Conditions: Non Small Cell Lung Cancer Medullary Thyroid Cancer RET Gene Mutation Metastatic Solid Tumor Advanced Solid Tumor
Keywords: Non small cell lung cancer Non-small cell lung cancer NSCLC Medullary Thyroid Cancer MTC RET gene mutation RET gene alteration Advanced non small cell lung cancer Advanced/metastatic disease lung cancer lung adenocarcinoma Metastatic solid tumor Advanced Solid Tumors RET gene fusion RET inhibitor SRC TPX-0046 Thyroid cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 41
Healthy volunteers: no

Brief summary:
A phase 1/2, first-in-human, open-label study to determine the safety, tolerability, PK, and preliminary efficacy of the novel RET/SRC inhibitor TPX-0046 in adult subjects with advanced or metastatic solid tumors harboring RET mutations or alterations. The study consists of three portions: 1) Phase 1 Dose Escalation and Food Effect Sub-study, and 2) Phase 1 dose expansion and 3) Phase 2 efficacy evaluation.

Detailed description:
Phase 1 Dose Escalation and Dose Expansion: To evaluate the overall safety profile, characterize the PK profiles and assess the preliminary efficacy of TPX-0046 in adults subjects with advanced solid tumors harboring oncogenic RET fusions or mutations.

Food Effect Sub-Study: To determine the effect of food on PK of TPX-0046 in adult subjects with advanced or metastatic solid tumors harboring oncogenic RET fusions or mutations.

Phase 2 Efficacy Evaluation: To determine the overall safety and anti-tumor efficacy of TPX-0046 in defined cohorts of subjects with advanced/metastatic solid tumors harboring oncogenic RET fusions or mutations.

Arms:
arm 1: The Phase 1 part of the study will determine the safety, tolerability, PK, MTD, and RP2D of TPX-0046.

The food-effect sub-study determines the effect of food on a dose of TPX-0046 at the RP2D dose level.

The Phase 2 part of the study will determine the safety, tolerability, PK, and preliminary efficacy in specific cohorts.

Phase 2 Cohorts:

* Cohort I (NSCLC + RET fusion, RET TKI Therapy Naive)
* Cohort II (NSCLC + RET fusion, RET TKI Therapy Pre-treated)
* Cohort III (MTC + RET mutation, RET TKI Therapy Naive)
* Cohort IV (MTC + RET mutation, RET TKI Therapy Pre-treated)
* Cohort V (advanced/metastatic tumor with RET fusion or mutation, RET TKI Therapy Naive)
* Cohort VI (advanced/metastatic tumor with RET fusion or mutation, RET TKI Therapy Pre-Treated)

Interventions: intervention 1: TPX-0046
Intervention descriptions: intervention 1: Oral TPX-0046 capsules

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title of Study: 
 
A Phase 1/2 Study of TPX-0046, A Novel Oral RET/SRC Inhibitor in Adult Subjects With 
Advanced/Metastatic Solid Tumors Harboring Oncogenic RET Fusions or Mutations 
 
 
NCT Number: NCT04161391 
 
Document Date (Date in which document was last revised): December 02, 2022 


Protocol TPX-0046-01 
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A PHASE 1/2 STUDY OF TPX-0046, A NOVEL ORAL RET/SRC 
INHIBITOR IN ADULT SUBJECTS WITH ADVANCED/METASTATIC 
SOLID TUMORS HARBORING ONCOGENIC RET FUSIONS OR 
MUTATIONS 
(SWORD-1) 
Investigational Product Number: 
TPX-0046 
Investigational Product Name: 
Not Yet Assigned 
United States (US) Investigational New 
Drug (IND) Number: 
144490 
European Clinical Trials Database 
(EudraCT) Number: 
2020-000781-42 
Protocol Number: 
TPX-0046-01 
Phase: 
1/2 
Protocol Version: 
Version 10.0 (02 December 2022) 
Sponsor Name and Address: 
Turning Point Therapeutics, Inc. 
10628 Science Center Drive, Suite 200 
San Diego, CA 92121 USA 
(a wholly owned subsidiary of Bristol Myers 
Squibb Company) 
Medical Monitor: 
 
 
Turning Point Therapeutics, Inc. 
10628 Science Center Drive, Suite 200 
San Diego, CA 92121 USA 
Confidentiality Statement 
The information contained in this document is confidential and proprietary property of Turning Point 
Therapeutics, Inc. Any distribution, copying, or disclosure is strictly prohibited unless federal 
regulations or state law requires such disclosure. Prior written authorization of Turning Point 
Therapeutics, Inc. is required for any disclosure or use of the information contained herein. Persons to 
whom the information is disclosed must know that it is confidential and that it may not be further 
disclosed by them. 
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TURNING POINT THERAPEUTICS APPROVALS 
Protocol Number: 
TPX-0046-01 
Version (Date):  
10.0 (02 December 2022) 
Protocol Title: 
A Phase 1/2 Study of TPX-0046, a Novel Oral RET/SRC Inhibitor in Adult 
Subjects with Advanced/Metastatic Solid Tumors Harboring Oncogenic 
RET Fusions or Mutations (SWORD-1) 
Date: 
 
 
Turning Point Therapeutics, Inc. 
 
 
07-Dec-2022 | 17:34 PST
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PRINCIPAL INVESTIGATOR STATEMENT OF AGREEMENT 
I, the undersigned Principal Investigator, have read and understood the following protocol, 
TPX-0046-01, Version 10.0, 02 December 2022, and its appendices. 
I promise to abide by the International Conference for Harmonisation (ICH) Guidelines for Good 
Clinical Practices (GCP), the Declaration of Helsinki, and all applicable laws and regulations, 
and agree that, in all cases, the most restrictive regulation related to a given aspect of research 
involving protection of human subjects will be followed. If I have a question regarding my 
obligations during the conduct of this protocol, I have ready access to these aforementioned 
regulations, as either my personal copy, or available on file from the Chairperson of the 
Institutional Review Board (IRB)/Ethics Committee (EC) or the Sponsor, via local authorities 
and, I am authorized to enter into this commitment to conduct the study outlined in this protocol, 
and my signature below signifies that I agree to conduct the study as outlined herein. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 
 
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TABLE OF CONTENTS 
TURNING POINT THERAPEUTICS APPROVALS ....................................................................2 
PRINCIPAL INVESTIGATOR STATEMENT OF AGREEMENT ..............................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................8 
ABBREVIATIONS AND DEFINITION OF TERMS ....................................................................9 
1. 
SYNOPSIS .................................................................................................................13 
2. 
INTRODUCTION ......................................................................................................24 
2.1. 
Mechanism of Action/Indication ................................................................................24 
2.2. 
Background .................................................................................................................24 
2.2.1. 
RET Targeted Therapies in RET+ Disease and Drug Resistance ...............................24 
2.3. 
Nonclinical Overview .................................................................................................25 
2.3.1. 
Nonclinical Pharmacology ..........................................................................................25 
2.3.2. 
Nonclinical Pharmacokinetics ....................................................................................29 
2.3.3. 
Nonclinical Toxicology ..............................................................................................29 
2.4. 
Basis of Clinical Starting Dose of TPX-0046-01 FIH Study .....................................30 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................30 
4. 
STUDY DESIGN .......................................................................................................31 
4.1. 
Overall Study Design ..................................................................................................31 
4.1.1. 
Phase 1 Dose Escalation .............................................................................................31 
4.2. 
Recommended Dose Modifications ............................................................................34 
4.2.1. 
Dose Interruptions ......................................................................................................35 
4.2.2. 
Dose Delays ................................................................................................................35 
4.2.3. 
Dose Reductions .........................................................................................................35 
4.2.4. 
Dose Modifications: 
 ...................................................39 
4.2.5. 
Dose Modifications:
 
 ................................................39 
5. 
SUBJECT ELIGIBILITY CRITERIA .......................................................................40 
5.1. 
Inclusion Criteria ........................................................................................................40 
5.2. 
Exclusion Criteria .......................................................................................................42 
6. 
STUDY TREATMENT ..............................................................................................44 
6.1. 
Allocation to Treatment ..............................................................................................44 
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6.2. 
Investigational Product Supplies ................................................................................44 
6.2.1. 
Dosage Forms and Packaging .....................................................................................44 
6.2.2. 
Investigational Product Storage and Accountability ..................................................45 
6.2.3. 
Destruction of Investigational Product Supplies ........................................................45 
6.3. 
Administration ............................................................................................................45 
6.3.1. 
Dose Escalation ..........................................................................................................46 
6.3.2. 
Food Requirements (except for the Food Effect Sub-study) ......................................46 
6.4. 
Subject Compliance ....................................................................................................46 
6.5. 
Concomitant Treatments .............................................................................................46 
6.5.1. 
Prohibited Concomitant Medications .........................................................................47 
6.5.2. 
Other Anti-tumor or Investigational Drugs ................................................................47 
6.5.3. 
Supportive Care ..........................................................................................................47 
6.5.4. 
Anti-diarrheal, Anti-emetic Therapy ..........................................................................47 
6.5.5. 
Anti-inflammatory Therapy ........................................................................................48 
6.5.6. 
Corticosteroids ............................................................................................................48 
6.5.7. 
Surgery ........................................................................................................................48 
7. 
STUDY ASSESSMENTS ..........................................................................................48 
7.1. 
Informed Consent .......................................................................................................48 
7.2. 
Physical Examination .................................................................................................48 
7.3. 
Performance Status .....................................................................................................49 
7.4. 
Subject Diary and Compliance ...................................................................................49 
7.5. 
Laboratory Assessments .............................................................................................49 
7.6. 
Cardiac Safety Monitoring .........................................................................................50 
7.7. 
Cardiac safety monitoring should be done based on symptomatology and at 
Investigator’s discretion. Tumor Response Assessments ...........................................50 
8. 
STUDY CONDUCT ...................................................................................................50 
8.1. 
Screening And Eligibility ...........................................................................................50 
8.2. 
Timing of Clinical Procedures ....................................................................................51 
8.3. 
Study Duration ............................................................................................................51 
8.4. 
Subject Treatment Discontinuation ............................................................................51 
8.5. 
End of Treatment Visit ...............................................................................................51 
8.6. 
Safety Follow-up Visit ................................................................................................51 
8.7. 
Subject Discontinuation and Withdrawal from Study ................................................51 
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8.7.1. 
Withdrawal of Consent ...............................................................................................52 
8.7.2. 
Lost to Follow-up .......................................................................................................52 
9. 
ADVERSE EVENT REPORTING ............................................................................53 
9.1. 
Adverse Events, Serious Adverse Events, and Anticipated Serious Adverse 
Events .........................................................................................................................53 
9.1.1. 
Definition of Adverse Events .....................................................................................53 
9.1.2. 
Definition of Serious Adverse Events ........................................................................53 
9.1.3. 
Definition of Anticipated Serious Adverse Events .....................................................54 
9.2. 
Relationship to the Investigational Product ................................................................55 
9.3. 
Reporting of Adverse Events and Serious Adverse Events ........................................56 
9.3.1. 
Reporting of Adverse Events ......................................................................................56 
9.3.2. 
Reporting of Serious Adverse Events .........................................................................56 
9.3.3. 
Deaths .........................................................................................................................57 
9.3.4. 
Follow-up of Adverse Events and Serious Adverse Events .......................................57 
9.4. 
Pregnancy ...................................................................................................................58 
9.4.1. 
Exposure During Pregnancy .......................................................................................58 
9.4.2. 
Pregnancy Reporting ..................................................................................................59 
9.4.3. 
Birth Defects and Abortions .......................................................................................59 
10. 
STATISTICAL METHOD ANALYSIS ....................................................................59 
10.1. 
Analysis Sets ...............................................................................................................59 
10.1.1. 
Full Analysis Set .........................................................................................................59 
10.1.2. 
Efficacy Evaluable Analysis Set .................................................................................59 
10.1.3. 
Safety Analysis Set .....................................................................................................60 
10.2. 
Sample Size Determinations .......................................................................................60 
10.2.1. 
Phase 1 Dose Escalation .............................................................................................60 
10.3. 
Statistical Analysis ......................................................................................................60 
10.3.1. 
General Considerations ...............................................................................................60 
10.3.2. 
Subject Disposition .....................................................................................................61 
10.3.3. 
Demographics and Baseline Characteristics ...............................................................61 
10.3.4. 
Efficacy Analyses .......................................................................................................61 
10.3.5. 
Safety Analyses ..........................................................................................................61 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................62 
12. 
DATA HANDLING AND RECORD KEEPING ......................................................62 
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12.1. 
Case Report Forms/Electronic Data Record ...............................................................62 
12.2. 
Study Monitoring, Audits, and Inspections ................................................................62 
12.3. 
Inspection of Records .................................................................................................63 
12.4. 
Record Retention ........................................................................................................63 
13. 
ETHICS ......................................................................................................................63 
13.1. 
Ethics Review .............................................................................................................63 
13.2. 
Protocol Compliance ..................................................................................................63 
13.3. 
Ethical Conduct of the Study ......................................................................................64 
13.4. 
Written Informed Consent ..........................................................................................64 
13.5. 
Subject Confidentiality ...............................................................................................64 
13.6. 
Post-Trial Access ........................................................................................................64 
14. 
PUBLICATION OF STUDY RESULTS ...................................................................65 
15. 
REFERENCES ...........................................................................................................66 
Appendix A. Strong CYP3A4/5 Inhibitors or Inducers, SENSITIVE CYP3A 
SUBSTRATES, and Medications that Cause QTc Prolongation ...............................68 
Appendix B. Contraceptive Requirements ..................................................................................70 
71 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities: Phase 1 Dose Escalation .......................................................22 
 
26 
Table 3: 
Summary of TPX-0046 Activities against RET in Cellular Assays ...........................26 
 
.30 
Table 5: 
TPX-0046 Dose Escalation Levels and Regimens .....................................................32 
Table 6: 
Criteria for Defining Dose-Limiting Toxicities ..........................................................33 
Table 7: 
Dose Modifications for Adverse Events (CTCAE version 5.0) .................................37 
Table 8: 
Recommended Dose Modification Guidelines 
 
 ....................................................................................................................39 
Table 9: 
Dose Modification Guidelines 
.........................39 
Table 10: TPX-0046 Investigational Product .............................................................................45 
Table 11: Safety Laboratory Tests ..............................................................................................49 
Table 12: Relationship of Adverse Events to Investigational Product .......................................55 
Table 13: Severity of Adverse Events ........................................................................................56 
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71 
 
LIST OF FIGURES 
 
 
27 
Figure 2: 
Study Design ...............................................................................................................31 
 
