Conditions: NSCLC, Stage IV NSCLC Stage IIIB NSCLC, Stage IIIC NSCLC, Recurrent EGFR Exon 20 Insertion Mutation HER2-activating Mutation ERBB Fusion NRG1 Fusion
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 41
Healthy volunteers: no

Brief summary:
Open-label, Phase 2, single treatment arm, 3 cohorts

Detailed description:

Arms:
arm 1: tarloxotinib bromide

Interventions: intervention 1: tarloxotinib bromide
Intervention descriptions: intervention 1: weekly intravenous infusion

Protocol document:
Prot_000.pdf: 
This study will be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP), with the Declaration of Helsinki and with other applicable regulatory 
requirements 
This document contains confidential information of Rain Therapeutics Inc. 
Do not copy or distribute without written permission from the Sponsor. 
CONFIDENTIAL 
 
 
STUDY RAIN-701 
 
A Phase 2 Study of Tarloxotinib in Patients with Select Gene Alterations and Non-Small 
Cell Lung Cancer or Other Advanced Solid Tumors 
 
Sponsor: 
Rain Therapeutics Inc. 
8000 Jarvis Avenue 
Suite 204 
Newark, CA 94560 
USA 
 
Sponsor Protocol No.: 
RAIN-701 
U.S. IND No.: 
112290 
Study Drug Name: 
Tarloxotinib bromide  
Phase: 
2 
 
 
 
 
Date of Protocol: 
 
 
14 December 2018 
06 March 2019 (Amendment 1) 
17 June 2019 (Amendment 2) 
11 November 2019 (Amendment 2.1) 
24 October 2020 (Amendment 3) 
 
 


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DOCUMENT HISTORY 
Version 
Replaces 
Description of Changes 
Amendment 3 
24 October 2020 
Amendment 2.1 
11 November 2019 
The protocol was amended to: 
• 
Revise the protocol title to reflect the additions of Cohorts B1 and D 
• 
Revise the protocol synopsis to align with changes made in the following sections of the protocol 
• 
Revise the Schedule of Events to add smoking history, clarify the QTcF criteria for ECGs, and add the 
allowable window for radiographic tumor assessments (every 8 weeks [± 5 days]) 
• 
Section 2:   
o 
Revise section headings for clarity 
o 
Section 2.3.1:  Add data on tarloxotinib-E potency in Ba/F3 cells with EGFR and HER2 mutations 
o 
Section 2.4.1:  Add further rationale for the patient population chosen for the study, based on 
preclinical data 
• 
Section 3: Revise text to reflect the addition of Cohorts B1 and D 
• 
Section 4:   
o 
Add Cohorts B1 and D 
o 
Increase the number of total patients enrolled from 91 patients to 248 patients to yield 215 evaluable 
patients (43 patients per cohort), as shown in Table 3  
o 
Update table of eligible mutations and gene fusions (Table 4) 
o 
Clarify the allowable window for radiographic tumor assessments (Every 8 weeks [± 5 days]) 
• 
Section 5:  Revise to add Cohorts B1 and D, and clarify the eligible mutations/gene fusions 
• 
Section 5.1:   
o 
Revise inclusion criteria #3 to #5 to add Cohorts B1 and D 
o 
Revise inclusion criterion #9 to require a calculated creatinine clearance ≥ 30 mL/min using Cockcroft-
Gault equation 


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o 
Revise inclusion criterion #10 to remove requirement for 3 ECG measurements 
o 
Revise inclusion criterion #14 and add inclusion criterion #15 to clarify contraception requirements. 
• 
Section 5.2:   
o 
Revise exclusion criterion #1 to add the following note for clarification: 
If another mutation is present but is deemed to be a tumor suppressor mutation or a variant of 
unknown significance then the patient may be enrolled with Sponsor approval of the mutation report. 
o 
Revise exclusion criterion #2 to reflect the addition of Cohorts B1 and D 
o 
Revise exclusion criterion #4 to change the allowable period of time since another investigational 
therapy from 28 days to 21 days and add the following note for clarification: 
Exceptions may be made with Medical Monitor approval for investigational therapies where the half-
life is unknown or shorter than 5 half-lives have passed between last dose of investigational therapy 
and Cycle 1 Day 1. 
o 
Revise exclusion criterion #5 for interstitial lung disease or interstitial pneumonitis to allow patient 
enrollment if there is documented resolution 
o 
Revise exclusion criterion #7 to add exceptions for certain patients with central nervous system 
malignancies and stipulate that patients must complete stereotactic radiosurgery 7 days prior to Cycle 1 
Day 1 and whole brain radiotherapy 21 days prior to Cycle 1 Day 1. 
o 
Revise exclusion criterion #8 to add the following clarification note for medications associated with QT 
prolongation: 
Exceptions may be made with Medical Monitor approval (e.g., for medications where the half-life is 
unknown or for QT prolonging medications not listed in Appendix B). 
• 
Section 5.3:   
o 
Specify that > 2 dose reductions is a reason for discontinuation from study treatment 
o 
Specify that missing 2 doses is a reason for discontinuation from study treatment unless there is 
agreement with the Medical Monitor 
o 
Add guidance for recording patient withdrawals due to COVID-19 


