1. 
Ethical Conduct of the Study ......................................................................................60 
9.1.1.2. 
Institutional Review Board .........................................................................................60 
9.1.1.3. 
Informed Consent .......................................................................................................60 

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9.1.2. 
Study Discontinuation and Closure ............................................................................61 
9.1.3. 
Confidentiality and Privacy ........................................................................................61 
9.1.4. 
Data Monitoring Committee .......................................................................................61 
9.1.5. 
Data Handling and Recordkeeping .............................................................................62 
9.1.6. 
Direct Access to Source Data/Documents ..................................................................62 
9.1.6.1. 
Study Monitoring ........................................................................................................62 
9.1.6.2. 
Audits and Inspections ................................................................................................63 
9.1.7. 
Future Use of Stored Specimens and Data .................................................................63 
9.1.8. 
Quality Control and Quality Assurance ......................................................................63 
9.1.9. 
Protocol Deviations ....................................................................................................63 
9.1.10. 
Publication Policy .......................................................................................................64 
9.2. 
Protocol Amendment History .....................................................................................65 
9.2.1. 
Version 2.0: 31 January 2022 .....................................................................................65 
9.2.2. 
Version 3.0: 28 April 2023 .........................................................................................65 
9.2.3. 
Version 4.0: 28 November 2023 .................................................................................88 
10. 
REFERENCES ...........................................................................................................90 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Assessments and Procedures ........................................................14 
Table 2: 
Interventions for Common Hematological Toxicities by Grade ................................33 
Table 3: 
Interventions for Nonhematological Toxicities by Grade ..........................................33 
Table 4: 
Relationship of Study Drug to Adverse Event ...........................................................49 
Table 5: 
Grading of Adverse Events .........................................................................................50 
Table 6: 
Investigator Site Requirements for Reporting Adverse Events ..................................50 
Table 7: 
Summary of Changes for Global Amendment Version 1.0 to Version 2.0 ................65 
Table 8: 
Summary of Changes From Global Protocol Version 2.0 to Version 3.0 ..................66 
Table 9: 
Germany: Summary of Changes From Local Amendment Version 2.3 to 
Global Amendment Version 3.0 .................................................................................71 
Table 10: Italy: Summary of Changes From Local Amendment Version 2.1 to Global 
Amendment Version 3.0 .............................................................................................74 
Table 11: Spain: Summary of Changes From Local Amendment Version 2.1 to Global 
Amendment Version 3.0 .............................................................................................78 

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Table 12: UK: Summary of Changes From Local Amendment Version 2.1 to Global 
Amendment Version 3.0 .............................................................................................83 
Table 13: Summary of Changes From Global Protocol Version 3.0 to 4.0 ................................88 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................30 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Specialist Term 
Explanation 
AE 
Adverse event 
AIC 
5-amino-imidazole-4-carboxamide 
ALT 
Alanine aminotransferase 
AME 
Absorption, metabolism, and excretion 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC0-t 
Area under the concentration versus time curve from time zero to the last 
sampled time or the last non-zero concentration 
BCRP 
Breast cancer resistance protein 
BIW 
Twice weekly 
BOR 
Best overall response 
CBC 
Complete blood count 
CBR 
Clinical benefit rate 
ccfDNA 
Circulating cell-free tumor DNA 
CL 
Clearance 
CMP 
Complete metabolic panel 
CNS 
Central nervous system 
CR 
Complete response 
CTCAE V5.0 
Common Terminology Criteria for Adverse Events Version 5.0 
CTFG 
Clinical Trials Facilitation and Coordination Group 
DCR 
Disease control rate 
DMC 
Data Monitoring Committee 
DoR 
Duration of response 
DTIC 
Dacarbazine 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ECOG 
Eastern Cooperative Oncology Group 
EOI 
End of infusion 
EORTC QLQ-C30 
30-item score European Organisation for the Research and Treatment of 
Cancer Quality-of-Life Questionnaire 
EOT 
End-of-treatment 
EQ-5D-5L 
EuroQol 5-level EQ-5D version 
FUP 
Follow-up 
GCP 
Good Clinical Practice 
HRQoL 
Health-related quality-of-life 
ICF 
Informed consent form 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
KM 
Kaplan-Meier 
LLN 
Lower limit of normal 
LMS 
Leiomyosarcoma 
MedDRA 
Medical Dictionary for Regulatory Affairs  
mITT 
Modified Intent-to-treat 
NCI 
National Cancer Institute 
OATP1B1, OATP1B2 
Organic anion transporter polypeptide transporters 
ORR 
Objective response rate 
OS 
Overall survival 

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Abbreviation or 
Specialist Term 
Explanation 
PFS 
Progression-free survival 
PLT 
Platelets 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic/s 
PR 
Partial response 
PRO 
Patient-reported outcome 
PS 
Performance status 
PT 
Prothrombin time 
Q21D 
Once every 21 days 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 dose 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SEER 
Surveillance, Epidemiology, and End Results 
sFUP 
Survival follow-up 
SOI 
Start of infusion 
SOP 
Standard operating procedures 
SSRI 
Selective serotonin reuptake inhibitor 
STS 
Soft-tissue sarcoma 
SUSAR 
Suspected unexpected serious adverse reaction  
TEAE 
Treatment-emergent adverse events 
ULN 
Upper limit of normal 
Vz 
Volume of distribution 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 

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1. 
INTRODUCTION 
1.1. 
Disease Background 
Leiomyosarcoma (LMS) is a common type of soft-tissue sarcoma (STS), comprising 10% to 
28% of all STS (Toro 2006, Ducimetière 2011, Ferrari 2011, Friedman 2018, Nagar 2018, Parikh 
2018, Saltus 2018, Bessen 2019). In 2021, it is estimated that there will be 13460 new cases of 
soft-tissue cancer, and an estimated 5350 people will die of this disease (Howlader 2021). The 5- 
and 10-year trends in incidence of new STS have been slowly increasing (<1%) for both sexes. 
Death rates have been rising at an average of 0.1% each year from 2010 through 2018. The 
estimated 5-year survival of all STS is 65% based on National Cancer Institute (NCI) 
Surveillance, Epidemiology, and End Results data collected from 2000 to 2017 (Howlader 
2021). 
The underlying etiology of LMS is poorly understood. These cancers of mesenchymal origin can 
arise from any site in the body with the most common locations including the abdomen, 
retroperitoneum, large blood vessels, and uterus (Gladdy 2013). These tumors display nuclear 
atypia and mitotic activity and are characterized by complex cytogenetic and molecular changes 
(Gibault 2011, Miettinen 2014, Guo 2015). The Cancer Genome Atlas project reported low 
mutational burden in LMS compared with other tumors (Cancer Genome Atlas Research 
Network 2017). 
LMS is one of the more aggressive sarcoma subtypes, with the highest risk of recurrence and 
decreased disease-speciﬁc survival (Pisters 1996, Svarvar 2007, Wang 2011, Gladdy 2013, 
Miettinen 2014, Worhunsky 2015, George 2018). The best chance for a cure in localized LMS is 
complete surgical resection, but complete resection at the time of diagnosis may be limited by 
anatomical constraints, and recurrence is common (George 2018). 
There has been little progress in the treatment of unresectable or metastatic, relapsed or 
refractory LMS. Due to the low mutational burden and lack of driver mutations in LMS (Cancer 
Genome Atlas Research Network 2017), the disease has not been amenable to treatment with 
immunological or targeted therapies. First-line treatments include the combinations of cytotoxic 
agents doxorubicin (with or without ifosfamide) and gemcitabine with docetaxel (Hensley 2008, 
Ratan 2016, In 2017, George 2018). 
Several chemotherapeutic agents and regimens have shown efficacy and are recommended in 
unresectable or metastatic, relapsed or refractory LMS as second-line treatment or later, 
including dacarbazine (DTIC), gemcitabine with docetaxel, trabectedin, and pazopanib (Ratan 
2016, George 2018). The cytotoxic agent trabectedin and the angiogenic receptor tyrosine kinase 
inhibitor pazopanib were approved for treatment of LMS in the second- or later-line setting and 
provide a progression-free survival (PFS) benefit of 4.2 to 4.6 months with no demonstrated 
improvement in overall survival (OS) (Van Der Graaf 2012, Demetri 2016). Due to the low 
mutational burden and lack of driver mutations in LMS (Cancer Genome Atlas Research 
Network 2017), the disease has not been amenable to treatment with immunological or targeted 
therapies. 

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Thus, the very modest improvements in PFS and lack of improvement in OS by these approved 
products suggest there remains an urgent and unmet medical need for new therapeutic options in 
LMS. There is no uniform consensus for the standard of care recommended for second-line 
therapy or beyond in STS (NCCN 2021). Current guidelines suggest that choice of treatment 
should be based on histology and molecular subtype, as well as patient characteristics (In 2017, 
Gronchi 2021). Participation in a clinical trial is strongly recommended by the National 
Comprehensive Cancer Network (NCCN 2020). 
1.2. 
Study Rationale 
Unesbulin is an investigational, orally bioavailable, novel small molecule being developed by 
PTC Therapeutics (PTC) for the treatment of LMS. Unesbulin binds to a unique site within the 
colchicine-binding site of tubulin, which is considered an important target for destabilization of 
tubulin polymerization and microtubule formation (Lu 2012, Jernigan 2021). By inhibiting 
microtubule formation, unesbulin arrests tumor cells, including cancer stem cells, in G2/M phase 
and induces tumor cell apoptosis. Microtubule-targeting agents have been successfully used for 
years as tumoricidal agents. However, their use has been limited by broad toxicities and poor 
pharmacologic properties until recent approvals of eribulin and nab-paclitaxel, both of which are 
administered intravenously and are associated with risk of peripheral neurotoxicity, but neither 
of which are approved for LMS (Kawai 2017). 
Unesbulin is administered orally and demonstrates attractive pharmacological properties and a 
favorable pharmacokinetic (PK) profile, including a long circulating half-life, effective 
biodistribution, and lack of P-glycoprotein (P-gp) substrate activity. P-gp is a promiscuous drug 
efflux pump, and elevated P-gp expression in cancer cells has been linked to reduced 
chemotherapeutic responses and poor clinical outcome in various cancer types including both 
blood cancers and solid tumors (Zhang 2018). Many commonly used anticancer drug classes 
such as taxanes (paclitaxel), vinca alkaloids (vinblastine), and anthracyclines (doxorubicin) are 
P-gp substrates and suffer from this limitation. Since unesbulin also crosses the blood-brain 
barrier, it is an attractive candidate for many oncological indications, including neuro-oncology. 
Furthermore, while most tubulin binding agents have been associated clinically with peripheral 
neuropathy (Kawai 2017), there has been no evidence of peripheral neuropathy with unesbulin. 
The antitumor efficacy of unesbulin was evaluated in vivo in studies utilizing xenograft models 
of LMS. Unesbulin as a single agent and in combination with other standard-of-care anticancer 
agents, including DTIC, has demonstrated efficacy in rodent models of LMS. Notably, in a study 
where the efficacy of unesbulin was evaluated as monotherapy and in combination with DTIC 
using an SK-LMS-1 mouse model of LMS, the combination of unesbulin and DTIC was 
markedly more effective than either agent alone. The combination of unesbulin (through Day 98) 
and DTIC (21 mg/kg intraperitoneal once daily for 5 days) was highly effective in suppressing 
tumor growth. At Day 165 (when the study ended), tumors were not visible in 5 of the original 
8 mice that received the combination treatment, whereas mice treated with unesbulin or DTIC 
alone showed progressive tumor growth. 

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Based on strong nonclinical data for the unesbulin and DTIC combination, along with an 
expected favorable toxicity profile for the combination, PTC initiated an ongoing, Phase 1b 
study of unesbulin in combination with DTIC for the treatment of unresectable or metastatic, 
relapsed or refractory LMS (Study PTC596-ONC-007-LMS). The primary objectives of the 
study are to determine the maximum tolerated dose, recommended Phase 2 dose (RP2D), and 
safety of unesbulin in combination with DTIC. Subjects are treated with unesbulin orally twice 
weekly (BIW) in combination with DTIC administered IV once every 21 days (Q21D). 
Preliminary results for the 18 subjects exposed to the combination therapy of unesbulin at 
various dose levels with DTIC in Study PTC596-ONC-007-LMS demonstrated that the 300 mg 
BIW dose exhibited favorable efficacy and safety profiles with manageable toxicity compared 
with the 400 and 200 mg dose levels. Most cases of Grade 3-4 neutropenia and 
thrombocytopenia resolved within days without the need for treatment discontinuation or 
administration of growth factors or immunostimulants. 
Together with the available nonclinical and PK data from the unesbulin clinical studies, PTC 
considers the dose of 300 mg unesbulin BIW in combination with DTIC to be the appropriate 
RP2D. 
In addition to Study PTC596-ONC-007-LMS, an initial Phase 1 study (PTC596-ONC-001-AST) 
in subjects with advanced solid tumors was completed, and 2 investigator-initiated Phase 1b 
studies, PTC596-ONC-004-OVA (subjects with newly diagnosed ovarian cancer) and 
PTC596-ONC-006-DPG (pediatric subjects with diffuse interstitial pontine glioma or high-grade 
glioma), are ongoing. 
For similar reasons in the design of Study PTC596-ONC-007-LMS, PTC considers DTIC to be 
the most appropriate comparator for the intended population in Study PTC596-ONC-008-LMS. 
DTIC induces cytotoxicity by acting as an alkylating agent. It is a widely available generic drug 
that is often used as monotherapy or in combination with other therapies in advanced STS. DTIC 
as a monotherapy can achieve a PFS of 1.5 to 2.6 months (Hensley 2017, Blay 2019), and it is an 
acceptable choice to consider in the refractory setting for LMS because it is relatively well 
tolerated and given on a convenient schedule. Additionally, there is existing precedent for DTIC 
use as a single-agent comparator in the development of new treatments for LMS. During the 
clinical development of trabectedin for LMS, single-agent DTIC was used as the comparator arm 
during randomized Phase 2 and 3 studies (Demetri 2016, Patel 2019). 
Additional information, including a description of unesbulin’s chemistry, pharmacology, safety, 
and preliminary antitumor activity in models of LMS is provided in the current version of the 
Investigator’s Brochure (IB). 

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1.3. 
Risk/Benefit Assessment 
The risk/benefit assessment of the addition of unesbulin to DTIC is driven by the unmet medical 
need associated with unresectable or metastatic, relapsed or refractory LMS. 
A Phase 1b study of unesbulin in combination with DTIC was initiated based on the compelling 
preclinical data for the unesbulin and DTIC combination, an expected favorable toxicity profile 
for the combination, noting the need for novel therapies in this disease, and specifically for an 
improvement over DTIC’s activity as monotherapy. The preliminary clinical data from 
Study PTC596-ONC-007-LMS are consistent with the promising nonclinical data and support 
the continuous development of unesbulin in combination with DTIC. DTIC was well tolerated in 
combination with unesbulin. The most common treatment-related Grade 3 or 4 treatment-
emergent adverse events (TEAEs) were associated with myelosuppression. These events 
occurred less frequently among subjects treated with unesbulin 300 mg as compared with 
unesbulin 400 mg, which further supports the selection of the unesbulin 300 mg dose. Most cases 
of Grade 3-4 neutropenia and thrombocytopenia resolved within days without the need for 
treatment discontinuation or administration of growth factors or immunostimulants. The 
observed adverse events (AEs) are expected to be manageable with regular clinical and 
laboratory monitoring, as with other cytotoxic therapies. 
The purpose of this Phase 2/3 study is to compare the efficacy and safety of unesbulin 300 mg 
plus DTIC versus placebo plus DTIC in subjects with unresectable or metastatic, relapsed or 
refractory LMS who have received at least 1 prior line of systemic therapy. To mitigate potential 
study drug-related toxicities, dose adjustment guidelines and stopping criteria are included. The 
study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and 
applicable regulatory requirements. 
Additional information and guidelines to mitigate potential risks of unesbulin, such as drug-drug 
interactions, are included in the IB. 
In consideration of the limited treatment options and unmet medical need for patients with 
advanced LMS, PTC believes unesbulin in combination with DTIC provides an acceptable 
benefit-risk profile for continued development in patients with unresectable or metastatic, 
relapsed or refractory LMS. 

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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Primary Objective 
The primary objective is to assess PFS of unesbulin plus DTIC versus placebo plus DTIC. 
2.2. 
Secondary Objectives 
• Evaluate OS of subjects treated with unesbulin plus DTIC versus placebo plus DTIC 
• Evaluate the antitumor activity of unesbulin plus DTIC versus placebo plus DTIC 
• Evaluate safety and tolerability of unesbulin plus DTIC versus placebo plus DTIC 
2.3. 
Exploratory Objectives 
• Evaluate the antitumor activity of unesbulin plus DTIC versus placebo plus DTIC in 
subjects with at least 4 prior lines of treatment 
• Evaluate the PK of unesbulin in the presence of DTIC in subjects with LMS 
• Evaluate the PK of DTIC/5-amino-imidazole-4-carboxamide (AIC) alone and in the 
presence of unesbulin in subjects with LMS 
• Compare the effect of unesbulin plus DTIC versus placebo plus DTIC on patient-
reported outcomes (PROs), including health-related quality-of-life (HRQoL) 
assessments 
• Measure genotype of subject tumors, assessed by blood sampling, at baseline and 
posttreatment 
2.4. 
Primary Endpoint 
• PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by an 
independent central imaging laboratory 
2.5. 
Secondary Endpoints 
The key secondary endpoint is OS. 
Other secondary efficacy endpoints: 
• Objective response rate (ORR; proportion of subjects with best overall response 
[BOR] of either complete response [CR] or partial response [PR])  
• Disease control rate (DCR) or clinical benefit rate (CBR), defined as the proportion of 
subjects with BOR of CR, PR, or at least 3 months of stable disease (SD)  
• Duration of response (DoR) 
Safety: 
• Vital signs, physical examination, electrocardiograms (ECG), laboratory 
abnormalities, Eastern Cooperative Oncology Group (ECOG) performance status 
(PS) scores, and AEs 

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2.6. 
Exploratory Endpoints 
Efficacy: 
• 
PFS, OS, ORR, DCR, and DoR in subjects with at least 4 prior lines of treatment 
PK: 
• PK parameters of unesbulin in subjects who receive unesbulin plus DTIC: Cmax, Tmax, 
and area under the concentration versus time curve from time zero to the last sampled 
time or the last non-zero concentration (AUC0-t)  
• PK parameters of DTIC and its inactive metabolite AIC in subjects who receive 
unesbulin plus DTIC and placebo plus DTIC: Cmax, Tmax, and AUC0-t 
PROs: 
• 30-item score European Organisation for the Research and Treatment of Cancer 
Quality-of-Life Questionnaire (EORTC QLQ-C30) 
• EuroQol 5-level EQ-5D version (EQ-5D-5L) 
Biomarkers: 
• Genetic evaluation of the tumors by analyzing circulating cell-free tumor DNA 
(ccfDNA) 

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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a randomized, double-blind, placebo-controlled, Phase 2/3 study to compare the efficacy 
and safety of unesbulin plus DTIC versus placebo plus DTIC in subjects with unresectable or 
metastatic, relapsed or refractory LMS who have received at least 1 prior line of systemic 
therapy. 
Figure 1: 
Study Schematic 
 
 
Abbreviations: AE, adverse event; BIW, twice weekly; DTIC, dacarbazine; EOT, end-of-treatment; FUP, follow-up; 
OS, overall survival; Q21D, once every 21 days 
Note: All subjects will receive treatment until evidence of disease progression, unacceptable toxicity, or other 
withdrawal criteria are met. An EOT assessment will be performed within 30 days after the end of treatment or until 
recovery or stabilization of the AE, whichever occurs latest. For subjects requiring immediate initiation of a new 
treatment option, an EOT visit may be completed earlier. A safety FUP assessment should be performed by phone at 
30 days (±3 days) after the EOT. Survival FUP assessments will occur by phone every 3 months (±7 days) after the 
EOT visit until the later of 184 events or 2 years after the last subject is randomized. 
Eligible subjects will be randomized 2:1 (unesbulin plus DTIC: placebo plus DTIC) to one of the 
following treatment groups: 
• Unesbulin plus DTIC: unesbulin 300 mg administered PO BIW in each 3-week 
treatment cycle. DTIC 1000 mg/m2 will be administered IV Q21D. 
• Placebo plus DTIC: matching placebo tablets administered PO BIW in each 3-week 
treatment cycle. DTIC 1000 mg/m2 will be administered IV Q21D. 
For subjects with 1 to 3 prior lines of treatment, randomization will be stratified as follows: 
• Number of prior systemic therapies (1 or >1) 
• ECOG PS score (0 or 1) 
• Histological tumor type (uterine versus nonuterine LMS) 
For subjects with at least 4 prior lines of treatment, randomization will be stratified as follows: 
• ECOG PS score (0 or 1) 
• Histological tumor type (uterine versus nonuterine LMS) 

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One treatment cycle will constitute 21 days. DTIC will be administered on Day 1 of each 3-week 
treatment cycle. Unesbulin or placebo tablets will be administered on Days 2 and 5 of Week 1 
and Days 1 and 4 of Weeks 2 and 3 of each 3-week treatment cycle (Note: the preferable 
duration between 2 doses of unesbulin/placebo is approximately 72 hours). Based on the results 
from a food effect assessment in the ongoing Phase 1b Study PTC596-ONC-007-LMS, it is 
recommended that unesbulin/placebo be administered with food. 
All subjects will receive treatment until evidence of disease progression, unacceptable toxicity, 
or other withdrawal criteria are met. No crossover will be permitted. 
Subjects will undergo weekly assessments throughout the study. The schedule of all study 
efficacy, safety, PK, and laboratory assessments is shown in Table 1, including a window for 
completion of the activities associated with each visit. Of note, activities designed to be 
completed in a single day, for example, PK sampling from before dosing to 8 hours postdose, 
may not be split up between the 2 days of a window. 
An end-of-treatment (EOT) assessment should be performed within 30 days after the end of 
treatment or until recovery from or stabilization of the AE, whichever occurs latest. For subjects 
requiring immediate initiation of a new treatment option, the EOT visit may be completed 
earlier. The EOT assessments are outlined in Table 1. A safety follow-up assessment should be 
performed by telephone call approximately 30 days (±3 days) after the EOT to assess AEs and 
concomitant medications. Survival follow-up (sFUP) assessments should be performed by phone 
every 3 months (±7 days) after the EOT until the later of 184 events or 2 years after the last 
subject is randomized. 
PK Assessment 
Approximately 12 randomized subjects will participate in a PK substudy at selected sites. These 
subjects will be assessed for PK of unesbulin, DTIC, and AIC. The target is for approximately 
7 PK evaluable subjects in the unesbulin group to complete Cycle 3. 
For the DTIC/AIC PK assessment, blood samples will be collected following an intensive 
schedule at predose and up to 24 hours postdose on Day 1 of Cycles 1 and 3. Sparse blood 
samples will be collected at predose and 1.25 and 4 hours postdose (start of infusion) on Day 1 
of Cycles 2 and 4. 
For unesbulin PK assessment, blood samples will be collected following an intensive schedule at 
predose and up to 24 hours postdose on Day 2 of Cycles 1 and 3. 
PK sample collection, processing, storage, and shipment will be performed according to 
instructions outlined in the laboratory manual separate from this protocol. The collected PK 
samples may also be used for further exploratory analysis of unesbulin and DTIC metabolism. 
Data Monitoring 
An independent Data Monitoring Committee (DMC) will be established and will review the 
interim safety data as per the DMC charter. In addition, one interim efficacy analysis will be 
performed (by an external vendor) and reviewed by the DMC. Based on the results of this 
interim analysis, the DMC will make recommendations to either continue or to stop the study. 
The DMC Charter (a separate document) and the DMC Statistical Analysis Plan (SAP) will 
provide detailed guidance for the conduct of the interim analysis. 