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ABBREVIATIONS AND DEFINITION OF TERMS  
Term 
Definition 
AE 
adverse event 
AKT 
protein kinase  
ALK 
anaplastic lymphoma kinase 
ASCO 
American Society of Clinical Oncology  
ATP 
adenosine triphosphate 
BICR 
Blinded Independent Central Review 
BID 
twice a day 
CBR 
clinical benefit rate 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
CYP 
cytochrome P450  
DLT 
dose-limiting toxicity 
DOR 
duration of response 
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Term 
Definition 
ECG 
electrocardiogram 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture  
EE 
Efficacy Evaluable  
EGFR 
epidermal growth factor receptor 
EOT 
end of treatment 
ERK 
extracellular signal-regulated kinase 
FAS 
Full Analysis Set 
FDA 
US Food and Drug Administration 
FGFR 
fibroblast growth factor receptor 
FIH 
first-in-human 
GCP 
Good Clinical Practice  
HDPE 
high-density polyethylene 
hERG 
human ether-à-go-go-related gene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severe toxic dose 
IC50 
half maximal inhibitory concentration 
IC90 
90% inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IC-ORR 
intracranial objective response rate 
IRB 
Institutional Review Board 
JAK 
Janus kinase 
KIF5B 
kinesin family 5B 
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Term 
Definition 
LVEF 
left ventricular ejection fraction  
MAPK 
mitogen-activated protein kinases 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEN2 
multiple endocrine neoplasia 2 
MRI 
magnetic resonance imaging 
MTC 
medullary thyroid cancer 
MTD 
maximum tolerated dose 
NSCLC 
non-small-cell lung cancer 
ORR 
objective response rate 
PD 
progressive disease 
PFS 
progression-free survival 
PI3K 
phosphoinositide 3-kinase 
PK 
pharmacokinetics 
PR 
partial response 
QD 
once daily 
QOL 
quality of life 
QT 
ECG interval measured from the onset of the QRS complex to the end of the T wave 
QTc 
QT interval corrected for heart rate 
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Term 
Definition 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RAS 
family of GTPase proteins that are essential components of signaling networks controlling 
cellular proliferation, differentiation, or survival 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RET 
rearranged during transfection 
ROS1 
receptor tyrosine kinase encoded by the ROS1 gene 
RP2D 
recommended Phase 2 dose 
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SOC 
standard of care 
SRC 
tyrosine kinase first identified in avian sarcoma virus 
STAT 
signal transducer and activator of transcription 
STD10 
severe toxic dose in 10% of the animals 
t1/2 
elimination half-life 
TEAE 
treatment-emergent adverse event 
TKI 
tyrosine kinase inhibitor 
TRK 
tropomyosin receptor kinase 
ULN 
upper limit of normal 
US 
United States 
VEGFR 
vascular endothelial growth factor receptor 
WOCBP 
women of childbearing potential 
WT 
wild type 
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1. 
SYNOPSIS 
Name of Sponsor/Company: 
Turning Point Therapeutics, Inc. (a wholly owned subsidiary of Bristol Myers Squibb Company) 
Title of Study:  
A Phase 1/2 Study of TPX-0046, a Novel Oral RET/SRC Inhibitor in Adult Subjects with 
Advanced/Metastatic Solid Tumors Harboring Oncogenic RET Fusions or Mutations (SWORD-1) 
Indication: 
Treatment of adult patients with advanced/metastatic solid tumors harboring oncogenic rearranged during 
transfection (RET) fusions or mutations. 
Name of Investigational Product: 
TPX-0046 
Study Site(s): 
Fifteen sites are participating in this study globally.  
Phase of Development: 
Phase 1/2 
Study Duration:  
Subjects will remain on study treatment until disease progression, development of unacceptable toxicity, the 
ability to move to alternative care is identified, or withdrawal of consent. Treatment beyond radiographic or 
clinical progression will not be allowed. 
Subjects discontinuing study treatment will have an end of treatment visit within 7 days after the last dose of 
investigational product. After treatment discontinuation, subjects will have a safety follow-up visit 
approximately 28 days after the last dose or before any new anticancer treatment is started. 
The study will close after the final safety follow up is complete. 
Study Objectives and Endpoints: 
Preliminary results from Phase 1 dose escalation indicate that TPX‑0046 has a 
. 
Based on the totality of clinical information available, the Sponsor has decided to discontinue further 
development of TPX-0046 due to the inability to achieve and optimize a dose that could provide a positive 
benefit-risk profile in the current treatment landscape for RET mutant TKI naïve and pretreated setting. This 
decision was communicated to study sites on 03 October 2022. As such, no new subjects will be enrolled in 
this study, which will close after all active subjects have completed treatment. Subjects currently receiving 
treatment in this study will continue treatment at the discretion of the Investigators until need for 
discontinuation or the ability to move to alternative care is identified. As such, a synoptic CSR will be 
generated and submitted to health authorities. 
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Primary Objectives 
Primary Endpoints 
Phase 1:  
• 
Evaluate the safety and tolerability of TPX-0046 
at selected doses  
• 
Determine the maximum tolerated dose (MTD) 
and/or Recommended Phase 2 Dose (RP2D) of 
TPX-0046  
Phase 1: 
• 
Incidence of first cycle dose-limiting 
toxicities (DLTs) of TPX-0046 
administered orally in a 28-day cycle  
• 
MTD and RP2D 
Overall Study Design: 
This is a Phase 1/2 multi-center, first-in-human (FIH), open-label study designed to evaluate the safety, 
tolerability, PK, and efficacy of the novel RET/SRC inhibitor TPX-0046 in adult subjects with 
advanced/metastatic solid tumors harboring oncogenic RET fusions or mutations. The global study consists 
of two portions as shown below in the Study Design schema: 1) Phase 1 Dose Escalation, Food Effect Sub-
study, and Dose Expansion in 6 cohorts, and 2) Phase 2 preliminary efficacy evaluation in six defined 
subject cohorts.  
As study enrollment will close prior to completing Phase 1 dose escalation, the Phase 1 food effect 
substudy, Phase 1 dose expansion, and Phase 2 activities will not take place. 
Study Design: 
Phase 1 Dose Escalation: 
The Phase 1 dose escalation portion will be conducted according to a 3+3 based design. Approximately 
60 subjects will be enrolled. Eligible subjects will be adults (≥ 18 years) with advanced/metastatic solid 
tumors harboring oncogenic RET fusions or mutations.  
Subjects will be screened for eligibility up to 28 days prior to enrollment (the first day of TPX-0046 
administration). 
 
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 Following 
completion 
, subjects will begin once daily (QD) dosing of TPX-0046 in 28-day 
continuous cycles. es Subjects may receive TPX-0046 until disease progression, unacceptable toxicity, the 
ability to move to alternative care is identified, or withdrawal of consent. Treatment beyond radiographic or 
clinical progression will not be allowed. An end of treatment (EOT) visit will be conducted within 7 days of 
the last dose of TPX-0046. A safety follow-up visit will be conducted within 28 days of the last dose. 
Dose Escalation Schema: 
The dose escalation schema is illustrated in the table below. No further dose escalation will occur after dose 
level 9. DLTs will be evaluated independently in any given dosing regimen.  
Dose Level 
Dose Regimen 
Daily Dose (mg/day) 
Increment from Previous Daily Dose  
1 
10 mg QD 
10 mg 
Not applicable 
2 
20 mg QD 
20 mg 
100% increase 
3 
10 mg BID 
4 
30 mg QD 
30 mg 
50% increase 
5 
20 mg QD to 30 mg QD 
20 mg (1st 14 days), then 30 mg 
6 
20 mg BID 
40 mg 
33% increase 
7 
20 mg QD to 40 mg QD 
20 mg (1st 14 days), then 40 mg 
8 
20 mg QD to 20 mg 
BID 
20 mg (1st 14 days), then 40 mg 
9 
10 mg QD to 10 mg 
BID 
10 mg (1st 14 days), then 20 mg 
50% decrease 
Criteria for Defining DLTs: 
The AEs described in the table below, excluding toxicities clearly related to disease progression or 
intercurrent illness, will be considered DLTs during the DLT evaluation period. The DLT evaluation period 
is defined as 28 days following the first 
 dose of the dose regimen administered in Cycle 1
 
 
. 
Category 
Criteria 
Toxicities resulting in an 
excessive number of missed doses 
Inability to deliver at least 75% of the planned dose intensity of TPX-0046 
treatment during the DLT evaluation period (ie, at least 21 days of dosing in a 
28-day cycle, beginning in Cycle 1) because of toxicity excluding toxicities 
clearly related to disease progression or intercurrent illness 
Hematologic toxicities  
• CTCAE grade ≥ 4 neutropenia (absolute neutrophil count [ANC] 
< 0.5 × 109/L)  
• CTCAE grade ≥ 4 platelet count decrease (platelets < 25 × 109/L) or 
CTCAE grade ≥ 3 (< 50× 109/L- 25 × 109/L) associated with clinically 
significant bleeding or requiring platelet transfusion 
• CTCAE grade ≥ 4 anemia  
• CTCAE grade ≥ 3 febrile neutropenia (defined as ANC < 1,000/mm3 with a 
single temperature of ≥ 38.3 °C [≥ 101 °F] or a sustained temperature of 
≥ 38 °C [≥ 100.4 °F] for > 1 hour) 
Renal 
• 
CTCAE grade ≥ 3 creatinine increase (> 3.0 x baseline or > 3-6 × upper 
limit of normal [ULN]) 
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Hepatic 
• CTCAE grade ≥ 3 total bilirubin elevation (> 3 × ULN) 
• CTCAE grade ≥ 2 total bilirubin elevation (> 1.5 × ULN) AND CTCAE 
grade ≥ 2 alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) elevation (> 3 × ULN)  
• CTCAE grade 3 ALT elevation (> 5 × ULN) that does not resolve to at 
least grade ≤ 1 within 7 days or any grade > 4 ALT elevation 
• CTCAE grade 3 AST elevation (> 5 × ULN) that does not resolve to at 
least grade ≤ 1 within 7 days or any grade > 4 AST elevation 
Pancreatic 
• CTCAE grade 3 serum 
 increased with clinical symptoms 
or any grade ≥ 4 serum 
  
Cardiac 
• CTCAE grade ≥ 3 
Other AEs  
• CTCAE grade 3 vomiting or nausea that does not resolve to grade ≤ 1 
within 4 days despite optimal anti-emetic therapy or any grade ≥ 4 
vomiting  
• CTCAE grade 3 diarrhea that does not resolve to grade ≤ 1 within 4 days 
despite optimal anti-diarrhea treatment or any grade ≥ 4 diarrhea 
• Any CTCAE grade ≥ 3 AE, except for the exclusions noted below 
• In view of the Investigators and Sponsor, any other unacceptable toxicity 
encountered 
Exceptions to DLT criteria 
• CTCAE grade 3 or 4 elevations in alkaline phosphatase (ALP)  
• CTCAE grade 3 electrolytes abnormalities that are adequately managed by 
intravenous (IV) or oral (PO) supplementation as evidenced by an 
improvement to grade ≤ 1 within 3 days 
• CTCAE grade 3 fatigue which resolves to grade ≤ 1 in ≤ 7 days 
• CTCAE grade 3 dizziness which resolves to grade ≤ 1 in ≤ 7 days 
• CTCAE grade 3 ataxia and weakness which resolves to grade ≤ 1 in 
≤ 7 days 
• Isolated grade 3 laboratory abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset 
In addition, 
 in the above criteria may be considered 
a DLT following review by the Sponsor and study Investigators. 
 should represent a 
 
 from baseline.  
Subjects are eligible for DLT evaluation if they experience a DLT after at least one dose of the TPX-0046, 
or do not experience a DLT after taking at least 75% of the doses expected during the DLT evaluation 
period).  
Determination of MTD: 
The MTD is defined as the highest dose level of TPX-0046 observed to cause a DLT in fewer than 33% of 
the treated subjects in the first treatment cycle (ie, Cycle 1, 28 days). If there are 2 subjects who experience 
DLTs among the first 3 subjects enrolled, or there is a second DLT in up to 6 subjects enrolled at any dose 
level, the MTD will have been exceeded, and no additional subjects will be enrolled at that dose level. The 
MTD will then be established at the prior dose level. If the prior dose cohort has only 3 enrolled subjects, 
the cohort will be expanded up to 6 total subjects.  
Safety Review Committee 
For the Phase 1 dose escalation, a Safety Review Committee comprised of at minimum the Sponsor Medical 
Monitor and Study Investigators will review all relevant safety and other relevant clinical data. 
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Number of subjects (planned): 
Phase 1 Dose Escalation: approximately 60 subjects 
Inclusion Criteria: 
1. Subjects with histological or cytological confirmation of advanced/metastatic solid tumors harboring 
oncogenic RET fusions or mutations, who either have disease progression on or are intolerant to 
standard therapy; OR are ineligible for standard therapy or for whom no standard therapy exists; OR 
are unlikely to tolerate or derive clinical benefit from standard therapy in the opinion of the 
Investigator OR have declined standard therapy. 
• 
Subjects must have a documented RET gene fusion or oncogenic RET mutation as 
determined by local testing in a Clinical Laboratory Improvement Amendments (CLIA)-
certified or equivalently accredited diagnostic lab. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. 
Age ≥ 18 years old (or age ≥ 20 as required by local regulation). 
5. 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.  
6. 
Presence of measurable disease (according to Response Evaluation Criteria in Solid Tumors 
[RECIST] v1.1 criteria). For Phase 2 only, prospectively confirmed measurable disease according 
to RECIST v1.1 by Blinded Independent Central Radiology Review (BICR), selected by Sponsor, 
PRIOR to enrollment.  
7. 
Life expectancy ≥ 12 weeks. 
8. 
Baseline laboratory values fulfilling the following requirements: 
Laboratory parameter 
ANC 
PLT 
Hgb 
Total bilirubin 
Liver transaminases (ALT/AST)  
ALP 
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Creatinine clearance by Cockcroft-Gault 
formula* 
Abbreviations: ALP = alkaline phosphatase; ANC = absolute neutrophil count; AST/ALT = alanine 
aminotransferase / aspartate aminotransferase; Hgb = hemoglobin; PLT = platelet count; 
 
 
*calculated by Cockcroft-Gault formula: (140 - age [yr]) x body weight [kg] x 1.23 x (0.85 if female) 
/ serum creatinine [µmol/L]. Measured creatine clearance is also acceptable. 
9. 
Subjects with primary CNS tumors or brain metastases who are eligible for the study must meet 
the following criteria:  
• 
A minimum of 14 days must have elapsed from the completion of whole brain radiation 
treatment (WBRT) before the start of treatment with TPX-0046, and all side effects (except for 
alopecia) from WBRT are resolved to CTCAE version 5.0 grade ≤ 1.  
• 
A minimum of 7 days must have elapsed from the completion of stereotactic radiosurgery 
before the start of treatment with TPX-0046, and all side effects (except for alopecia) from 
stereotactic radiosurgery are resolved to CTCAE version 5.0 grade ≤ 1.  
• 
Subjects requiring steroids at a stable or decreasing dose (≤ 12 mg/day dexamethasone or 
equivalent) for at least 14 days are eligible.  
• 
Subjects on stable doses of levetiracetam (same dose for 14 days) are eligible to be enrolled.  
10. 
For subjects who received prior cytotoxic chemotherapy or prior targeted small molecule therapy 
at the time of starting treatment with TPX-0046, at least 14 days or five half-lives (whichever is 
shorter) must have elapsed after discontinuation (or at least 42 days for prior nitrosoureas, 
mitomycin C, and liposomal doxorubicin; for vandetanib and cabozantinib at least 14 days must 
have elapsed after discontinuation), and all AEs from prior treatments must have resolved to 
grade ≤ 1 CTCAE version 5.0 with the exception of alopecia or other AEs that the Investigator 
does not consider to be a risk to subject safety.  
11. 
Prior radiotherapy is allowed at least 14 days prior to starting treatment with TPX-0046. All AEs 
from prior treatments must have resolved to grade ≤ 1 CTCAE version 5.0 except for alopecia or 
other AEs that the Investigator does not consider to be a risk to subject safety. 
12. 
Prior immunotherapy or prior antibody targeted therapies for advanced/metastatic disease is 
allowed. At least 3 weeks must have elapsed after discontinuation of immunotherapy or 
therapeutic antibodies and all AEs from prior treatments must have resolved to grade ≤ 1 CTCAE 
version 5.0 except for alopecia or other AEs that the Investigator does not consider to be a risk to 
subject safety. 
13. 
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test during 
Screening and be neither breastfeeding nor intending to become pregnant during study 
participation; and agree to use 2 effective contraceptive methods (combination of any of these 
options: hormonal, barrier method, or intrauterine device) OR be abstinent OR be surgically sterile 
prior to study entry OR have a vasectomized partner, for the duration of study participation, and up 
 after discontinuation of study treatment. Male subjects or male partners of female 
subjects of childbearing potential must take appropriate precautions to avoid fathering a child from 
the time of screening 
 after last dose of study treatment and to use appropriate barrier 
contraception, maintain true abstinence, or have had a vasectomy. Highly effective contraceptive 
methods are described in Appendix B.  
14. 
Male subjects must refrain from sperm donation from screening through 
 after the 
last dose of study drug. 
15. 
Female subjects must refrain from egg donation from screening through 
 after the 
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last dose of study drug. 
16. 
Ability to complete all study-required procedures and assessments. 
17. 
Provision of written informed consent signed and dated by the subject and the Investigator, before 
any study interventions are performed. 
Exclusion Criteria: 
1. 
Locally advanced/metastatic solid tumor that is a candidate for curative treatment through radical 
surgery and/or radiotherapy, or chemotherapy.  
2. 
Presence or history of any other active malignancy within 3 years other than a history of 
adequately treated basal or squamous cell carcinoma of the skin, or any adequately treated in situ 
carcinoma. 
3. 
Presence of only one measurable tumor lesion that has already been resected or irradiated before 
enrollment in the study.  
4. 
Known presence of RET gatekeeper mutation(s) (eg, RET V804X) based on most recent 
applicable molecular testing. 
5. 
Exposure to more than 1 prior selective RET inhibitor (eg, pralsetinib (BLU-667), or selpercatinib 
(LOXO-292),) unless a subject has discontinued a RET inhibitor treatment due to intolerance in 
which case Sponsor approval for eligibility is required.  
6. 
Major surgery within 4 weeks of the start of study.  
7. 
Clinically significant cardiovascular disease (either active or within 6 months before enrollment): 
myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure (New York Heart Association Classification Class ≥ II), cerebrovascular 
accident or transient ischemic attack, symptomatic bradycardia, requirement for anti-arrhythmic 
medication. Ongoing cardiac dysrhythmias of CTCAE version 5.0 grade ≥ 2. 
8. 
Any of the following cardiac criteria: 
• 
Mean resting corrected QT interval (electrocardiogram [ECG] interval measured from the 
onset of the QRS complex to the end of the T wave) for heart rate (QTcF) > 470 msec 
obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value 
• 
For patients with QRS > 120 msec: QTcF > 500 
• 
Any clinically important abnormalities in rhythm, conduction, or morphology of resting 
ECG (eg, complete left bundle branch block, third degree heart block, second degree 
heart block, PR interval > 250 msec) 
• 
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such 
as heart failure, congenital long QT syndrome, family history of long QT syndrome, or 
any concomitant medication known to prolong the QT interval  
9. 
 
10. 
 