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• 
Section 6.2.3:  Clarify text for handling dose delays and missed doses of tarloxotinib.  Added instructions 
for what to do in the event of dose delays due to COVID-19. 
• 
Section 6.4:  Revised guidance for potassium supplementation and specified that tarloxotinib will not be 
administered if the serum potassium level is < 3.5 mEq/L. 
• 
Section 6.5:  Revise treatment and retreatment criteria according to: 
o 
QTcF levels (e.g., ≥ 601 msec and ≥ 501 msec and < 601 msec) observed during previous infusion 
o 
Serum electrolytes 
• 
Section 6.6:  Add the text, Patients may receive palliative radiation to disease sites of progression, 
including brain metastases, following discussion with and approval by the Medical Monitor (or designee). 
• 
Sections 6.7 and 6.7.1:  Revise the thresholds for QTcF prolongation to better align with NCI CTCAE 
criteria 
• 
Section 6.9.1:  Revise to align with the Schedule of Events 
• 
Section 6.9.2.1:  Added this subsection to specify the ECG guidance  
• 
Section 7:  Revised to reflect the allowable window for radiographic tumor assessments (Every 8 weeks 
[± 5 days]) 
• 
Section 8.1.1.5:  Removed mandatory reporting of SAEs of QTc prolongation to Health Canada.  
• 
Section 8.5:  Revise text to align with the NCI CTCAE grading for QTc prolongation and clarify that only 
Grade 3 events of QTc prolongation require expedited reporting. 
• 
Section 8.7:  Remove the requirement for 3 ECG tracings and clarify the requirements for ECGs in 
patients with QT prolongation during a previous infusion 
• 
Section 8.10:  Text revised to specify that male patients must use a condom and refrain from sperm 
donation during the study and for at least 30 days after the last dose of study treatment 
• 
Section 8.13:  Revise the window for PK blood samples from 5 minutes to 5 or 10 minutes 
• 
Section 9.1:  Modify text to reflect that all cohorts will use a Simon’s 2-stage minimax design 
• 
Section 9.2.3:  Revise text to specify which patients are considered evaluable for response: 
o 
All enrolled patients who receive study treatment, have a baseline tumor assessment with 
documentation of measurable disease, have at least 1 on-study tumor assessment, whether or not this 
occurs at the specified imaging interval, and have no major protocol violations including 


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inclusion/exclusion criteria or prohibited concomitant medication while on study, will be considered 
evaluable for response.  Patients who are treated and removed from study prior to on-study tumor 
assessments for reasons other than clinical progression will be considered unevaluable for response 
and may be replaced.  In addition, if a patient is enrolled without central laboratory confirmation of 
the specific gene alteration, and then is subsequently found not to have the specific gene alteration by 
central review, this patient will not be included in the efficacy evaluable (evaluable for response) 
population. 
• 
Section 9.6.1.2:  Revise statistical methods to clarify how analyses will be conducted with respect to 
efficacy evaluable patients. 
• 
Section 9.7.1:  Revise QTc interval thresholds to align with the NCI CTCAE grading for QTc 
prolongation 
• 
Section 11.3:  Extend the expected study duration from 24 months to 36 months to allow for 24 months of 
accrual 
• 
Section 12:  Revise wording to allow for remote monitoring 
• 
Section 14:  Updated reference list to reflect citations added. 
• 
Appendix B:  Update the list of medications with a known risk for TdP 
• 
Include additional minor changes for clarity and consistency 