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3.2. 
Number of Subjects 
Assuming 19 months of enrollment time and a minimum of 6 months of follow-up for the 
primary endpoint, approximately 345 subjects are planned to be randomized: 300 subjects with 
1 to 3 prior lines of systemic therapy and an additional 45 subjects with at least 4 prior lines of 
systemic therapy. Enrollment into both cohorts will occur in parallel, but enrollment will be 
capped at 45 in the cohort of subjects with 4 or more prior lines of systemic therapy. 
3.3. 
Dose Adjustment and Stopping Criteria 
Tumor response assessments should continue uninterrupted every 6 to 9 weeks regardless of 
DTIC dosing/interruptions (see Schedule of Assessments). 
Safety laboratory assessments (ie, complete blood count [CBC] and complete metabolic panel 
[CMP]) will continue as per the Schedule of Assessments regardless of DTIC 
dosing/interruptions. 
The dose of unesbulin/placebo should not be reduced or held. However, any subject who 
experiences an intolerable toxicity should be withdrawn from the study drug if continuing would 
place them at risk based on ongoing benefit-risk assessment by the Investigator as described in 
Section 6.1.2. 
If treatment-related toxicities are observed, a stepped reduction in the dose of DTIC is permitted 
throughout the study, from the starting DTIC dose of 1000 to 850 mg/m2, followed by 700, 600, 
and 500 mg/m2. The following guidelines should be observed: 
• If a subject requires a dose reduction of DTIC to less than 500 mg/m2, then DTIC 
should be discontinued. 
• Subjects should receive all necessary supportive care including blood products, 
platelet transfusions, antiemetics, and antibiotics while being treated on this study. 
• The use of granulocyte colony-stimulating factor (eg, pegfilgrastim) and 
erythropoietin or thrombopoietin-stimulating agents is permitted per institutional 
practice and is encouraged prophylactically. 
If/when DTIC is on hold, unesbulin/placebo administration should continue uninterrupted BIW. 
DTIC should be reintroduced as soon as possible upon resolution of the hematological or 
nonhematological toxicity to a clinically acceptable level. Study staff should adhere to the 
following steps when DTIC is held due to toxicity during any treatment cycle: 
• All procedures should be completed as per the Schedule of Assessments while 
unesbulin/placebo dosing continues. 
• DTIC should be reintroduced at least 48 hours after unesbulin dosing. After DTIC is 
reintroduced, dosing should continue every 21 days regardless of when it is introduced in 
a 3-week treatment cycle with unesbulin/placebo. DTIC should not be administered on 
the same day as unesbulin/placebo dosing. 
• At the time when DTIC is reintroduced, clinical laboratory (ie, CBC and CMP) and body 
weight assessments must be performed within 24 hours prior to DTIC reintroduction. A 
single ECG must also be performed approximately 2 hours after reintroduction of DTIC 
if the interruption occurs within the first 3 treatment cycles. If DTIC is interrupted or held 

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in Cycle 3, then the same intensive PK sampling schedule for DTIC and 
unesbulin/placebo should be followed in the subsequent cycle as described in footnote 
“n” of the Schedule of Assessments. 
For instructions for managing hematological and nonhematological toxicities, refer to Table 2 
and Table 3, respectively. 
Table 2: 
Interventions for Common Hematological Toxicities by Grade 
Toxicity Grade 
DTIC Intervention 
Neutropenia 
Grade 1 (ANC <1500/mm3 to <LLN) 
Maintain same dose.  
Grade 2 (ANC 1000/mm3 to <1500/mm3) 
Maintain same dose. 
Grade 3 (ANC 500 to <1000/mm3) 
Hold DTIC until resolved to ≤Grade 2, then: 
If resolved ≤7 days, resume at original dose level. 
If resolved >7 days or second or subsequent 
occurrence, resume DTIC at one dose level lower. 
Consider addition of colony-stimulating factor (eg, 
pegfilgrastim) if not already employed. 
Grade 4 (ANC <500/mm3 or febrile 
neutropenia) 
Hold DTIC until resolved to ≤Grade 2, then restart at 
one dose level lower. 
Consider addition of colony-stimulating factor (eg, 
pegfilgrastim) if not already employed. 
Thrombocytopenia 
Grade 1 (PLT 75000 to <LLN) 
Maintain same dose. 
Grade 2 (PLT 50000 to <75000)  
Hold DTIC until resolved to ≤Grade 1, then: 
If resolved ≤7 days, resume at original dose level. 
If resolved >7 days or second or subsequent 
occurrence, resume DTIC at one dose level lower.  
Grade 3 (PLT 25000 to <50000)  
Hold DTIC until resolved to ≤Grade 1, then restart at 
one dose level lower.  
Grade 4 (PLT <25000) or thrombocytopenia 
with clinically significant bleeding 
Abbreviations: ANC, absolute neutrophil count; DTIC, dacarbazine; LLN, lower limit of normal; PLT, platelets 
Table 3: 
Interventions for Nonhematological Toxicities by Grade 
Toxicity Grade 
DTIC Intervention 
Grade 1 or 2 
Maintain same dose. 
Grade 3 or 4 
Manageable with supportive care 
Hold treatment until Grade ≤2, then restart at one dose 
level lower. 
Grade 3 or 4 
Not manageable with supportive care 
Hold treatment until Grade ≤2, then restart at one dose 
level lower. 
Abbreviations: DTIC, dacarbazine 
Note: Supportive care includes blood products, platelet transfusions, antiemetics, and antibiotics while being treated 
on this study. The use of granulocyte colony-stimulating factor (eg, pegfilgrastim) is permitted as per institutional 
practice and is encouraged prophylactically. 
3.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last subject in the study. 
3.5. 
Criteria for Study Termination 
Treatment will continue for each subject until evidence of unacceptable toxicity, disease 
progression, or another reason as detailed in Section 6. 

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4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
The following eligibility criteria are designed to select subjects for whom study participation is 
considered appropriate. All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject. Eligibility 
criteria may not be waived. Any questions regarding eligibility should be discussed with the PTC 
Medical Monitor before enrollment. 
4.1. 
Subject Inclusion Criteria 
Subjects must meet all criteria to be eligible for enrollment into the study. 
1. Subject is willing and able to provide informed consent 
2. Willingness and ability to comply with scheduled visits, drug administration plan, 
laboratory tests, other study procedures, and study restrictions 
3. Disease status including all of the following: 
a. Histological or cytological confirmation of LMS arising at any anatomic site except 
bone sarcoma 
b. Unresectable or metastatic, relapsed or refractory disease 
c. Measurable disease per RECIST 1.1 criteria 
d. Disease progression on previous treatment before screening or intolerability to other 
oncology treatments. 
Demographics: 
4. Age ≥18 years 
5. Male or female 
Performance status: 
6. ECOG PS score of 0 or 1 
Hematopoietic: 
7. Absolute neutrophil count ≥1500/mm3 without the use of growth factors in the past 
7 days 
8. Platelet count ≥100000/mm3 without platelet transfusion in the past 14 days 
9. Hemoglobin ≥9 g/dL (packed red blood cell transfusion is not allowed within 7 days) 
Hepatic: 
10. Bilirubin ≤ upper limit of normal (ULN) except for those patients with Gilbert’s 
syndrome 
11. Aspartate aminotransferase and alanine aminotransferase <3 times ULN 
12. Subjects with liver metastases may be enrolled 

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Pulmonary: 
13. Subjects with well-controlled asthma (eg, use of rescue medications <2 times per week 
over the last 12 months) or chronic obstructive pulmonary disease (eg, no exacerbations 
over the prior 3 months) may be enrolled. 
Renal: 
14. Creatinine <1.5 times normal OR creatinine clearance ≥60 mL/min 
Prior therapeutics: 
15. Toxicity from prior therapies recovered to Grade ≤1 or subject’s baseline, except for 
alopecia. In addition, endocrinopathies associated with prior immunotherapy-based 
treatments which are well controlled on replacement medication are not exclusionary. 
Chemotherapy and targeted therapy: 
16. At least 1 prior systemic cytotoxic or targeted therapy regimen for LMS, which may 
include but is not limited to single-agent doxorubicin or other anthracycline, doxorubicin 
plus ifosfamide, trabectedin, pazopanib, or gemcitabine with or without docetaxel 
Surgery: 
17. At least 4 weeks since prior surgery and recovered in opinion of investigator 
Other: 
18. Capable of swallowing oral medication 
19. Women of childbearing potential (WOCBP; as defined by the Clinical Trials Facilitation 
and Coordination Group [CTFG]) must have a negative serum pregnancy test at 
screening and agree to abstinence or the use of at least one of the following highly 
effective forms of contraception (with a failure rate of <1% per year when used 
consistently and correctly) (Clinical Trials Facilitation and Coordination Group 2020). 
Contraception or abstinence must be continued for the duration of the study and for at 
least 6 months after the last dose of study drug: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 
− Injectable 
− Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 

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• Bilateral tubal occlusion 
• Vasectomized partner with confirmed azoospermia 
All females will be considered of childbearing potential unless they are postmenopausal (at least 
12 months consecutive amenorrhea in the appropriate age group without other known or 
suspected cause) or have been sterilized surgically (eg, bilateral salpingectomy, hysterectomy, 
bilateral oophorectomy). 
20. Lactating females are not eligible unless they have agreed not to breastfeed their infants 
during treatment and for a period of 1 month following completion of treatment. 
21. Males who are sexually active with WOCBP and who have not had a vasectomy must 
agree to use a barrier method of birth control from the start of study drug administration 
through at least 6 months after the last dose of study drug. Males should not donate sperm 
from the start of study treatment through at least 6 months after the last dose of study 
drug. 
4.2. 
Subject Exclusion Criteria 
Subjects meeting any of the following criteria will not be eligible for enrollment: 
1. Received temozolomide or DTIC at any time 
2. Any other systemic anticancer therapy, including investigational agents, ≤3 weeks before 
initiation of study treatment. Additionally, subjects may not have received radiation 
≤3 weeks before initiation of study treatment. 
3. Known intolerance to DTIC or one or more of the excipients in unesbulin 
4. Co-existing active infection or any co-existing medical condition likely to interfere with 
study procedures, including: 
a. Significant cardiovascular disease (New York Heart Association Class III or IV 
cardiac disease), myocardial infarction within the past 6 months, unstable angina, 
congestive heart failure requiring therapy, unstable arrhythmia or a need for 
antiarrhythmic therapy, or evidence of ischemia on ECG, marked baseline 
prolongation of QT/QTc (corrected QT interval) interval, eg, repeated demonstration 
of a QTc interval >500 msec (Long QT Syndrome [congenital]) 
5. Human immunodeficiency virus, hepatitis B virus, or hepatitis C virus positivity 
6. History of solid organ transplantation 
Therapeutics: 
7. Known or suspected allergy or immediate or delayed hypersensitivity to unesbulin or 
DTIC, their excipients, or any agent given in this study 
Gastrointestinal: 
8. Bowel obstruction, malabsorption, or other contraindication to oral medication 
9. Gastrointestinal disease or other conditions that could affect absorption. Active peptic 
ulcer disease, active gastritis, or previous history of gastric perforation within the last 
2 years. 

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10. Inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), 
diverticulitis, cholecystitis, symptomatic cholangitis, or appendicitis 
Wounds/surgery: 
11. Serious non-healing wound, ulcer, or bone fractures 
12. Major surgery, open biopsy, or significant traumatic injury that has not recovered, in the 
opinion of the investigator, within 28 days of baseline 
13. Mucosal or internal bleeding 
Concomitant medications: 
14. Concomitant strong CYP1A2 inhibitors (such as fluoroquinolones [broad spectrum 
quinolone antibiotics, including enoxacin and ciprofloxacin] and selective serotonin 
reuptake inhibitor [SSRI] agents fluvoxamine and fluoxetine) should be avoided on the 
same day that DTIC or unesbulin/placebo is administered. CYP1A2 inhibitors may 
inhibit the conversion of DTIC to its active metabolite and may increase the exposure of 
unesbulin. 
15. Concomitant use of moderate CYP1A2 inducers (such as phenytoin, rifampin, ritonavir, 
teriflunomide, and barbiturates). Chronic use of marijuana should be avoided, but 
irregular recreational use may be permitted at the discretion of the treating Investigator. 
CYP1A2 inducers may increase the conversion of DTIC to its active metabolites. 
16. Coadministration of acid-reducing agents should be avoided approximately 4 hours 
before and after unesbulin/placebo administration. 
17. Immunization with a live vaccine within 30 days before starting study drug due to the 
risk of serious and life-threatening infections. 
Other: 
18. Prior malignancies, other than LMS, that required treatment or have shown evidence of 
recurrence (except for non-melanoma skin cancer or adequately treated cervical 
carcinoma in situ, prostate cancer in situ or any other low risk malignancy that is 
approved by the medical monitor) during the 5 years before initiation. Cancer treated 
with curative intent more than 5 years previously and without evidence of recurrence is 
not an exclusion. 
19. Known coagulopathy or bleeding diathesis. Subjects on anticoagulation should be 
monitored closely and International Normalized Ratio and/or activated partial 
thromboplastin time (APTT)/prothrombin time (PT) should be within the required range 
where applicable. 
20. Prior or ongoing clinically significant illness, medical or psychiatric condition, medical 
history, physical findings, ECG findings, or laboratory abnormality that, in the 
investigator’s opinion, could affect the safety of the subject, or alter the absorption, 
distribution, metabolism, or excretion of the study drugs, or could impair the assessment 
of study results. 
21. History of brain metastases or leptomeningeal disease at any time in subject’s history, 
including treated central nervous system (CNS) disease. 

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4.3. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but do not 
meet eligibility criteria. Individuals who do not meet the criteria for participation in this study 
due to a laboratory test result may be retested once within the screening period. Subjects who fail 
screening may be considered for rescreening after consultation with the PTC Medical Monitor. 

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5. 
STUDY INTERVENTION MATERIALS AND MANAGEMENT 
5.1. 
Description of Study Drug 
Unesbulin drug product is an immediate-release tablet formulation for oral use, manufactured 
following current GMP. Unesbulin tablets for oral administration will be provided in strengths of 
50 mg (white to off-white round tablets) and 200 mg (white to off-white oval tablets). Matching 
placebo tablets for oral administration will also be provided. Unesbulin and placebo tablets will 
be provided in high-density polyethylene bottles with a heat induction seal. 
DTIC for injection will be provided (by the site or the sponsor) and will be reconstituted with 
Sterile Water for Injection, USP. The resulting solution contains 10 mg/mL of DTIC having a pH 
of 3.0 to 4.0. The reconstitution step may be modified based on institutional policy and or the 
availability of a specific strength of the DTIC vial to obtain a resulting DTIC solution of 
10 mg/mL. 
5.2. 
Study Intervention Preparation and Administration 
Unesbulin 300 mg or placebo will be administered PO BIW in combination with DTIC 
1000 mg/m2 administered IV Q21D. Participants should be instructed to not take 
unesbulin/placebo on the same day as DTIC administration. Additionally, unesbulin/placebo 
should not be dosed on consecutive days, and preferably at least 3 days (72 hours) between each 
unesbulin/placebo dose. If a subject misses a dose of unesbulin/placebo, then every attempt 
should be made to administer within 24 hours. Otherwise, the subject should skip the dose and 
take unesbulin/placebo at the next scheduled dosing day. 
Coadministration of acid-reducing agents should be avoided approximately 4 hours before and 
after unesbulin/placebo administration. 
Placebo tablets will be supplied and administered in a blinded manner to subjects BIW in 
combination with DTIC per the same dosing schedule as for unesbulin. 
Based on the results from a food effect assessment in the ongoing Phase 1b 
Study PTC596-ONC-007-LMS, it is recommended that unesbulin/placebo be administered with 
food. 
For subjects who cannot swallow the whole tablet, unesbulin/placebo tablets can be dispersed in 
water at the same dose level at which the tablets are being dosed and be administered orally. The 
entire dispersion is administered to the subject and taken as soon as possible (within 15 minutes 
of mixing), ensuring consumption of the entire content with adequate rinsing. Please refer to the 
Pharmacy Manual for additional details. 
If a subject vomits following dosing with unesbulin/placebo, then the unesbulin/placebo tablet 
may be readministered if the vomiting occurs within 3 minutes of dosing and the tablet contents 
(white matter) can be seen in the vomitus. If these 2 conditions are not met, then 
unesbulin/placebo should not be readministered until the next scheduled dosing day. 
After DTIC is reconstituted (Section 5.1), the calculated dose of the resulting solution is drawn 
into a syringe. The reconstituted solution is further diluted with 5% Dextrose Injection, USP or 
0.9% Sodium Chloride, USP and administered as an IV infusion over 1 hour ±30 minutes. 
Within 30 minutes before DTIC administration, the following premedication regimen is 
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16 mg PO once. The premedication regimen as per institutional practice is allowed. Refer to 
Section 3.3 for instructions on DTIC dose interruptions and dose modifications due to toxicity. 
5.3. 
Storage, Handling, and Accountability 
5.3.1. 
Storage 
Unesbulin/placebo tablets should be stored at controlled room temperature (68°F-77°F [20°C-
25°C]) with excursions allowed between 59°F and 86°F (15°C-30°C). 
After reconstitution and before use, DTIC solution in the vial may be stored at 4°C for up to 
72 hours or at normal room conditions (temperature and light) for up to 8 hours. If the 
reconstituted solution is further diluted in 5% Dextrose Injection, USP or 0.9% Sodium Chloride, 
USP, the resulting solution may be stored at 4°C for up to 24 hours or at normal room conditions 
for up to 8 hours. 
5.3.2. 
Handling and Accountability 
Study personnel must ensure that all study drug supplies are kept in a secure locked area with 
access limited to authorized personnel. Study drug must not be used outside the context of this 
protocol. Under no circumstances should the investigator or site personnel supply study drug to 
other investigators or clinics or allow study drug to be used other than as directed by this 
protocol. 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
PTC or designee including, but not limited to, the date received, lot number, amount received, 
amount returned, and the disposition of all study drug products. Drug accountability records that 
include the subject’s assigned study number, date and amount of study drug dispensed, and 
relevant lot numbers must also be maintained by the site. 
Unused clinical supplies or study drug must be returned to PTC or its designee. Records 
documenting the date of study drug destruction or shipping, relevant lot numbers, and amount 
destroyed or shipped should be kept in the investigator site study file. Study drug must be 
returned to PTC or its designee, except where sites are destroying study drug per their local 
standard operating procedures (SOPs). In order for a site to destroy study drug on site, the site 
must submit their SOP to PTC for review to confirm adequacy and fulfill PTC requirements. 
5.4. 
Study Intervention and Compliance 
A subject medication diary will be given to subjects to record unesbulin/placebo dosing at home 
and will be dispensed at Day 1 of each cycle or at other visits, as needed, to ensure compliance. 
Subjects should bring the diary back at the scheduled visits for review with the research staff to 
assess treatment compliance. 
5.5. 
Concomitant Medications 
To the extent possible, administration of any prescription or over-the-counter drug products other 
than study drug should be minimized during the study period and the investigator and/or staff 
should be informed. Subjects should be discouraged from use of street drugs, herbal remedies, 
self-prescribed drugs, tobacco products, or excessive use of caffeinated products and alcohol at 
any time during their participation in the study. 