 
11. 
Known clinically significant active infections not controlled with systemic treatment (bacterial, 
fungal, viral including human immunodeficiency virus [HIV] positivity). Subjects with chronic 
HIV must have a CD4+ T cell count ≥ 350 cell/microliter for eligibility. Subjects with chronic 
hepatitis B virus infection must have an undetectable viral load (and start antiviral therapy if 
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required according to local or regional guidelines) prior to start of TPX-0046. Subjects with a 
history of hepatitis C viral infection must have an undetectable viral load. 
12. 
Gastrointestinal disease (eg, Crohn’s disease, ulcerative colitis, or short gut syndrome) or other 
malabsorption syndromes that would impact drug absorption. 
13. 
Concurrent participation in another therapeutic clinical study. 
14. 
Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may 
increase the risk associated with study participation or TPX-0046 administration, or that may 
interfere with the interpretation of study results and, in the judgment of the Investigator, would 
make the subject inappropriate for entry into this study, or could compromise protocol objectives 
in the opinion of the Investigator and/or Sponsor. 
15. 
The concomitant use of known strong CYP3A4 inhibitors or inducers is prohibited including their 
administration within at least 2 weeks prior to the first TPX-0046 dose and throughout the study. 
Subjects should avoid grapefruit juice or grapefruit/grapefruit-related citrus fruits (Seville 
oranges, pomelos). See Appendix A for a list of known CYP3A4 inhibitors and inducers. 
16. 
Current or anticipated use of drugs that are known to be sensitive substrates of CYP3A or 
CYP2B6 is not permitted, including their administration within at least 2 weeks prior to the first 
TPX-0046 dose and throughout the study. Concomitant medication suspected of sensitive CYP3A 
or CYP2B6 (eg, bupropion, efavirenz) substrates must be approved by the Sponsor. See 
Appendix A for a list of known sensitive substrates of CYP3A. 
17. 
Current or anticipated need for drugs that are sensitive CYP2C9 substrates with narrow 
therapeutic indices, such as celecoxib, phenytoin, or warfarin is not permitted including their 
administration at least within 2 weeks prior to the first TPX-0046 dose and throughout the study. 
Concomitant medication suspected of being a CYP2C9 substrate with narrow therapeutic index 
must be approved by the Sponsor. 
18. 
Current or anticipated use of drugs that are known to be 
 
 is not permitted, including their administration within at 
least 2 weeks prior to the first TPX-0046 dose and throughout the study. Concomitant medication 
suspected of 
 
must be approved by the Sponsor. 
19. 
Known oncogene drivers other than RET including, eg, anaplastic lymphoma kinase [ALK], 
ROS1 [receptor tyrosine kinase encoded by the ROS1 gene], or epidermal growth factor receptor 
[EGFR]) conferring sensitivity to targeted therapies. 
Investigational Product/Dosage Formulation:  
TPX-0046 drug product is supplied as 
 capsules. 
Dose Regimen and Route of Administration:  
Initially, TPX-0046 will be taken orally QD under fasting conditions (1 hour before, 2 hours after dosing) as 
follows.  
• Phase 1 Dose Escalation: as allocated by dose level. The study will begin with TPX-0046 10 mg 
QD. 
 
  
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Study Assessments: 
Safety observations include physical examinations, body weight, ECOG score, clinical AEs, (hematology, 
serum chemistries, and urinalysis), ECG, vital signs, 
. As no new 
subjects will be enrolled in this study, Investigators will follow assessments for subjects currently enrolled 
as described in the schedule of activities for Phase 1 dose escalation (Table 1). Additional testing considered 
necessary for safety related to study drug may be performed at the discretion of the Investigator. 
Sample Size Determinations: 
For the Phase 1 dose escalation, 41 subjects have enrolled across 9 dose levels. Enrollment is 
closed. 
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Table 1: 
Schedule of Activities: Phase 1 Dose Escalation 
 
Screening 
(≤28 Days)  
Cycle 1 
(28 days) 
Cycle 2 
(28 days) 
Cycle 3 
(28 
days) 
Cycle 4 
and 
Beyond  
(28 days) 
End of 
Treatment 
Safety 
Follow-up 
Protocol Activity 
 
Day 
1 
Day 
8 
Day 
14/15 
Day 
22 
Day  
1 
Day  
15 
Day  
1 
Day  
1 
 
 
Visit Windowa 
NA 
 
 
±1 
±1 
±1 
±2 
±2 
±2 
±2 
+7 
+28 days 
of last dose  
Informed Consentb 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense TPX-0046 and 
Subject Diaryfg 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
TPX-0046 Compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory assessments beyond Cycle 3 should be done based on symptomatology and per investigator discretion. 
Complete Blood Count with 
Differentialc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Complete Chemistry Paneld 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Coagulatione 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Cardiac Safety Monitoring should be done based on symptomatology and at investigators discretion. 
Tumor Assessment should be done per standard of care. 
Other Clinical Assessments 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications and 
Non-Drug Supportive 
Interventionsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviation: 
  
Note: Regardless of dose interruptions, cycle lengths will remain 28 days and evaluations are to be performed according to the schedules. 
a. Visit Window: The 28-day screening period starts on the day informed consent is signed by the subject. All study visits (visit date calculations) are based off of the Cycle 1 Day 
1 visit date, regardless of dose interruptions; and evaluations are to be performed according to the schedules. The safety follow-up visit should be within 28 days from the last 
dose of TPX-0046. 
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b. Informed Consent: Must be obtained before undergoing any protocol-specific procedures. 
c. Complete Blood Count with Differential: White blood cell count, hemoglobin, platelets, absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils, 
and absolute basophils.  
d. Complete Chemistry Panel: Sodium, potassium, chloride, bicarbonate, 
 blood urea nitrogen or urea, creatinine, magnesium, phosphorus, total calcium, uric 
acid, total protein, albumin, glucose (non-fasted), lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase.  
e. Coagulation: Prothrombin time/international normalized ratio (PT/INR), partial thromboplastin time (PTT).  
f. 
TPX-0046 administration (QD or BID): TPX-0046 (capsules) will be administered orally as a 
 
. On Cycle 1 Day 1 TPX-0046 will be administered either QD or BID per the dosing regimen with approximately 8-oz water (240 mL) 
 in 28-day 
continuous cycles. 
 
g. TPX-0046 administration 
: TPX-0046 (capsules) will be administered orally 
 
 On Cycle 1 Day 1 TPX-0046 will be administered either QD or BID per the dosing regimen with approximately 8-oz water (240 mL) 
. 
 
 
h. Concomitant Medications and Non-Drug Supportive Interventions: All concomitant medications and non-drug supportive interventions should be recorded in the CRF. 
 
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2. 
INTRODUCTION 
2.1. 
Mechanism of Action/Indication 
TPX-0046 is a RET/SRC kinase inhibitor with a compact three-dimensional macrocyclic 
structure designed to efficiently target the RET active kinase conformation and to inhibit 
clinically-relevant RET fusion proteins and mutations. TPX-0046 has demonstrated potent 
nonclinical activities against RET and clinically-relevant mutant RETs, especially the SFMs 
which will potentially confer resistance to current investigational RET inhibitors, and approved 
TKIs that have RET inhibitory activity which represents a potential unmet medical need. 
TPX-0046 has minimal activity against the gatekeeper mutation family RET V804X, which 
includes V804M/L/E. TPX-0046 also inhibits SRC and SRC family members that have the 
potential to reduce bypass resistance and therefore increase its therapeutic effect. 
Polypharmacological inhibition of RET and SRC is expected to provide strong anti-tumor 
efficacy for patients with advanced/metastatic solid cancers harboring oncogenic RET fusions or 
mutations, especially patients who have developed resistance from current investigational RET 
inhibitor treatment. The comprehensive nonclinical pharmacology, pharmacokinetic and 
toxicology evaluation results strongly support a FIH Phase 1/2 clinical trial with TPX-0046 in 
adult subjects (≥ 18 years) with advanced/metastatic solid tumors harboring oncogenic RET 
fusions or mutations. 
2.2. 
Background 
The RET gene was originally identified as an oncogene in 1985 (Takahashi, 1985) and 
characterized as a receptor tyrosine kinase (Takahashi, 1987). RET activation regulates multiple 
signaling pathways (eg, RAS/MAPK/ERK, PI3K/protein kinase [AKT], JAK-STAT) leading to 
cellular proliferation, migration, and differentiation (Mulligan, 2014). RET plays an essential 
role in the development and maturation of diverse tissues (Mulligan, 2018). Gain-of-function 
mutations of RET including amplification, activating point mutations or genomic rearrangements 
lead to ligand-independent kinase activation have been found in heritable and sporadic tumors. 
Thyroid carcinoma is the most common endocrine malignancy and accounts for 3%–4% of all 
cancers in the US with an estimated incidence of 57,000 and deaths of 2000 in 2017 
(Siegel, 2017). Germline mutations of RET are found in multiple endocrine neoplasia 2A 
(MEN2A), MEN2B, and familial medullary thyroid carcinoma (MTC) (Mulligan, 2018). 
Mutations in RET have been reported in 43% to 71% of sporadic MTC (Moura, 2009). The 
somatically occurring rearrangements of the RET gene have been identified in 20%–40% of 
papillary thyroid carcinomas (PTCs) and ~1%–2% NSCLCs (Mulligan, 2018). In addition, RET 
fusions have been discovered in Spitzoid tumors (~3%), chronic myelomonocytic leukemia, 
breast, colon, ovarian, salivary gland and inflammatory myofibroblastic tumors 
(Mulligan, 2018). RET fusions have also been found as a resistance mechanism to EGFR-TKIs in 
EGFR-mutant NSCLC patients (Bronte, 2019). 
2.2.1. 
RET Targeted Therapies in RET+ Disease and Drug Resistance 
Multi-kinase inhibitors with activity against RET have been approved for the treatment of a 
variety of solid and hematological malignancies, such as cabozantinib, vandetanib, lenvatinib, 
sorafenib for thyroid cancers and ponatinib, alectinib, sunitinib, nintedanib, and regorafenib for 
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other indications. Multi-kinase inhibitors with moderate activity against RET can achieve 
confirmed responses in certain patients with RET-rearranged or RET-mutant cancers but the 
ORR and DOR are significantly lower than those observed in other oncogene-driven, advanced-
stage tumors with matched targeted therapies (Drilon, 2018a). The potent and selective RET 
inhibitors with minimal off-target activities are likely required for achieving long lasting anti-
tumor activity in patients with advanced/metastatic solid tumors harboring an abnormal RET 
gene. Two selective RET inhibitors, pralsetinib (BLU-667) and selpercatinib (LOXO-292) have 
achieved marked anti-tumor activity in both NSCLC and thyroid cancers (Drilon, 2018b and 
Subbiah, 2018). Accordingly, selpercatinib was approved by the US Food and Drug 
Administration (FDA) for adult patients with metastatic RET fusion positive NSCLC and adult 
and pediatric patients 12 years of age and older with RET mutant MTC or RET fusion positive 
thyroid cancer refractory to radioactive iodine therapy (Retevmo™ USPI, 2020). 
Multiple resistance mutations to vandetanib and cabozantinib, including gatekeeper mutations 
V804X and SFMs G810X have been reported from preclinical studies (Liu, 2018). The 
development of RET solvent front mutations have also been reported as resistance mechanisms 
following treatment with selective RET inhibitors (Solomon, 2020). In RET-rearranged NSCLC, 
the type of upstream RET fusion partner produced different sensitivity to multi-kinase inhibitors. 
Lower ORR and shorter median PFS in patients with kinesin family 5B (KIF5B)-RET+ NSCLC 
treated with multi-kinase drugs were observed relative to other RET rearrangements (Yoh, 2017; 
Drilon, 2017). KIF5B-RET leads to a substantial increased RET transcription (Kohno, 2012) and 
strongly activate a RET-SRC-EGFR-FGFR signaling hub (Das, 2017). Inhibition of SRC kinase 
may interrupt recruitment of multiple receptor tyrosine kinases (RTKs). SRC family tyrosine 
kinases are known to regulate MTC cellular proliferation in vitro (Liu, 2004). Therefore, a dual 
inhibitor of both RET and SRC represents a highly-desired therapeutic intervention to maximally 
target abnormal RET signaling in cancers. 
2.3. 
Nonclinical Overview  
2.3.1. 
Nonclinical Pharmacology 
A comprehensive program, including in vitro and in vivo assessments, was conducted on 
TPX-0046 to evaluate its primary and secondary pharmacodynamic properties, as well as the 
safety pharmacology to support a FIH Phase 1/2 clinical trial with TPX-0046 in patients with 
advanced solid tumors harboring genetic alternations in RET. Primary pharmacodynamics of 
TPX-0046 began with biochemical potency assessments via inhibition of the catalytic activities 
for multiple recombinant kinases, including the oncogenic RET fusion proteins and mutants as 
shown 
. In cellular assays, the effect of TPX-0046 on RET autophosphorylation, 
downstream signal effectors, and cell proliferation in human primary cancer cell lines and 
engineered stable cell lines expressing the targeted fusion RET oncogenes was evaluated as 
shown in Table 3. Target human plasma exposure to be associated with pharmacological activity 
for TPX-0046 is 
, the calculated IC90 value of KIF5B-RET solvent front mutation 
G810R determined in in vitro cell proliferation assays. The in vivo assessment of TPX-0046 on 
the efficacy of tumor growth inhibition and pharmacodynamic target modulation were performed 
in a series of mouse xenograft tumor models – both cell line and patient-derived as shown in 
Figure 1. 
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Table 3: 
Summary of TPX-0046 Activities against RET in Cellular Assays 
  
Cell Line 
TPX-0046 
Cell Proliferation 
IC50 (nM) 
 
 
  
 
 
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In the secondary pharmacodynamic studies, TPX-0046 was screened in biochemical assays at 
100 nM in two kinase panels: 374 recombinant protein kinases (Reaction Biology) and 
157 recombinant kinases (Eurofins). Kinases inhibited by TPX-0046 greater than 90% in either 
panel were followed up by determining half maximal inhibitory concentration (IC50) values 
along with selected RTKs which are often inhibited by multi-kinase RET inhibitors 
. 
Kinases inhibited in biochemical assays with IC50 < 10 nM were subjected to further testing in 
cellular assays that measure either cell proliferation or target engagement 
 
TPX-0046 is highly selective with only 
 kinases of the 
 kinases inhibited with less than 
 selectivity over WT RET potency. 
 
 
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Kinases inhibited in biochemical assays with IC50 < 10 nM 
were subjected to further testing in cellular assays that measure either cell proliferation or target 
engagement 
. Many kinases with IC50 values < 10 nM in biochemical assays did not 
translate to potency in cellular assays likely due to either the artificial nature of the recombinant 
kinase protein or the low concentration of the competitive ligand (
 ATP in biochemical 
assay, > 1 mM in cells). 
 
. SRC family kinases were evaluated in nanoBRET assays 
 
and found to have IC50 > 
 but the assays may have flaws. 
 states “for 
the 
 SRC assay, a luciferase (NanoLuc) is fused to the C-terminal tail of SRC which 
has an autoinhibitory phosphorylation site at Tyr530. This construct design might affect the 
regulation of SRC kinase conformation”. As such, 
 potency from SRC, SRC family 
kinases, and janus kinases are not reported. There were kinases inhibited by TPX-0046 in 
cellular assays within 100-fold of TPX-0046 potency toward RET 
: FGFR1/2, 
TRKA/B/C, ROS1, and TXK. TPX-0046 inhibits fibroblast growth factor (FGF) receptors with 
 in biochemical assays as determined in multiple studies (in the 
presence of 
 ATP). These results were confirmed in 
 cellular assays with IC50 
values of 
 for FGFR1, FGFR2 and FGFR3, respectively. In 
biochemical assays, 
 In TRK-
dependent cell proliferation assays, TPX-0046 has IC50 values of 
 in 
 cells with 
TPM3-TRKA, 
 in Ba/F3 cells with TEL-TRKB, and 
 in Ba/F3 cells with TEL-
TRKC. ROS1 had an IC50 of 
 in a biochemical assay and 
 in a cell proliferation 
assay. For TXK, TPX-0046 had a biochemical IC50 = 
 and a cellular IC50 = 
. 
Kinases inhibited by TPX-0046 with IC50 < 10 nM that have only biochemical potency (SRC 
family kinases, PEAK1, TIE2) may not all have potent cellular potency. Pseudopodium enriched 
atypical kinase 1 (PEAK1) is a pseudokinase with controversial non-receptor tyrosine kinase 
activity and has not been reported to be an oncogenic driver as its function is as a molecular 
scaffold (O’Rourke, 2018). Taken together, TPX-0046 is highly potent for TPX-0046 with only 
one kinase (TRKA) displaying cellular potency within 10-fold of RET cellular potency.  
In additional secondary pharmacodynamic studies of 44 purified receptors, ion channels, 
transporters, and enzymes, TPX-0046 at 
 only inhibited 
 and 
 
 with IC50 values of 
, respectively. TPX-0046 had minimal effects on 
human ion channels of hNav1.5 (
 HEK293 cells) and human L-type Cav1.2 
(IC50 
, HEK293 cells), and moderate effect on human ether-à-go-go-related gene 
(hERG) (
, CHO cells). 
Taken together, TPX-0046 has demonstrated potent nonclinical activities against RET and 
clinically-relevant mutant RETs, especially the SFMs which will likely confer resistance to any 
therapy that has RET inhibitory activity, including investigational selective RET inhibitors, 
which represents a potential unmet medical need. TPX-0046 is an inhibitor of SRC tyrosine 
kinase in in vitro assays. Aberrant activation of SRC signaling contributes to diverse aspects of 
tumor development and treatment resistance. The inhibition of the SRC kinase has the potential 
to reduce the recruitment of multiple RTKs involved in bypass resistance and therefore increase 
the therapeutic effect of TPX-0046. Therefore, pharmacological inhibition by TPX-0046 of a 
broad range of oncogenic RET mutations and fusion proteins is expected to provide anti-tumor 
efficacy for RET+ cancer patients, especially patients who have developed resistance. These 
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comprehensive in vitro and in vivo evaluation results strongly support a FIH Phase 1/2 clinical 
trial with TPX-0046 in adult patients with advanced solid tumors harboring an oncogenic RET 
fusion or mutation. 
2.3.2. 
Nonclinical Pharmacokinetics 
The absorption, distribution, metabolism, excretion (ADME) properties as well as drug-drug 
interaction profile of TPX-0046 were characterized in various animal and human in vitro and in 
vivo systems.  
Oral bioavailability was 
 (at 
) and 
 (at 
) 
following single administration of TPX-0046 in a suspension. A new formulation of the 
TPX-0046 capsule was developed to improve consistency across batches. In a study in monkeys 
to assess the comparability of pharmacokinetic profiles of batches, the new TPX-0046 capsule 
formulations exhibited similar exposures compared to the original clinical formulation. TPX-
0046 has a predicted human CL of 
, a Vss of 
, an effective t½ of 
 hours, and an oral bioavailability of 
.  
TPX-0046 equally distributed into plasma and red blood cells. Binding to plasma proteins was 
 animal species and humans. 
Reaction phenotyping studies using human recombinant cytochrome P450 (CYP) enzymes 
suggested that 
 
 
 
 
 
 
 
 
 
 
 
 
 
These in vitro drug-drug interaction assessments suggest TPX-0046 may 
 
Overall, the nonclinical ADME, and drug-drug interaction assessments of TPX-0046 support the 
advancement for clinical evaluation.  
2.3.3. 
Nonclinical Toxicology  
A comprehensive IND-enabling nonclinical safety assessment program has been conducted 
consistent with the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guideline, “Nonclinical Evaluation for Anticancer 
Pharmaceuticals (S9),” and is comprised of single- and repeat-dose exploratory toxicology 
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studies and definitive 28-day toxicology studies conducted in two mammalian species (rat and 
monkey), selected based on comparable metabolite profiles in humans, using the 
clinically-relevant route (oral) and schedule (once daily) of administration 
(ICH Guidance: S9, 2009). The pivotal 28-day repeat dose toxicity studies in rats and 
cynomolgus monkeys demonstrated evidence of inflammatory stimulation, effects on growing 
bone physes, and soft tissue mineralization, with adequate exposure margins for the adult patient 
population.  
2.4. 
Basis of Clinical Starting Dose of TPX-0046-01 FIH Study 
For the recommended starting dose of TPX-0046-01 FIH study, an integrated approach in 
accordance with regulatory guidance, scientifically justified using all available nonclinical data 
including PK, pharmacodynamics, and toxicity was applied. Based on the projected human PK at 
the proposed starting dose of 10 mg QD, the exposure-based margins relative to the toxicokinetic 
parameters at STD10 or highest non-severe toxic dose (HNSTD) are summarized 
.  
 