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Amendment 2.1 
11 November 2019 
Amendment 2 
17 June 2019 
The protocol was amended to: 
• 
Section 4:  Modify total number of patients to 83 (20 patients in Cohorts A and B and 43 patients in 
Cohort C) and add that Cohort C will use a Simon 2-stage design 
• 
Section 4.2.1 Increase confirmation of primary endpoint from 4 weeks to 8 weeks after initial 
documentation 
• 
Section 5.1:  Add details of prior therapy for Cohort C  
• 
Section 5.2:  Add exclusion criteria for upper limit of ALT, AST, and bilirubin values 
• 
Section 6.7:  Clarify treatment guidelines for QTc prolongation  
• 
Section 8.5:  Clarify reporting procedures for QTc prolongation 
• 
Section 9.1:  Add determination of Cohort C sample size 
• 
Include additional minor changes for clarity and consistency 
Amendment 2 
17 June 2019 
Amendment 1 
01 March 2019 
The protocol was amended to: 
• 
Revise the protocol title to reflect the addition of Cohort C  
• 
Add new Section 2.2.2:  Add study population background and rationale for the inclusion of patients with 
solid tumors and NRG1/HER-family gene fusions (Cohort C)  
• 
Section 4 (and throughout):  Include a 3rd cohort (Cohort C) of patients with advanced solid tumors that 
harbor NRG1 or HER-family gene fusions 
• 
Section 4:  Modify total number of patients to 60 (20 patients each in Cohorts A, B, and C) and add that 
Cohort C will use a Simon’s 2-stage design 
• 
Section 5:  Expand Table 3 to include NRG1 and HER-family gene fusions 
• 
Section 5.1:  Add details of prior therapy for Cohort C  
• 
Section 6.4:  Revise potassium supplementation guidelines. 
• 
Section 6.7:  Provide further description of the QTc prolongation observed in prior tarloxotinib studies 
and clarify treatment guidelines for QTc prolongation  
• 
Section 6.9.2:  Clarify that a window of ± 10 minutes is acceptable for all timed assessments relative to 
infusions 


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• 
Section 6.9.2:  Clarify that the optional tumor biopsy may be performed after any study treatment infusion 
in consenting patients 
• 
Created new Section 8.1.1.5:  Move the information on SUSAR reporting timeframe out of Section 8.3 
(SAEs) 
• 
Section 8.5:  Clarify reporting procedures for QTc prolongation 
• 
Section 9.1:  Add determination of Cohort C sample size 
• 
Additional minor changes were made for clarity and consistency. 
Amendment 1 
06 March 2019 
Original Protocol 
14 December 2018 
 
Following review and comments by Health Canada, the following edits were made to the protocol and a revised 
document submitted to Health Canada:  
• 
Section 2.9:  To add text regarding symptoms associated with QT prolongation and language regarding 
limiting sun exposure due to potential phototoxicity 
• 
Section 4.1, Section 4.4, Section 5.3:  To add text specifying that hepatotoxicity meeting Hy’s Law 
criteria is defined as unacceptable toxicity  
• 
Section 5.2:  To clarify Exclusion Criteria #7 to exclude all medications that prolong QT interval, with a 
risk of causing Torsade de Pointes (TdP) regardless of stable dose 
• 
Section 6.7.3, Table 8:  To add the following, tarloxotinib will be permanently discontinued for 
tarloxotinib-related toxicity meeting the definition of Hy’s Law 
• 
Section 6.10.1:  To add text stating that all medications that prolong QT interval, with a risk of causing 
Torsade de Pointes (TdP) regardless of stable dose at study entry are prohibited 
• 
Section 8.1, Section 8.2.3:  To state that all adverse events will be followed until stabilization or 
resolution  
• 
Section 8.3:  To state that Rain Therapeutics will report all serious unexpected adverse drug reactions to 
regulatory agencies per local requirements and that all serious QT prolongations will be reported to Health 
Canada  
• 
Section 12.4:  To add a statement that Rain Therapeutics will maintain copies of study records for a period 
of no less than 25 years  
• 
Schedule of Events (Appendix A):  Correction of typographical error regarding Footnote 2 and 
Footnote 3.  In addition, the protocol was amended to:  
o 
Allow baseline labs to be obtained within 7 days rather than 3 days before Cycle 1 Day 1 


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o 
Remove the requirement of triplicate ECGs being obtained and transmitted to a central reader; triplicate 
ECGs will be replaced by a single locally read ECG 
o 
Remove ECOG assessments after eligibility determination  
• 
Additional minor edits may have been made for clarity and consistency. 