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If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator. Neither approved 
nor guideline-recommended therapy options should be withheld from subjects if the investigator 
determines it is in the best interest of the subject. The decision to authorize the use of any drug 
other than study drug should account for subject safety, the medical need, the potential for drug 
interactions, the possibility for masking symptoms of a more significant underlying event, and 
whether use of the drug will compromise the outcome or integrity of the study. 
Immunization with live vaccines should be avoided throughout treatment and at least 30 days 
before or after treatment due to the risk of serious and life-threatening infections. 
Subjects should receive full supportive care, including antiemetics and antidiarrheals as 
appropriate. 
Conversion of DTIC to the pharmacologically active metabolite is mainly mitigated by CYP1A2, 
and to a lesser degree by CYP1A1. The metabolism of unesbulin is mitigated by multiple 
CYP450 enzymes, mainly by CYP1A2, while CYP2D6, CYP2E1, and CYP3A4 may also be 
involved. Coadministration of a strong CYP1A2 inhibitor may increase unesbulin exposure. 
Concomitant use of strong CYP1A2 inhibitors (such as fluoroquinolones [broad spectrum 
quinolone antibiotics, including enoxacin and ciprofloxacin] and SSRI agents fluvoxamine and 
fluoxetine) should be avoided on the same day that DTIC or unesbulin/placebo is administered. 
Unesbulin is identified as a strong CYP1A2 inhibitor and should not be administered with DTIC 
at the same time. Concomitant use of moderate CYP1A2 inducers (such as phenytoin, rifampin, 
ritonavir, teriflunomide, and barbiturates) should be avoided. Chronic use of marijuana should be 
avoided, but irregular recreational use may be permitted at the discretion of the treating 
Investigator. CYP1A2 inducers may increase the conversion of DTIC to its active metabolites. 
Coadministration of acid-reducing agents (eg, antacids, histamine H2-receptor antagonists, and 
proton pump inhibitors) should be avoided approximately 4 hours before and after 
unesbulin/placebo administration. As a reminder, subjects should not have active peptic ulcer 
disease, active gastritis, or previous history of gastric perforation within the last 2 years. 
For orally administered medications, breast cancer resistance protein (BCRP)-mediated PK-
related interactions could contribute to interactions within the gastrointestinal tract due to the 
expression of BCRP in that region. However, the absolute bioavailability following oral 
administration of unesbulin in fasted cynomolgus monkeys was estimated to be 100%. A 
relatively high absolute bioavailability is also expected in humans, which would limit the impact 
of BCRP-mediated interactions with unesbulin. This will be investigated in a human absorption, 
metabolism, and excretion (AME) study. Until results from the AME study are available, it is 
recommended that BCRP substrates, inhibitors, and inducers (such as curcumin, orange juice, 
apple juice, cranberry juice, and grape juice) be avoided within 4 hours before or after 
unesbulin/placebo administration. 
Interactions of unesbulin with the substrates of the organic anion transporter polypeptide 
transporters, OATP1B1 and OATP2B1, have not been assessed clinically. Therefore, caution 
should be exercised if coadministration of unesbulin/placebo is required with OATP1B1 and 
OATP2B1 substrates. Investigators are encouraged to consult with PTC for further guidance. 

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5.6. 
Randomization and Blinding 
Subjects will be randomized 2:1 to either unesbulin plus DTIC or placebo plus DTIC using a 
central randomization process. For subjects with 1 to 3 prior lines of treatment, randomization 
will be stratified by the number of prior systemic therapies (1 or >1), ECOG PS score (0 or 1), 
and histological tumor type (uterine or nonuterine LMS). For subjects with at least 4 prior lines 
of treatment, randomization will be stratified by ECOG PS score (0 or 1) and histological tumor 
type (uterine or nonuterine LMS). 
The investigator and study staff (including processing lab personnel), the subjects, and the 
sponsor’s staff (with exception of Pharmacovigilance staff for the purposes of suspected 
unexpected serious adverse reaction [SUSAR] reporting) will remain blinded until the primary 
analysis is completed. The investigational drug and its matching placebo are indistinguishable 
and will be packaged in the same way. 
The randomization code will be kept strictly confidential. Further details are provided in the 
Pharmacy Manual. 
5.6.1. 
Emergency Procedure for Unblinding 
The investigator and the study staff must remain blinded to the subject’s treatment assignment. 
The blind may be broken by the investigator only if specific emergency treatment would be 
dictated by knowing the treatment assignment. The investigators have the ability to unblind via 
the Interactive Response Technology system. 
In all cases, PTC must be informed as soon as possible before or after the code break. 
Any code break must be documented in a detailed report with the date and time of the code break 
and signed by the investigator. 

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6. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
6.1.1. 
Discontinuation of Study Intervention 
If after appropriate consideration of study drug interruption/modification and consultation with 
the PTC Medical Monitor, it is not appropriate for a subject to continue with study treatment, 
then the study drug must be permanently discontinued. After permanent discontinuation of study 
drug for a safety concern, and if the initial event was reported as a serious adverse event (SAE) 
then a follow-up SAE report form should be completed. In the case of a treatment 
discontinuation due to an event that is not an SAE, the PTC Medical Monitor should be notified. 
In addition, details regarding the reasons for discontinuation and the AEs leading to the 
discontinuation should be recorded in the source documents and in the appropriate electronic 
case report form (eCRF). 
The EOT visit should be completed within 30 days after the end of treatment (Table 1) or until 
recovery from or stabilization of the AE, whichever comes last. For subjects requiring immediate 
initiation of a new treatment option, an EOT visit may be completed earlier. 
6.1.2. 
Participant Discontinuation/Withdrawal from the Study Drug or Study 
All subjects who receive study drug should remain in the study whenever possible. However: 
• The subject has the right to withdraw consent and discontinue study drug or the study 
at any time. 
• Any subject who experiences progression of disease (per RECIST 1.1) must 
discontinue the study drug. 
• Any subject whose condition substantially changes or experiences intolerable toxicity 
after entering the study should be carefully evaluated by the investigator in 
consultation with the PTC Medical Monitor. Such subjects should be withdrawn from 
the study drug if continuing would place them at risk. 
• Any subject who becomes pregnant must discontinue the study drug. 
• Any subject who becomes significantly noncompliant with study drug administration, 
study procedures, or study requirements should be withdrawn from study drug. 
• The investigator may withdraw the subject from study drug if, in the investigator’s 
clinical judgment, it is not in the subject’s best interest to continue. 
• This study may be discontinued by the relevant regulatory authority and/or PTC at 
any time. 
The date that study drug is discontinued and the reason for discontinuation will be recorded in 
the source documents and in the eCRF. The PTC Medical Monitor (or designee) should be 
informed via email when a subject discontinues study drug or withdraws from the study. 
When study drug is discontinued, the investigator is expected to perform all evaluations required 
at the EOT visit and any additional evaluations that may be necessary to ensure that the subject is 
free of untoward effects. 

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6.1.3. 
Lost to Follow-up 
A subject who repeatedly fails to return for scheduled visits and is unable to be contacted by the 
study site will be considered lost to follow-up. 
The following actions should be taken if a subject fails to return to the clinic for a required study 
visit: 
• Attempt to contact the subject and reschedule the missed visit as soon as possible and 
counsel the subject on the importance of maintaining the assigned visit schedule and 
determine whether or not the subject wishes to and/or should continue in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to contact the subject. These contact attempts should be documented in 
the subject’s medical record. 

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7. 
STUDY ASSESSMENT AND PROCEDURES 
7.1. 
Assessment of Efficacy 
Response assessments will be performed by radiological imaging using RECIST 1.1 criteria 
every 6 weeks (±7 days) until disease progression. After Cycle 8, scans may be performed every 
9 weeks. If any subject responds with a CR or PR at any assessment, then the subsequent 
confirmatory scan should be performed 4 weeks (+5 days) after the previous scan where the 
objective response was first evidenced. Assessment of response and the primary endpoint, PFS, 
will be assessed by an independent central reader who will be blinded to treatment assignment. 
Subjects should be followed with the same imaging procedure throughout the study. Computed 
tomography scans or magnetic resonance imaging may be used as clinically indicated. If the 
subject withdraws for reasons other than tumor progression, an EOT scan should be performed if 
the last scan was ≥3 weeks earlier. 
Survival follow-up will continue by phone every 3 months until the later of 184 events or 2 years 
after the last subject is randomized. 
7.2. 
Assessment of Safety 
7.2.1. 
Safety Parameters 
Subjects will be monitored closely for AEs and laboratory abnormalities during the study. All 
AEs that occur after any subject has been enrolled, before treatment, during treatment, or within 
30 days following the cessation of treatment, whether or not they are related to the study, must 
be recorded on forms provided by PTC. 
For AEs and laboratory abnormalities, the investigator should use his/her judgment in 
determining whether the event or abnormality is clinically significant, whether diagnostic 
evaluation is warranted, and whether potential interruption of study drug therapy is appropriate. 
In general, life-threatening (Grade 4) or severe (Grade 3) AEs or laboratory abnormalities should 
be considered clinically significant, although recurrent or persistent moderate events (Grade 2) 
may also be considered clinically significant in certain circumstances. Reference should be made 
to the NCI Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE V5.0) for 
grading the severity of AEs and laboratory abnormalities. 
While specific monitoring, diagnostic testing, and supportive care measures must be instituted 
based on the clinical judgment of the investigator, investigators should contact the PTC Medical 
Monitor to obtain guidance and to ascertain whether similar events are being seen at other sites. 
The PTC Medical Monitor should be notified of any AE or laboratory abnormality that leads to 
dose interruption and should be apprised of ancillary laboratory or other diagnostic findings and 
the evolving data from any work-up of the initial abnormality. The PTC Medical Monitor may 
suggest review of the case with consultants or with other experts (either at the site or retained by 
PTC). 
Additional safety assessments include vital signs, ECGs, physical examinations, and ECOG PS 
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7.3. 
Adverse Events and Serious Adverse Events 
7.3.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence after exposure to a drug in humans, whether or not it 
is considered related to the drug. An AE can therefore be any unfavorable or unintended sign 
(including an abnormal laboratory finding), symptom, or disease in a study subject who is 
administered study drug in this study. 
For this protocol, untoward medical occurrences that should be reported as AEs include the 
following: 
• All AEs during treatment with study drug administration 
• All AEs resulting from medication misuse, abuse, withdrawal, or overdose of study 
drug 
• All AEs resulting from medication errors such as dispensing or administration error 
outside of what is described in the protocol 
• Apparently unrelated illnesses, including worsening of a preexisting illness 
• Injury or accidents. Note that if a medical condition is known to have caused the 
injury or accident (a fall secondary to dizziness), the medical condition (dizziness) 
and the accident (fall) should be reported as 2 separate AEs. The outcome of the 
accident (hip fracture secondary to the fall) should be recorded in source documents. 
• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test) 
• Laboratory or ECG abnormalities that require clinical intervention or further 
investigation (beyond ordering a repeat [confirmatory] test) unless they are associated 
with an already reported clinical event. Laboratory abnormalities associated with a 
clinical event should be captured in the source documents. Laboratory abnormalities 
not requiring clinical intervention or further investigation will be captured as part of 
overall laboratory monitoring and should not be reported as AEs. 
• A preexisting condition (eg, allergic rhinitis) must be noted on the appropriate eCRF 
but should not be reported as an AE unless the condition worsens, or episodes 
increase in frequency during the AE reporting period. 
• Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, 
should not be reported as AEs. However, the medical condition for which the 
procedure was performed should be reported if it meets the definition of an AE. For 
example, an acute appendicitis that occurs during the treatment with study drug 
should be reported as the AE and the resulting appendectomy should be recorded in 
the source documents and eCRF. If a surgical procedure was planned before entry 
into the study, and the surgery is not performed because of a worsening of a baseline 
condition, this should not be reported as an AE. Note that, as described in 
Section 7.3.2, any hospitalization occurring as the consequence of an AE during the 
study period should be reported as an SAE. 

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Each AE is to be classified as serious or nonserious by the investigator using medical and 
scientific judgment. 
7.3.2. 
Definition of Serious Adverse Events 
An SAE is an untoward medical occurrence or effect that occurs after exposure to a study drug at 
any dose, regardless of whether it is considered to be related to the study drug, which results in 
one of the following: 
• Results in death. This includes all deaths on treatment or within 30 days after last 
study drug administration, including deaths due to disease progression. Any death 
occurring later than 30 days following the last dose need not be reported as an SAE 
unless it is a result of an event that started within the period covered by the on-study 
definition. The reported AE should be the event that caused the death. In addition, 
any AE resulting in death that occurs subsequent to the AE reporting period and that 
the investigator assesses as possibly related to the study drug should also be reported 
as serious. 
• Is life-threatening. This refers to an event in which the subject was at risk of death at 
the time of the event. It does not include an event that, had it occurred in a more 
severe form, hypothetically might have caused death. 
• Requires hospitalization or prolongation of existing hospitalization (excluding 
hospitalizations for administration of the study drug, procedures required by the study 
protocol, or treatment-related diagnostic procedures; other planned hospitalizations; 
or hospitalizations related only to progression of disease). 
• Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed in the definition above. These should also usually be considered 
serious. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
• Additionally, hospitalization should be used as an indicator of the seriousness of the 
AE and should only be used for situations where the AE truly fits this definition and 
not for hospitalizations associated with less serious events (eg, a hospital visit where 
subject is admitted for observation or minor treatment [eg, hydration] and released in 
less than 24 hours). Furthermore, hospitalization for PK sampling, if needed, is not an 
AE. 
• Results in persistent or significant disability or incapacity or substantial disruption of 
the ability to conduct normal life functions, not related to cancer. 
• Any other medically important event that the investigator or PTC judges to be serious 
or which is defined as serious by the regulatory agency in the local country. These are 
AEs that might not be immediately life-threatening or result in death or 
hospitalization but might jeopardize the subject or might require intervention to 
prevent one of the other outcomes listed above. Medical judgment should be 

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exercised in deciding whether an AE is serious based on above definition. Examples 
of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
• A pregnancy resulting in spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly (including that in an aborted fetus). 
Note that any SAEs occurring from signing of consent form through 30 days after the end of the 
subject’s participation in the study (last dose) should be reported to PTC if the investigator 
becomes aware of them. 
7.3.2.1. 
Disease Progression 
An event need not be reported as an SAE if it exclusively represents a relapse or an expected 
change or progression of the baseline cancer. In case of fatal outcome with disease progression, 
it should be reported in “Results in death” subsection (refer to Section 7.3.2). 
7.3.3. 
Unexpected Adverse Events 
The Reference Safety Information (RSI) will be used for assessing expectedness. The RSI for the 
purpose of expedited safety reporting for unesbulin is located in Section 7 of the Unesbulin IB. 
The RSI for DTIC may be found in local dacarbazine Product Information or Summary of 
Product Characteristics. 
If an event is not listed in the RSI, it should be considered unexpected, or if the AE occurs at a 
greater severity, specificity, or frequency, it should be considered unexpected. 
7.3.4. 
Eliciting Adverse Event Information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
subject. In addition, each study subject will be questioned about AEs at each scheduled clinic 
visit after study drug administration or during any telephone contact with the subject. The type of 
question asked should be open-ended, for example, “How have you been feeling?” or a similar 
type of query. 
7.3.5. 
Recording Nonserious Adverse Events 
All AEs (both serious and nonserious) that occur in subjects during the AE reporting period must 
be recorded, whether or not the event is considered drug related. In addition, any untoward event 
that occurs subsequent to the AE reporting period that the investigator assesses as possibly 
related to the investigational drug/product should also be recorded as an AE. 
All AEs are to be recorded in the source documents and on the eCRF using concise medical 
terminology; whenever possible, terms contained in the Medical Dictionary for Regulatory 
Activities (MedDRA) should be employed. In addition, the following information should be 
recorded: 
• Indication of whether the event is nonserious or serious (see Section 7.3.1 and 
Section 7.3.2, respectively) 
• Relationship to study drug (see Section 7.3.6) 

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• Severity of the event (see Section 7.3.7) 
• Onset date 
• Date of resolution or date of death 
• Action taken 
• Outcome of the event 
• Whether the AE resulted in discontinuation from the study or treatment 
Classification of the event as serious or nonserious determines the reporting procedures to be 
followed. 
7.3.6. 
Describing Adverse Event Relationship to Study Drug 
The investigator should provide an assessment of the relationship of the AE to the study drug 
(ie, whether there is a reasonable possibility that the study drug caused the AE) using the 
considerations outlined in Table 4. 
Table 4: 
Relationship of Study Drug to Adverse Event 
Relationship Category 
Description 
Probable 
A clinical event in which a relationship to the study drug seems probable 
because of such factors as consistency with known effects of the drug; a 
clear temporal association with the use of the drug; improvement upon 
withdrawal of the drug; recurrence upon rechallenge with the drug; lack of 
alternative explanations for the event. 
Possible 
A clinical event occurring coincident with administration of the study drug 
and which may or may not be explained by concurrent disease or other 
drugs or chemicals. Information on drug withdrawal or rechallenge may be 
lacking. 
Unlikely  
A clinical event with a temporal relationship to the study drug exposure that 
does not preclude causality but for which there is a clear alternate cause 
that is more likely to have caused the adverse event than study drug. Such 
alternatives include a concomitantly administered drug, the subject’s 
disease state, other medical conditions, or environmental factors. 
Unrelated 
A clinical event, for which a relationship to the study drug seems 
improbable because of factors such as inconsistency with known effects of 
the study drug, lack of a temporal association with study drug 
administration, lack of association of the event with study drug withdrawal 
or rechallenge, and/or presence of alternative explanations for the event. 
Alternative explanations might include a known relationship of the adverse 
event to a concomitant drug, medical history of a similar event, the subject’s 
disease state, other medical conditions, or environmental factors. 
7.3.7. 
Grading of Severity of Adverse Event 
The severity of AE will be graded using the latest version of the NCI CTCAE V5.0 (refer to 
Study Manual). For each episode, the highest severity grade attained should be reported. 
If an NCI CTCAE V5.0 criterion does not exist, the investigator should use the grade or 
adjectives: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the AE. For purposes of consistency with 
the NCI CTCAE V5.0, these intensity grades are defined in Table 5. 

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Table 5: 
Grading of Adverse Events 
Grade 
Severity Grade 
Description 
1 
Mild 
Sign or symptom is present, but it is easily tolerated, is not 
expected to have a clinically significant effect on the subject’s 
overall health and well-being, does not interfere with the 
subject’s usual function, and is not likely to require medical 
attention 
2 
Moderate 
Sign or symptom causes interference with usual activity or 
affects clinical status, and may require medical intervention 
3 
Severe 
Sign or symptom is incapacitating or significantly affects 
clinical status and likely requires medical intervention and/or 
close follow-up 
4 
Life-threatening 
Sign or symptom results in a potential threat to life 
5 
Fatal 
Sign or symptom results in death 
7.3.8. 
Reporting Adverse Events 
Investigator site reporting requirements for AEs are summarized in Table 6. 
Table 6: 
Investigator Site Requirements for Reporting Adverse Events 
Event 
Recorded in the 
eCRF 
Reported on the SAE Report Form to PTC 
Pharmacovigilance Within 24 Hours of Awareness 
Serious AE 
All 
All 
Nonserious AE 
All 
None 
Exposure to 
the study drug 
during 
pregnancy or 
breastfeeding, 
and 
occupational 
exposure 
All (regardless of 
whether associated 
with an AE), except 
occupational exposure 
Exposure during pregnancy, exposure via breastfeeding, 
occupational exposure (regardless of whether associated 
with an AE) 
Abbreviations: AE, adverse event; eCRF, electronic case report form; SAE, serious adverse event 
All AEs should be followed up by the investigator until they are resolved, or the investigator 
assesses them as chronic or stable. The investigator should consider protocol guidelines and use 
his/her discretion in ordering additional tests as necessary to monitor the resolution of such 
events. In the event of additional investigations, the PTC Pharmacovigilance Department or 
designee should be informed via email or fax. A subject withdrawn from the study because of an 
AE must be followed by the investigator until clinical recovery is complete and laboratory results 
have returned to normal, or until progression has been stabilized. Follow-up may need to 
continue after the subject has discontinued from the study, and additional investigations may be 
requested by the PTC Medical Monitoring team. 
The first day of AE reporting will coincide with the date of signing of the informed consent form 
(ICF) and will include a minimum of 30 calendar days after the last administration of study drug. 
7.3.9. 
Serious Adverse Events Reporting 
All SAEs occurring from the signing of the ICF through 30 days after the end of the subject’s 
participation in the study (last dose) should be reported via the SAE report form to PTC 
immediately but no later than 24 hours of becoming aware of the event(s). In addition, the AE 
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The SAE report form should be signed by the investigator; however, if the investigator is unable 
to sign at the time of the event or within 24 hours, the form should be signed by the clinical staff 
member reporting the SAE (eg, the study coordinator). The SAE report form must be faxed or 
emailed to the PTC Pharmacovigilance Department or designee and to the site Institutional 
Review Board (IRB) or Institutional Ethics Committee (IEC) (if required by local regulations) 
within 24 hours. 
Follow-up information to the SAE should be clearly documented as “follow-up” in the SAE 
report form and must also be faxed or emailed to the same party. All follow-up SAE report forms 
for the event must be signed by the investigator. Any source documents (eg, progress notes, 
nurses’ notes, laboratory and diagnostic test results, discharge summaries) provided to PTC 
should be redacted so that the subject’s name, address, and other personal identity information 
are obscured. Only the subject’s study number and initials are to be provided (in regions where 
the provision of such information is permitted). The information in the AE portion of the eCRF 
and the SAE report form(s) must match or be reconciled. Where the same data are collected, the 
forms must be completed in a consistent manner. For example, the same AE term should be used 
on both forms. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (for example, if a subject initially seeks treatment elsewhere), the investigator is to 
report the event within 24 hours after learning of it and to document his/her first awareness of the 
AE. 
The PTC Pharmacovigilance Department contact information for reporting SAEs is provided 
below. This information is also provided in the SAE report form. 
PTC Therapeutics Safety Department 
Attention: Pharmacovigilance 
Email: Pharmacovigilance@ptcbio.com 
Facsimile (USA): +1 (908) 325-0355 
7.3.10. 
Contraception 
For pregnancy testing and contraception requirements in WOCBP and contraception 
requirements and sperm donation limitations in males who are sexually active with WOCBP, see 
the corresponding inclusion criteria in Section 4.1. 
7.3.11. 
Reporting Pregnancy 
PTC should be notified if a female subject in the study, or a female partner of a male subject in 
the study, becomes pregnant on study or within 30 days of the last administration of study drug. 
The pregnancy must be reported on a Pregnancy Notification Form (see Study Manual for 
details). 
This must be done whether or not an AE has occurred and within 24 hours of awareness of the 
pregnancy. The information submitted should include the anticipated date of birth or pregnancy 
termination. 
Written consent is required before collecting and reporting any information on a female partner 
of a male subject in the study. 