 
 
 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
Preliminary results from Phase 1 dose escalation indicate that TPX‑0046 has a 
 
. Based on the totality of clinical information available, the Sponsor has 
decided to discontinue further development of TPX-0046 due to the inability to achieve and 
optimize a dose that could provide a positive benefit-risk profile in the current treatment 
landscape for RET mutant TKI naïve and pretreated setting. This decision was communicated to 
study sites on 03 October 2022. As such, no new subjects will be enrolled in this study, which 
will close after all active subjects have completed treatment. Subjects currently receiving 
treatment in this study will continue treatment at the discretion of the Investigators until need for 
discontinuation (Section 8.7) or ability to move to alternative care is identified. As such, a 
synoptic CSR will be generated and submitted to health authorities. 
Primary Objectives 
Primary Endpoints 
Phase 1:  
• 
Evaluate the safety and tolerability of TPX-0046 
at selected doses  
• 
Determine the maximum tolerated dose (MTD) 
and/or Recommended Phase 2 Dose (RP2D) of 
TPX-0046  
Phase 1: 
• 
Incidence of first cycle dose-limiting 
toxicities (DLTs) of TPX-0046 
administered orally in a 28-day cycle  
• MTD and RP2D 
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4. 
STUDY DESIGN 
4.1. 
Overall Study Design 
This is a Phase 1/2 multi-center, first-in-human (FIH), open-label study designed to evaluate the 
safety, tolerability, PK, and efficacy of the novel RET/SRC inhibitor TPX-0046 in adult subjects 
with advanced/metastatic solid tumors harboring oncogenic RET fusions or mutations. The 
global study consists of two portions as shown in Figure 2: 1) Phase 1 Dose Escalation, Food 
Effect Sub-study, and Dose Expansion in 6 cohorts, and 2) Phase 2 preliminary efficacy 
evaluation in six defined subject cohorts.  
As the study enrollment will close prior to completing Phase 1 dose escalation, the Phase 1 food 
effect substudy, Phase 1 dose expansion, and Phase 2 activities will not take place. 
Figure 2: 
Study Design  
 
4.1.1. Phase 1 Dose Escalation 
The Phase 1 dose escalation portion will be conducted according to a 3+3 based design. 
Approximately 60 subjects will be enrolled. Eligible subjects will be adults (≥ 18 years) with 
advanced/metastatic solid tumors harboring oncogenic RET fusions or mutations.  
Subjects will be screened for eligibility up to 28 days prior to enrollment (the first day of 
TPX-0046 administration). On 
 subjects will receive a 
 
 post-dose to evaluate 
 TPX-0046 
 
Following completion of the 
, subjects will begin QD dosing of TPX-0046 in 
28-day continuous cycles. Dose escalation levels are presented in Table 5). Subjects may receive 
TPX-0046 until disease progression, unacceptable toxicity, the ability to move to alternative care 
is identified, or withdrawal of consent,. Treatment beyond radiographic or clinical progression 
will not be allowed. 
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An EOT visit will be conducted within 7 days of the last dose of TPX-0046. A safety follow-up 
visit will be conducted within 28 days of last dose. 
Table 5: 
TPX-0046 Dose Escalation Levels and Regimens 
Dose Level 
Dose Regimen 
Daily Dose (mg/day) 
Increment from Previous Daily Dose  
1 
10 mg QD 
10 mg 
Not applicable 
2 
20 mg QD 
20 mg 
100% increase 
3 
10 mg BID 
4 
30 mg QD 
30 mg 
50% increase 
5 
20 mg QD to 30 mg QD 
20 mg (1st 14 days), then 30 mg 
6 
20 mg BID 
40 mg 
33% increase 
7  
20 mg QD to 40 mg QD 
20 mg (1st 14 days), then 40 mg 
8  
20 mg QD to 20 mg BID 
20 mg (1st 14 days), then 40 mg 
9  
10 mg QD to 10 mg BID 
10 mg (1st 14 days), then 20 mg 
50% decrease 
Abbreviations: BID = twice daily; QD = once daily. 
 
 
4.1.1.1. 
Dose Escalation Schema 
The dose escalation schema is illustrated in Table 5. No further dose escalation will occur; dose 
level 9 was the last to enroll subjects prior to closing study enrollment. DLTs will be evaluated 
independently in any given dosing regimen. 
4.1.1.2. 
Dose-Limiting Toxicity 
Subjects are eligible for DLT evaluation if they experience a DLT after at least one dose of the 
TPX-0046, or do not experience a DLT after taking at least 75% of the doses expected during the 
DLT evaluation period. Subjects who do not fulfill these requirements and who discontinue 
study participation before completing the DLT evaluation period will not be replaced. The DLT 
evaluation period is defined as 28 days following the first 
 dose of the dose regimen 
administered in Cycle 1 
 
 
 
 
The following AEs, excluding toxicities clearly related to disease progression or intercurrent 
illness, will be considered DLTs (Table 6). 
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Table 6: 
Criteria for Defining Dose-Limiting Toxicities 
Category 
Criteria 
Toxicities resulting in an 
excessive number of missed 
doses 
Inability to deliver at least 75% of the planned dose intensity of TPX-0046 
treatment during the DLT evaluation period (ie, at least 21 days of dosing in 
a 28-day cycle, beginning in Cycle 1) because of toxicity excluding toxicities 
clearly related to disease progression or intercurrent illness 
Hematologic toxicities  
• CTCAE grade ≥ 4 neutropenia (absolute neutrophil count [ANC] 
< 0.5 × 109/L)  
• CTCAE grade ≥ 4 platelet count decrease (platelets < 25 × 109/L) or 
CTCAE grade ≥ 3 (< 50× 109/L- 25 × 109/L) associated with clinically 
significant bleeding or requiring platelet transfusion 
• CTCAE grade ≥ 4 anemia  
• CTCAE grade ≥ 3 febrile neutropenia (defined as ANC < 1,000/mm3 
with a single temperature of ≥ 38.3 °C [≥ 101 °F] or a sustained 
temperature of ≥ 38 °C [≥ 100.4 °F] for > 1 hour) 
Renal 
• 
CTCAE grade ≥ 3 creatinine increase (> 3.0 x baseline or > 3-6 × upper 
limit of normal [ULN]) 
Hepatic 
• CTCAE grade ≥ 3 total bilirubin elevation (> 3 × ULN) 
• CTCAE grade ≥ 2 total bilirubin elevation (> 1.5 × ULN) AND CTCAE 
grade ≥ 2 alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) elevation (> 3 × ULN)  
• CTCAE grade 3 ALT elevation (> 5 × ULN) that does not resolve to at 
least grade ≤ 1 within 7 days or any grade > 4 ALT elevation 
• CTCAE grade 3 AST elevation (> 5 × ULN) that does not resolve to at 
least grade ≤ 1 within 7 days or any grade > 4 AST elevation 
Pancreatic 
• CTCAE grade 3 serum 
 increased with clinical 
symptoms or any grade ≥ serum 
  
Cardiac 
• CTCAE grade ≥ 3 
Other AEs  
• CTCAE grade 3 vomiting or nausea that does not resolve to grade ≤ 1 
within 4 days despite optimal anti-emetic therapy or any grade ≥ 4 
vomiting  
• CTCAE grade 3 diarrhea that does not resolve to grade ≤ 1 within 4 days 
despite optimal anti-diarrhea treatment or any grade ≥ 4 diarrhea 
• Any CTCAE grade ≥ 3 AE, except for the exclusions noted below 
• In view of the Investigators and Sponsor, any other unacceptable toxicity 
encountered 
Exceptions to DLT criteria 
• CTCAE grade 3 or 4 elevations in ALP  
• CTCAE grade 3 electrolytes abnormalities that are adequately managed 
by IV or PO supplementation as evidenced by an improvement to 
grade ≤ within 3 days 
• CTCAE grade 3 fatigue which resolves to grade ≤ 1 in ≤ 7 days 
• CTCAE grade 3 dizziness which resolves to grade ≤ 1 in ≤ 7 days 
• CTCAE grade 3 ataxia and weakness which resolves to grade ≤ 1 in 
≤ 7 days 
• Isolated grade 3 laboratory abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset 
Abbreviations: AE = adverse event; ANC = absolute neutrophil count; ALP = alkaline phosphatase; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events, version 5.0; 
IV = intravenous; PO = per os (by mouth); ULN = upper limit of normal. 
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In addition, 
 not included in the above criteria may be 
considered a DLT following review by the Sponsor and study Investigators. 
 should 
represent a 
. 
To fully characterize the safety of TPX-0046, subjects who are discontinued from treatment 
before completing the DLT evaluation period (28 days, beginning in Cycle 1) due to disease 
progression or other events unrelated to TPX-0046 will be replaced. 
 for subjects experiencing a DLT 
Subjects who experience a DLT are 
. The treatment of these 
subjects will be evaluated on a case by case basis in consultation with the Investigator and 
Medical Monitor. 
Subjects who experience a DLT 
 (if applicable) 
once adequate recovery is achieved and in the opinion of the Investigator and Medical Monitor 
the subject is benefiting from therapy. 
4.1.1.3. 
Maximum Tolerated Dose 
The MTD is defined as the highest dose level of TPX-0046 observed to cause a DLT in fewer 
than 33% of the treated subjects in the first treatment cycle (ie, Cycle 1, 28 days). If there are 
2 subjects who experience DLTs among the first 3 subjects enrolled, or there is a second DLT in 
up to 6 subjects enrolled at any dose level, the MTD will have been exceeded, and no additional 
subjects will be enrolled at that dose level. The MTD will then be established at the prior dose 
level. If the prior dose cohort has only 3 enrolled subjects, the cohort will be expanded in up to 
6 total subjects. 
4.1.1.4. 
Safety Review Committee 
For Phase 1 dose escalation of the study, a Safety Review Committee comprised of at minimum 
the Sponsor Medical Monitor and study Investigators will review all relevant safety and other 
relevant clinical data (including DLTs).  
4.2. 
Recommended Dose Modifications 
Every effort should be made to administer TPX-0046 on the planned dose and schedule. 
In the event of significant toxicity, dosing may be delayed and/or reduced as described below. In 
the event of multiple toxicities, dose modification should be based on the worst toxicity 
observed. Subjects are to be instructed to notify the Investigators at the first occurrence of any 
adverse symptom. 
Dose modifications may occur in one of three ways: 
• Within a cycle: dosing interruption until adequate recovery, and dose reduction, if 
required, during a given treatment cycle;  
• Between cycles: next cycle administration may be delayed due to persisting toxicity when 
a new cycle is due to start; 
• In the next cycle: dose reduction may be required in a subsequent cycle based on toxicity 
experienced in the previous cycle. 
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4.2.1. 
Dose Interruptions 
Dose interruptions may occur in the event of a treatment-related toxicity or a non-treatment-
related issue (eg, elective surgery). 
Appropriate follow-up assessments should be done until adequate recovery occurs as assessed by 
the Investigator. Criteria required before treatment can resume are described in the dose 
modification table (see Table 7). 
Doses may be held as needed until toxicity resolution. Depending on when the AE is resolved, a 
treatment interruption may lead to the subject missing all subsequent planned doses within that 
same cycle or even to delay the initiation of the subsequent cycle. Subjects not recovering from 
TPX-0046-related toxicity to grade ≤ 1 
 since the last dose must discontinue 
TPX-0046 treatment. 
If the AE that led to the treatment interruption recovers within the same cycle, then re-dosing in 
that cycle is allowed. Doses omitted for toxicity are not replaced within the same cycle. The need 
for a dose reduction at the time of treatment resumption should be based on the criteria defined 
in Table 7 unless otherwise agreed to following discussion between the Investigator and the 
Medical Monitor. 
In the event of a treatment interruption for reasons other than treatment-related toxicity (eg, 
elective surgery) lasting 
, treatment resumption must be discussed with the Medical 
Monitor. 
Every effort should be made to maintain the tumor assessments and visit scheduling as described 
in the Schedules of Activities.: Regardless of dose interruptions, cycle lengths will remain 
28 days and evaluations are to be performed according to the schedules. 
4.2.2. 
Dose Delays 
Re-treatment following treatment interruption for treatment-related toxicity may not occur until 
the event has resolved to grade ≤ 1 or baseline 
 of the event. 
If a treatment delay results from worsening of hematologic or biochemical parameters, the 
frequency of relevant laboratory assessments may be increased as clinically indicated. 
Refer to the Dose Reductions section for AEs requiring dose reduction at the time of treatment 
resumption (Section 4.2.3).  
If subjects require discontinuation of TPX-0046 for 
 at any time during the 
study, then study treatment should be permanently discontinued, unless the Investigator’s 
benefit/risk assessment suggests otherwise after discussion with the Medical Monitor. 
Regardless of dose interruptions, cycle lengths will remain 28 days and evaluations are to be 
performed according to the schedules. 
4.2.3. 
Dose Reductions 
Following dosing interruption or cycle delay due to toxicity, the TPX-0046 dose may need to be 
reduced when treatment is resumed. No further dose reduction for the remaining subjects will be 
allowed. 
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Dose reduction of TPX-0046 by one and, if needed, 2 dose levels (Table 7) will be allowed 
depending on the type and severity of toxicity encountered. As a guide, subjects currently being 
treated at 30 mg QD should reduce one dose level to 20 mg QD. If a subject is being treated at 
40 mg QD and requires dose reduction, they should dose reduce to 30 mg QD initially and then 
20 mg QD if needed. 
For subjects who undergo a dose reduction for an AE other than a protocol-defined DLT, a 
subsequent re-escalation of the dose may be considered appropriate if deemed safe by the 
Investigator and after consultation with the Sponsor’s Medical Monitor. Subjects requiring more 
than 2 dose reductions will be discontinued from the treatment and entered in the follow-up 
phase, unless otherwise agreed between the Investigator and Medical Monitor. All dose 
modifications/adjustments must be clearly documented in the subject’s source notes and case 
report form (CRF).  
All dose reduction cases should be discussed with the Medical Monitor unless specifically 
outlined in the protocol. In cases where no specific dose adjustment requirements for CTCAE 
version 5.0 grade 2 treatment-related toxicity exist, Investigators should always manage their 
subjects according to their medical judgment, which may include dose reduction or interruption 
based on the particular clinical circumstances in consultation with the Medical Monitor. 
 for subjects with DLTs is not allowed in the Phase 1 study. Subjects 
experiencing a DLT 
 (if applicable) once 
adequate recovery is achieved. 
Recommended dose reductions are described in Table 7. 
 
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Table 7: Dose Modifications for Adverse Events (CTCAE version 5.0) 
Toxicity 
CTCAE Grade 1* 
CTCAE Grade 2* 
CTCAE Grade 3 
CTCAE Grade 4 
Hematologic 
Continue at same dose level. 
Continue at same dose 
level. 
Withhold dose until toxicity is 
grade ≤ 2, or has returned to 
baseline, then resume treatment 
at the same dose level or reduce 
by one dose level as per the 
Investigator’s discretion. 
Grade 3 lymphopenia without 
other dose- limiting events (eg, 
opportunistic infection) may 
continue study treatment without 
interruption. 
Discontinue treatment 
permanently. 
Non-Hematologic 
Continue at same dose level. 
Continue at same dose 
level.  
Withhold dose until toxicity is 
grade ≤ 1 or has returned to 
baseline, then reduce by one 
dose level and resume treatment. 
Discontinue treatment 
permanently.  
 