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STATEMENT OF THE SPONSOR 
 
Protocol Title:   A Phase 2 Study of Tarloxotinib in Patients with Select Gene 
Alterations and Non-Small Cell Lung Cancer or Other Advanced Solid 
Tumors 
 
 
 
This study was designed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and is consistent with Good Clinical Practice (GCP) and applicable 
regulatory requirements.  Foreseeable risks and inconveniences have been weighed against the 
anticipated benefit for the individual trial patient and society.  Review of the available 
nonclinical and clinical information support this study and the anticipated benefits justify the 
risks.   
The rights, safety, and well-being of the trial patients are the most important consideration.  
While foreseeable risks have been identified, strategies are included to help mitigate both 
anticipated and unanticipated risks.   
This clinical trial is scientifically sound, and the study design is clearly described in this 
document.  
 
 
Lucio Tozzi 
VP, Head of Clinical Operations 
Rain Therapeutics Inc.  
 
 
 
 
 
 
Date 
Robert C Doebele, MD, PhD 
Acting Chief Medical Officer 
Rain Therapeutics Inc.  
 
Date 


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SYNOPSIS 
Study Number  
RAIN-701 
Sponsor  
Rain Therapeutics Inc. 
Phase  
2 
Objectives 
Primary Objective 
• 
The primary objective of this study is to evaluate the objective response rate 
(ORR) of tarloxotinib according to Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1. 
Secondary Objectives 
• 
To evaluate further measures of antitumor activity of tarloxotinib including best 
overall response (BOR), duration of response (DOR), disease control rate 
(DCR), progression-free survival (PFS), and overall survival (OS)  
• 
To investigate the pharmacokinetics (PK) of tarloxotinib and tarloxotinib-E 
using population PK (PopPK) methods and explore correlations between PK, 
exposure, response, and/or safety findings 
• 
To evaluate the safety and tolerability of tarloxotinib in this population 
including to determine whether there is an association between plasma exposure 
to tarloxotinib and effects on cardiac repolarization 
Exploratory Objectives 
• 
To evaluate the concordance of epidermal growth factor receptor (EGFR) 
mutation, ERBB2 (HER2) mutation, and NRG1, EGFR, ERBB2 (HER2), and 
ERBB4 (HER4) fusion detection between tissue and plasma using circulating 
tumor deoxyribonucleic acid (ctDNA) 
• 
To evaluate exploratory biomarkers of hypoxia in tumor tissue including 
6 transmembrane epithelial antigen of the prostate, family member 4 (STEAP4) 
expression and ERBB family and cancer cell signaling pharmacodynamic 
markers 
• 
To evaluate the pharmacokinetics of tarloxotinib and tarloxotinib-E in tumor 
tissue 
Study Design  
This is a Phase 2 multicenter, open-label study to evaluate the antitumor effect of 
tarloxotinib in patients with: 
• 
Previously treated advanced/metastatic non-small cell lung cancer (NSCLC) 
who have a tumor harboring one of the following:   
o 
An EGFR exon 20 insertion (Cohort A) 
o 
A HER2-activating mutation (including HER2 exon 20 insertions) who have 
not received prior HER2-directed therapy (Cohort B)  
o 
A HER2-activating mutation (including HER2 exon 20 insertions) who have 
received prior HER2 antibodies or antibody-drug conjugates (Cohort B1)   
• 
Previously treated advanced solid tumors harboring: 
o 
NRG1 or ERBB/HER-family gene fusions (Cohort C) 
o 
HER2-activating mutations (including HER2 exon 20 insertions), excluding 
NSCLC (Cohort D)   
Cohorts B1 and/or D may not be pursued, at the discretion of the Sponsor. All cohorts 
will use a Simon’s 2-stage minimax design.  In the first stage, 21 patients will be 
accrued.  If more than 3 patients in a cohort have a partial or complete response, up to 


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22 additional patients may be enrolled to the cohort, for up to a total of 43 patients per 
cohort.  However, if there are 3 or fewer responses among these patients the cohort 
will be stopped based on futility.  Patients who are not evaluable for tumor response 
assessment may be replaced.   
 