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If possible, the investigator should follow the subject, or the pregnant female partner of a male 
subject, until completion of the pregnancy and notify the PTC Medical Monitor of the outcome 
within 5 days or as specified below. The investigator will provide this information as a follow-up 
to the initial Pregnancy Notification Form via the Pregnancy Outcome Form (see Study Manual 
for details). 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(ie, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus]), the investigator should follow the procedures for reporting SAEs, ie, report the 
event to the PTC Pharmacovigilance Department or designee and follow up by submission of 
appropriate AE eCRFs (see Section 7.3.9). 
7.3.12. 
PTC Safety Reporting Requirement 
In compliance with local requirements, PTC shall immediately notify the investigators of any 
new or emerging safety information that impacts the benefit-risk ratio of the drug, once 
confirmed by the executive safety review board. This will include any urgent measures that need 
to be taken with respect to the protocol. 
As the sponsor of the study, PTC is responsible for reporting certain safety information, 
particularly SUSARs and other significant findings, as appropriate per local reporting 
requirements, to each investigator in an expedited manner. If PTC is notified of a SUSAR 
requiring expedited reporting to investigators, PTC or its designated representative will contact 
each investigational site participating in this study by email, fax, and/or overnight mail such that 
the investigator can promptly notify the site IRB/IEC per their local requirements. The initial 
expedited safety report will be provided as required according to local regulations (eg, within 
15 days) after the earliest date PTC or an agent of PTC (eg, a site monitor) becomes aware of an 
SAE. This awareness date is the date the regulatory reporting clock begins, and the date is 
considered Day 0. 
7.4. 
Pharmacokinetics 
For the subset of subjects who provide consent, blood samples per PK sample interval will be 
collected for the determination of DTIC, AIC, and unesbulin. PK sample collection, processing, 
storage, and shipment will be performed according to instructions outlined in the laboratory 
manual separate from this protocol. The collected PK samples may also be used for further 
exploratory analysis of unesbulin and DTIC metabolism. 
Approximately 12 subjects will be assessed for PK of unesbulin, DTIC, and AIC. Blood samples 
will be collected according to the schedule shown in Table 1. 
Plasma samples may be used to explore metabolism and additional biomarkers post-PK analysis 
if remaining volume of sample is sufficient. If such exploratory analyses are to proceed, then the 
study will be conducted at a designated laboratory, and a separate report may be issued. 
7.5. 
Patient-Reported Outcomes 
HRQoL will be assessed using the EORTC QLQ-C30 and the EQ-5D-5L according to the 
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The EORTC QLQ-C30 is a widely used, validated 30-item, quality-of-life questionnaire 
developed by the European Organisation for Research and Treatment of Cancer (Aaronson 1993, 
Giesinger 2016). This health-related questionnaire encompasses 15 outcomes in total: 
5 functional scales (physical, role, cognitive, emotional, and social functioning), a global quality-
of-life scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items 
(appetite loss, diarrhea, dyspnea, constipation, insomnia, and financial impact).  
The EQ-5D-5L is a frequently used, standardized patient-reported HRQoL that measures 
5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression (Herdman 2011). Each dimension has 5 levels: no problems, slight problems, 
moderate problems, severe problems, and extreme problems. 
7.6. 
Biomarkers 
Blood samples (10 mL) will be collected at screening (predose) and prior to dosing on Day 1 of 
Cycle 3 and at the time of disease progression or EOT for all subjects for analyzing ccfDNA. By 
targeted DNA sequencing, the presence of ccfDNA containing known mutations associated with 
LMS will be assessed. Samples will be retained for no more than 5 years after collection. 

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8. 
STATISTICS 
A SAP will be prepared and approved before the interim analysis to provide a more detailed 
description of the nature of the analyses and the manner in which results will be compiled. The 
SAP will include details of the statistical models to be used and the test statistics to be employed. 
8.1. 
Statistical Hypotheses 
The null hypothesis for the primary efficacy endpoint is that there is no difference in PFS 
between unesbulin plus DTIC versus placebo plus DTIC. The alternative hypothesis is that 
unesbulin plus DTIC increases PFS. The null hypothesis corresponding to the key secondary 
endpoint is that there is no difference in OS between subjects treated with unesbulin plus DTIC 
when compared to those treated with placebo plus DTIC. The alternative hypothesis is that 
unesbulin plus DTIC increases OS. 
8.2. 
Sample Size Determination 
The sample size for the primary analysis was computed based on the comparison of PFS between 
subjects randomized to unesbulin plus DTIC and subjects randomized to placebo plus DTIC. The 
median PFS was assumed to be approximately 1.5 to 2.5 months for the placebo plus DTIC 
group and more than 4 months for the unesbulin plus DTIC group. With an overall one-sided 
alpha level of 0.025, a total of 245 events are required to achieve at least 90% power at a hazard 
ratio of 0.5. Assuming 19 months of enrollment time, a minimum follow-up period of 6 months 
for the primary endpoint, and approximately 11.5% uniform dropout rate, a total of 300 subjects 
are planned to be randomized. 
One interim analysis will be performed when approximately 36% of the PFS events occur 
(approximately 88 events). The study may stop for both efficacy and futility. The study may stop 
for efficacy if the observed hazard ratio is less than 0.447, and the study may stop for futility if 
the observed hazard ratio is more than 0.67. 
The alpha allocation will be controlled separately at the interim and the final analysis timepoints 
by using the Lan-DeMets spending function that approximates the O’Brien-Fleming approach. 
The family-wise significance level is 0.025, with 0.000184 allocated at the interim analysis and 
0.024816 at the final analysis. 
For the key secondary endpoint OS, sample size is based on detecting a hazard ratio of 0.625 
(median OS of 10 months versus 16 months, for placebo plus DTIC vs unesbulin plus DTIC, 
respectively) and a minimum 15-month follow-up. With 184 events (among 265 subjects) a 
1-sided 0.025 level log-rank test will have approximately 84% power. 
A separate group sequential design and monitoring will be performed for OS, with one interim 
analysis performed when at least 60% of the OS events occur and a final OS analysis when 
184 events occur. The alpha allocation will be controlled by using the Lan-DeMets spending 
function that approximates the O’Brien-Fleming approach.  
Data from the additional 45 subjects enrolled with at least 4 prior lines of therapy will not be 
included in the primary analysis; rather, the efficacy analysis of data from these subjects will be 
considered exploratory and included as a sensitivity analysis only. 

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8.3. 
Analysis Populations 
Intent-to-treat (ITT) population: will include all randomized subjects. Subjects will be 
grouped based on the group they are randomized to. If a subject receives treatment in the group 
different from the one to which he/she was randomized, the subject’s efficacy data will be 
analyzed “as randomized.” The ITT population will be used as sensitivity analysis for all 
efficacy analysis. 
Modified Intent-to-treat (mITT) population: will include randomized subjects with 3 or less 
line of therapy. The mITT population will be used in all the efficacy analysis, including analyses 
of the primary and secondary endpoints. Subjects will be grouped based on the group they are 
randomized to. If a subject receives treatment in the group different from the one to which he/she 
was randomized, the subject’s efficacy data will be analyzed “as randomized.” 
Safety population: will include all subjects who received at least one dose of study drug 
(unesbulin/placebo or DTIC). If a subject receives treatment in the group different from the one 
to which he/she was randomized, the subject’s safety data will be analyzed “as treated.” The 
Safety population will be used in the statistical analyses for safety. 
PK population: will include safety population subjects who have at least one plasma 
concentration of unesbulin, DTIC, or AIC. 
8.4. 
Statistical Analyses 
8.4.1. 
General Approach 
Summary tables for continuous variables will contain the following statistics: N, mean, median, 
standard deviation, standard error, minimum, maximum, and 95% CIs as appropriate. Summary 
tables for categorical variables will include N and percentage in each category. Graphical 
techniques will be used when such methods are appropriate and informative. By-subject listings 
will be created. 
Transformations of the data may be explored if warranted by the distribution of the data. 
8.4.2. 
Analysis of Primary Efficacy Endpoints 
The primary endpoint in this study is PFS. PFS is defined as the time from the randomization 
date to the date of the first documented tumor progression as determined by the independent, 
blinded radiologist using RECIST 1.1 or death due to any cause, whichever occurs first. Clinical 
deterioration in the absence of unequivocal evidence of progression (per RECIST 1.1) is not 
considered progression for purposes of determining PFS. Subjects who die without a reported 
prior progression will be considered to have progressed on the date of their death. Subjects who 
did not progress or die will be censored on the date of their last evaluable tumor assessment if 
they did not receive subsequent anticancer therapy (including on-treatment palliative 
radiotherapy of non-target bone lesions, skin lesions, or CNS lesions). Subjects who received any 
subsequent anticancer therapy without a prior reported progression will be censored at the last 
evaluable tumor assessment before or on the date of initiation of the subsequent anticancer 
therapy. 
All hypotheses testing will be one-sided based on a significance level of 0.025 based on the 
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The distribution of PFS will be compared in the unesbulin and placebo groups via a log-rank test. 
For subjects with 1 to 3 prior lines of systemic therapy, this will be stratified by prior lines of 
therapy (1 versus >1), ECOG PS score (0 versus 1), and LMS origin (uterine versus nonuterine). 
For subjects with at least 4 prior lines of systemic therapy, this will be stratified by ECOG PS 
score (0 versus 1) and LMS origin (uterine versus nonuterine). The hazard ratio and the 
corresponding 95% CI will be estimated in a stratified Cox proportional hazards model using 
randomized group as the single covariate. The PFS curves for each randomized group will be 
estimated using the Kaplan-Meier (KM) product-limit method. Two-sided, 95% CIs for median 
PFS will be computed by Brookmeyer and Crowley method (using log-log transformation). PFS 
rates at 3, 6, 12, 18, 24, and 30 months will also be estimated using KM estimates on the PFS 
curve for each randomized group. Associated two-sided 95% CIs will be calculated using the 
Greenwood formula. 
8.4.3. 
Analysis of Key Secondary Efficacy Endpoint 
The key secondary endpoint is OS. OS is defined as the time from the randomization date to the 
date of death from any cause. For subjects who are alive, survival time will be censored at the 
date of last contact (“last known alive date”). 
OS will be compared between the two treatment groups, provided the primary endpoint PFS is 
statistically significant favoring the test treatment arm. A hierarchical testing procedure will be 
utilized. 
Two analyses are planned for OS: the first (interim) at the time of the final analysis for PFS 
(provided PFS is significant), at which point the information fraction for OS will be at least 60% 
and a second (final) analysis when 184 events have accumulated. Details will be provided in the 
study SAP. 
8.4.4. 
Analysis of Other Secondary Efficacy Endpoints 
Other secondary efficacy endpoints include ORR, DCR or CBR, and DoR. 
ORR is defined as the proportion of subjects who achieve a confirmed best response of CR or PR 
using RECIST 1.1 as per independent radiologist assessment. BOR is defined as the best 
response designation recorded between randomization date and the date of objectively 
documented progression per RECIST 1.1 or the date of initiation of subsequent therapy or 
palliative local therapy, whichever occurs first. For subjects without documented progression or 
subsequent therapy or palliative local therapy, all available response designations will contribute 
to the BOR determination. 
DCR or CBR is defined as the proportion of subjects with BOR of CR, PR, or at least 3 months 
of SD. 
DoR is defined as the time from the date of first confirmed response to the date of the first 
documented tumor progression (per RECIST 1.1) or death due to any cause, whichever occurs 
first. Subjects who neither progress nor die will be censored on the date of their last evaluable 
tumor assessment. Subjects who started any subsequent anticancer therapy without a prior 
reported progression will be censored at the last evaluable tumor assessment before or on the 
date of initiation of the subsequent anticancer therapy. DoR will be evaluated for responders 
only. 

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The same statistical models applied to the analysis of PFS will be applied to the analysis of OS 
(Section 8.4.2). 
BOR will be summarized by response category for each treatment group. ORR will be computed 
in each treatment group along with the exact 95% CI using Clopper-Pearson method. An 
estimate of the difference in ORRs and corresponding 95% CI will be calculated using Cochran-
Mantel-Haenszel methodology and adjusted by the same stratification factors as in primary 
analysis of PFS. 
DCR will be analyzed the same way as ORR. 
DoR in each treatment group will be estimated using KM product-limit method for subjects who 
achieve PR or CR. Median values along with two-sided 95% CI will be calculated. 
8.4.5. 
Safety Analyses 
The safety analysis will be performed for all treated subjects. Descriptive statistics of safety will 
be presented using NCI CTCAE V5.0 by treatment group. All TEAEs will be tabulated by 
system organ class and MedDRA preferred term. On-study laboratory abnormalities including 
hematology and chemistry will be summarized using worst grade per NCI CTCAE V5.0 criteria. 
8.4.5.1. 
Adverse Events 
AEs will be tabulated using the MedDRA classification system. The frequency of subjects 
experiencing a specific AE will be tabulated by treatment group, system organ class, preferred 
term, seriousness (nonserious versus serious), worst severity, outcome, and relationship to study 
drug. Subject with AEs leading to death or to discontinuation from treatment, and SAEs will be 
listed. 
An AE will be defined as treatment emergent if one of the following criteria is met:  
• A new AE has an onset date on or after the date that study drug (unesbulin/placebo or 
DTIC) is first administered through 30 days after the last dose of study drug.  
• A preexisting AE worsens in severity on or after the date that study drug is first 
administered through 30 days after the last dose of study drug. 
8.4.5.2. 
Laboratory Abnormalities 
The severity of laboratory abnormalities will be graded using the NCI CTCAE V5.0 whenever 
possible. The frequency of subjects experiencing a specific laboratory abnormality will be 
tabulated by treatment group and worst severity. In addition, the number and percentage of 
subjects experiencing a specific laboratory abnormality will be tabulated similarly. 
8.4.5.3. 
Other Safety Assessments 
The results of vital sign measurements, body weight assessments, ECG assessments, ECOG PS 
score determinations, and screening/baseline physical examination will be summarized by 
treatment group by using appropriate descriptive statistics. 

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8.4.6. 
Baseline Descriptive Statistics 
8.4.6.1. 
Disposition 
Subjects who did not complete the treatment or study will be summarized. Reasons for 
treatment/study discontinuation will be summarized. 
8.4.6.2. 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics at study entry will be summarized with 
frequency tables for categorical variables and descriptive statistics such as the mean, standard 
deviation, median, and range, as appropriate, for quantitative variables.  
8.4.6.3. 
Medical History and Prior Medication 
Medical history and prior medication information will be summarized by treatment group. 
8.4.7. 
Extent of Exposure, Treatment Compliance, and Concomitant Medications 
Exposure to study drug will be summarized descriptively by treatment group. 
Treatment compliance will be assessed in terms of the percentage of drug actually taken relative 
to the amount that should have been taken during the study. 
Concomitant medication information will be summarized by treatment group. 
8.4.8. 
Exploratory Analyses 
8.4.8.1. 
Pharmacokinetics 
Unesbulin, DTIC, and AIC plasma concentrations will be determined by the bioanalytical 
laboratory at ICON, Lenexa, Kansas, USA, using validated liquid chromatography with tandem 
mass spectrometry (LC-MS/MS) methods. 
PK parameters for unesbulin, DTIC, and AIC will be calculated using the actual sample 
collection times. PK variables will be calculated from the plasma concentration data using 
standard compartmental or noncompartmental methods, as appropriate for the data. Variables of 
interest include Tmax, Cmax, area under the concentration-time curve (AUC), T½ for all 
compounds (ie, unesbulin, DTIC, and AIC), and clearance (CL) and volume of distribution (Vz) 
for DTIC only. Plasma concentrations and PK parameter results will be presented in tabular and 
graphic form by cycle and dose level. 
8.4.8.2. 
Patient-Reported Outcomes 
HRQoL will be assessed using the EORTC QLQ-C30 and the EQ-5D-5L. PROs will be 
summarized descriptively. 
8.4.8.3. 
Biomarkers 
Biomarkers will be summarized descriptively by treatment group. Relationship of biomarkers 
with PFS and OS will be explored. 

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8.4.9. 
Planned Interim Analysis 
One interim analysis is planned when approximately 36% of PFS events occur (approximately 
88 events). For additional details, refer to Section 8.2. 
8.4.10. 
Subgroup Analyses 
The primary endpoint (PFS), key secondary endpoint (OS), and ORR will be summarized by 
subgroups of the stratification factors using the mITT population. 
Efficacy endpoints for the subgroup of subjects with at least 4 prior lines of treatment will be 
analyzed separately. 

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9.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
9.1. 
Regulatory, Ethical, and Study Oversight Considerations
9.1.1. 
Ethics
9.1.1.1. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements, 
and the PTC’s policy on Bioethics. 
9.1.1.2. 
Institutional Review Board 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. In addition, the IRB or IEC must 
approve all advertising used to recruit patients for the study. The investigator must submit 
written approval to PTC before he or she can enroll any subject into the study. All materials 
approved by the IRB for this study including the ICF and recruitment materials must be 
maintained by the investigator and made available for inspection. 
The investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements. The protocol must be re-approved by the IRB or IEC 
upon receipt of amendments and annually, as local regulations require. 
The investigator is also responsible for providing the IRB with reports of any reportable serious 
adverse drug reactions from any other study conducted with the investigational product. PTC 
will provide this information to the investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
9.1.1.3. 
Informed Consent 
By signing the protocol, the investigator assures that informed consent will be obtained from 
each subject before study entry and that the informed consent will be obtained in accordance 
with current regulations. 
The investigator or site delegate will give each subject full and adequate verbal and written 
information regarding the objectives and procedures of the study and the possible risks involved. 
An informed consent document will be provided to each subject in a language in which the 
subject is fluent. This information must be provided to the subject before undertaking any study-
related procedure. Adequate time should be provided for the subject to read the informed 
consent, to understand the risks and benefits of participating in the study, and to ask any 
questions that the subject may have about the study. The subject should be able to ask additional 
questions as and when needed during the conduct of the study. The subject’s signature on the 
ICF should be obtained at the investigator site in the presence of the investigator or a qualified 
representative (eg, site delegate). 
Each subject will be given a copy of the signed consent form. The original signed ICFs will be 
retained by the investigator with the study records. 

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The written subject information must not be changed without prior approval by PTC and the 
IRB. 
9.1.2. 
Study Discontinuation and Closure 
PTC reserves the right to discontinue the study before inclusion of the intended number of 
subjects. The investigator, after consultation with the PTC Medical Monitor, reserves the right to 
discontinue the study at the investigator site for safety reasons at any time. 
After a decision to terminate the study, investigators must contact all subjects who are continuing 
their participation in the study and must do so within a period set by PTC. As directed by PTC, 
all study materials must be collected, and all electronic data entry forms completed to the 
greatest extent possible. 
9.1.3. 
Confidentiality and Privacy 
Research records will be collected and stored in a manner that protects the confidentiality of 
subject information. The names and identities of all research subjects will be kept in strict 
confidence and will not appear on eCRFs or other records provided to or retained by PTC (or its 
authorized designee). The names and identities of the subjects need not be divulged; however, 
the records must nevertheless be inspected. This will be accomplished by blanking out the 
subject’s name and replacing the name with the subject’s study identification number on any 
record provided to or retained by PTC. The ICF must include appropriate statements explaining 
these requirements. 
By signing this protocol, the investigator affirms to PTC that the investigator will maintain, in 
confidence, information furnished by PTC and will divulge such information to the IRB under an 
appropriate understanding of confidentiality with such board. 
9.1.4. 
Data Monitoring Committee 
External oversight for this study will be provided by a DMC. The primary responsibility of the 
DMC is to protect the safety and welfare of subjects participating in this clinical study and to 
ensure the integrity of the clinical study. To maintain the blinding and integrity of the study, 
procedures will be implemented to ensure the DMC and independent statistician have sole access 
to unblinded safety data. 
Specifically, for this study, the DMC will be responsible for: 
• Examining accumulated safety data and compliance data to make recommendations 
concerning continuation, termination, or modification of the study based on the safety 
of the interventions under study 
• Reviewing the general progress of the study including accrual, protocol violations, 
and study conduct 
The DMC will review the interim efficacy and safety data as described in Section 8.2. The DMC 
may review the efficacy and safety data at other times as warranted by emerging results. Based 
on review of the efficacy and safety data, the DMC can recommend continuation of the study 
unchanged, study interruption, study termination, modification of the study, or alteration. Full 
details of the DMC procedures, including primary responsibilities, will be documented in a DMC 
Charter. 