Pneumonitis  
(occurred in the absence 
of disease progression, 
pulmonary embolism, 
positive cultures or 
radiation effect) 
Asymptomatic, radiographic 
findings only: No need for dose 
adjustment. Initiate appropriate 
monitoring. 
 
Symptomatic: Withhold 
current dose until toxicity has 
returned to baseline. Rule out 
infection and consider 
initiating treatment with 
corticosteroids. Then resume 
treatment at the same dose. 
Discontinue permanently if 
pneumonitis recurs or if failure 
to recover after 6 weeks of 
study treatment hold and 
steroid treatment. 
Withhold current dose 
until toxicity has 
returned to baseline. 
Rule out infection and 
consider initiating 
treatment with 
corticosteroids. Then 
resume treatment at one 
dose level lower. 
Discontinue 
permanently if 
pneumonitis recurs or if 
failure to recover after 6 
weeks of study 
treatment hold and 
steroid treatment. 
Discontinue treatment 
permanently. 
Discontinue treatment 
permanently. 
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Toxicity 
CTCAE Grade 1* 
CTCAE Grade 2* 
CTCAE Grade 3 
CTCAE Grade 4 
AST or ALT elevation 
Continue at same dose level. 
Continue at same dose 
level. 
Withhold current dose if 
concurrent CTCAE 
grade ≥ 2 total bilirubin 
elevation (> 1.5 x 
ULN). 
Withhold current dose until 
resolves to grade ≤ 1. 
Discontinue treatment 
permanently. 
Prolonged QTc 
Assess electrolytes and 
concomitant medications. 
 
Correct any electrolyte 
abnormalities, or hypoxia. 
 
Continue at the same 
dose level. 
Assess electrolytes and 
concomitant 
medications. 
 
Correct any electrolyte 
abnormalities, or 
hypoxia. 
 
Continue at the same 
dose level. 
Withhold dose. 
 
Assess electrolytes and 
concomitant medications. 
 
Correct any electrolyte 
abnormalities, or hypoxia. 
 
Upon recovery to grade ≤ 1: if 
no other cause for QTc 
prolongation is found or is 
considered drug-related resume 
treatment at 1 dose level lower. 
Discontinue treatment 
permanently. 
Dizziness ataxia, or 
weakness 
Continue at same dose level 
Withhold current dose 
until toxicity is grade ≤1 
or has returned to 
baseline 
 
Withhold dose until toxicity is 
grade ≤1 or has returned to 
baseline 
Withhold dose until toxicity is 
grade ≤1 or has returned to 
baseline, then reduce by 1 dose 
level and resume treatment; or 
discontinue treatment as per the 
Investigator’s discretion after 
discussion with Medical 
Monitor 
Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; CNS = central nervous system; CTCAE = Common Terminology Criteria for Adverse 
Events, version 5.0; ULN = upper limit of normal 
*Cycle will not be extended to cover for the missing doses. In cases where no specific dose adjustments for CTCAE grade 1 or grade 2 treatment-related toxicity are provided, 
Investigators should always manage their subjects according to their medical judgment, which may include dose reduction or interruption based on the particular clinical 
circumstances. 
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4.2.4. 
Dose Modifications: 
 
In all subjects, 
 treatment options for 
mitigating 
 should be discussed with the Medical Monitor. Additional dosing 
guidelines for 
 are provided in Table 8. 
Table 8: Recommended Dose Modification Guidelines 
 
 
TPX-0046 Dose Modificationa 
aDose reduction or interruption should be implemented upon consultation with the Medical Monitor. 
4.2.5. 
Dose Modifications: 
 
 
 exams including 
 will be conducted per the Schedules of Activities 
For 
 adverse reactions 
 
 follow the dose modification guidelines provided in Table 9. 
Table 9: 
Dose Modification Guidelines 
 
CTCAE Grade 
* 
Parameters 
TPX-0046 Dose Modification 
1 
Asymptomatic; clinical or diagnostic 
observations only 
Withhold current dose until toxicity has returned to 
baseline. If resolves within 4 weeks, resume 
 
. Then, consider re-escalation if no 
recurrence for 4 weeks. If stable for 2 consecutive 
 
exams but not resolved, resume 
 
2 
Symptomatic; moderate decrease in 
 
 and 
 or 
less decreased 
 from known 
baseline) 
Withhold current dose until toxicity has returned to 
baseline. If resolves within 4 weeks, may resume 
 
 
3 
Symptomatic with marked decrease 
in 
 
 or more than 
 of decreased 
 from 
known baseline, 
 
Withhold current dose until toxicity has returned to 
baseline. If resolves within 4 weeks, may resume 
 
 
4 
Best corrected 
 
 or worse in the 
 
Discontinue treatment permanently 
*National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. 
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5. 
SUBJECT ELIGIBILITY CRITERIA 
Each subject must meet all of the following inclusion criteria and none of the exclusion criteria 
to be enrolled in the study. 
5.1. 
Inclusion Criteria  
1. 
Subjects with histological or cytological confirmation of advanced/metastatic solid 
tumors harboring oncogenic RET fusions or mutations, who either have disease 
progression on or are intolerant to standard therapy; OR are ineligible for standard 
therapy or for whom no standard therapy exists; OR are unlikely to tolerate or derive 
clinical benefit from standard therapy in the opinion of the Investigator OR have declined 
standard therapy. 
• Subjects must have a documented RET gene fusion or oncogenic RET mutation as 
determined by local testing in a Clinical Laboratory Improvement Amendments 
(CLIA)-certified or equivalently accredited diagnostic lab. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. 
Age ≥ 18 years old (or age ≥ 20 as required by local regulation). 
5. 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.  
6. 
Presence of measurable disease (according to Response Evaluation Criteria in Solid 
Tumors [RECIST] v1.1 criteria). For Phase 2 only, prospectively confirmed measurable 
disease according to RECIST v1.1 by Blinded Independent Central Radiology Review 
(BICR), selected by Sponsor, PRIOR to enrollment.  
7. 
Life expectancy ≥ 12 weeks. 
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8. 
Baseline laboratory values fulfilling the following requirements: 
Laboratory Parameter 
Result 
ANC 
PLT 
Hgb 
Total bilirubin 
Liver transaminases (ALT/AST)  
ALP 
Creatinine clearance by Cockcroft-Gault formula* 
Abbreviations: ALP = alkaline phosphatase; ANC = absolute neutrophil count; AST/ALT = alanine aminotransferase / 
aspartate aminotransferase; Hgb = hemoglobin; PLT = platelet count; 
  
*calculated by Cockcroft-Gault formula: (140 - age [yr]) x body weight [Kg] x 1.23 x (0.85 if female) / serum creatinine 
[µmol/L]. Measured creatine clearance is also acceptable. 
9. 
Subjects with primary CNS tumors or brain metastases who are eligible for the study 
must meet the following criteria.  
• A minimum of 14 days must have elapsed from the completion of whole brain 
radiation treatment (WBRT) before the start of treatment with TPX-0046, and all side 
effects (except for alopecia) from WBRT are resolved to CTCAE version 5.0 grade 
≤1.  
• A minimum of 7 days must have elapsed from the completion of stereotactic 
radiosurgery before the start of treatment with TPX-0046, and all side effects (except 
for alopecia) from stereotactic radiosurgery are resolved to CTCAE version 5.0 grade 
≤1.  
• Subjects requiring steroids at a stable or decreasing dose (≤12 mg/day dexamethasone 
or equivalent) for at least 14 days are eligible.  
• Subjects on stable doses of levetiracetam (same dose for 14 days) are eligible to be 
enrolled.  
10. 
For subjects who received prior cytotoxic chemotherapy or prior targeted small molecule 
therapy at the time of starting treatment with TPX-0046, at least 14 days or five half-lives 
(whichever is shorter) must have elapsed after discontinuation (or at least 42 days for 
prior nitrosoureas, mitomycin C, and liposomal doxorubicin; for vandetanib and 
cabozantinib at least 14 days must have elapsed after discontinuation), and all AEs from 
prior treatments must have resolved to grade ≤1 CTCAE version 5.0 with the exception 
of alopecia or other AEs that the Investigator does not consider to be a risk to subject 
safety. 
11. 
Prior radiotherapy is allowed at least 14 days prior to starting treatment with TPX-0046. 
All AEs from prior treatments must have resolved to grade ≤1 CTCAE version 5.0 except 
for alopecia or other AEs that the Investigator does not consider to be a risk to subject 
safety. 
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12. 
Prior immunotherapy or prior antibody targeted therapies for advanced/metastatic disease 
is allowed. At least 3 weeks must have elapsed after discontinuation of immunotherapy or 
therapeutic antibodies and all AEs from prior treatments must have resolved to grade ≤1 
CTCAE version 5.0 except for alopecia or other AEs that the Investigator does not 
consider to be a risk to subject safety. 
13. 
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test 
during Screening and be neither breastfeeding nor intending to become pregnant during 
study participation; and agree to use 2 effective contraceptive methods (combination of 
any of these options: hormonal, barrier method, or intrauterine device) OR be abstinent 
OR be surgically sterile prior to study entry OR have a vasectomized partner,  for the 
duration of study participation, and 
 after discontinuation of study treatment. 
Male subjects or male partners of female subjects of childbearing potential must take 
appropriate precautions to avoid fathering a child from the time of screening 
 
after last dose of study treatment and to use appropriate barrier contraception, maintain 
true abstinence, or have had a vasectomy. Highly effective contraceptive methods are 
described in Appendix B. 
14. 
Male subjects must refrain from sperm donation from screening through 
 
after the last dose of study drug. 
15. 
Female subjects must refrain from egg donation from screening through 
 
after the last dose of study drug. 
16. 
Ability to complete all study-required procedures and assessments. 
17. 
Provision of written informed consent signed and dated by the subject and the 
Investigator, before any study interventions are performed. 
5.2. 
Exclusion Criteria  
1. 
Locally advanced/metastatic solid tumor that is a candidate for curative treatment through 
radical surgery and/or radiotherapy, or chemotherapy. 
2. 
Presence or history of any other active malignancy within 3 years other than a history of 
adequately treated basal or squamous cell carcinoma of the skin, or any adequately 
treated in situ carcinoma. 
3. 
Presence of only one measurable tumor lesion that has already been resected or irradiated 
before enrollment in the study.  
4. 
Known presence of RET gatekeeper mutation(s) (eg, RET V804X) based on most recent 
applicable molecular testing. 
5. 
Exposure to more than 1 prior selective RET inhibitor (eg, pralsetinib [BLU-667], or 
selpercatinib [LOXO-292]) unless a subject has discontinued a RET inhibitor treatment 
due to intolerance in which case Sponsor approval for eligibility is required.  
6. 
Major surgery within 4 weeks of the start of study.  
7. 
Clinically significant cardiovascular disease (either active or within 6 months before 
enrollment): myocardial infarction, unstable angina, coronary/peripheral artery bypass 
graft, symptomatic congestive heart failure (New York Heart Association Classification 
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Class ≥ II), cerebrovascular accident or transient ischemic attack, symptomatic 
bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac dysrhythmias 
of CTCAE version 5.0 grade ≥ 2. 
8. 
Any of the following cardiac criteria: 
• Mean resting corrected QT interval (ECG interval measured from the onset of the 
QRS complex to the end of the T wave) for heart rate (QTcF) > 470 msec obtained 
from 3 ECGs, using the screening clinic ECG machine-derived QTc value 
− For patients with QRS > 120 msec: QTcF > 500 
• Any clinically important abnormalities in rhythm, conduction, or morphology of 
resting ECG (eg, complete left bundle branch block, third degree heart block, second 
degree heart block, PR interval > 250 msec) 
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, congenital long QT syndrome, family history of long QT 
syndrome, or any concomitant medication known to prolong the QT interval  
9. 
  
10. 
 
11. 
Known clinically significant active infections not controlled with systemic treatment 
(bacterial, fungal, viral including HIV positivity). Subjects with chronic HIV must have a 
CD4+ T cell count ≥ 350 cell/microliter for eligibility. Subjects with chronic hepatitis B 
virus infection must have an undetectable viral load (and start antiviral therapy if required 
according to local or regional guidelines) prior to start of TPX-0046. Subjects with a 
history of hepatitis C viral infection must have an undetectable viral load.  
12. 
Gastrointestinal disease (eg, Crohn’s disease, ulcerative colitis, or short gut syndrome) or 
other malabsorption syndromes that would impact drug absorption.  
13. 
Concurrent participation in another therapeutic clinical study. 
14. 
Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or TPX-0046 
administration, or that may interfere with the interpretation of study results and, in the 
judgment of the Investigator, would make the subject inappropriate for entry into this 
study, or could compromise protocol objectives in the opinion of the Investigator and/or 
Sponsor. 
15. 
The concomitant use of known strong CYP3A4 inhibitors or inducers is prohibited 
including their administration within at least 2 weeks prior to the first TPX-0046 dose 
and throughout the study. Subjects should avoid grapefruit juice or grapefruit/grapefruit-
related citrus fruits (Seville oranges, pomelos). See Appendix A for a list of known 
CYP3A4 inhibitors and inducers. 
16. 
Current or anticipated use of drugs that are known to be sensitive substrates of CYP3A or 
CYP2B6 should be avoided, including their administration within at least 2 weeks prior 
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to the first TPX-0046 dose and throughout the study. Concomitant medication suspected 
of sensitive CYP3A or CYP2B6 (eg, bupropion, efavirenz) substrates must be approved 
by the Sponsor. See Appendix A for a list of known sensitive substrates of CYP3A. 
17. 
Current or anticipated need for drugs that are sensitive CYP2C9 substrates with narrow 
therapeutic indices, such as celecoxib, phenytoin, or warfarin is not permitted including 
their administration at least within 2 weeks prior to the first TPX-0046 dose and 
throughout the study. Concomitant medication suspected of being a CYP2C9 substrate 
with narrow therapeutic index must be approved by the Sponsor. 
18. 
Current or anticipated use of drugs that are known to be
 
 
is not permitted, 
including their administration within at least 2 weeks prior to the first TPX-0046 dose 
and throughout the study. Concomitant medication suspected of
 
 must be approved by the Sponsor. 
19. 
Known oncogene drivers other than RET including, eg, anaplastic lymphoma kinase 
[ALK], ROS1 [receptor tyrosine kinase encoded by the ROS1 gene], or epidermal growth 
factor receptor [EGFR]) conferring sensitivity to targeted therapies. 
6. 
STUDY TREATMENT  
6.1. 
Allocation to Treatment 
All subjects will be allocated to receive TPX-0046. For the Phase 1 dose-escalation portion of 
the study, subjects will be assigned according to the currently open dosing level at the time of 
enrollment.  
Dose level allocation will be performed by the Sponsor after subjects have given their written 
informed consent and have completed the necessary baseline assessments. The site staff will 
complete a Registration Form for the designated Sponsor study team member or designee. The 
Sponsor will assign a subject identification number and supply this number to the site. The 
subject identification number will be used on all study related documentations at the site. 
No subject shall receive TPX-0046 until the Investigator or designee has received the following 
information in writing from the Sponsor: 
• Confirmation of the subject’s enrollment; 
• Specification of the dose level for that subject and;  
• Permission to proceed with dosing the subject. 
6.2. 
Investigational Product Supplies 
6.2.1. 
Dosage Forms and Packaging 
The investigational TPX-0046 drug product is supplied as 
 
 capsules (Table 10). TPX-0046 capsules are 
 
capsules manufactured for use in the proposed clinical program. High-density polyethylene 
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(HDPE) bottles induction sealed with child resistance caps were selected as the container 
closure. TPX-0046 will be supplied in bottles containing 30 capsules of a single strength. TPX-
0046 will be supplied by the Sponsor. See the Investigator's Brochure for details on the original 
and new formulations. 
Table 10: 
TPX-0046 Investigational Product 
Product Name: 
TPX-0046 
Dosage Form: 
Capsules 
Unit Dose: 
  
  
Route of Administration: 
Oral 
Physical Description: 
 
 
NOTE: Drug product will not be available past July 2023. 
6.2.2. 
Investigational Product Storage and Accountability 
TPX-0046 will be stored at 20 °C – 25 °C (68 °F – 77 °F) with excursions permitted between 
15 °C and 30 °C (59 °F – 86 °F). Subjects should be instructed to keep their medication in its 
original container and stored at 15 °C to 30 °C (59 °F to 86 °F). Returned medication should be 
stored separately from medication that is yet to be dispensed. The TPX-0046 capsule bottle must 
be stored as indicated. Deviations from the storage requirements, including any actions taken, 
must be documented and reported to the Sponsor. 
6.2.3. 
Destruction of Investigational Product Supplies 
At each cycle visit, and at the end of the treatment study, all unused or partially used bottles must 
be returned by subjects to the Investigator and the Sponsor will provide instructions as to 
disposition of any unused TPX-0046. If the Sponsor authorizes destruction at the study site, the 
Investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by the 
Sponsor. Destruction must be adequately documented. 
6.3. 
Administration 
TPX-0046 (capsules) will be administered orally according to the assigned dose regimen with 
approximately 8-oz water (240 mL) 
 in 28-day continuous cycles. If a 
subject misses a daily dose, they must be instructed not to “make it up” the next day. If a subject 
vomits at any time after taking a dose, they must be instructed not to “make it up,” but to resume 
subsequent doses as prescribed. If a subject inadvertently takes 1 extra dose during a day, the 
subject should not take the next dose of TPX-0046. Subjects should also be instructed to swallow 
the trial medication whole and not chew the capsule prior to swallowing. No capsule should be 
ingested if it is broken, cracked, or otherwise not intact. 
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6.3.1. 
Dose Escalation 
TPX-0046 (capsules) will be administered orally as a 
 
 On Cycle 1 Day 1, TPX-0046 will be administered either QD or 
BID per the dosing regimen with approximately 8-oz water (240 mL) 
 in 
28-day continuous cycles.
 