Number of Patients by Cohort  
Cohort 
Description 
N 
A: 
• 
Patients with advanced NSCLC harboring an EGFR 
exon 20 insertion mutation 
• 
Patients who have received at least 1 platinum-based 
chemotherapy-containing regimen 
43 
B: 
 
• 
Patients with advanced NSCLC harboring a HER2-
activating mutation 
• 
Patients who have received at least 1 platinum-based 
chemotherapy-containing regimen 
• 
Patients who have not received prior HER2-directed 
therapy 
43  
B1*: 
• 
Patients with advanced NSCLC harboring a HER2-
activating mutation 
• 
Patients who have received at least 1 platinum-based 
chemotherapy-containing regimen 
• 
Patients who have received prior HER2 antibodies or 
antibody-drug conjugates 
43 
C: 
• 
Patients with advanced solid tumors who have failed 
all standard therapies appropriate for their tumor type 
and stage of disease, or, in the opinion of the 
Investigator, would be unlikely to tolerate or derive 
clinically meaningful benefit from appropriate 
standard-of-care therapy 
• 
Patients with tumors harboring an NRG1 gene fusion, 
EGFR gene fusion, EGFR kinase domain duplication, 
ERBB2 gene fusion, or ERBB4 gene fusion 
43 
D*: 
• 
Patients with advanced solid tumors who have failed 
all standard therapies appropriate for their tumor type 
and stage of disease, or, in the opinion of the 
Investigator, would be unlikely to tolerate or derive 
clinically meaningful benefit from appropriate 
standard-of-care therapy 
• 
Patients with tumors (excluding NSCLC) harboring a 
HER2-activating mutation 
43 
 
Total 
215 
 
*Cohorts B1 and/or D may not be pursued, at the discretion of the Sponsor. 


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Treatment  
Tarloxotinib 150 mg/m2 will be administered as a 1-hour intravenous (IV) infusion 
weekly until progressive disease or unacceptable toxicity.  
Study Schema (Not to Scale) 
                                                                      
  
Treatment Period 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
   
Screening  
  
Cycles 1 to 3 
  
Additional Cycles  
  EOT   
Safety 
FUP 
  
   
 
 
 
 
  
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  Tarloxotinib Infusion1 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
  
 
 
 
 
  
  Tumor Assessment2 
<-----------------------X2----------------------------> 
  
 
 
 
 
  
  
  
  
1 Days 1, 8, 15, and 22 of every 28-day cycle  
  
  
2 Every 8 weeks( ± 5 days) from Cycle 1 Day 1 
  
                                                                      
EOT = End-of-Treatment Visit; FUP = Follow-up Visit 
Eligibility  
Inclusion Criteria 
1. ≥ 18 years old 
2. Signed and dated written informed consent  
3. Histologically and/or cytologically confirmed primary diagnosis of cancer  
a. Cohorts A, B and B1:  NSCLC, (Stage IV, Stage IIIB, or IIIC) not 
amenable to definitive curative-intent therapy, or recurrent disease after 
prior diagnosis of Stage I-III disease  
Note:  NSCLC staging is according to American Joint Committee on 
Cancer, 8th edition, lung cancer staging criteria. 
b. Cohort C and D:  Locally advanced or metastatic solid tumor  
4. Progression of disease on or after a platinum-based chemotherapy regimen 
(Cohorts A, B, and B1) or after standard of care (Cohorts C and D) 
a. Cohorts C and D: Must have received all standard therapy appropriate for 
their tumor type and stage of disease, or, in the opinion of the Investigator, 
would be unlikely to tolerate or derive clinically meaningful benefit from 
appropriate standard-of-care therapy 
Note: If it is determined by the Investigator that a patient would be unlikely 
to tolerate or derive clinically meaningful benefit from standard-of-care 
therapy, the specific reason(s) for such a determination will be documented 
in the electronic case report form. 
5. CLIA diagnosis of cancer mutation or fusion  
a. Cohort A:  EGFR exon 20 insertion mutation  
b. Cohort B, B1, and D:  HER2-activating mutation  
c. Cohort C:  NRG1 or ERBB family gene fusions  
6. Must have at least 1 target lesion evaluable by RECIST v1.1 
7. Eastern Cooperative Oncology Group performance status of 0 or 1 
8. Minimum life expectancy of 3 months or more 
9. Clinical laboratory values meeting the following criteria within the 7 days prior to 
Cycle 1 Day 1: 
a. Calculated creatinine clearance ≥ 30 mL/min using Cockcroft-Gault 
equation 
b. Total bilirubin  
• ≤ 1.5 x upper limit of normal (ULN) or  
• ≤ 3 x ULN in the presence of liver metastases 
c. Aspartate aminotransferase and alanine aminotransferase 
• ≤ 2.5 x ULN,  
•  ≤ 5 x ULN, in the presence of liver metastases 