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9.1.5. 
Data Handling and Recordkeeping 
To enable evaluations and/or audits from regulatory authorities or PTC, the investigator agrees to 
keep accurate and complete records, including the identity of all participating subjects (sufficient 
information to link eCRFs and clinic records/source documents), all original signed ICFs, 
electronic copies (ie, CD-ROM, USB, etc.) or paper copies of the data that have been captured in 
the eCRF for each subject, and detailed records of study drug disposition. All records and 
documents pertaining to the study will be maintained by the investigator until notification is 
received from PTC that the records no longer need to be retained. 
The investigator must obtain written permission from PTC before disposing of any records. The 
investigator will promptly notify PTC in the event of accidental loss or destruction of any study 
records. If the investigator relocates, retires, or for any reason withdraws from the study, the 
study records may be transferred to an acceptable designee, such as another investigator, another 
institution, or to PTC, as applicable. 
If it becomes necessary for PTC or the Regulatory Authority to review any documentation 
relating to the study, the investigator must permit access to such records. 
9.1.6. 
Direct Access to Source Data/Documents 
9.1.6.1. 
Study Monitoring 
In accordance with 21 Code of Federal Regulations Part 312.56 and/or relevant ICH guidelines, 
PTC or a designee will periodically inspect all eCRFs, study documents, research facilities, and 
clinical laboratory facilities associated with this study at mutually convenient times, before, 
during, and after completion of the study. As required by applicable regulations (Responsibilities 
of Sponsors and Investigators), the monitoring visits provide PTC with the opportunity to 
evaluate the progress of the study; verify the accuracy and completeness of data in the eCRFs; 
ensure that all protocol requirements, relevant regulations, and investigator’s obligations are 
being fulfilled; and resolve any inconsistencies in the study records. This includes inspection of 
all documents and records required to be maintained by the investigator, including but not 
limited to medical records (office, clinic, or hospital) for the subjects in this study. The names 
and identities of all research subjects will be kept in strict confidence and will not appear on 
eCRFs or other records provided to or retained by PTC. 
The investigator/institution guarantees direct access to source documents, the drug storage area, 
drug accountability records, and other study-related records and areas by PTC and appropriate 
regulatory authorities. It is important that the investigator and relevant institutional personnel are 
available during the monitoring visits and possible audits or inspections, and that sufficient time 
is devoted to the process. 

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9.1.6.2. 
Audits and Inspections 
To ensure compliance with GCP and all applicable regulatory requirements, PTC, PTC’s 
representatives, a regulatory authority, or IRB may conduct a quality assurance audit. Reasons 
for quality assurance audit may include but are not limited to random selection, geographic 
proximity, suspected GCP violation, high enrolling site, recurring protocol deviations, etc. The 
purpose of a PTC audit or inspection is to systematically and independently examine all study-
related activities and documents to determine whether these activities were conducted, and data 
were recorded, analyzed, and accurately reported according to the protocol, GCP guidelines of 
the ICH, and any applicable regulatory requirements. The investigator should contact PTC 
immediately if contacted by a regulatory agency about an inspection. 
9.1.7. 
Future Use of Stored Specimens and Data 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for exploratory research. The investigator or authorized designee will explain to each subject the 
objectives of the exploratory research and make clear that their participation is optional. 
PTC will have access to de-identified subject data regarding mutations that are identified through 
genetic sequencing of tumor biopsy(ies). 
9.1.8. 
Quality Control and Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, PTC may conduct a 
quality assurance audit. Please see Section 9.1.6.2 for more details regarding the audit process. 
9.1.9. 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. Deviations may result from the action or 
inaction of the subject, investigator, or site staff. Examples of deviations include, but are not 
limited to: 
• Failure to adhere to study exclusion and inclusion criteria 
• Failure to comply with dispensing or dosing requirements 
• Use of medications that are specifically prohibited in the protocol 
• Missed or out-of-window visits 
• Drug dosing not administered within the time frame specified in the protocol 
• Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, PK blood draws, medical history, etc—either tests not done, incorrect 
tests done, or not done within the time frame specified in the protocol 
• Procedural deviations such as incorrect storage of study drug, failure to update the 
ICF when new risks become known, or failure to obtain IRB approvals for the 
protocol and ICF revisions 

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At the outset of the study, a process for defining and handling protocol deviations will be 
established with the site. This will include determining which deviations will be designated 
significant; thus, requiring immediate notification to the PTC Medical Monitor and/or other PTC 
designee. 
Prospective deviations (eg, protocol waivers) are prohibited per PTC policy. 
Significant deviations are any deviations that impact subject eligibility (ie, protocol 
inclusion/exclusion violations), subject safety, or a subject’s ability to continue in the clinical 
study. 
The investigator is responsible for seeing that any known protocol deviations are recorded and 
handled as agreed. 
9.1.10. 
Publication Policy 
The information developed during the conduct of this clinical study is considered confidential by 
PTC. This information may be disclosed as deemed necessary by PTC. 
PTC intends that the data from this study will be presented and published. The PTC staff under 
the direction of the PTC or designee in collaboration with the investigator will be responsible for 
writing presentations and manuscripts for publication. Investigators will not be allowed to 
publish or present the data from this study without prior agreement with PTC. 
The investigator is obliged to provide PTC with complete test results and all study data. During 
the study, only PTC may make study information available to other study investigators or to 
regulatory agencies, except as required by law or regulation. Except as otherwise allowable in 
the Clinical Study Site Agreement, any public disclosure (including publicly accessible websites) 
related to the protocol or study results, other than study recruitment materials and/or 
advertisements, is the sole responsibility of PTC. 
PTC may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail. 
Data from all sites participating in the study will be pooled and analyzed by PTC or PTC’s 
designee. The first publication of the study results shall be made in conjunction with the results 
from other study sites as a multicenter publication. If a multicenter publication is not 
forthcoming within 24 months of completion of the study at all sites, the investigator may 
publish or present the results generated at his or her site. 

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The investigator will provide PTC with a copy of any proposed publication or presentation for 
review and comment at least 60 days before such presentation or submission for publication. 
PTC shall inform the investigator in writing of any changes or deletions in such presentation or 
publication required to protect PTC’s confidential and proprietary technical information and to 
address inaccurate data or inappropriate interpretations in the context of any pooled multicenter 
results. At the expiration of such 60-day period, the investigator may proceed with the 
presentation or submission for publication unless PTC has notified the institution or the 
investigator in writing that such proposed publication or presentation discloses PTC’s 
confidential and proprietary technical information. Further, upon the request of PTC, the 
investigator will delay the publication or presentation for an additional 90 days to permit PTC to 
take necessary actions to protect its intellectual property interests. 
9.2. 
Protocol Amendment History 
Original Protocol Issued: 20 December 2021 
Version 2.0: 31 January 2022 
Version 3.0: 28 April 2023 
Version 4.0: 28 November 2023 
9.2.1. 
Version 2.0: 31 January 2022 
Overall reason for Version 2.0: The overall reason for Version 1.0 of the protocol was to 
modify the timing and description of the interim analysis for futility and efficacy evaluation. 
Table 7: 
Summary of Changes for Global Amendment Version 1.0 to Version 2.0 
Item 
No. 
Protocol 
Section 
Summary of Change 
Reason/ 
Rationale 
1 
Protocol 
The version number and date were updated throughout. 
The synopsis was updated to be consistent with the changes in 
the protocol.  
Update 
2 
Signature 
Page 
The company title was updated for a Responsible Medical 
Officer.  
Update 
2 
Schedule of 
Assessments 
A “X” was added in the Screening column to indicate that the 
ECOG assessment is to be done as part of Screening. 
Clarification 
3 
Table 2 
The lower limit of Grade 1 thrombocytopenia platelet count was 
changed from 750000 to 75000. 
Clarification 
4 
Synopsis, 
Section 8.2 
Section 8.4.9 
Section 9.1.4 
The timing and description of the interim analysis for futility and 
efficacy evaluation were modified. 
Update 
Abbreviations: ECOG, Eastern Cooperative Oncology Group 
9.2.2. 
Version 3.0: 28 April 2023 
Overall reason for Version 3.0: The overall reason for Version 3.0 of the protocol is to 
incorporate comprehensively all modifications requested by country-specific health authorities 
and Ethics Committees in response to the Clinical Trial Application. Additional updates were 
made for improved clarity and study conduct. A summary of changes from global Version 2.0 to 
Version 3.0 is presented below, along with country-specific summaries of changes from the 
latest local amendment to Version 3.0. 

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Table 8: 
Summary of Changes From Global Protocol Version 2.0 to Version 3.0 
Item 
No. 
Protocol Section 
Summary of Change 
Reason/ 
Rationale 
1 
Protocol 
The version number and date were updated 
throughout. The synopsis was updated to be 
consistent with the changes in the protocol. The 
title page was modified to conform with the new 
clinical trial protocol template. 
Update 
2 
Global Update 
Minor editorial changes were made throughout for 
grammar and clarity. 
Update 
3 
Global Update 
Considering the study is blinded, “placebo” was 
added to statements pertaining to the 
administration and handling of both unesbulin and 
placebo, where applicable. 
Update/ 
clarification 
4 
Protocol Identifiers 
and Study Personnel 
Changes in PTC study staff and contact 
information. 
Update 
5 
Synopsis, Section 2.5, 
Section 8.4.3, and 
Section 8.4.10 
It was specified that OS is the key secondary 
endpoint. Additional details describing the 
analysis of this key secondary endpoint were 
added to the Synopsis, Section 8.4.3, and 
Section 8.4.10. 
Health authority 
request 
6 
Synopsis, Section 2.5, 
and Section 8.4.4  
Clarified that at least 3 months of stable disease 
was required in the definition of DCR and CBR. 
Clarification 
7 
Synopsis, Section 3.1, 
and Section 7.4  
Clarified that approximately 12 subjects will be 
assessed for PK. 
Clarification 
8 
Synopsis and 
Section 3.1  
The DMC will not review the interim data for 
sample size re-evaluation; this has been clarified. 
The timing for the DMC meetings was removed 
and replaced with a reference to the DMC charter. 
It was clarified that the interim efficacy analysis 
will be performed by an external vendor. 
Update and 
clarification 
9 
Synopsis, Schedule of 
Assessments, and 
Section 3.3  
It was clarified that no dose reduction of 
unesbulin/placebo is permitted. For subjects who 
have interruptions in DTIC due to toxicities, 
detailed instructions on timing of assessments 
relative to continued unesbulin/placebo dosing 
were added to the protocol.  
Clarification 
10 
Synopsis and 
Section 4.1  
An exception to Inclusion Criterion #10 was added 
for patients with Gilbert’s syndrome who have 
elevated bilirubin values. 
Update based 
on feedback 
from 
investigators 
11 
Synopsis and 
Section 4.1  
Inclusion Criterion #11 was modified to increase 
the eligibility limit for AST and ALT from 1.5 to 3 
times the ULN. 
Update based 
on feedback 
from 
investigators 
12 
Synopsis and 
Section 4.1  
It was clarified in Inclusion Criterion #16 that prior 
lines of treatment may include but are not limited 
to single-agent doxorubicin or other anthracycline, 
doxorubicin plus ifosfamide, trabectedin, 
pazopanib, or gemcitabine with or without 
docetaxel. 
Health authority 
request 

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Item 
No. 
Protocol Section 
Summary of Change 
Reason/ 
Rationale 
13 
Synopsis Inclusion 
Criterion #19, 
Section 4.1, and 
Section 7.3.11  
Contraception or abstinence was extended from 
90 days to 6 months for WOCBP as per CTFG 
guidance, Section 2.2.2, for products with 
demonstrated or suspected human 
teratogenicity/fetotoxicity. Pregnancy reporting 
was updated accordingly.  
Align with CTFG 
guidelines and 
DTIC Technical 
Data Sheet 
14 
Synopsis Inclusion 
Criterion #21, 
Section 4.1, and 
Section 7.3.11  
Contraception, including avoidance of sperm 
donation, was extended from 90 days to 6 months 
for men as per the Technical Data Sheet for DTIC. 
Pregnancy reporting for female partners of male 
subjects were updated accordingly. 
Align with DTIC 
Technical Data 
Sheet 
15 
Synopsis and 
Section 4.2  
Exclusion Criterion #5: Removed “known” prior to 
human immunodeficiency virus, hepatitis B virus, 
or hepatitis C virus positivity because viral testing 
will be required for all subjects at screening. 
Clarification 
16 
Synopsis, Section 4.2, 
and Section 5.5  
The criterion excluding the concomitant use of 
NSAIDs was deleted because the potential risk for 
gastrointestinal perforation was mitigated by 
adding gastritis to Exclusion Criterion #9. 
A statement was added to the Concomitant 
Medication Section 5.5 as a reminder that 
subjects should not have active peptic ulcer 
disease, active gastritis, or previous history of 
gastric perforation within the last 2 years. 
Update based 
on feedback 
from 
investigators 
17 
Synopsis, Section 4.2, 
and Section 5.5  
Exclusion Criterion #15 was modified to provide 
clarifications on the chronic use of marijuana. 
Clarification 
18 
Synopsis, Section 4.2, 
and Section 5.5  
Administration of live vaccines was added as an 
Exclusion Criterion (#17) and as a concomitant 
medication. 
Health authority 
request 
19 
Synopsis, Section 4.2  
APTT/PT assessments were added to Exclusion 
Criterion #19 to monitor subjects on 
anticoagulation where applicable. It was clarified 
that coagulation tests should fall within the 
required range (instead of “normal”) considering 
the patient disease and demographic 
characteristics. 
Health authority 
request and 
investigator 
feedback 
20 
Synopsis, Section 3.1, 
and Section 5.2  
Based on the results from a food effect 
assessment in the ongoing Phase 1b Study 
PTC596-ONC-007-LMS, it is recommended that 
unesbulin/placebo be administered with food. 
Update 
21 
Synopsis and 
Section 5.1  
PTC may provide DTIC to sites that are unable to 
procure it locally. 
Procedural 
change 
22 
Synopsis and 
Section 5.1  
Instructions to reconstitute DTIC were added to 
accommodate variation in institutional policies.  
Update 
23 
Synopsis and 
Section 5.2  
The window to administer DTIC was widened from 
1 hour ± 5 minutes to 1 hour ± 30 minutes to allow 
sites more flexibility to administer this study drug. 
Procedural 
change 
24 
Synopsis and 
Section 7.1  
To align with the Schedule of Assessments, 
clarified that after Cycle 8, scans may be 
performed every 9 weeks. 
Clarification 

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Item 
No. 
Protocol Section 
Summary of Change 
Reason/ 
Rationale 
25 
Synopsis, Schedule of 
Assessments 
(footnote “k”), and 
Section 7.1  
It was clarified that either MRI or CT could be 
used as clinically indicated. 
Health authority 
request 
26 
Schedule of 
Assessments, 
Figure 1, Section 3.1, 
and Section 6.1.1  
To accommodate patient management and care 
and AE stabilization (as applicable), a more 
flexible timeframe for the EOT visit was provided. 
Update 
27 
Schedule of 
Assessments 
For urinalysis, an “X” was added to EOT. 
Update 
28 
Schedule of 
Assessments 
Footnote “f”: It was clarified that weight must be 
assessed on the day of DTIC administration. 
Clarification 
29 
Schedule of 
Assessments 
Footnote “g”: It was clarified that local laboratory 
testing is acceptable. The window of clinical 
laboratory testing on Day 1 of Cycle 1 prior to the 
first dose of study drug was extended to up to 
72 hours to allow sites flexibility over weekends. 
After Cycle 3, monthly clinical laboratory testing 
will be adjusted in the protocol so that sampling 
will be performed once every cycle instead of on a 
weekly basis. 
The urinalysis assessment in the footnote was an 
error; this was replaced with a CMP to be 
performed at the same frequency as the CBC 
assessments. Instructions for performing 
laboratory assessments were added in case DTIC 
is interrupted/held due to toxicity. 
Request by 
participating 
sites to 
decrease 
subject and staff 
burden 
30 
Schedule of 
Assessments 
For serum pregnancy testing, an “X” was deleted 
from Day 5 of Cycle 2 and added to Day 1 of 
Cycle 2. A pregnancy test prior is required within 
24 hours or dosing on C1D1, and this may be 
assessed with a urine test. In footnote “h”, it was 
also clarified that a urine or serum pregnancy test 
should be performed 24 hours prior to dosing on 
Day 1 of Cycle 2 and continuing every 2 cycles 
beginning with Cycle 4. 
Clarification and 
health authority 
request 
31 
Schedule of 
Assessments 
Footnotes “i” and “j”: Instructions were added for 
performing the single ECG in cases if/when DTIC 
is interrupted or held. 
ECGs will not be required after Cycle 3. 
Clarification and 
procedural 
change based 
on cumulative 
safety data in 
the clinical 
program 
32 
Schedule of 
Assessments 
The following text in footnote “j” was deleted: “On 
Day 1 of all other cycles and at the time of 
collection for sparse PK samples, approximately 
2 hours after DTIC infusion.” and was replaced 
with “Approximately 2 hours after DTIC infusion 
on Cycle 2.” 
Clarification 

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Item 
No. 
Protocol Section 
Summary of Change 
Reason/ 
Rationale 
33 
Synopsis, Schedule of 
Assessments 
(footnote “m”), and 
Section 7.6  
Timing and mandatory collection of biomarker 
samples was clarified. Footnote “m” was updated 
as follows: “Blood samples (10 mL) to assess 
circulating biomarkers will be collected at 
screening (predose) and prior to dosing on Day 1 
of Cycle 3 and at the time of disease progression 
or EOT. Samples will be processed, stored, and 
shipped according to instructions in the laboratory 
manual.” 
Clarification 
34 
Schedule of 
Assessments 
Footnote “n”: Instructions for performing PK 
sampling in case of DTIC interruption/hold were 
added. 
Clarification 
35 
Schedule of 
Assessments 
(footnote “o”) and 
Section 5.4  
Subjects are encouraged to bring back the patient 
diary at all scheduled visits. 
Procedural 
change 
36 
Schedule of 
Assessments and 
Section 5.2  
Footnote “p”: Reference to Section 3.3 was added 
for instructions on DTIC dosing in case of toxicity. 
Clarification 
37 
Schedule of 
Assessments 
Footnote “q”: Instructions were added for 
administering unesbulin/placebo in case of DTIC 
interruption. 
Clarification 
38 
Section 1.1  
A reference to the ESMO-EURACAN-GENTURIS 
(European Society for Medical Oncology; 
European Reference Network for Rare Adult Solid 
Cancers; European Reference Network for  
Genetic Tumour Risk Syndromes) Clinical 
Practice Guidelines by Gronchi et al was added. 
Health authority 
request 
39 
Section 1.3  
A statement was added in Section 1.3 referring 
investigators to the Investigator’s Brochure for 
additional information and guidance on mitigating 
potential drug-drug interactions. 
Health authority 
request 
40 
Schedule of 
Assessments and 
Section 3.3  
Procedural guidelines for DTIC interruptions were 
added. Instructions for modifying dose of DTIC in 
the case of nonhematological toxicities were 
added. It was clarified that the dose of 
unesbulin/placebo should not be reduced or 
withheld. 
Clarification and 
Health authority 
request 
41 
Section 3.4  
A definition of the end of study was added to the 
protocol. 
Health authority 
request 
42 
Section 5.2  
Instructions were added for subjects who cannot 
swallow the whole tablet. Specifically, tablets can 
be dispersed in water at the same dose level at 
which the tablets are being dosed and be 
administered orally. Instructions were added to 
provide guidance in cases of a subject who 
misses a dose of unesbulin/placebo or vomits 
after unesbulin/placebo dosing. It was clarified 
that coadministration of acid-reducing agents 
should be avoided approximately 4 hours before 
and after unesbulin/placebo administration to 
make instructions in this section consistent with 
other sections. 
Clarifications 
and process 
updates 

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Item 
No. 
Protocol Section 
Summary of Change 
Reason/ 
Rationale 
43 
Section 5.5  
It was added that neither approved nor guideline-
recommended therapy options should be withheld 
from subjects if the investigator determines it is in 
the best interest of the subject. Immunization with 
live vaccines should be avoided. Updated 
guidelines were added for mitigating potential 
BCRP, OATP1B1, and OATP2B2 interactions with 
unesbulin. Clarifications on chronic use of 
marijuana was added, along with a reminder on 
enrolling subjects with active peptic ulcer disease, 
active gastritis, or history of gastric perforation 
within the last 2 years. 
Update based 
on new data and 
Health authority 
request 
44 
Section 5.6.1  
The following statement was removed: “Before 
unblinding, the investigator must make every 
attempt to discuss the intended code break with 
PTC.” 
Health authority 
request 
45 
Synopsis and 
Section 7.1  
It was clarified that survival follow-up will continue 
every 3 months as per the Schedule of 
Assessments. 
Clarification 
46 
Section 7.3.1 and 
Section 7.3.2  
AE and SAE definitions revised as per PTC 
template language; revisions had no effect on 
reporting. 
Update 
47 
Section 7.3.3  
The locations of the Reference Safety Information 
for unesbulin and DTIC were clarified. 
Health authority 
request 
48 
Section 7.3.9  
Serious Adverse Events Reporting: the existing 
“within 24 hours” was updated to “immediately but 
no later than 24 hours” 
Health authority 
request 
49 
Section 8.4.4  
Content that was previously in Section 8.4.3 was 
moved to this new section and entitled “Analysis 
of Other Secondary Efficacy Endpoints.” 
Update 
50 
Section 8.4.5.1  
Treatment-emergent adverse events were 
defined. 
Update 
51 
Section 9.1.1.3  
It was clarified that the informed consent may be 
delegated to a site delegate and not limited to a 
subinvestigator. 
Clarification 
52 
Section 9.1.7  
It was clarified that a subject’s participation in the 
exploratory part of the study is optional. 
Clarification 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; 
AST, aspartate aminotransferase; BCRP, breast cancer resistance protein; CBC, complete blood count; CBR, clinical 
benefit rate; CMP, complete metabolic panel; CT, computed tomography; CTFG, Clinical Trial Facilitation and 
Coordination Group; DCR, disease control rate; DMC, data monitoring committee; DTIC, dacarbazine; ECG, 
electrocardiogram; EOT, end of treatment; MRI, magnetic resonance imaging; NSAID, nonsteroidal anti-inflammatory 
drug; OATP1B1 and OATP1B2, organic anion transporter polypeptide transporters; OS, overall survival; PK, 
pharmacokinetic; PT, prothrombin time; SAE, serious adverse event; ULN, upper limit of normal; WOCBP, women of 
childbearing potential 