  
For the QD regimen, TPX-0046 will be administered orally approximately twenty-four hours 
apart. Subjects should take their medication at approximately the same time each day and not 
take more than the prescribed dose at any time. However, a variance of up to 12 hours is allowed 
for any given dose, rather than miss a day’s dose for subjects on QD regimen. 
For the BID regimen, TPX-0046 will be administered orally approximately twelve hours apart. 
Subjects should take their medication at approximately the same time each day and not take 
more than the prescribed dose at any time. However, a variance of up to 6 hours is allowed for 
any given dose, rather than miss a day’s dose for subjects on BID regimen.   
For the 
, a 
 dose of TPX-0046 (eg, 
) will be administered as 
. On Cycle 1 Day 1, 
the 
 dose will be administered 
. If tolerated (
 treatment 
related adverse events), patients will have their doses 
 to a 
 
 If not tolerated, patient 
 should be discussed with the Sponsor Medical 
Monitor.   
6.3.2. 
Food Requirements (except for the Food Effect Sub-study) 
TPX-0046 capsules will be administered orally every day with approximately 8-oz (240 mL) of 
water 
. The subject should refrain from 
 
 for at least 
. 
 will 
be allowed ad libitum except for 1 hour before and 1 hours after drug administration. This 
requirement may be removed pending receipt of data from the food effect sub-study.  
6.4. 
Subject Compliance 
All doses of TPX-0046 will be dispensed by the appropriately designated study staff at the 
investigational site. 
Subjects will be required to bring the dosing diary and all empty and partially used TPX-0046 
bottles and any leftover TPX-0046 to every visit. The number of capsules returned by the subject 
will be counted, documented, and recorded. Treatment compliance will be evaluated by noting 
the discrepancy among the assigned dose, the dose administered, and the reason for the 
discrepancy will be recorded in the source documents. 
6.5. 
Concomitant Treatments 
The CRF must capture all concomitant medications, blood products, as well as non-drug 
interventions (eg, paracentesis) received by subjects from the date of signed informed consent 
until the EOT visit. The Investigator should be alerted if the subject is taking any agent known to 
affect or with the potential for drug interactions. 
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6.5.1. 
Prohibited Concomitant Medications  
The concomitant use of known strong CYP3A4 inhibitors is prohibited including their 
administration at least within 2 weeks prior to the first TPX-0046 dose and throughout the study. 
Subjects should avoid grapefruit juice or grapefruit/grapefruit-related citrus fruits (Seville 
oranges, pomelos). Coadministration of TPX-0046 in combination with strong CYP3A4 inducers 
is prohibited including their administration at least within 2 weeks prior to the first TPX-0046 
dose and throughout the study. See Appendix A for a list of known CYP3A4 inhibitors and 
inducers. 
Current or anticipated use of drugs that are known to be sensitive substrates of CYP3A or 
CYP2B6 should be avoided, including their administration within at least 2 weeks prior to the 
first TPX-0046 dose and throughout the study. Concomitant medication suspected of sensitive 
CYP3A or CYP2B6 (eg, bupropion, efavirenz) substrates must be approved by the Sponsor. See 
Appendix A for a list of known sensitive substrates of CYP3A. 
Current or anticipated use for drugs that are sensitive CYP2C9 substrates with narrow 
therapeutic indices, such as celecoxib, phenytoin, or warfarin is not permitted including their 
administration at least within 2 weeks prior to the first TPX-0046 dose and throughout the study. 
Concomitant medication suspected of being a CYP2C9 substrate with narrow therapeutic index 
must be approved by the Sponsor.  
Concomitant use of drugs that are known to be
 
is prohibited including their administration at least 
within 2 weeks prior to the first TPX-0046 dose and throughout the study. Concomitant 
medication suspected of
 
 must be approved by the 
Sponsor.  
If there is a question about a particular concomitant medication, discuss with the Medical 
Monitor. 
6.5.2. 
Other Anti-tumor or Investigational Drugs 
Additional systemic anti-tumor therapy is not permitted while subjects are receiving study 
therapy. 
6.5.3. 
Supportive Care 
Palliative and supportive care for disease-related symptoms may be administered at the 
Investigator’s discretion and according to the specific supportive care product Prescribing 
Information or the current American Society of Clinical Oncology (ASCO) guidelines. 
6.5.4. 
Anti-diarrheal, Anti-emetic Therapy  
Primary prophylaxis of diarrhea, nausea, and vomiting is 
 in the first cycle in the 
Phase 1 dose escalation portion of the study. Primary prophylaxis in subsequent cycles is at the 
Investigator’s discretion. The choice of the prophylactic drug as well as the duration of treatment 
is up to the Investigator with Sponsor approval assuming there is no known or expected drug-
drug interaction and assuming the drug is not included in the Concomitant Treatments section. 
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6.5.5. 
Anti-inflammatory Therapy 
Anti-inflammatory or narcotic analgesic may be offered as needed assuming there is no known 
or expected drug-drug interaction and assuming the drug is not included in the Concomitant 
Treatments section. 
6.5.6. 
Corticosteroids 
Chronic systemic corticosteroid use (prednisone ≥ 12.5 mg/day or dexamethasone ≥ 2 mg/day) 
for palliative or supportive purpose is not permitted (unless administered for adrenal 
insufficiency). Acute emergency administration, topical application, inhaled sprays, eyedrops or 
local injections are permitted. 
6.5.7. 
Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study. The 
appropriate interval of time between surgery and TPX-0046 required to minimize the risk of 
 has not been determined. Stopping TPX-0046 is 
recommended at least 2 days prior to surgery. Postoperatively, the decision to reinitiate 
TPX-0046 treatment should be based on a clinical assessment of satisfactory 
 
recovery from surgery. 
7. 
STUDY ASSESSMENTS 
As no new subjects will be enrolled in this study, Investigators will follow assessments for 
subjects currently enrolled as described in the schedule of activities for Phase 1 dose escalation 
(Table 1). Additional testing considered necessary for safety related to study drug may be 
performed at the discretion of the Investigator. 
7.1. 
Informed Consent 
Prior to conducting protocol-specific assessments for Phase 1 (dose escalation, dose expansion, 
and food effect) and Phase 2, written informed consent and any other authorizations must be 
signed and dated by the subject or subject’s legal representative. 
Remaining subjects will be notified of the close of enrollment and termination of development of 
the protocol via informed consent. 
7.2. 
Physical Examination 
A complete physical examination, including a targeted neurological examination, will be 
performed by either the Investigator or a sub-Investigator according to the Schedules of 
Activities. 
Height and weight will be collected as part of the physical exam. Height will be collected at 
Screening only. 
Clinically significant abnormal findings must be recorded in the applicable electronic CRF and 
followed by the Investigator, sub-Investigator, or other qualified site staff at the next scheduled 
visit or earlier as clinically indicated. 
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7.3. 
Performance Status 
The ECOG performance scale will be assessed at Screening and according to the Schedules of 
Activities. 
7.4. 
Subject Diary and Compliance 
All doses of TPX-0046 will be dispensed by the appropriately designated study staff at the 
investigational site. 
Subjects will be required to bring the dosing diary and all empty and partially used TPX-0046 
bottles and any leftover TPX-0046 to every visit. The number of tablets returned by the subject 
will be counted, documented, and recorded. Treatment compliance will be evaluated by noting 
the discrepancy between the assigned dose and the dose administered, and the reason for the 
discrepancy will be recorded in the source documents. 
7.5. 
Laboratory Assessments 
Laboratory assessments as described in Table 11 will be performed per Schedule of Activities 
(Table 1). Assessments beyond Cycle 3 will be done based on symptomatology and per 
Investigator discretion. 
Table 11: 
Safety Laboratory Tests 
Hematology 
Complete Blood Count with Differential: Hemoglobin, platelets, WBC, Absolute 
Neutrophils, Absolute Lymphocytes, Absolute Monocytes, Absolute Eosinophils, 
Absolute Basophils or % reticulocytes 
Chemistry 
ALT, AST, ALP, Sodium, Potassium, Magnesium, Chloride, Total calcium, Total 
bilirubin, BUN or Urea, Creatinine, Uric Acid, Glucose (nonfasted), Lipid panel 
(total cholesterol, LDL, HDL, triglycerides), Albumin, Phosphorus or Phosphate, 
Bicarbonate, Total protein, Lactate dehydrogenase, 
 
Coagulation 
PT or INR, PTT 
Urinalysis 
Urine dipstick for urine protein: If positive and clinically significant, microscopic 
(Reflex Testing) 
Urinalysis includes the analysis of protein, glucose, ketones, blood, and specific 
gravity. A microscopic (white blood cells/high-power field [HPF], red blood 
cells/HPF, and any additional findings) exam will be performed only if the 
urinalysis result is abnormal. 
Pregnancy Test 
Serum pregnancy test for female subjects of childbearing potential 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; HDL = high-density lipoprotein; INR = International normalized ratio; LDL = low-
density lipoprotein; PT = prothrombin; PTT = prothrombin time; WBC = white blood cell. 
*For potential Hy’s Law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, 
creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, prothrombin time 
(PT)/INR, alkaline phosphatase, total bile acids and acetaminophen drug and/or protein adduct levels. 
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7.6. 
Cardiac Safety Monitoring 
7.7. 
Cardiac safety monitoring should be done based on symptomatology 
and at Investigator’s discretion. Tumor Response Assessments 
Tumor response assessments will be performed per standard of care. 
Imaging studies will include a computerized tomography (CT) or magnetic resonance imaging 
(MRI) scan of the brain, chest, abdomen, pelvis. For subjects diagnosed with primary brain 
tumors, only the MRI of the brain will be required at Screening and during the study. 
Tumor assessments will include all known or suspected disease sites and will be performed per 
specified timepoints according to the Schedules of Activities. For all tumor assessments, the 
method of assessment that was used at Screening should be the same method used throughout the 
study.  
For all subjects, radiographic confirmation of objective tumor response or disease progression 
will be based on RECIST v1.1 and assessed locally. 
Subjects discontinuing study treatment before documented radiographic progression will 
complete an EOT visit and safety follow-up visit per Section 8.4. 
For subjects discontinuing the study treatment due to documented radiographic progression 
survival status will be obtained via a phone call or medical chart review, including information 
about subsequent anticancer therapies (including best response) every three months until death, 
loss of follow-up, or withdrawal of consent, whichever comes first. 
8. 
STUDY CONDUCT 
Scheduled protocol-related activities will be performed at specified timepoints and within 
windows as outlined in the Schedule of Activities for Dose Escalation (Table 1). If a visit is 
missed for any reason, the next scheduled visit should occur as originally planned. 
8.1. 
Screening And Eligibility 
All patients being considered for the study and are eligible for screening must provide informed 
consent for the study prior to completing any study-specific procedures (up to 28 days prior to 
initial dose). A patient number will be assigned. Subjects will be screened within 28 days prior to 
the administration of TPX-0046 to confirm that they meet the eligibility criteria. Subjects 
participating in the Phase 1 Dose Escalation, Dose Expansion (QD, BID, and 
 