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d. Absolute neutrophil count ≥ 1,500 cells/μL 
e. Hemoglobin ≥ 9 g/dL or 5.6 mmol/L 
f. Platelet count ≥ 100,000/μL 
10. Adequate cardiac function meeting all of the following electrocardiogram (ECG) 
criteria:  
a. No evidence of second- or third-degree atrioventricular block  
b. No clinically significant arrhythmia (i.e., pauses > 4 seconds, ventricular 
tachycardia of any duration, supraventricular tachycardia of > 4 
beats/minute)  
c. QRS interval ≤ 110 msec  
d. QTc interval of < 450 msec as calculated according to Fridericia’s formula 
(QTcF = QT/[R to R interval]0.33)  
e. PR interval ≤ 200 msec (does not apply to people with chronic stable atrial 
fibrillation or atrial flutter as determined by the Investigator)  
11. Adequate pretreatment tumor sample (125 µm of formalin-fixed paraffin 
embedded block or at least 8 to 10 prepared slides) 
Note:  Tumor tissue should be from the most recent pretreatment biopsy; if 
only archival tissue from the initial biopsy is available, it is acceptable.  
12. All toxicities from prior therapy (except alopecia and neuropathy) must have 
resolved to baseline or to ≤ Grade 2 according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 prior to 
Cycle 1 Day 1 
13. For women of childbearing potential (WOCBP), documentation of negative serum 
pregnancy test (β-human chorionic gonadotropin) within 7 days prior to Cycle 1 
Day 1   
Note:  WOCBP is defined as fertile, following menarche and until 
becoming post-menopausal (no menses for 12 months without an 
alternative medical cause) unless permanently sterile (had a hysterectomy, 
bilateral salpingectomy, or bilateral oophorectomy). 
14. For WOCBP, agreement to use a highly effective method of contraception during 
the study and for at least 90 days after the last dose of study treatment   
Note:  Highly effective birth control includes a) intrauterine device; b) oral, 
implantable or injectable combined hormonal (estrogen and progestogen 
containing) or progestogen-only contraceptive associated with inhibition of 
ovulation; c) intrauterine hormone-releasing system; or d) bilateral tubal 
occlusion, vasectomized partner, sexual abstinence. 
15. For male patients, agreement to use a condom and a highly effective method of 
contraception during the study and for at least 30 days after the last dose of study 
treatment.  Male patients should also refrain from sperm donation during this time 
period. 
16. Willingness and ability to comply with scheduled visits and study procedures 
Exclusion Criteria 
1. Has another known activating oncogene-driver mutation, including, but not 
limited to KRAS, ALK, ROS1, RET, BRAF, NTRK1/2/3, MET, MEK1, NRAS, 
and HRAS.   
Note:  If another mutation is present but is deemed to be a tumor suppressor 
mutation or a variant of unknown significance then the patient may be 
enrolled with Sponsor approval of the mutation report. 
2. Cohorts A, B, B1, and D only:  Previously received anti-EGFR or anti-HER2 
tyrosine kinase inhibitors including but not limited to erlotinib, gefitinib, afatinib, 
dacomitinib, osimertinib, poziotinib, TAK788, nazartinib, lapatinib, or neratinib   
3. Cohorts A and B only:  Previously received anti-EGFR or anti-HER2 monoclonal 
antibodies or EGFR or HER2 antibody-drug conjugates including, but not limited 