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Table 9: 
Germany: Summary of Changes From Local Amendment Version 2.3 to Global 
Amendment Version 3.0 
Item No. 
Protocol Section 
Summary of Change 
Reason/ 
Rationale 
1 
Protocol 
The version number and date were updated 
throughout. The synopsis was updated to be 
consistent with the changes in the protocol. The 
title page was modified to conform with the new 
clinical trial protocol template. 
Update 
2 
Global Update 
Minor editorial changes were made throughout for 
grammar and clarity. 
Update 
3 
Global Update 
Considering the study is blinded, “placebo” was 
added to statements pertaining to the 
administration and handling of both unesbulin and 
placebo, where applicable. 
Update/ 
clarification 
4 
Protocol Identifiers 
and Study 
Personnel 
Changes in PTC study staff and contact 
information 
Update 
5 
Synopsis, 
Section 2.5, 
Section 8.4.3, and 
Section 8.4.10  
It was specified that OS is the key secondary 
endpoint. Additional details describing the 
analysis of this key secondary endpoint were 
added to the Synopsis, Section 8.4.3, and 
Section 8.4.10. 
Health authority 
request 
6 
Synopsis, 
Section 2.5, and 
Section 8.4.3  
Clarified that at least 3 months of stable disease 
was required in the definition of DCR and CBR. 
Clarification 
7 
Synopsis, 
Section 3.1, and 
Section 7.4  
Clarified that approximately 12 subjects will be 
assessed for PK. 
Clarification 
8 
Synopsis and 
Section 3.1  
The DMC will not review the interim data for 
sample size re-evaluation; this has been clarified. 
The timing for the DMC meetings was removed 
and replaced with a reference to the DMC charter. 
It was clarified that the interim efficacy analysis 
will be performed by an external vendor. 
Update and 
clarification 
9 
Synopsis, Schedule 
of Assessments, 
and Section 3.3  
It was clarified that no dose reduction of 
unesbulin/placebo is permitted. For subjects who 
have interruptions in DTIC due to toxicities, 
detailed instructions on timing of assessments 
relative to continued unesbulin/placebo dosing 
were added to the protocol.  
Clarification 
10 
Synopsis and 
Section 4.1  
An exception to Inclusion Criterion #10 was added 
for patients with Gilbert’s syndrome who have 
elevated bilirubin values. 
Update based 
on feedback 
from 
investigators 
11 
Synopsis and 
Section 4.1  
Inclusion Criterion #11 was modified to increase 
the eligibility limit for AST and ALT from 1.5 to 3 
times the ULN. 
Update based 
on feedback 
from 
investigators 
12 
Synopsis Exclusion 
Criterion #5 and 
Section 4.2  
Removed “known” prior to human 
immunodeficiency virus, hepatitis B virus, or 
hepatitis C virus positivity because all subjects will 
be required for viral testing at screening. 
Clarification 

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Item No. 
Protocol Section 
Summary of Change 
Reason/ 
Rationale 
13 
Synopsis, 
Section 4.2, and 
Section 5.5  
The criterion excluding the concomitant use of 
NSAIDs was deleted because the potential risk for 
gastrointestinal perforation was mitigated by 
adding gastritis to Exclusion Criterion #9. 
A statement was added to the Concomitant 
Medication Section 5.5 as a reminder that 
subjects should not have active peptic ulcer 
disease, active gastritis, or previous history of 
gastric perforation within the last 2 years. 
Update based 
on feedback 
from 
investigators 
14 
Synopsis, 
Section 4.2, and 
Section 5.5  
Exclusion Criterion #15 was modified to provide 
clarifications on the chronic use of marijuana. 
Clarification 
15 
Synopsis and 
Section 4.2  
It was clarified in Exclusion Criterion #19 that 
coagulation tests should fall within the required 
range (instead of “normal”) considering the patient 
disease and demographic characteristics. 
Investigator 
feedback 
16 
Synopsis, 
Section 3.1, and 
Section 5.2  
Based on the results from a food effect 
assessment in the ongoing Phase 1b Study 
PTC596-ONC-007-LMS, it is recommended that 
unesbulin/placebo be administered with food. 
Update 
17 
Synopsis and 
Section 5.1  
PTC will provide DTIC to sites that are unable to 
procure it locally. 
Procedural 
change 
18 
Synopsis and 
Section 5.1  
Instructions to reconstitute DTIC were added to 
accommodate variation in institutional policies.  
Update 
19 
Synopsis and 
Section 5.2  
The window to administer DTIC was widened from 
1 hour ± 5 minutes to 1 hour ± 30 minutes to allow 
sites more flexibility to administer this study drug. 
Procedural 
change 
20 
Synopsis and 
Section 7.1  
To align with the Schedule of Assessments, 
clarified that after Cycle 8, scans may be 
performed every 9 weeks. 
Clarification 
21 
Synopsis, Schedule 
of Assessments 
(footnote “k”), and 
Section 7.1  
It was clarified that either MRI or CT could be 
used as clinically indicated. 
Health authority 
request 
22 
Synopsis, Schedule 
of Assessments 
(footnote “m”), and 
Section 7.6  
Timing and mandatory collection of biomarker 
samples was clarified. Footnote “m” was updated 
as follows: “Blood samples (10 mL) to assess 
circulating biomarkers will be collected at 
screening (predose) and prior to dosing on Day 1 
of Cycle 3 and at the time of disease progression 
or EOT. Samples will be processed, stored, and 
shipped according to instructions in the laboratory 
manual.” 
Clarification 
23 
Schedule of 
Assessments 
Figure 1, 
Section 3.1, and 
Section 6.1.1  
To accommodate patient management and care 
and AE stabilization (as applicable), a more 
flexible timeframe for the EOT visit was provided. 
Update 
24 
Schedule of 
Assessments 
For urinalysis, an “X” was added to EOT and 
deleted from Day 1 of Cycle 2. 
Update 
25 
Schedule of 
Assessments 
Footnote “f”: It was clarified that weight must be 
assessed on the day of DTIC administration. 
Clarification 

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Page 73 of 92 
Item No. 
Protocol Section 
Summary of Change 
Reason/ 
Rationale 
26 
Schedule of 
Assessments 
Footnote “g”: It was clarified that local laboratory 
testing is acceptable. The window of clinical 
laboratory testing on Day 1 of Cycle 1 prior to the 
first dose of study drug was extended to up to 72 
hours to allow sites flexibility over weekends. After 
Cycle 3, monthly clinical laboratory testing will be 
adjusted in the protocol so that sampling will be 
performed once every cycle instead of on a 
weekly basis. 
The urinalysis assessment in the footnote was an 
error; this was replaced with a CMP to be 
performed at the same frequency as the CBC 
assessments. Instructions for performing 
laboratory assessments were added in case DTIC 
is interrupted/held due to toxicity. 
Request by 
participating 
sites to 
decrease 
subject and 
staff burden 
27 
Schedule of 
Assessments 
A pregnancy test prior is required within 24 hours 
of dosing on Day 1 of Cycle 1, and this may be 
assessed with a urine pregnancy test. In footnote 
“h”, it was also clarified that a urine or serum 
pregnancy test should be performed 24 hours 
prior to dosing on Day 1 of Cycle 2 and continuing 
every 2 cycles beginning with Cycle 4. 
Clarification 
and health 
authority 
request 
28 
Schedule of 
Assessments 
Footnotes “i” and “j”: Instructions were added for 
performing the single ECG in cases if/when DTIC 
is interrupted or held. 
ECGs will not be required after Cycle 3. 
Clarification 
and procedural 
change based 
on cumulative 
safety data in 
the clinical 
program 
29 
Schedule of 
Assessments 
The following text in footnote “j” was deleted: “On 
Day 1 of all other cycles and at the time of 
collection for sparse PK samples, approximately 2 
hours after DTIC infusion.” and was replaced with 
“Approximately 2 hours after DTIC infusion on 
Cycle 2.” 
Clarification 
30 
Schedule of 
Assessments 
Footnote “n”: Instructions for performing PK 
sampling in case of DTIC interruption/hold were 
added. 
Clarification 
31 
Schedule of 
Assessments 
(footnote “o”) and 
Section 5.4  
Subjects are encouraged to bring back the patient 
diary at all scheduled visits. 
Procedural 
change 
32 
Schedule of 
Assessments and 
Section 5.2  
Footnote “p”: Reference to Section 3.3 was added 
for instructions on DTIC dosing in case of toxicity. 
Clarification 
33 
Schedule of 
Assessments 
Footnote “q”: Instructions were added for 
administering unesbulin/placebo in case of DTIC 
interruption. 
Clarification 
34 
Section 1.3  
A statement was added in Section 1.3 referring 
investigators to the Investigator’s Brochure for 
additional information and guidance on mitigating 
potential drug-drug interactions. 
Health authority 
request 

PTC596-ONC-008-LMS 
Clinical Protocol 
V4.0 
PTC Therapeutics - Confidential 
Page 74 of 92 
Item No. 
Protocol Section 
Summary of Change 
Reason/ 
Rationale 
35 
Schedule of 
Assessments and 
Section 3.3  
Procedural guidelines for DTIC interruptions were 
added. Instructions for modifying dose of DTIC in 
the case of nonhematological toxicities were 
added. It was clarified that the dose of 
unesbulin/placebo should not be reduced or 
withheld. 
Clarification 
and Health 
authority 
request 
36 
Section 5.2  
Instructions were added for subjects who cannot 
swallow the whole tablet. Specifically, tablets can 
be dispersed in water at the same dose level at 
which the tablets are being dosed and be 
administered orally. Instructions were added to 
provide guidance in cases of a subject who 
misses a dose of unesbulin/placebo or vomits 
after unesbulin/placebo dosing. It was clarified 
that coadministration of acid-reducing agents 
should be avoided approximately 4 hours before 
and after unesbulin/placebo administration to 
make instructions in this section consistent with 
other sections. 
Clarifications 
and process 
updates 
37 
Synopsis and 
Section 7.1  
It was clarified that survival follow-up will continue 
every 3 months as per the Schedule of 
Assessments. 
Clarification 
38 
Section 7.3.1 and 
Section 7.3.2  
AE and SAE definitions revised as per PTC 
template language; revisions had no effect on 
reporting. 
Update 
39 
Section 8.4.4  
Content that was previously in Section 8.4.3 was 
moved to this new section and entitled “Analysis 
of Other Secondary Efficacy Endpoints.” 
Update 
40 
Section 8.4.5.1  
Treatment-emergent adverse events were 
defined. 
Update 
41 
Section 9.1.1.3  
It was clarified that the informed consent may be 
delegated to a site delegate and not limited to a 
subinvestigator 
Clarification 
42 
Section 9.1.7  
It was clarified that a subject’s participation in the 
exploratory part of the study is optional. 
Clarification 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; 
AST, aspartate aminotransferase; CBC, complete blood count; CBR, clinical benefit rate; CMP, complete metabolic 
panel; CT, computed tomography; CTFG, Clinical Trial Facilitation and Coordination Group DCR, disease control 
rate; DMC, data monitoring committee; DTIC, dacarbazine; ECG, electrocardiogram; EOT, end of treatment; MRI, 
magnetic resonance imaging; NSAID, nonsteroidal anti-inflammatory drug; OS, overall survival; PK, pharmacokinetic; 
PT, prothrombin time; SAE, serious adverse event; ULN, upper limit of normal; WOCBP, women of childbearing 
potential 
Table 10: 
Italy: Summary of Changes From Local Amendment Version 2.1 to Global 
Amendment Version 3.0 
Item No. 
Protocol Section 
Summary of Change 
Reason/ 
Rationale 
1 
Protocol 
The version number and date were updated 
throughout. The synopsis was updated to be 
consistent with the changes in the protocol. The 
title page was modified to conform with the new 
clinical trial protocol template. 
Update 
2 
Global Update 
Minor editorial changes were made throughout 
for grammar and clarity. 
Update 

PTC596-ONC-008-LMS 
Clinical Protocol 
V4.0 
PTC Therapeutics - Confidential 
Page 75 of 92 
Item No. 
Protocol Section 
Summary of Change 
Reason/ 
Rationale 
3 
Global Update 
Considering the study is blinded, “placebo” was 
added to statements pertaining to the 
administration and handling of both unesbulin 
and placebo, where applicable. 
Update/ 
clarification 
4 
Protocol Identifiers 
and Study 
Personnel 
Changes in PTC study staff and contact 
information 
Update 
5 
Synopsis, 
Section 2.5, 
Section 8.4.3, , 
and Section 8.4.10  
It was specified that OS is the key secondary 
endpoint. Additional details describing the 
analysis of this key secondary endpoint were 
added to the Synopsis, Section 8.4.3, and 
Section 8.4.10. 
Health authority 
request 
6 
Synopsis, 
Section 2.5, and 
Section 8.4.4 
Clarified that at least 3 months of stable disease 
was required in the definition of DCR and CBR. 
Clarification 
7 
Synopsis, 
Section 3.1, and 
Section 7.4  
Clarified that approximately 12 subjects will be 
assessed for PK. 
Clarification 
8 
Synopsis and 
Section 3.1 
The DMC will not review the interim data for 
sample size re-evaluation; this has been clarified. 
The timing for the DMC meetings was removed 
and replaced with a reference to the DMC 
charter. It was clarified that the interim efficacy 
analysis will be performed by an external vendor. 
Update and 
clarification 
9 
Synopsis, 
Schedule of 
Assessments, and 
Section 3.3  
It was clarified that no dose reduction of 
unesbulin/placebo is permitted. For subjects who 
have interruptions in DTIC due to toxicities, 
detailed instructions on timing of assessments 
relative to continued unesbulin/placebo dosing 
were added to the protocol.  
Clarification 
10 
Synopsis and 
Section 4.1  
An exception to Inclusion Criterion #10 was 
added for patients with Gilbert’s syndrome who 
have elevated bilirubin values. 
Update based 
on feedback 
from 
investigators 
11 
Synopsis and 
Section 4.1  
Inclusion Criterion #11 was modified to increase 
the eligibility limit for AST and ALT from 1.5 to 3 
times the ULN. 
Update based 
on feedback 
from 
investigators 
12 
Synopsis 
Exclusion Criterion 
#5 and Section 4.2  
Removed “known” prior to human 
immunodeficiency virus, hepatitis B virus, or 
hepatitis C virus positivity because all subjects 
will be required for viral testing at screening. 
Clarification 
13 
Synopsis, 
Section 4.2, and 
Section 5.5  
The criterion excluding the concomitant use of 
NSAIDs was deleted because the potential risk 
for gastrointestinal perforation was mitigated by 
adding gastritis to Exclusion Criterion #9.  
A statement was added to the Concomitant 
Medication Section 5.5 as a reminder that 
subjects should not have active peptic ulcer 
disease, active gastritis, or previous history of 
gastric perforation within the last 2 years. 
Update based 
on feedback 
from 
investigators 

PTC596-ONC-008-LMS 
Clinical Protocol 
V4.0 
PTC Therapeutics - Confidential 
Page 76 of 92 
Item No. 
Protocol Section 
Summary of Change 
Reason/ 
Rationale 
14 
Synopsis, 
Section 4.2, and 
Section 5.5  
Exclusion Criterion #15 was modified to provide 
clarifications on the chronic use of marijuana. 
Clarification 
15 
Synopsis, 
Section 4.2  
Added APTT/PT assessments to Exclusion 
Criterion #19 to monitor subjects on 
anticoagulation where applicable. It was clarified 
that coagulation tests should fall within the 
required range (instead of “normal”) considering 
the patient disease and demographic 
characteristics. 
Health authority 
request 
16 
Synopsis, 
Section 3.1, and 
Section 5.2  
Based on the results from a food effect 
assessment in the ongoing Phase 1b Study 
PTC596-ONC-007-LMS, it is recommended that 
unesbulin/placebo be administered with food. 
Update 
17 
Synopsis and 
Section 5.1  
PTC may provide DTIC to sites that are unable to 
procure it locally. 
Procedural 
change 
18 
Synopsis and 
Section 5.1  
Instructions to reconstitute DTIC were added to 
accommodate variation in institutional policies.  
Update 
19 
Synopsis and 
Section 5.2  
The window to administer DTIC was widened 
from 1 hour ± 5 minutes to 1 hour ± 30 minutes 
to allow sites more flexibility to administer this 
study drug. 
Procedural 
change 
20 
Synopsis and 
Section 7.1 
To align with the Schedule of Assessments, 
clarified that after Cycle 8, scans may be 
performed every 9 weeks. 
Clarification 
21 
Synopsis, 
Schedule of 
Assessments 
(footnote “k”), and 
Section 7.1  
It was clarified that either MRI or CT could be 
used as clinically indicated. 
Health authority 
request 
22 
Synopsis, 
Schedule of 
Assessments 
(footnote “m”), and 
Section 7.6  
Timing and mandatory collection of biomarker 
samples was clarified. Footnote “m” was updated 
as follows: “Blood samples (10 mL) to assess 
circulating biomarkers will be collected at 
screening (predose) and prior to dosing on Day 1 
of Cycle 3 and at the time of disease progression 
or EOT. Samples will be processed, stored, and 
shipped according to instructions in the 
laboratory manual.” 
Clarification 
23 
Schedule of 
Assessments, 
Figure 1, 
Section 3.1, and 
Section 6.1.1  
To accommodate patient management and care 
and AE stabilization (as applicable), a more 
flexible timeframe for the EOT visit was provided. 
Update 
24 
Schedule of 
Assessments 
For urinalysis, an “X” was added to EOT and 
deleted for Day 1 of Cycle 2. 
Update 
25 
Schedule of 
Assessments 
A pregnancy test prior is required within 24 hours 
of dosing on Day 1 of Cycle 1, and this may be 
assessed with a urine pregnancy test. In footnote 
“h”, it was also clarified that a urine or serum 
pregnancy test should be performed 24 hours 
prior to dosing on Day 1 of Cycle 2 and 
continuing every 2 cycles beginning with Cycle 4.  
Clarification and 
health authority 
request 

PTC596-ONC-008-LMS 
Clinical Protocol 
V4.0 
PTC Therapeutics - Confidential 
Page 77 of 92 
Item No. 
Protocol Section 
Summary of Change 
Reason/ 
Rationale 
26 
Schedule of 
Assessments 
Footnote “f”: It was clarified that weight must be 
assessed on the day of DTIC administration. 
Clarification 
27 
Schedule of 
Assessments 
Footnote “g”: It was clarified that local laboratory 
testing is acceptable. The window of clinical 
laboratory testing on C1D1 prior to the first dose 
of study drug was extended to up to 72 hours to 
allow sites flexibility over weekends. After 
Cycle 3, monthly clinical laboratory testing will be 
adjusted in the protocol so that sampling will be 
performed once every cycle instead of on a 
weekly basis. 
The urinalysis assessment in the footnote was an 
error; this was replaced with a CMP to be 
performed at the same frequency as the CBC 
assessments. Instructions for performing 
laboratory assessments were added in case 
DTIC is interrupted/held due to toxicity. 
Request by 
participating 
sites to 
decrease 
subject and staff 
burden 
28 
Schedule of 
Assessments 
Footnotes “i” and “j”: Instructions were added for 
performing the single ECG in cases if/when DTIC 
is interrupted or held. 
ECGs will not be required after Cycle 3. 
Clarification and 
procedural 
change based 
on cumulative 
safety data in 
the clinical 
program 
29 
Schedule of 
Assessments 
The following text in footnote “j” was deleted: “On 
Day 1 of all other cycles and at the time of 
collection for sparse PK samples, approximately 
2 hours after DTIC infusion.” and was replaced 
with “Approximately 2 hours after DTIC infusion 
on Cycle 2.” 
Clarification 
30 
Schedule of 
Assessments 
Footnote “n”: Instructions for performing PK 
sampling in case of DTIC interruption/hold were 
added. 
Clarification 
31 
Schedule of 
Assessments 
(footnote “o”) and 
Section 5.4  
Subjects are encouraged to bring back the 
patient diary at all scheduled visits. 
Procedural 
change 
32 
Schedule of 
Assessments and 
Section 5.2 
Footnote “p”: Reference to Section 3.3 was 
added for instructions on DTIC dosing in case of 
toxicity. 
Clarification 
33 
Schedule of 
Assessments 
Footnote “q”: Instructions were added for 
administering unesbulin/placebo in case of DTIC 
interruption. 
Clarification 
34 
Section 1.3  
A statement was added in Section 1.3 referring 
investigators to the Investigator’s Brochure for 
additional information and guidance on mitigating 
potential drug-drug interactions. 
Health authority 
request 
35 
Schedule of 
Assessments and 
Section 3.3  
Procedural guidelines for DTIC interruptions 
were added. Instructions for modifying dose of 
DTIC in the case of nonhematological toxicities 
were added. It was clarified that the dose of 
unesbulin/placebo should not be reduced or 
withheld. 
Clarification and 
Health authority 
request 