) and Food effect Sub-study must have eligibility confirmed 
 
. 
The following items must be completed as part of the screening procedures: 
• Eligibility checklist (see complete list in Sections Section 5.1 and Section 5.2) must 
be completed for each subject and sent to the Sponsor for eligibility confirmation 
before enrollment 
• Source documents for molecular pathology report, detailing the specific test that 
confirms RET gene fusion, should be submitted for the Sponsor’s approval of 
eligibility 
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• Imaging studies (CT or MRI of the chest, abdomen, and pelvis and MRI of the brain) 
should be submitted and confirmed by BICR (Phase 2 only) 
8.2. 
Timing of Clinical Procedures 
On visits that require in-clinic dosing, clinical assessments should be conducted as described in 
Table 1. 
8.3. 
Study Duration 
Subjects will remain on study treatment until disease progression, development of unacceptable 
toxicity, the ability to move to alternative care is identified, or withdrawal of consent.   
8.4. 
Subject Treatment Discontinuation 
Subjects discontinuing the study treatment prior to documented radiographic progression will 
complete an EOT visit (Section 8.5) and safety follow-up visit (Section 8.6). 
8.5. 
End of Treatment Visit 
For subjects who discontinue study drug, the EOT visit should occur as soon as possible (within 
7 days) after the last dose of investigational product. 
8.6. 
Safety Follow-up Visit 
The safety follow-up visit should occur approximately 28 days after the last dose or before any 
new anticancer treatment is started. 
8.7. 
Subject Discontinuation and Withdrawal from Study 
A subject may be discontinued from study treatment at any time if the subject, the Investigator, 
or the Sponsor Medical Monitor determine that it is not in the subject’s best interest to continue 
on study. The following is a list of possible reasons for early discontinuation of study treatment: 
• Disease progression (treatment beyond radiographic or clinical progression will not 
be allowed) 
• Any adverse event that cannot be adequately managed with dose modifications, 
including dose interruption > 28 days (unless there is reasonable evidence of clinical 
benefit to justify continuation on the protocol - which must be previously discussed 
with Turning Point Therapeutics) 
• Protocol violation requiring discontinuation of study treatment 
• Subject is not compliant with study procedures 
• Lost to follow-up 
• Subject withdrawal of consent for further treatment 
• Investigator identifies alternative treatment option for the patient  
• Turning Point Therapeutics' early termination of study. Reasons for terminating the 
study may include, but are not limited to, the following: 
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− All enrolled subjects have discontinued study treatment 
− The incidence or severity of AEs in this or other studies indicates a potential 
health hazard to subjects 
− Subject enrollment is unsatisfactory 
Data to be collected for the EOT visit are described in the Schedules of Assessments. 
Subjects will be followed for at least 28 calendar days after the last dose of TPX-0046. If a 
subject is discontinued from treatment due to an AE, the subject will be followed until the AE 
has resolved or stabilized as per Section 9.3.4. 
8.7.1. 
Withdrawal of Consent  
A subject may withdraw consent for any further contact with him or her or persons previously 
authorized by the subject to provide this information. Subjects should notify the Investigator in 
writing of the decision to withdraw consent from future follow up, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the Investigator, as 
to whether the withdrawal is only from further receipt of the investigational product or also from 
study procedures and/or posttreatment study follow up and entered on the appropriate CRF page. 
If vital status (whether the subject is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in accordance 
with local law. 
8.7.2. 
Lost to Follow-up 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow up with persons authorized by the subject as noted above. Lost to 
follow up is defined by the inability to reach the subject after a minimum of 2 documented phone 
calls, faxes, or e mails as well as lack of response by the subject to 1 registered mail letter. All 
attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use locally permissible methods to obtain the date and cause of 
death. If the Investigator’s use of a third-party representative to assist in the follow-up part of the 
study has been included in the subject’s informed consent, then the Investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining the subject’s contact 
information or other public vital status data necessary to complete the follow-up part of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, to obtain updated contact information. If, after all attempts, the 
subject remains lost to follow up, then the last known alive date as determined by the 
Investigator should be reported and documented in the subject’s medical records. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record. In any circumstance, every effort should be 
made to document subject outcome, if possible. The Investigator should inquire about the reason 
for withdrawal, request that the subject return all unused investigational product, request that the 
subject return for a final visit, if applicable, and follow up with the subject regarding any 
unresolved AEs. 
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If the subject refuses further visits, no further study-specific evaluations should be performed, 
and no additional data should be collected. The Sponsor may retain and continue to use any data 
collected before such withdrawal of consent. 
9. 
ADVERSE EVENT REPORTING 
Adverse event assessments will be performed at times specified at each clinic visit as specified in 
the Schedules of Activities:  
Events that are clearly consistent with the expected pattern of progression of the underlying 
disease should not be reported as an AE or serious adverse event (SAE). Radiographic 
progression according to RECIST v1.1 criteria should be documented to support disease 
progression. If there is any uncertainty as to whether an event is due to disease progression, it 
should be reported as an AE. 
Adverse events will be graded according to CTCAE version 5.0. The type, incidence, severity, 
timing, seriousness, and relatedness of AEs and laboratory abnormalities will be reported. 
9.1. 
Adverse Events, Serious Adverse Events, and Anticipated Serious 
Adverse Events 
9.1.1. 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.  
An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related to the medicinal product. For this study, AEs will be 
recorded starting at the time of first administration of the investigational product through the last 
follow-up visit for all dose levels/cohorts.  
AEs include, but are not limited to, (1) a worsening or change in nature, severity, or frequency of 
condition(s) present at the start of the study; (2) subject deterioration due to primary illness; (3) 
intercurrent illness; and (4) drug interaction. For recording purposes, pregnancy in the partner of 
a healthy male subject is a medical condition and is not considered an AE. 
Subjects should be questioned in a general way, without leading the subject or asking about the 
occurrence of any specific symptom.  
The Investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. The diagnosis and not the individual signs/symptoms should be 
documented as the AE. For example, if the underlying disease process is a gastric ulcer, it would 
not be appropriate to record the AE by describing the symptoms “stomach pain,” “indigestion,” 
or “appetite loss”. The AE medical term of “gastric ulcer” should be recorded as the AE. 
9.1.2. 
Definition of Serious Adverse Events 
A serious AE (SAE) (an experience or a reaction) is an AE that leads to one or more of the 
following: 
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• Death – An AE that causes or contributes to a fatal outcome 
• Is life-threatening – Refers to an event/reaction, in the view of the Investigator, places 
the subject at immediate risk of death. It does not refer to an event/reaction that 
hypothetically might cause death if it were more severe 
• Requires inpatient hospitalization or prolongation of existing hospitalization, except 
for the following: 
− Hospitalization for respite care or social admissions (eg, lack of housing, 
economic inadequacy, family circumstances) 
− Hospitalization solely for coordination of care, including hospice arrangements 
− Hospitalization due solely to progression of the underlying cancer 
− Hospitalization that was necessary solely because of subject requirement for 
outpatient care outside of normal outpatient clinic operating hours 
− Hospitalization for same day surgeries (as outpatient/same day/ambulatory 
procedures) 
− Planned hospitalization required by the protocol (eg, for study drug administration 
or insertion of access device for study drug administration) 
− Hospitalization for a preexisting condition, provided that the hospitalization was 
planned prior to the study or was scheduled during the study when elective 
surgery became necessary because of the expected normal progression of the 
disease and the subject has not experienced an adverse event 
• Results in persistent or significant disability/incapacity (ie, the adverse event results 
in substantial disruption of the subject’s ability to conduct normal life functions) 
• Congenital anomaly/birth defect 
• Important medical events, when based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed above 
9.1.3. 
Definition of Anticipated Serious Adverse Events 
Anticipated SAEs are SAEs that could be anticipated due to the underlying metastatic disease in 
the population being studied in this clinical trial. This list of possible anticipated SAEs by the 
Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms was adapted from 
Hyde, 1974; Chute, 1985; and Silvestri, 1995. 
• Cough 
• Abnormal loss of weight 
• Weight decreased  
• Dyspnoea  
• Chest pain 
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• Neck pain  
• Hemoptysis  
• Cancer pain 
• Bone pain  
• Dysphonia  
• Musculoskeletal pain  
• Headache 
• Muscular weakness 
• Lymphadenopathy  
• Malignant neoplasm  
9.2. 
Relationship to the Investigational Product 
The Investigator will document his or her opinion of the relationship of the AE to treatment with 
the investigational product using the criteria outlined in Table 12. A “reasonable possibility” that 
the investigational product caused the AE means there is evidence to suggest a causal 
relationship between the investigational product and the AE.  
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable,” the event will be considered related to the investigational product. 
Table 12: Relationship of Adverse Events to Investigational Product 
Relationship 
Description 
Related 
1. A clinical event, including a laboratory test abnormality, with a reasonable time 
sequence to administration of the investigational product, unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and which follows 
a clinically reasonable response on withdrawal (de-challenge) 
2. An event that could also be explained by concurrent disease or other drugs or 
chemicals where information on investigational product withdrawal may be 
lacking or unclear 
3. Re-challenge or de-challenge information is not required to fulfill this definition 
Not Related 
4. A clinical event, including a laboratory test abnormality, with sufficient 
evidence to accept that there is no causal relationship to investigational product 
administration (eg, no temporal relationship to investigational product 
administration, because the investigational product was administered after the 
onset of the event; investigation shows that the drug was not administered; 
proof of other cause) 
5. An event with a temporal relationship to investigational product administration, 
which makes a causal relationship improbable, and other drugs, chemicals, or 
underlying disease provide plausible explanations 
Adverse events will be assessed using CTCAE version 5.0. AEs must be assessed for severity 
(mild, moderate, severe, life-threatening, or fatal), and must be entered on the AE page of the 
eCRF. The CTCAE version 5.0 grade refers to the severity of the AE. The CTCAE version 5.0 
grading system and severity assessments are described in Table 13. It should be noted that the 
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term “severe” is used to grade intensity and is not synonymous with the term “serious.”  The 
assessment of severity is made regardless of the investigational product relationship or the 
seriousness of the AE. 
Table 13: Severity of Adverse Events 
Grade Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting age-
appropriate instrumental activities of daily livinga 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily 
livingbc 
4 
Life-threatening consequences or urgent intervention indicatedd 
5 
Death related to adverse eventd 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using the 
toilet, and taking medications, as performed by subjects who are not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a SAE per the definition of SAE. 
d Grade 4 and 5 events must be reported as SAEs per the definition of SAE. 
9.3. 
Reporting of Adverse Events and Serious Adverse Events 
9.3.1. 
Reporting of Adverse Events 
Adverse event data will be collected from the time of first dose until 28 days after last dose.  
All AEs, whether believed by the Investigator to be related or unrelated to the investigational 
product, must be documented in the subject’s medical records, in accordance with the 
Investigator’s normal clinical practice and on the AE CRF. Each AE is to be evaluated for 
duration, intensity, frequency, seriousness, outcome, other actions taken, and relationship to the 
investigational product. Redacted medical record source documents will be requested for all 
SAEs and emergency room visits. 
9.3.2. 
Reporting of Serious Adverse Events 
In agreeing to the provisions of this protocol, the Investigator accepts all responsibilities for 
immediately reporting SAEs to the Sponsor. Immediate reporting implies within 24 hours of 
becoming aware of the occurrence of an SAE. 
After informed consent for the clinical trial has been obtained but prior to initiation of study 
drug, only SAEs related to protocol-mandated assessments should be reported. 
SAE data will be collected from the time of the first dose until 28 day after the last dose.  
The Investigator will assess whether the event is causally related to the investigational product. 
The Sponsor will also assess whether the event is causally related to the investigational product, 
in addition to assessing the overall safety profile of the investigational product. If an Investigator 
becomes aware of an SAE that may be attributable to the investigational product at any time after 
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the end of the study, the Sponsor should be notified immediately (ie, within 24 hours) by 
completing and sending a Serious Adverse Event Report Form. 
The Investigator must report SAEs by completing and sending a Serious Adverse Event Report 
Form and completing the AE/SAE CRF section.  
Investigators should record all case details that can be gathered immediately (ie, within 24 hours 
after learning of the event) on the SAE report form and submit the report via fax or email (please 
refer to the Study Manual).  
The Sponsor or designee will notify the appropriate regulatory authorities in accordance with 
local government regulations.  
Following the initial report, any additional information obtained by the Investigator about the 
SAE must be reported promptly to the Sponsor in the same manner as described above for the 
initial SAE report. Redacted medical record source documents will be requested for all SAEs and 
emergency room visits. 
9.3.3. 
Deaths 
Death due to disease progression will not be reportable as an SAE. All deaths, regardless of 
relationship to study drug, must be recorded on the Death CRF and on the Adverse Event CRF if 
considered an adverse event. 
Death should be considered an outcome and not a distinct event. The event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on 
the Adverse Event CRF. Generally, only one such event should be reported. The term "sudden 
death" should be used only for the occurrence of an abrupt and unexpected death due to 
presumed cardiac causes in a subject with or without preexisting heart disease, within 1 hour 
after the onset of acute symptoms or, in the case of an unwitnessed death, within 24 hours after 
the subject was last seen alive and stable. If the cause of death is unknown and cannot be 
ascertained at the time of reporting, "unexplained death" should be recorded on the Adverse 
Event CRF. If the cause of death later becomes available (eg, after autopsy), "unexplained death" 
should be replaced by the established cause of death. 
9.3.4. 
Follow-up of Adverse Events and Serious Adverse Events 
All AEs must be followed until the AE resolves, is no longer of clinical concern, has stabilized 
or is otherwise explained, or the subject is lost to follow-up. 
AEs ongoing at the final follow-up assessment that are deemed to be “related” to the 
investigational product or of other clinical significance must be followed for as long as necessary 
to adequately evaluate the safety of the subject or until the event stabilizes, resolves, or is no 
longer of clinical concern. If resolved, a resolution date for the AE should be documented in the 
CRF. The Investigator must ensure that follow-up includes any supplemental investigations 
indicated to elucidate the nature and/or causality of the AE. This may include additional 
laboratory tests or investigations, or consultation with other healthcare professionals, as 
considered clinically appropriate by the Investigator. 
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9.4. 
Pregnancy 
9.4.1. 
Exposure During Pregnancy 
For investigational products and for marketed products, an exposure during pregnancy occurs if: 
• A female becomes, or is found to be, pregnant either while receiving or having been 
exposed to (eg, because of treatment or environmental exposure) the investigational 
product; or the female becomes, or is found to be, pregnant after discontinuing and/or 
being exposed to the investigational product. An example of environmental exposure 
would be a case involving direct contact with the TPX-0046 product in a pregnant 
woman (eg, a nurse reports that she is pregnant and has been exposed to 
chemotherapeutic products). 
• A male subject has been exposed (eg, because of treatment or environmental 
exposure) to the investigational product before or around the time of conception 
and/or is exposed during his partner’s pregnancy. 
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
subject’s treatment or within 
 after the last dose of the investigational product, 
for female subjects and male subjects respectively, the Investigator must submit this information 
to 
 on a Pregnancy Report Form In addition, the Investigator must submit 
information regarding environmental exposure to a Sponsor product in a pregnant woman (eg, a 
subject reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage). This must be done regardless of whether an AE has occurred and within 24 hours of 
awareness of the exposure. The information submitted should include the anticipated date of 
delivery (see below for information related to termination of pregnancy). 
The Investigator will follow the pregnancy until completion or until pregnancy termination and 
notify the Sponsor’s Medical Monitor/or designee of the outcome as a follow-up to the initial 
pregnancy report. In the case of a live birth, the structural integrity of the neonate can be 
assessed at the time of birth. In the event of a termination, the reason(s) for the termination 
should be specified and, if clinically possible, the structural integrity of the terminated fetus 
should be assessed by gross visual inspection (unless pre-procedure test findings are conclusive 
for a congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a live-
born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the Investigator 
should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported as SAEs follows: 
• Spontaneous abortion to include miscarriage and missed abortion. 
• Neonatal deaths that occur within one month of birth should be reported, without 
regard to causality, as SAEs. In addition, infant deaths after one month should be 
reported as SAEs when the Investigator assesses the infant death as related or 
possibly related to exposure to the investigational product. 
Additional information regarding the exposure during pregnancy may be requested by the 
Investigator. Further follow-up of birth outcomes will be handled on a case-by-case basis (eg, 
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follow-up on preterm infants to identify developmental delays). In the case of paternal exposure, 
the Investigator will request consent from the study subject and partner for additional 
information. The Investigator must document in the source documents that consent was 
requested. 
9.4.2. 
Pregnancy Reporting 
Female subjects or partners of male subjects of childbearing potential will be instructed to 
immediately inform the Investigator if they become pregnant during the study or within 
 
 after the last dose of the investigational product, for female subjects and male subjects 
respectively.  
The Investigator should discontinue the investigational product and counsel the subject or partner 
of a male subject, discussing the risks of the pregnancy and the possible effects on the fetus. 
Monitoring should continue until conclusion of the pregnancy. Any SAEs associated with the 
pregnancy (eg, an event in the fetus, an event in the mother during or after the pregnancy, or a 
congenital anomaly/birth defect in the child) should be reported and submitted within 24 hours. 
9.4.3. 
Birth Defects and Abortions 
Any congenital anomaly/birth defect in a child born to a female subject or partner of a male 
subject exposed to the investigational product should be classified as an SAE and reported as 
such. Any spontaneous abortion or miscarriage should be reported in the same fashion 
(therapeutic abortions are excluded from expedited reporting and would be captured as 
pregnancy outcome information). 
For additional guidance regarding use of contraceptives see Appendix B. 
10. 
STATISTICAL METHOD ANALYSIS 
Detailed methodology for summary and statistical analyses of the data collected in this trial will 
be documented in a Statistical Analysis Plan (SAP), which will be maintained by the Sponsor or 
their designee. The SAP may modify the initial analysis plan outlined in the protocol; however, 
any major modifications of the primary endpoint and/or analysis methods will also be reflected 
in a protocol amendment. 
10.1. 
Analysis Sets 
10.1.1. 
Full Analysis Set 
The Full Analysis Set (FAS) consists of all subjects who receive at least one full or partial dose 
of TPX-0046. This will be the same as the Safety Analysis Set. The FAS set will be used for the 
summary of subject dispositions, demographics, and baseline characteristics, and safety analysis.  
10.1.2. 
Efficacy Evaluable Analysis Set 
Efficacy Evaluable (EE) Analysis Set will include all enrolled subjects who (1) have received at 
least one dose of study treatment; (2) RET fusion+ or mutation+ from local testing (LTD) can be 
confirmed by central lab; (3) have a baseline tumor assessment with measurable disease and have 
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at least 1 on-study tumor assessment per RECIST v1.1; and (4) have no major protocol violations 
that could affect efficacy. 
The EE analysis set will be used for efficacy analyses for Phase 1. 
10.1.3. 
Safety Analysis Set 
The Safety Analysis Set includes all enrolled subjects who receive at least one dose of 
TPX-0046. Each subject will be classified into and analyzed consistently within one treatment 
group. 
10.2. 
Sample Size Determinations 
10.2.1. 
Phase 1 Dose Escalation 
For Phase 1 dose escalation, 41 subjects have enrolled across 9 dose levels. Enrollment is closed. 
10.3. 
Statistical Analysis 
10.3.1. 
General Considerations 
10.3.1.1. Software 
All data listings, summaries and statistical analyses will be generated using SAS® Version 9 or 
above, or equivalent statistical software. 
10.3.1.2. Missing Data 
All analyses and descriptive summaries will be based on the observed data. Unless otherwise 
specified missing data will not be imputed. Partial dates for AEs and concomitant medications 
will be imputed using the most conservative rules. 
10.3.1.3. Baseline Measurements 
The last measurement on or prior to the date of the first dose will serve as the baseline 
measurement and should be within 28 days of first dose. 
10.3.1.4. Data Presentation 
Categorical variables will be summarized in frequency tables, with the counts and percentage of 
subjects in each category. Percentages given in the summary tables will be rounded and thus may 
not always add up to exactly 100 percent. For continuous variables, summary statistics will 
include N, mean, standard deviation, median, and minimum and maximum values (range). 
10.3.1.5. Duration 
Duration, except for duration of treatment, is calculated as: 
Duration (days): 
 (End Date – Start Date + 1)   
Duration (weeks): 
 (End Date – Start Date + 1)/7 
Duration (months): 
 (End Date – Start Date + 1)/30.4375* 
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Duration (years): 
 (End Date – Start Date + 1)/365.25** 
*Average number of days in a month = 30.4375, which is based on 365.25/12 where 365.25 represents the average 
number of days in a year and 12 represents the number of months in a year 
**Average number of days in a year = 365.25, reflecting the Julian Year of three years with 365 days each and one 
leap year of 366 days. 
10.3.2. 
Subject Disposition 
A disposition table will summarize the number of subjects enrolled, treated, discontinued from 
study treatment and the reasons for treatment discontinuation, and end-of-study and reasons. The 
reason for discontinuation and end-of-study will be summarized using the categories specified in 
the Study Discontinuation, and End-of-Study CRF page, by cohort. 
10.3.3. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics including disease staging, histology, smoking history, 
ECOG performance status, CNS metastasis at baseline, prior treatment history, and molecular 
diagnostic test results on oncogenic RET fusions or mutations will be summarized from the CRF 
data for all subjects in the FAS by cohort. 
10.3.4. 
Efficacy Analyses 
Radiologic assessments evaluated by the Investigator will be explored for Phase I in efficacy 
analysis set. Number of subjects with ORR will be summarized. 
10.3.4.1. Objective Response Rate 
The ORR will be defined as the proportion of subjects with a confirmed complete response (CR) 
or partial response (PR). A confirmed response is a response that persists on a repeat imaging 
performed at least 4 weeks after initial documentation of response. Subjects with a confirmed 
objective response (CR or PR) will be referred to as responders. Non-responders will include 
subjects without a confirmed objective response, stable disease (SD), progressive disease (PD), 
not evaluable (NE), or non-CR/non-PD (NN).  
10.3.5. 
Safety Analyses 
Safety analyses will be performed using the Safety Population for each cohort, as well as for all 
cohorts combined. 
10.3.5.1. Extent of Exposure 
Exposure analysis will be based on the actual dose administered for the investigational product. 
Duration of treatment will be calculated as the last dose date minus the first dose date plus one 
day. Duration of treatment and total daily dose amount will be summarized using descriptive 
statistics. The number of subjects treated by cycles will be summarized. 
10.3.5.2. Adverse Events 
AEs will be graded according to the CTCAE version 5.0 and coded to preferred term and system 
organ class using the MedDRA version 21.1 or higher. 
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All AEs reported during the AE reporting period (inclusive AEs after the 
 