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to, cetuximab, necitumumab, panitumumab, trastuzumab, trastuzumab emtansine 
(TDM-1), or pertuzumab 
4. Received other recent antitumor therapy including: 
a. Investigational therapy administered within the 21 days prior to Cycle 1 
Day 1 or 5 half-lives, whichever is shorter.  
Note:  Exceptions may be made with Medical Monitor approval for 
investigational therapies where the half-life is unknown or shorter than 5 
half-lives have passed between last dose of investigational therapy and 
Cycle 1 Day 1. 
b. Any standard chemotherapy or radiation within 14 days prior to Cycle 1 
Day 1   
Note:  Adequate time must have passed from the last treatment to first 
scheduled treatment in this study to clear the timeframe for actual or 
anticipated toxicities of such treatment 
c. Any immunotherapy (e.g., pembrolizumab, nivolumab, atezolizumab, or 
durvalumab) within 21 days prior to Cycle 1 Day 1 
5. Clinically active or symptomatic interstitial lung disease (ILD) or interstitial 
pneumonitis.   
Note:  A patient with a history of clinically significant ILD or radiation 
pneumonitis with documented resolution will be eligible for enrollment. 
6. Has any of the following within 28 days prior to the first dose of study drug: 
• Alanine aminotransferase and aspartate aminotransferase > 3 × ULN if 
no hepatic metastases are present; > 5 × ULN if hepatic metastases are 
present 
• Total bilirubin > 1.5 × ULN; > 3 × ULN with direct bilirubin 
> 1.5 × ULN in the presence of Gilbert’s syndrome 
7. Untreated central nervous system (CNS) metastases and/or untreated/treated 
leptomeningeal disease. 
Note:  Patients who require steroids for CNS metastases must be on a stable 
or tapering dose of corticosteroids for at least 2 weeks prior to Cycle 1 
Day 1 to be eligible for the trial. If applicable, patients must complete 
stereotactic radiosurgery 7 days prior to Cycle 1 Day 1 and whole brain 
radiotherapy 21 days prior to Cycle 1 Day 1. 
8. Receiving medication that prolongs QT interval, with a risk of causing Torsade de 
Pointes (TdP), per protocol Appendix B, unless one of the following criteria are 
met: 
a. Enrollment is allowed if discontinuation of such medication occurs at least 
5 half-lives before Cycle 1 Day 1 OR 
b. The patient is on a stable dose of a concomitant medication listed in 
Appendix B, prior to study entry and Sponsor approval is obtained 
Note:  Exceptions may be made with Medical Monitor approval (e.g., for 
medications where the half-life is unknown or for QT prolonging 
medications not listed in Appendix B). 
9. Personal or familial history of Long QT Syndrome, sudden death, or TdP  
10. History of significant cardiovascular disease, including: 
a. Cardiac failure New York Heart Association class III or IV or LVEF 
< 55% 
b. Myocardial infarction, severe or unstable angina within 6 months prior to 
enrollment 
c. TdP, ventricular arrhythmia (i.e., ventricular tachycardia or ventricular 
fibrillation) 
d. Clinically significant thrombotic or embolic events within 3 months prior 
to enrollment  


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Note:  Significant thrombotic or embolic events include but are not limited 
to stroke or transient ischemic attack.  Catheter-related thrombosis is not a 
cause for exclusion.  Diagnosis of deep vein thrombosis or pulmonary 
embolism is allowed. 
e. Any uncontrolled or severe cardiovascular disease 
11. Known concurrent malignancy that is expected to require active treatment within 
2 years or may interfere with the interpretation of the efficacy and safety 
outcomes of this study in the opinion of the treating Investigator and confirmed by 
the Medical Monitor   
Note:  Prior malignancy that is at a low risk of progression or recurrence 
(e.g., superficial bladder cancer, non-melanoma skin cancers, or low-grade 
prostate cancer not requiring therapy) may be allowed after discussion and 
approval by the Medical Monitor. 
12. Major surgery within 4 weeks prior to Cycle 1 Day 1  
13. Infection requiring systemic treatment within the 7 days prior to Cycle 1 Day 1   
14. History of severe allergic or anaphylactic reactions or hypersensitivity to 
compounds of similar chemical or biologic composition as tarloxotinib 
15. Known human HIV infection or active hepatitis B or C  
16. Women who are pregnant or breastfeeding 
17. Any other medical condition (e.g., alcohol abuse) or psychiatric condition that, in 
the opinion of the Investigator, might interfere with the patient’s participation in 
the trial or interfere with the interpretation of trial results   
Criteria for Efficacy 
Evaluation  
The primary efficacy endpoint is ORR, based on patients who had complete response 
or partial response or by RECIST v1.1 as determined by the Investigator. 
Secondary efficacy endpoints include:  BOR, DOR, DCR, PFS and OS, as measured 
from the date of first study drug dose to the date of death by any cause. 
Criteria for Safety 
Evaluation 
Safety endpoints include the incidence of treatment-emergent AEs; changes in clinical 
laboratory parameters (hematology, serum chemistry, urinalysis, and serum pregnancy 
test), vital signs, and ECG parameters; physical examination results; and use of 
concomitant medications. 
Statistical Methods  
Analysis Populations 
• 
The Safety Population will consist of all patients who received at least 1 dose of 
tarloxotinib.  The Safety Population will be the analysis population for the 
safety and primary efficacy analyses. 
Analysis  
• 
ORR and DCR will be summarized by cohort along the corresponding 2-sided 
95% confidence intervals (CIs).  
• 
Time-to-event endpoints (DOR, PFS, and OS) will be summarized using the 
Kaplan-Meier method and displayed graphically when appropriate.  Median 
event times and the corresponding 2-sided 95% CIs for each cohort will be 
provided.  Kaplan-Meier estimates and survival curves will also be presented for 
each treatment group.  
• 
Incidence of treatment-emergent AEs and use of concomitant medications will 
be summarized descriptively by cohort and total.  Results for clinical laboratory 
parameters, vital signs, ECGs, and physical examinations will be summarized 
by cohort and by study visits.  Descriptive summary statistics in observed values 
as well as changes from baseline will be presented.  In addition, thresholds of 
marked laboratory abnormalities based on NCI CTCAE v5.0 will be predefined 
for specific safety parameters. 
 