PTC596-ONC-008-LMS 
Clinical Protocol 
V4.0 
PTC Therapeutics - Confidential 
Page 78 of 92 
Item No. 
Protocol Section 
Summary of Change 
Reason/ 
Rationale 
36 
Section 5.2  
Instructions were added for subjects who cannot 
swallow the whole tablet. Specifically, tablets can 
be dispersed in water at the same dose level at 
which the tablets are being dosed and be 
administered orally. Instructions were added to 
provide guidance in cases of a subject who 
misses a dose of unesbulin/placebo or vomits 
after unesbulin/placebo dosing. It was clarified 
that coadministration of acid-reducing agents 
should be avoided approximately 4 hours before 
and after unesbulin/placebo administration to 
make instructions in this section consistent with 
other sections. 
Clarifications 
and process 
updates 
37 
Section 5.5  
Updated guidelines were added for mitigating 
potential BCRP, OATP1B1, and OATP2B2 
interactions with unesbulin. Clarifications on 
chronic use of marijuana was added, along with 
a reminder on enrolling subjects with active 
peptic ulcer disease, active gastritis, or history of 
gastric perforation within the last 2 years. 
Update based 
on new data and 
Health authority 
request 
38 
Synopsis and 
Section 7.1  
It was clarified that survival follow-up will 
continue every 3 months as per the Schedule of 
Assessments. 
Clarification 
39 
Section 7.3.1 and 
Section 7.3.2  
AE and SAE definitions revised as per PTC 
template language; revisions had no effect on 
reporting. 
Update 
40 
Section 8.4.4  
Content that was previously in Section 8.4.3 was 
moved to this new section and entitled “Analysis 
of Other Secondary Efficacy Endpoints.” 
Update 
41 
Section 8.4.5.1  
Treatment-emergent adverse events were 
defined. 
Update 
42 
Section 9.1.1.3  
It was clarified that the informed consent may be 
delegated to a site delegate and not limited to a 
subinvestigator 
Clarification 
43 
Section 9.1.7  
It was clarified that a subject’s participation in the 
exploratory part of the study is optional. 
Clarification 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; 
AST, aspartate aminotransferase; BCRP, breast cancer resistance protein; CBC, complete blood count; CBR, clinical 
benefit rate; CMP, complete metabolic panel; CT, computed tomography; CTFG, Clinical Trial Facilitation and 
Coordination Group DCR, disease control rate; DMC, data monitoring committee; DTIC, dacarbazine; ECG, 
electrocardiogram; EOT, end of treatment; MRI, magnetic resonance imaging; NSAID, nonsteroidal anti-inflammatory 
drug; OATP1B1 and OATP1B2, organic anion transporter polypeptide transporters; OS, overall survival; PK, 
pharmacokinetic; PT, prothrombin time; SAE, serious adverse event; ULN, upper limit of normal; WOCBP, women of 
childbearing potential 
Table 11: 
Spain: Summary of Changes From Local Amendment Version 2.1 to Global 
Amendment Version 3.0 
Item No. 
Protocol 
Section 
Summary of Change 
Reason/ 
Rationale 
1 
Protocol 
The version number and date were updated 
throughout. The synopsis was updated to be 
consistent with the changes in the protocol. The title 
page was modified to conform with the new clinical 
trial protocol template. 
Update 

PTC596-ONC-008-LMS 
Clinical Protocol 
V4.0 
PTC Therapeutics - Confidential 
Page 79 of 92 
Item No. 
Protocol 
Section 
Summary of Change 
Reason/ 
Rationale 
2 
Global Update 
Minor editorial changes were made throughout for 
grammar and clarity. 
Update 
3 
Global Update 
Considering the study is blinded, “placebo” was 
added to statements pertaining to the administration 
and handling of both unesbulin and placebo, where 
applicable. 
Update/ 
clarification 
4 
Protocol 
Identifiers and 
Study Personnel 
Changes in PTC study staff and contact information 
Update 
5 
Synopsis, 
Section 2.5, 
Section 8.4.3, 
and 
Section 8.4.10  
It was specified that OS is the key secondary 
endpoint. Additional details describing the analysis 
of this key secondary endpoint were added to the 
Synopsis, Section 8.4.3, and Section 8.4.10. 
Health authority 
request 
6 
Synopsis, 
Section 2.5, and 
Section 8.4.4  
Content that was previously in Section 8.4.3 was 
moved to this new section and entitled “Analysis of 
Other Secondary Efficacy Endpoints.” 
Update 
7 
Synopsis, 
Section 2.5, and 
Section 8.4.4   
Clarified that at least 3 months of stable disease 
was required in the definition of DCR and CBR. 
Clarification 
8 
Synopsis, 
Section 3.1, and 
Section 7.4  
Clarified that approximately 12 subjects will be 
assessed for PK. 
Clarification 
9 
Synopsis and 
Section 3.1 
The DMC will not review the interim data for sample 
size re-evaluation; this has been clarified. The 
timing for the DMC meetings was removed and 
replaced with a reference to the DMC charter. It was 
clarified that the interim efficacy analysis will be 
performed by an external vendor. 
Update and 
clarification 
10 
Synopsis, 
Schedule of 
Assessments, 
and Section 3.3  
It was clarified that no dose reduction of 
unesbulin/placebo is permitted. For subjects who 
have interruptions in DTIC due to toxicities, detailed 
instructions on timing of assessments relative to 
continued unesbulin/placebo dosing were added to 
the protocol.  
Clarification 
11 
Synopsis and 
Section 4.1  
An exception to Inclusion Criterion #10 was added 
for patients with Gilbert’s syndrome who have 
elevated bilirubin values. 
Update based 
on feedback 
from 
investigators 
12 
Synopsis and 
Section 4.1  
Inclusion Criterion #11 was modified to increase the 
eligibility limit for AST and ALT from 1.5 to 3 times 
the ULN. 
Update based 
on feedback 
from 
investigators 
13 
Synopsis 
Exclusion 
Criterion #5 and 
Section 4.2  
Removed “known” prior to human immunodeficiency 
virus, hepatitis B virus, or hepatitis C virus positivity 
because all subjects will be required for viral testing 
at screening. 
Clarification 

PTC596-ONC-008-LMS 
Clinical Protocol 
V4.0 
PTC Therapeutics - Confidential 
Page 80 of 92 
Item No. 
Protocol 
Section 
Summary of Change 
Reason/ 
Rationale 
14 
Synopsis, 
Section 4.2, and 
Section 5.5  
The criterion excluding the concomitant use of 
NSAIDs was deleted because the potential risk for 
gastrointestinal perforation was mitigated by adding 
gastritis to Exclusion Criterion #9. 
A statement was added to the Concomitant 
Medication Section 5.5 as a reminder that subjects 
should not have active peptic ulcer disease, active 
gastritis, or previous history of gastric perforation 
within the last 2 years. 
Update based 
on feedback 
from 
investigators 
15 
Synopsis, 
Section 4.2, and 
Section 5.5  
Exclusion Criterion #15 was modified to provide 
clarifications on the chronic use of marijuana. 
Clarification 
16 
Synopsis, 
Section 4.2  
Added that APTT/PT assessments to Exclusion 
Criterion #19 to monitor subjects on anticoagulation 
where applicable. It was clarified that coagulation 
tests should fall within the required range (instead of 
“normal”) considering the patient disease and 
demographic characteristics. 
Health authority 
request and 
investigator 
feedback 
17 
Synopsis, 
Section 3.1, and 
Section 5.2  
Based on the results from a food effect assessment 
in the ongoing Phase 1b Study PTC596-ONC-007-
LMS, it is recommended that unesbulin/placebo be 
administered with food. 
Update 
18 
Synopsis and 
Section 5.1  
PTC may provide DTIC to sites that are unable to 
procure it locally. 
Procedural 
change 
19 
Synopsis and 
Section 5.1  
Instructions to reconstitute DTIC were added to 
accommodate variation in institutional policies.  
Update 
20 
Synopsis and 
Section 5.2  
The window to administer DTIC was widened from 1 
hour ± 5 minutes to 1 hour ± 30 minutes to allow 
sites more flexibility to administer this study drug. 
Procedural 
change 
21 
Synopsis, 
Schedule of 
Assessments 
(footnote “k”), 
and Section 7.1  
It was clarified that either MRI or CT could be used 
as clinically indicated. 
Health authority 
request 
22 
Synopsis, 
Schedule of 
Assessments 
(footnote “m”), 
and Section 7.6  
Timing and mandatory collection of biomarker 
samples was clarified. Footnote “m” was updated as 
follows: “Blood samples (10 mL) to assess 
circulating biomarkers will be collected at screening 
(predose) and prior to dosing on Day 1 of Cycle 3 
and at the time of disease progression or EOT. 
Samples will be processed, stored, and shipped 
according to instructions in the laboratory manual.” 
Clarification 
23 
Schedule of 
Assessments, 
Figure 1, 
Section 3.1, and 
Section 6.1.1  
To accommodate patient management and care 
and AE stabilization (as applicable), a more flexible 
timeframe for the EOT visit was provided. 
Update 
24 
Schedule of 
Assessments 
For urinalysis, an “X” was added to EOT and 
deleted from Day 1 of Cycle 2. 
Update 

PTC596-ONC-008-LMS 
Clinical Protocol 
V4.0 
PTC Therapeutics - Confidential 
Page 81 of 92 
Item No. 
Protocol 
Section 
Summary of Change 
Reason/ 
Rationale 
25 
Schedule of 
Assessments 
A pregnancy test prior is required within 24 hours of 
dosing on Day 1 of Cycle 1, and this may be 
assessed with a urine pregnancy test. In footnote 
“h”, it was also clarified that a urine or serum 
pregnancy test should be performed 24 hours prior 
to dosing on Day 1 of Cycle 2 and continuing every 
2 cycles beginning with Cycle 4.  
Clarification and 
health authority 
request 
26 
Schedule of 
Assessments 
Footnote “f”: It was clarified that weight must be 
assessed on the day of DTIC administration. 
Clarification 
27 
Schedule of 
Assessments 
Footnote “g”: It was clarified that local laboratory 
testing is acceptable. The window of clinical 
laboratory testing on Day 1 of Cycle 1 prior to the 
first dose of study drug was extended to up to 72 
hours to allow sites flexibility over weekends. After 
Cycle 3, monthly clinical laboratory testing will be 
adjusted in the protocol so that sampling will be 
performed once every cycle instead of on a weekly 
basis. 
The urinalysis assessment in the footnote was an 
error; this was replaced with a CMP to be performed 
at the same frequency as the CBC assessments. 
Instructions for performing laboratory assessments 
were added in case DTIC is interrupted/held due to 
toxicity. 
Request by 
participating 
sites to 
decrease 
subject and staff 
burden 
28 
Schedule of 
Assessments 
Footnotes “i” and “j”: Instructions were added for 
performing the single ECG in cases if/when DTIC is 
interrupted or held. 
ECGs will not be required after Cycle 3. 
Clarification and 
procedural 
change based 
on cumulative 
safety data in 
the clinical 
program 
29 
Schedule of 
Assessments 
The following text in footnote “j” was deleted: “On 
Day 1 of all other cycles and at the time of collection 
for sparse PK samples, approximately 2 hours after 
DTIC infusion.” and was replaced with 
“Approximately 2 hours after DTIC infusion on Cycle 
2.” 
 
30 
Schedule of 
Assessments 
Footnote “n”: Instructions for performing PK 
sampling in case of DTIC interruption/hold were 
added. 
Clarification 
31 
Schedule of 
Assessments 
(footnote “o”) 
and Section 5.4  
Subjects are encouraged to bring back the patient 
diary at all scheduled visits. 
Procedural 
change 
32 
Schedule of 
Assessments 
and Section 5.2 
Footnote “p”: Reference to Section 3.3 was added 
for instructions on DTIC dosing in case of toxicity. 
Clarification 
33 
Schedule of 
Assessments 
Footnote “q”: Instructions were added for 
administering unesbulin/placebo in case of DTIC 
interruption. 
Clarification 

PTC596-ONC-008-LMS 
Clinical Protocol 
V4.0 
PTC Therapeutics - Confidential 
Page 82 of 92 
Item No. 
Protocol 
Section 
Summary of Change 
Reason/ 
Rationale 
34 
Section 1.1  
A reference to the ESMO-EURACAN-GENTURIS 
(European Society for Medical Oncology; European 
Reference Network for Rare Adult Solid Cancers; 
European Reference Network for  
Genetic Tumour Risk Syndromes) Clinical Practice 
Guidelines by Gronchi et al was added. 
Health authority 
request 
35 
Section 1.3  
A statement was added in Section 1.3 referring 
investigators to the Investigator’s Brochure for 
additional information and guidance on mitigating 
potential drug-drug interactions. 
Health authority 
request 
36 
Schedule of 
Assessments 
and Section 3.3  
Procedural guidelines for DTIC interruptions were 
added. Instructions for modifying dose of DTIC in 
the case of nonhematological toxicities were added. 
It was clarified that the dose of unesbulin/placebo 
should not be reduced or withheld. 
Clarification and 
Health authority 
request 
37 
Section 3.4  
A definition of the end of study was added to the 
protocol. 
Health authority 
request 
38 
Section 5.2  
Instructions were added for subjects who cannot 
swallow the whole tablet. Specifically, tablets can be 
dispersed in water at the same dose level at which 
the tablets are being dosed and be administered 
orally. Instructions were added to provide guidance 
in cases of a subject who misses a dose of 
unesbulin/placebo or vomits after unesbulin/placebo 
dosing. It was clarified that coadministration of acid-
reducing agents should be avoided approximately 4 
hours before and after unesbulin/placebo 
administration to make instructions in this section 
consistent with other sections. 
Clarifications 
and process 
updates 
39 
Section 5.5  
It was added that neither approved nor guideline-
recommended therapy options should be withheld 
from subjects if the investigator determines it is in 
the best interest of the subject. Updated guidelines 
were added for mitigating potential BCRP, 
OATP1B1, and OATP2B2 interactions with 
unesbulin. Clarifications on chronic use of marijuana 
was added, along with a reminder on enrolling 
subjects with active peptic ulcer disease, active 
gastritis, or history of gastric perforation within the 
last 2 years. 
Update based 
on new data and 
Health authority 
request 
40 
Section 5.6.1  
The following statement was removed: “Before 
unblinding, the investigator must make every 
attempt to discuss the intended code break with 
PTC.” 
Health authority 
request 
41 
Synopsis and 
Section 7.1  
It was clarified that survival follow-up will continue 
every 3 months as per the Schedule of 
Assessments. 
Clarification 
42 
Section 7.3.1 
and 
Section 7.3.2  
AE and SAE definitions revised as per PTC 
template language; revisions had no effect on 
reporting. 
Update 
43 
Section 7.3.9  
Serious Adverse Events Reporting: the existing 
“within 24 hours” was updated to “immediately but 
no later than 24 hours.” 
Health authority 
request 

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Item No. 
Protocol 
Section 
Summary of Change 
Reason/ 
Rationale 
44 
Section 8.4.4  
Content that was previously in Section 8.4.3 was 
moved to this new section and entitled “Analysis of 
Other Secondary Efficacy Endpoints.” 
Update 
45 
Section 8.4.5.1  
Treatment-emergent adverse events were defined. 
Update 
46 
Section 9.1.1.3  
It was clarified that the informed consent may be 
delegated to a site delegate and not limited to a 
subinvestigator 
Clarification 
47 
Section 9.1.7  
It was clarified that a subject’s participation in the 
exploratory part of the study is optional. 
Clarification 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; 
AST, aspartate aminotransferase; BCRP, breast cancer resistance protein; CBC, complete blood count; CBR, clinical 
benefit rate; CMP, complete metabolic panel; CT, computed tomography; CTFG, Clinical Trial Facilitation and 
Coordination Group DCR, disease control rate; DMC, data monitoring committee; DTIC, dacarbazine; ECG, 
electrocardiogram; EOT, end of treatment; MRI, magnetic resonance imaging; NSAID, nonsteroidal anti-inflammatory 
drug; OATP1B1 and OATP1B2, organic anion transporter polypeptide transporters; OS, overall survival; PK, 
pharmacokinetic; PT, prothrombin time; SAE, serious adverse event; ULN, upper limit of normal; WOCBP, women of 
childbearing potential 
Table 12: 
UK: Summary of Changes From Local Amendment Version 2.1 to Global 
Amendment Version 3.0 
Item No. 
Protocol 
Section 
Summary of Change 
Reason/ 
Rationale 
1 
Protocol 
The version number and date were updated 
throughout. The synopsis was updated to be 
consistent with the changes in the protocol. The title 
page was modified to conform with the new clinical 
trial protocol template. 
Update 
2 
Global Update 
Minor editorial changes were made throughout for 
grammar and clarity. 
Update 
3 
Global Update 
Considering the study is blinded, “placebo” was 
added to statements pertaining to the administration 
and handling of both unesbulin and placebo, where 
applicable. 
Update/ 
clarification 
4 
Protocol 
Identifiers and 
Study Personnel 
Changes in PTC study staff and contact information 
Update 
5 
Synopsis, 
Section 2.5, 
Section 8.4.3, 
and 
Section 8.4.10  
It was specified that OS is the key secondary 
endpoint. Additional details describing the analysis 
of this key secondary endpoint were added to the 
Synopsis, Section 8.4.3, and Section 8.4.10. 
Health authority 
request 
6 
Synopsis, 
Section 2.5, and 
Section 8.4.4  
Clarified that at least 3 months of stable disease 
was required in the definition of DCR and CBR. 
Clarification 
7 
Synopsis, 
Section 3.1, and 
Section 7.4  
Clarified that approximately 12 subjects will be 
assessed for PK. 
Clarification 
8 
Synopsis and 
Section 3.1 
The DMC will not review the interim data for sample 
size re-evaluation; this has been clarified. The 
timing for the DMC meetings was removed and 
replaced with a reference to the DMC charter. It was 
clarified that the interim efficacy analysis will be 
performed by an external vendor. 
Update and 
clarification 

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Item No. 
Protocol 
Section 
Summary of Change 
Reason/ 
Rationale 
9 
Synopsis, 
Schedule of 
Assessments, 
and Section 3.3  
It was clarified that no dose reduction of 
unesbulin/placebo is permitted. For subjects who 
have interruptions in DTIC due to toxicities, detailed 
instructions on timing of assessments relative to 
continued unesbulin/placebo dosing were added to 
the protocol.  
Clarification 
10 
Synopsis and 
Section 4.1  
An exception to Inclusion Criterion #10 was added 
for patients with Gilbert’s syndrome who have 
elevated bilirubin values. 
Update based 
on feedback 
from 
investigators 
11 
Synopsis and 
Section 4.1  
Inclusion Criterion #11 was modified to increase the 
eligibility limit for AST and ALT from 1.5 to 3 times 
the ULN. 
Update based 
on feedback 
from 
investigators 
12 
Synopsis and 
Section 4.1  
It was clarified in Inclusion Criterion #16 that prior 
lines of treatment may include but are not limited to 
single-agent doxorubicin or other anthracycline, 
doxorubicin plus ifosfamide, trabectedin, pazopanib, 
or gemcitabine with or without docetaxel. 
Health authority 
request 
13 
Synopsis 
Exclusion 
Criterion #5 and 
Section 4.2  
Removed “known” prior to human immunodeficiency 
virus, hepatitis B virus, or hepatitis C virus positivity 
because viral testing will be required for all subjects 
at screening. 
Clarification 
14 
Synopsis, 
Section 4.2, and 
Section 5.5  
The criterion excluding the concomitant use of 
NSAIDs was deleted because the potential risk for 
gastrointestinal perforation was mitigated by adding 
gastritis to Exclusion Criterion #9. 
A statement was added to the Concomitant 
Medication Section 5.5 as a reminder that subjects 
should not have active peptic ulcer disease, active 
gastritis, or previous history of gastric perforation 
within the last 2 years. 
Update based 
on feedback 
from 
investigators 
15 
Synopsis, 
Section 4.2, and 
Section 5.5  
Exclusion Criterion #15 was modified to provide 
clarifications on the chronic use of marijuana. 
Clarification 
16 
Synopsis, 
Section 4.2, and 
Section 5.5  
Administration of live vaccines was added as an 
Exclusion Criterion (#17) and as a concomitant 
medication. 
Health authority 
request 
17 
Synopsis, 
Section 4.2  
Added that APTT/PT assessments to monitor 
subjects on anticoagulation where applicable. It was 
clarified that coagulation tests should fall within the 
required range (instead of “normal”) considering the 
patient disease and demographic characteristics. 
Health authority 
request and 
investigator 
feedback 
18 
Synopsis, 
Section 3.1, and 
Section 5.2  
Based on the results from a food effect assessment 
in the ongoing Phase 1b Study PTC596-ONC-007-
LMS, it is recommended that unesbulin/placebo be 
administered with food. 
Update 
19 
Synopsis and 
Section 5.1  
PTC may provide DTIC to sites that are unable to 
procure it locally. 
Procedural 
change 
20 
Synopsis and 
Section 5.1  
Instructions to reconstitute DTIC were added to 
accommodate variation in institutional policies.  
Update 

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Item No. 
Protocol 
Section 
Summary of Change 
Reason/ 
Rationale 
21 
Synopsis and 
Section 5.2  
The window to administer DTIC was widened from 1 
hour ± 5 minutes to 1 hour ± 30 minutes to allow 
sites more flexibility to administer this study drug. 
Procedural 
change 
22 
Synopsis and 
Section 7.1 
To align with the Schedule of Assessments, clarified 
that after Cycle 8, scans may be performed every 9 
weeks. 
Clarification 
23 
Synopsis, 
Schedule of 
Assessments 
(footnote “k”), 
and Section 7.1  
It was clarified that either MRI or CT could be used 
as clinically indicated. 
Health authority 
request 
24 
Synopsis, 
Schedule of 
Assessments 
(footnote “m”), 
and Section 7.6  
Timing and mandatory collection of biomarker 
samples was clarified. Footnote “m” was updated as 
follows: “Blood samples (10 mL) to assess 
circulating biomarkers will be collected at screening 
(predose) and prior to dosing on Day 1 of Cycle 3 
and at the time of disease progression or EOT. 
Samples will be processed, stored, and shipped 
according to instructions in the laboratory manual.” 
Clarification 
25 
Schedule of 
Assessments, 
Figure 1, 
Section 3.1, and 
Section 6.1.1  
To accommodate patient management and care 
and AE stabilization (as applicable), a more flexible 
timeframe for the EOT visit was provided. 
Update 
26 
Schedule of 
Assessments 
For urinalysis, an “X” was added to EOT and 
deleted from Day 1 of Cycle 2. 
Update 
27 
Schedule of 
Assessments 
Footnote “f”: It was clarified that weight must be 
assessed on the day of DTIC administration. 
Clarification 
28 
Schedule of 
Assessments 
Footnote “g”: It was clarified that local laboratory 
testing is acceptable. The window of clinical 
laboratory testing on Day 1 of Cycle 1 prior to the 
first dose of study drug was extended to up to 72 
hours to allow sites flexibility over weekends. After 
Cycle 3, monthly clinical laboratory testing will be 
adjusted in the protocol so that sampling will be 
performed once every cycle instead of on a weekly 
basis. 
The urinalysis assessment in the footnote was an 
error; this was replaced with a complete metabolic 
panel (CMP) to be performed at the same frequency 
as the CBC assessments. Instructions for 
performing laboratory assessments were added in 
case DTIC is interrupted/held due to toxicity. 
Request by 
participating 
sites to 
decrease 
subject and staff 
burden 
29 
Schedule of 
Assessments 
A pregnancy test prior is required within 24 hours or 
dosing on Day 1 of Cycle 1, and this may be 
assessed with a urine test. In footnote “h”, it was 
also clarified that a urine or serum pregnancy test 
should be performed 24 hours prior to dosing on 
Day 1 of Cycle 2 and continuing every 2 cycles 
beginning with Cycle 4. 
Health authority 
feedback 