 post last dose of the investigational product) will be considered as treatment-emergent 
adverse events (TEAEs). 
For the dose escalation phase, the number of subjects with DLTs by dose level will be listed. 
Incidence rates will be summarized with frequency and percentage by MedDRA SOC and 
preferred term. In addition, AE incidence rates will also be summarized by severity and 
relationship to investigational product. Treatment-related AEs are those judged by the 
Investigator to be at least possibly related to the investigational product. Subjects with multiple 
occurrences of events will be counted only once at the maximum severity to investigational 
product for each preferred team, SOC, and overall. Deaths that occur within 28 days after the last 
dose of the investigational product are defined as on-study deaths and reported as SAEs within 
the required reporting period. 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
It is the Investigator’s responsibility to ensure the accuracy, completeness, and timeliness of the 
data reported for each subject. Source documentation supporting the data should indicate the 
subject’s participation in the study and should document the dates and details of study 
procedures, AEs, and subject status. 
To ensure compliance with Good Clinical Practice (GCP) and all applicable regulatory 
requirements, the Sponsor may conduct a quality assurance audit. 
12. 
DATA HANDLING AND RECORD KEEPING 
12.1. 
Case Report Forms/Electronic Data Record 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. Queries will be 
entered, tracked, and resolved directly through the electronic data capture (EDC) system. The 
study database will be updated in accordance with the resolved queries. All changes to the study 
database will be documented. 
12.2. 
Study Monitoring, Audits, and Inspections 
Site visits will be conducted by an authorized Sponsor representative, who will inspect study 
data, subjects’ medical records, and CRFs according to GCP, the FDA, and the International 
Conference on Harmonisation (ICH) guidelines. In addition to monitoring by the Sponsor or its 
designees, the study may be audited by representatives of the FDA or other regulatory 
authorities, who will also be permitted access to study documents. The Investigator should 
immediately notify the Sponsors’ Clinical Operations department or designee of any proposed or 
scheduled audits by regulatory authorities. 
The Investigator will permit authorized representatives of the Sponsor or designee and national 
or local health authorities to inspect facilities and records relevant to this study. 
The Investigator must obtain Institutional Review Board (IRB)/IEC approval for the 
investigation. Initial IRB/IEC approval and all materials approved by the IRB/IEC for this study, 
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including the subject consent form and recruitment materials, must be maintained by the 
Investigator and made available for inspection. 
12.3. 
Inspection of Records 
The Sponsor and designees of the Sponsor will be allowed to conduct site visits to the 
investigational facilities for monitoring any aspect of the study. The Investigator agrees to allow 
Sponsor representatives to inspect the drug storage area, investigational product inventory, drug 
accountability records, subject charts and study source documents, and other records relative to 
the study conduct. 
12.4. 
Record Retention 
The Investigator will coordinate with the study site to ensure all documentations relating to the 
study for a period of 2 years after marketing application approval or, if not approved, 2 years 
after the notification to the FDA of the discontinuance of the investigational product for 
investigation. If it becomes necessary for the Sponsor or the Regulatory Authority to review any 
documentation relating to the study, the Investigator must permit access to such records. 
The records should be retained by the Investigator according to ICH, local regulations, or as 
specified in the Clinical Trial Agreement, whichever is longer; but at a minimum, all study 
documentation must be retained for 2 years after the last marketing application approval in an 
ICH region or after at least 2 years have elapsed since formal discontinuation of clinical 
development of TPX-0046. 
13. 
ETHICS 
13.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB/IEC, as appropriate. The Investigator must submit written 
approval to the Sponsor before he or she can present informed consent and begin screening 
activities for any subject in the study. 
The Investigator is responsible for informing the IRB/IEC of any amendment(s) to the protocol 
in accordance with local requirements. In addition, the IRB/IEC must approve all advertising 
used to recruit subjects for the study, if applicable. The protocol must be re approved by the 
IRB/IEC upon receipt of amendments and annually, as local regulations require. 
The Investigator is also responsible for providing the IRB/IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the investigational product. 
The Sponsor will provide this information to the Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB/IEC according to local regulations and guidelines. 
13.2. 
Protocol Compliance 
The Investigator will conduct the trial in compliance with the protocol provided by the Sponsor. 
Modifications to the protocol may not be made without agreement of both the Investigator and 
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the Sponsor. Changes to the protocol will require a written IRB/IEC approval/favorable opinion 
before implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to subjects. The IRB/IEC may provide, if applicable, regulatory authority(ies) permit, 
and expedited review and approval/favorable opinion for minor change(s) in ongoing trials that 
have the approval/favorable opinion of the IRB/IEC. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor/Designee and/or the Study Monitor, if 
circumstances permit, to discuss the planned course of action. Any departures from the protocol 
must be fully documented on the appropriate CRF and in the source documentation and reported 
to the IRB/IEC per institutional and/or local requirements. 
13.3. 
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 Sponsors’ (or its designee’s) applicable policies and standard operating procedures 
(SOPs). 
13.4. 
Written Informed Consent 
The Investigator at the study center will ensure that the subject is given full and adequate oral 
and written information about the nature, purpose, possible risk(s), and benefit(s) of the study. 
Subjects must also be notified that they are free to withdraw from the study at any time. The 
subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The subject’s signed and dated ICF must be obtained before conducting any study procedures. 
The Investigator must maintain the original signed ICF. A copy of the signed ICF must be given 
to the subject. 
13.5. 
Subject Confidentiality 
To maintain subject privacy, data capture tools, investigational product accountability records, 
study reports, and communications will identify the subject only by initials and the assigned 
subject number. The Investigator will grant monitor(s) and auditor(s) from the Sponsor or its 
designee and regulatory authority(ies) access to the subject’s original medical records, including 
medical history, laboratory studies, and medication administrations, for verification of data 
gathered and to audit the data collection process. This information will be accessed for the 
duration of the research study for data reconciliation purposes. The subject’s confidentiality will 
be maintained and will not be made publicly available to the extent permitted by the applicable 
laws and regulations. 
13.6. 
Post-Trial Access 
A subject will not be eligible to receive study drug after the end of the study since the Sponsor 
has decided to discontinue development of TPX-0046. 
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14. 
PUBLICATION OF STUDY RESULTS 
All information regarding the investigational product supplied by the Sponsor to the Investigator 
is privileged and confidential information. The Investigator agrees to use this information to 
accomplish the study and will not use it for any other purposes without written consent from the 
Sponsor. It is understood that there is an obligation to provide the Sponsor with complete data 
obtained during the study. The information obtained from the clinical study will be used toward 
the development of the Sponsors' investigational product program and may be disclosed to 
regulatory authority(ies), other Investigators, corporate partners, shareholders, or consultants as 
required. 
Additionally, the Investigator should obtain authorization from the clinical trial subjects in 
writing and ensure that all 18 identifiers (outlined in the Health Insurance Portability and 
Accountability Act ([HIPAA]) Privacy Rule (November 26, 2012) have been removed from the 
data. 
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer-reviewed scientific or medical journal. Investigator publication rights will be 
provided in the clinical trial agreement. Additionally, the Investigator should obtain 
authorization from the clinical trial subjects in writing and ensure that all 18 identifiers (outlined 
in the HIPAA Privacy Rule [November 26, 2012]) have been removed from the data. 
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15. 
REFERENCES 
Bronte G, Ulivi P, Verlicchi A, et al. Targeting RET-rearranged non-small-cell lung cancer: 
future prospects. Lung Cancer (Auckl). 2019;10:27-36. 
 
 
Chute CG, Greenberg ER, Baron J, et al. Presenting conditions of 1539 population-based lung 
cancer patients by cell type and stage in New Hampshire and Vermont. Cancer. 
1985;56(8):2107-2111. 
 
 
 
 
Das TK and Cagan RL. KIF5B-RET Oncoprotein Signals through a Multikinase Signaling Hub. 
Cell Rep. 2017;20(10):2368-2383 
Drilon AE, Liu S, Doebele R, et al. A phase 1 b study of RXDX-1 05, a VEGFR-sparing potent 
RET inhibitor, in RETi-naive patients with RET fusion-positive NSCLC. Ann Oncol. 
2017;28(Suppl. 5). 
Drilon A, Hu ZI, Lai GGY. Targeting RET-driven cancers: lessons from evolving preclinical and 
clinical landscapes. Nat Rev Clin Oncol. 2018a;15(3):151-167. 
Drilon AE, Subbiah V, Oxnard GR, et al. A phase 1 study of LOX0-292, a potent and highly 
selective RET inhibitor, in patients with RET-altered cancers. J Clin Oncol. 
2018b;36(15_suppl):102. 
Hyde L, Hyde CI. Clinical manifestations of lung cancer. Chest.1974;65(3):299-306. 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use. ICH Tripartite Guideline. Nonclinical evaluation for anticancer pharmaceuticals 
(S9). October 2009. 
Kohno T, Ichikawa H, Totoki Y, et al. KIFSB-RET fusions in lung adenocarcinoma. Nat Med. 
2012;18(3):375–7. 
Liu Z, Falola J, Zhu X, et al. Antiproliferative Effects of Src Inhibition on Medullary Thyroid 
Cancer. J Clin Endocrinol Metab. 2004;89(7):3503–3509. 
Liu X, Shen T, Mooers BHM, et al. Drug resistance profiles of mutations in the RET kinase 
domain. British Journal of Pharmacology. 2018(17);175:3504–3515. 
Moura MM, Cavaco BM, Pinto AE, et al. Correlation of RET somatic mutations with 
clinicopathological features in sporadic medullary thyroid carcinomas. Br J Cancer. 
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Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer. 
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Mulligan LM. 65 Years of The Double Helix: Exploiting insights on the RET receptor for 
personalized cancer medicine. Endocr Relat Cancer. 2018;25(8):T189-T200. 
O’Rourke RK, Daly RJ. The pseudokinases SgK269 and SgK223: A novel oncogenic alliance in 
human cancer. Cell Adh Migr 2018;12(6):524 – 528, doi: 10.1080/19336918.2017.1394570. 
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Retevmo™ (selpercatinib) [package insert]. Indianapolis, IN: Eli Lilly and Company;  2020. 
Siegel RL, Miller KD, Jemal AJ. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. 
Silvestri GA, Littenberg B, Colice GL. The clinical evaluation for detection of metastatic lung 
cancer. A meta-analysis. Am J Respir Crit Care Med. 1995;152(1):225-230. 
Solomon BJ, Tan L, Lin JJ, et al. RET Solvent Front Mutations Mediate Acquired Resistance to 
Selective RET Inhibition in RET-Driven Malignancies. J Thorac Oncol. 2020;15(4):541-549. 
doi:10.1016/j.jtho.2020.01.006. 
Subbiah V, Gainor JF, Rahal R, et al. Precision Targeted Therapy with BLU-667 for RET- 
Driven Cancers. Cancer Discov. 2018;8(7):836–849. 
Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA 
rearrangement. Cell. 1985;42(2):581-588. 
Takahashi M, Cooper GM. Ret Transforming Gene Encodes a Fusion Protein Homologous to 
Tyrosine Kinases. Mol Cell Biol. 1987;7(4):1378-1385. 
 
 
US Department of Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER). Guidance for Industry: Food Effect Bioavailability and Fed 
Bioequivalence Studies. December 2002. 
 
 
Yoh K, Seto T, Satouchi M, et al. Vandetanib in patients with previously treated RET- 
rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicenter phase 2 
trial. Lancet Respir Med. 2017;5(1):42–50. 
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Appendix A. 
Strong CYP3A4/5 Inhibitors or Inducers, SENSITIVE 
CYP3A SUBSTRATES, and Medications that Cause QTc 
Prolongation 
Strong CYP3A4/5 Inhibitors or Inducers of CYP3A4/5 
Strong CYP3A4/5 Inhibitors 
Strong CYP3A4/5 Inducers 
Macrolide antibiotics: clarithromycin and 
telithromycin 
Carbamazepine 
Efavirenz 
Anti-fungal: itraconazole, ketoconazole, 
voriconazole, posaconazole 
Phenobarbital 
Phenytoin 
Anti-virals: lopinavir, indinavir, nelfinavir, 
ritonavir, saquinavir, amprenavir 
Rifampin 
Rifabutin 
Conivaptan 
Rifapentin 
Mibefradil 
St John’s wort 
Nefazodone 
Troleandomycin 
Miscellaneous: Grapefruit juice 
Sensitive CYP3A Substrates 
alfentanil 
avanafil 
buspirone 
conivaptan 
darifenacin 
darunavir 
ebastine 
everolimus 
ibrutinib 
lomitapide 
lovastatin 
midazolam 
nisoldipine 
saquinavir 
simvastatin 
sirolimus 
tacrolimus 
tipranavir 
triazolam 
vardenafil 
budesonide 
dasatinib 
dronedarone 
eletriptan 
eplerenone 
felodipine 
indinavir 
lurasidone 
maraviroc 
quetiapine 
sildenafil 
ticagrelor 
tolvaptan 
naloxegol 
 
 
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Medications That Cause QTc Prolongation 
Amiodarone 
Astemizole 
Azithromycin 
Chlorpromazine 
Disopyramide 
Terfenadine 
Clarithromycin 
Haloperidol 
Dofetilide 
Chloroquine 
Erythromycin 
Mesoridazine 
Flecainide 
Halofantrine 
Moxifloxacin 
Pimozide 
Ibutilide 
Probucol 
Sparfloxacin 
Thioridazine 
Procainamide 
Pentamidine 
Domperidone 
Levomethadyl 
Quinidine 
Bepridil 
Droperidol 
Methadone 
Sotalol 
Arsenic trioxide 
Vavdetanib 
Citalopram 
Cisapride 
 
 
 
 
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Appendix B. 
Contraceptive Requirements 
In this study, women of childbearing potential (WOCBP) will receive TPX-0046, a compound 
for which the teratogenic risk is currently unknown. Effective methods of contraception 
(combination of any of these options; hormonal, barrier method, or intrauterine device), or 
abstinence, or be surgically sterile prior to study entry, for the duration of study participation, 
for participating WOCBP and for men should be used during the study treatment and 
 
 following the last dose of any study medication, and include 
the following:  
1. Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, injectable, implantable). The hormonal contraception method 
must be supplemented with a barrier method by the male partner (preferably male condom). 
2. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, implantable). The hormonal contraception method must be supplemented with a 
barrier method by the male partner (preferably male condom). 
3. Correctly placed copper-containing intrauterine device or intrauterine hormone-releasing 
system. 
4. Male sterilization with appropriately confirmed absence of sperm in the post-vasectomy 
ejaculate. 
5. Participating men can be fertile or vasectomized. Fertile men are advised to use effective 
methods of barrier contraception during the study and 
 after administration of 
the last dose of any study medication. The Investigator, at each study visit, will discuss with 
the subject the need to use highly effective contraception consistently and correctly and 
document such conversation in the subject chart. In addition, the Investigator will instruct the 
subject to call immediately if a selected birth control method is discontinued or if pregnancy 
is known or suspected. 
6. Female patients will be considered of childbearing potential unless they have undergone 
permanent contraception or are postmenopausal. Post menopause is defined as at least 
12 months without menses with no other medical reasons (eg, chemical menopause due to 
anticancer treatment).  
7. True abstinence: acceptable if evaluated as consistent with the preferred and the usual 
lifestyle of the subject. Periodic abstinence is not an acceptable method of contraception. 
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v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 5.0, 30 March 2020 
 
Confidential 
Page 139 of 141 
Approved
5.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 5.0, 30 March 2020 
 
Confidential 
Page 140 of 141 
Approved
5.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 5.0, 30 March 2020 
 
Confidential 
Page 141 of 141 
 
Approved
5.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 4.0, 08 January 2020 
Confidential 
Page 124 of 134 
 
 
 
 
 
 
 
 
 
 
 
 
Approved
4.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 4.0, 08 January 2020 
 
Confidential 
Page 125 of 134 
Approved
4.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 4.0, 08 January 2020 
 
Confidential 
Page 126 of 134 
Approved
4.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 4.0, 08 January 2020 
 
Confidential 
Page 127 of 134 
Approved
4.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 4.0, 08 January 2020 
 
Confidential 
Page 128 of 134 
Approved
4.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 4.0, 08 January 2020 
 
Confidential 
Page 129 of 134 
Approved
4.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 4.0, 08 January 2020 
 
Confidential 
Page 130 of 134 
Approved
4.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 4.0, 08 January 2020 
 
Confidential 
Page 131 of 134 
Approved
4.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 4.0, 08 January 2020 
 
Confidential 
Page 132 of 134 
Approved
4.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 4.0, 08 January 2020 
 
Confidential 
Page 133 of 134 
Approved
4.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 4.0, 08 January 2020 
 
Confidential 
Page 134 of 134 
 
Approved
4.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 3.0, 23 September 2019 
Confidential 
Page 127 of 135 
 
 
 
 
 
   
 
 
 
Approved
3.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 3.0, 23 September 2019 
 
Confidential 
Page 128 of 135 
Approved
3.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 3.0, 23 September 2019 
 
Confidential 
Page 129 of 135 
Approved
3.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 3.0, 23 September 2019 
 
Confidential 
Page 130 of 135 
Approved
3.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 3.0, 23 September 2019 
 
Confidential 
Page 131 of 135 
Approved
3.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 3.0, 23 September 2019 
 
Confidential 
Page 132 of 135 
Approved
3.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 3.0, 23 September 2019 
 
Confidential 
Page 133 of 135 
Approved
3.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 3.0, 23 September 2019 
 
Confidential 
Page 134 of 135 
Approved
3.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 3.0, 23 September 2019 
 
Confidential 
Page 135 of 135 
 
Approved
3.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 2.0, 20 September 2019 
Confidential 
Page 125 of 126 
 
 
 
 
 
   
 
 
 
Approved
2.0
v
Approved
1.0
v


Protocol TPX-0046-01 
Turning Point Therapeutics, Inc. 
Version 2.0, 20 September 2019 
 
Confidential 
Page 126 of 126 
 
Approved
2.0
v
Approved
1.0
v