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Item No. 
Protocol 
Section 
Summary of Change 
Reason/ 
Rationale 
30 
Schedule of 
Assessments 
Footnotes “i” and “j”: Instructions were added for 
performing the single ECG in cases if/when DTIC is 
interrupted or held. 
ECGs will not be required after Cycle 3. 
Clarification and 
procedural 
change based 
on cumulative 
safety data in 
the clinical 
program 
31 
Schedule of 
Assessments 
The following text in footnote “j” was deleted: “On 
Day 1 of all other cycles and at the time of collection 
for sparse PK samples, approximately 2 hours after 
DTIC infusion.” and was replaced with 
“Approximately 2 hours after DTIC infusion on Cycle 
2.” 
Clarification 
32 
Schedule of 
Assessments 
Footnote “n”: Instructions for performing PK 
sampling in case of DTIC interruption/hold were 
added. 
Clarification 
33 
Schedule of 
Assessments 
(footnote “o”) 
and Section 5.4  
Subjects are encouraged to bring back the patient 
diary at all scheduled visits. 
Procedural 
change 
34 
Schedule of 
Assessments 
and Section 5.2 
Footnote “p”: Reference to Section 3.3 was added 
for instructions on DTIC dosing in case of toxicity. 
Clarification 
35 
Schedule of 
Assessments 
Footnote “q”: Instructions were added for 
administering unesbulin/placebo in case of DTIC 
interruption. 
Clarification 
36 
Section 1.1  
A reference to the ESMO-EURACAN-GENTURIS 
(European Society for Medical Oncology; European 
Reference Network for Rare Adult Solid Cancers; 
European Reference Network for  
Genetic Tumour Risk Syndromes) Clinical Practice 
Guidelines by Gronchi et al was added. 
Health authority 
request 
37 
Section 1.3  
A statement was added in Section 1.3 referring 
investigators to the Investigator’s Brochure for 
additional information and guidance on mitigating 
potential drug-drug interactions. 
Health authority 
request 
38 
Schedule of 
Assessments 
and Section 3.3  
Procedural guidelines for DTIC interruptions were 
added. Instructions for modifying dose of DTIC in 
the case of nonhematological toxicities were added. 
It was clarified that the dose of unesbulin/placebo 
should not be reduced or withheld. 
Clarification and 
Health authority 
request 
39 
Section 3.4  
A definition of the end of study was added to the 
protocol. 
Health authority 
request 

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Item No. 
Protocol 
Section 
Summary of Change 
Reason/ 
Rationale 
40 
Section 5.2  
Instructions were added for subjects who cannot 
swallow the whole tablet. Specifically, tablets can be 
dispersed in water at the same dose level at which 
the tablets are being dosed and be administered 
orally. Instructions were added to provide guidance 
in cases of a subject who misses a dose of 
unesbulin/placebo or vomits after unesbulin/placebo 
dosing. It was clarified that coadministration of acid-
reducing agents should be avoided approximately 4 
hours before and after unesbulin/placebo 
administration to make instructions in this section 
consistent with other sections. 
Clarifications 
and process 
updates 
41 
Section 5.5  
It was added that neither approved nor guideline-
recommended therapy options should be withheld 
from subjects if the investigator determines it is in 
the best interest of the subject. Immunization with 
live vaccines should be avoided. Updated guidelines 
were added for mitigating potential BCRP, 
OATP1B1, and OATP2B2 interactions with 
unesbulin. Clarifications on chronic use of marijuana 
was added, along with a reminder on enrolling 
subjects with active peptic ulcer disease, active 
gastritis, or history of gastric perforation within the 
last 2 years. 
Update based 
on new data and 
Health authority 
request 
42 
Synopsis and 
Section 7.1  
It was clarified that survival follow-up will continue 
every 3 months as per the Schedule of 
Assessments. 
Clarification 
43 
Section 7.3.1 
and 
Section 7.3.2  
AE and SAE definitions revised as per PTC 
template language; revisions had no effect on 
reporting. 
Update 
44 
Section 7.3.9  
Serious Adverse Events Reporting: the existing 
“within 24 hours” was updated to “immediately but 
no later than 24 hours” 
Health authority 
request 
45 
Section 8.4.4  
Content that was previously in Section 8.4.3 was 
moved to this new section and entitled “Analysis of 
Other Secondary Efficacy Endpoints.” 
Update 
46 
Section 8.4.5.1  
Treatment-emergent adverse events were defined. 
Update 
47 
Section 9.1.1.3  
It was clarified that the informed consent may be 
delegated to a site delegate and not limited to a 
subinvestigator 
Clarification 
48 
Section 9.1.7  
It was clarified that a subject’s participation in the 
exploratory part of the study is optional. 
Clarification 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; 
AST, aspartate aminotransferase; BCRP, breast cancer resistance protein; CBC, complete blood count; CBR, clinical 
benefit rate; CMP, complete metabolic panel; CT, computed tomography; CTFG, Clinical Trial Facilitation and 
Coordination Group DCR, disease control rate; DMC, data monitoring committee; DTIC, dacarbazine; ECG, 
electrocardiogram; EOT, end of treatment; MRI, magnetic resonance imaging; NSAID, nonsteroidal anti-inflammatory 
drug; OATP1B1 and OATP1B2, organic anion transporter polypeptide transporters; OS, overall survival; PK, 
pharmacokinetic; PT, prothrombin time; SAE, serious adverse event; ULN, upper limit of normal; WOCBP, women of 
childbearing potential 

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9.2.3. 
Version 4.0: 28 November 2023 
Overall reason for Version 4.0: The main reasons for Version 4.0 were to clarify study 
procedures in cases of DTIC interruption and revise the analysis of the key secondary endpoint 
(OS). Additional updates were made to reflect changes in study staff, improved clarity, and to 
address clerical errors. A summary of changes from global Version 3.0 to Version 4.0 is 
presented below. 
Table 13: 
Summary of Changes From Global Protocol Version 3.0 to 4.0 
Item No. 
Protocol Section 
Summary of Change 
Reason/ Rationale 
1 
Title Page 
ClinicalTrials.gov study number was 
revised. 
The ClinicalTrials.gov 
identifier number was 
corrected. 
2 
Signature Page 
Titles of PTC signatories were 
updated. 
Change in signatory 
titles. 
3 
Protocol Identifiers and 
Study Personnel 
Study personnel was updated 
Change in PTC study 
staff. 
4 
Synopsis, Section 8.2, 
Section 8.4.3  
It was clarified that a hierarchical 
testing procedure will be utilized. 
 
The power calculation and analyses 
of OS were revised to specify that 
the interim analysis will occur when 
at least 60% of the events have 
accumulated and the final analysis 
will occur when 184 events have 
accumulated. 
Revisions were made 
to address the FDA 
comments and to 
provide more flexibility 
in the timing of the 
interim OS analysis, 
which is planned to be 
done at the time of the 
final efficacy analysis 
for PFS. 
5 
Synopsis, Section 4.1  
Inclusion criterion #11 revised as 
follows:  
Old version: “AST or ALT <3 times 
the ULN” New version: “AST and 
ALT <3 times the ULN.” 
Correction of clerical 
error 
6 
Synopsis, and 
Section 5.1  
The 200 mg/vial DTIC strength was 
removed, along with volume of 
Sterile Water for reconstitution. 
 
New text: DTIC for injection will be 
provided (by the site or by the 
sponsor) and will be reconstituted 
with Sterile Water for Injection, USP. 
Text revised to allow for 
site- and country-
specific variations in 
specific strengths of 
DTIC. 
7 
Synopsis, Footnote “a” 
in Schedule of 
Assessments, Figure 1 
footnote, Section 3.1, 
Section 7.1  
New text added (indicated in bold): 
Survival follow-up will continue every 
3 months until the later of 
184 events or 2 years after the last 
subject is randomized 
Revision made to 
ensure that sufficient 
events are achieved for 
analysis of OS. 
8 
Schedule of 
assessments,  
Footnote b 
“Window” was substituted with 
“span” to clarify that procedures 
performed on Cycle 1 Day 1 and 
Cycle 2 Day 1 can be done over a 
48-hour period. 
Clarification 

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Item No. 
Protocol Section 
Summary of Change 
Reason/ Rationale 
9 
Schedule of 
assessments,  
Footnote g 
For subjects who have DTIC 
interrupted or held, it was added that 
clinical laboratory assessments will 
be required weekly for the first 
3 weeks after DTIC reintroduction. 
For subsequent cycles, the clinical 
laboratory assessments may be 
performed at a minimum of once per 
cycle or more frequently per the 
investigator’s discretion to ensure 
that the subject meets the protocol-
defined safety criteria.   
Improved safety 
monitoring for subjects 
who require 
interruptions in DTIC 
10 
Schedule of 
assessments,  
Footnote q 
In footnote q, the bolded text was 
added: If DTIC is interrupted in 
Cycle 3 then PK sampling should be 
performed upon reintroduction of 
DTIC as described in footnote “n”  
Clarification 
11 
Section 3.3  
The following statement was added: 
DTIC should be reintroduced at least 
48 hours after unesbulin dosing 
Additional instructions 
for clarity 
12 
Section 4.3  
The following statement was added: 
Subjects who fail screening may be 
considered for rescreening after 
consultation with the PTC Medical 
Monitor. 
Procedural change 
13 
Section 5.6  
Bolded text added: The investigator 
and study staff (including processing 
laboratory personnel), the subjects, 
and the sponsor’s staff (with 
exception of Pharmacovigilance 
staff for the purposes of SUSAR 
reporting) will remain blinded until 
the primary analysis is completed. 
Clarified that study will 
remain blinded until the 
primary analysis is 
completed rather than 
study closure, which 
could be later than the 
primary analysis. It was 
also clarified that 
certain 
Pharmacovigilance 
staff at PTC will unblind 
some subjects for 
SUSAR reporting 
purposes. 
14 
Section 8.1  
Null and alternative hypotheses for 
the key secondary endpoint were 
added. 
Clarification  
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; DTIC, dacarbazine; OS, overall 
survival; PFS, progression-free survival; PK, pharmacokinetic; SUSAR, suspected unexpected serious adverse 
reaction; ULN, upper limit of normal 

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10. 
REFERENCES 
Aaronson, NK, Ahmedzai, S, Bergman, B, Bullinger, M, Cull, A, Duez, NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-376. 
Bessen, T, Caughey, GE, Shakib, S, Potter, JA, Reid, J, Farshid, G, et al. A Population-Based 
Study of Soft Tissue Sarcoma Incidence and Survival in Australia: An Analysis of 26,970 Cases. 
Cancer Epidemiol 2019;63:101590. 
Blay, JY, Schoffski, P, Bauer, S, Krarup-Hansen, A, Benson, C, D'Adamo, DR, et al. Eribulin 
Versus Dacarbazine in Patients With Leiomyosarcoma: Subgroup Analysis From a Phase 3, 
Open-Label, Randomised Study. Br J Cancer 2019;120(11):1026-1032. 
Cancer Genome Atlas Research Network. Comprehensive and Integrated Genomic 
Characterization of Adult Soft Tissue Sarcomas. Cell 2017;171(4):950-965.e928. 
Clinical Trials Facilitation and Coordination Group (2020). Recommendations Related to 
Contraception and Pregnancy Testing in Clinical Trials, Version 1.1. 
Demetri, GD, Von Mehren, M, Jones, RL, Hensley, ML, Schuetze, SM, Staddon, A, et al. 
Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or 
Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III 
Randomized Multicenter Clinical Trial. J Clin Oncol 2016;34(8):786-793. 
Ducimetière, F, Lurkin, A, Ranchère-Vince, D, Decouvelaere, A-V, Péoc'h, M, Istier, L, et al. 
Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study 
with central pathology review and molecular testing. PloS one 2011;6(8):e20294-e20294. 
Ferrari, A, Sultan, I, Huang, TT, Rodriguez-Galindo, C, Shehadeh, A, Meazza, C, et al. Soft 
tissue sarcoma across the age spectrum: a population-based study from the Surveillance 
Epidemiology and End Results database. Pediatr Blood Cancer 2011;57(6):943-949. 
Friedman, CF and Hensley, ML. Options for Adjuvant Therapy for Uterine Leiomyosarcoma. 
Curr Treat Options Oncol 2018;19(2):7. 
George, S, Serrano, C, Hensley, ML and Ray-Coquard, I. Soft Tissue and Uterine 
Leiomyosarcoma. J Clin Oncol 2018;36(2):144-150. 
Gibault, L, Pérot, G, Chibon, F, Bonnin, S, Lagarde, P, Terrier, P, et al. New Insights in Sarcoma 
Oncogenesis: A Comprehensive Analysis of a Large Series of 160 Soft Tissue Sarcomas With 
Complex Genomics. The Journal of pathology 2011;223(1):64-71. 
Giesinger, JM, Kieffer, JM, Fayers, PM, Groenvold, M, Petersen, MA, Scott, NW, et al. 
Replication and Validation of Higher Order Models Demonstrated That a Summary Score for the 
EORTC QLQ-C30 Is Robust. J Clin Epidemiol 2016;69:79-88. 
Gladdy, RA, Qin, LX, Moraco, N, Agaram, NP, Brennan, MF and Singer, S. Predictors of 
Survival and Recurrence in Primary Leiomyosarcoma. Ann Surg Oncol 2013;20(6):1851-1857. 
Gronchi, A, Miah, AB, Dei Tos, AP, Abecassis, N, Bajpai, J, Bauer, S, et al. Soft Tissue and 
Visceral Sarcomas: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for Diagnosis, 
Treatment and Follow-up. Ann Oncol 2021. 

PTC596-ONC-008-LMS 
Clinical Protocol 
V4.0 
PTC Therapeutics - Confidential 
Page 91 of 92 
Guo, X, Jo, VY, Mills, AM, Zhu, SX, Lee, CH, Espinosa, I, et al. Clinically Relevant Molecular 
Subtypes in Leiomyosarcoma. Clin Cancer Res 2015;21(15):3501-3511. 
Hensley, ML, Blessing, JA, Degeest, K, Abulafia, O, Rose, PG and Homesley, HD. Fixed-Dose 
Rate Gemcitabine Plus Docetaxel as Second-Line Therapy for Metastatic Uterine 
Leiomyosarcoma: a Gynecologic Oncology Group Phase II Study. Gynecol Oncol 
2008;109(3):323-328. 
Hensley, ML, Patel, SR, von Mehren, M, Ganjoo, K, Jones, RL, Staddon, A, et al. Efficacy and 
Safety of Trabectedin or Dacarbazine in Patients With Advanced Uterine Leiomyosarcoma After 
Failure of Anthracycline-Based Chemotherapy: Subgroup Analysis of a Phase 3, Randomized 
Clinical Trial. Gynecol Oncol 2017;146(3):531-537. 
Herdman, M, Gudex, C, Lloyd, A, Janssen, M, Kind, P, Parkin, D, et al. Development and 
Preliminary Testing of the New Five-Level Version of EQ-5D (EQ-5D-5L). Qual Life Res. 
2011;20:1727–1736. 
Howlader, N, Noone, A, Krapcho, M, Miller, D, Brest, A, Yu , M, et al. (2021). "Surveillance, 
Epidemiology, and End Results (SEER) Cancer Statistics Review, 1975-2016, Based on 
November 2020 SEER Data Submission. National Cancer Institute; Bethesda, MD." Published 
April 2021. Accessed June 2021, from https://seer.cancer.gov/csr/1975_2018/. 
In, GK, Hu, JS and Tseng, WW. Treatment of Advanced, Metastatic Soft Tissue Sarcoma: Latest 
Evidence and Clinical Considerations. Ther Adv Med Oncol 2017;9(8):533-550. 
Jernigan, F, Branstrom, A, Baird, J, Cao, L, Dali, M, Furia, B, et al. Preclinical and Early 
Clinical Development of PTC596, a Novel Small-Molecule Tubulin-Binding Agent. Mol Cancer 
Ther 2021. 
Kawai, A, Yonemori, K, Takahashi, S, Araki, N and Ueda, T. Systemic Therapy for Soft Tissue 
Sarcoma: Proposals for the Optimal Use of Pazopanib, Trabectedin, and Eribulin. Adv Ther 
2017;34(7):1556-1571. 
Lu, Y, Chen, J, Xiao, M, Li, W and Miller, DD. An Overview of Tubulin Inhibitors That Interact 
With the Colchicine Binding Site. Pharm Res 2012;29(11):2943-2971. 
Miettinen, M. Smooth Muscle Tumors of Soft Tissue and Non-Uterine Viscera: Biology and 
Prognosis. Mod Pathol 2014;27 Suppl 1:S17-29. 
Nagar, SP, Mytelka, DS, Candrilli, SD, D'Yachkova, Y, Lorenzo, M, Kasper, B, et al. Treatment 
Patterns and Survival Among Adult Patients With Advanced Soft Tissue Sarcoma: A 
Retrospective Medical Record Review in the United Kingdom, Spain, Germany, and France. 
Sarcoma 2018;2018:5467057. 
NCCN. Clinical Practice Guidelines in Oncology. Uterine Neoplasms. Version 1.2021. National 
Comprehensive Cancer Network, Inc., Oct 2020.  2020. 
NCCN. Clinical Practice Guidelines in Oncology. Soft Tissue Sarcoma. Version 2.2021. 
National Comprehensive Cancer Network, Inc., Apr 2021.  2021. 
Parikh, RC, Lorenzo, M, Hess, LM, Candrilli, SD, Nicol, S and Kaye, JA. Treatment Patterns 
and Survival Among Older Adults in the United States With Advanced Soft-Tissue Sarcomas. 
Clin Sarcoma Res 2018;8:8. 

PTC596-ONC-008-LMS 
Clinical Protocol 
V4.0 
PTC Therapeutics - Confidential 
Page 92 of 92 
Patel, S, von Mehren, M, Reed, DR, Kaiser, P, Charlson, J, Ryan, CW, et al. Overall Survival 
and Histology-Specific Subgroup Analyses From a Phase 3, Randomized Controlled Study of 
Trabectedin or Dacarbazine in Patients With Advanced Liposarcoma or Leiomyosarcoma. 
Cancer 2019;125(15):2610-2620. 
Pisters, PW, Leung, DH, Woodruff, J, Shi, W and Brennan, MF. Analysis of Prognostic Factors 
in 1,041 Patients With Localized Soft Tissue Sarcomas of the Extremities. J Clin Oncol 
1996;14(5):1679-1689. 
Ratan, R and Patel, SR. Chemotherapy for soft tissue sarcoma. Cancer 2016;122(19):2952-2960. 
Saltus, CW, Calingaert, B, Candrilli, S, Lorenzo, M, D'Yachkova, Y, Otto, T, et al. 
Epidemiology of Adult Soft-Tissue Sarcomas in Germany. Sarcoma 2018;2018:5671926. 
Svarvar, C, Bohling, T, Berlin, O, Gustafson, P, Folleras, G, Bjerkehagen, B, et al. Clinical 
Course of Nonvisceral Soft Tissue Leiomyosarcoma in 225 Patients From the Scandinavian 
Sarcoma Group. Cancer 2007;109(2):282-291. 
Toro, JR, Travis, LB, Wu, HJ, Zhu, K, Fletcher, CD and Devesa, SS. Incidence Patterns of Soft 
Tissue Sarcomas, Regardless of Primary Site, in the Surveillance, Epidemiology and End Results 
Program, 1978-2001: An Analysis of 26,758 Cases. Int J Cancer 2006;119(12):2922-2930. 
Van Der Graaf, WT, Blay, J-Y, Chawla, SP, Kim, D-W, Bui-Nguyen, B, Casali, PG, et al. 
Pazopanib for Metastatic Soft-Tissue Sarcoma (PALETTE): A Randomised, Double-Blind, 
Placebo-Controlled Phase 3 Trial. Lancet 2012;379(9829):1879-1886. 
Wang, WL, Soslow, R, Hensley, M, Asad, H, Zannoni, GF, de Nictolis, M, et al. Histopathologic 
Prognostic Factors in Stage I Leiomyosarcoma of the Uterus: A Detailed Analysis of 27 Cases. 
Am J Surg Pathol 2011;35(4):522-529. 
Worhunsky, DJ, Gupta, M, Gholami, S, Tran, TB, Ganjoo, KN, Van De Rijn, M, et al. 
Leiomyosarcoma: One Disease or Distinct Biologic Entities Based on Site of Origin? Journal of 
surgical oncology 2015;111(7):808-812. 
Zhang, J, Du, Z, Pan, S, Shi, M, Li, J, Yang, C, et al. Overcoming Multidrug Resistance by 
Codelivery of MDR1-Targeting siRNA and Doxorubicin Using EphA10-Mediated pH-Sensitive 
Lipoplexes: In Vitro and In Vivo Evaluation. ACS Appl Mater Interfaces 2018;10(25):21590-
21600.