 


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Schedule of Events  
S 
C 
R 
Cycle 1 
(Day) 
Cycle 2  
(Day) 
Cycles 3+ 
(Day) 
O 
B 
X 
E 
O 
T 
F 
U 
P 
 
1 
8 
15 
22 
1 
8 
15 22 
1 
8 
15 
22 
 
 
 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Disease History/ 
Smoking History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination  
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X X 
ECOG  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X X 
Vital Signs  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X X 
Pre-infusion 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
EOI 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
30, 60, and 90 min after EOI† 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Electrocardiogram (12-lead)1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X X 
Pre-infusion 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 EOI 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
1 h after EOI† 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
2 h after EOI† 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
3 h after EOI† 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
4 h after EOI† 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
hourly thereafter as needed† 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Hematology Panel  
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X X 
Serum Chemistry Panel  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X X 
Serum Potassium  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOI 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
3 h after EOI† 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
Pregnancy Test 2 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
PK Samples  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-infusion‡ 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
EOI‡ 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
3 h after EOI‡ 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
7 h after EOI‡ 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
at optional tumor biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
4 
 
 
Biomarker Sample 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X
4 
X 
 
Potassium Supplementation5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Tarloxotinib Infusion 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Tumor Tissue 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional Tumor Biopsy 
 
 
 
X4 
 
 
 
 
 
 
 
 
 
X
4 
X
6 
 
Tumor Assessment7 
X 
 Every 8 weeks (± 5 days) from Cycle 1 Day 1→ 
 
 
 
Concomitant Medications 
X 
 Every Visit → 
X X 
 
Adverse Events Assessment 
 
 Every Visit → 
X X X 


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CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; EOT = End-of-
Treatment Visit; FUP = Follow-up Visit; MRI = magnetic resonance imaging; OBX = optional biopsy; PET = 
positron emissions tomography; PK = pharmacokinetic; QTcF = corrected QT interval as calculated according to 
Fridericia’s formula; SCR = Screening Period  
* Patients will be asked about their previous smoking history (including cigarettes, cigars, pipes, and vaping 
devices).  
† For patients with Grade 3 QTcF prolongation (≥ 501 msec or > 60 msec increase compared to pre-infusion), repeat 
ECG every 15 to 30 minutes until resolved to Grade 2 (481 to 500 msec) or lower (≤480 msec) and then obtain 
ECGs every hour.   
‡ Can be made ± 5 minutes (pre-infusion and EOT) and ± 10 minutes (3 hours and 7 hours) of scheduled event. 
1 = For patients with ≥ Grade 3 (≥ 501 msec) QTcF prolongation with current or prior infusion 
2 = Serum pregnancy at baseline, then urine dipstick, for women of childbearing potential 
3 = In a subset of patients 
4 = Collect blood (plasma samples for PK and biomarker including circulating tumor deoxyribonucleic acid) at time 
of biopsy 
5 = If applicable (see Section 6.4) 
6 = Collect blood (plasma sample for biomarker) at time of biopsy 
7 = Perform radiographic tumor assessments according to institutional practice; include CT or MRI of the chest and 
abdomen, brain scan, and bone scan at baseline.  The baseline radiographic tumor assessment is required within 
28 days prior to the first dose of tarloxotinib.  A recently completed negative PET scan can be substituted for the 
baseline bone scan.  The same imaging modality used for baseline imaging (i.e., CT or MRI) must be used for 
subsequent tumor assessments in each patient.   
Note:  Day 1 of Cycles 2+ is Day 29 of the prior cycle.  The EOT Visit should be conducted within ± 7 days of the 
last dose of tarloxotinib, and the safety FUP should occur 30 days (± 7 days) after the last dose of tarloxotinib.   
 
 


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TABLE OF CONTENTS 
Document History ......................................................................................................................... 2 
Statement of the Sponsor.............................................................................................................. 9 
Synopsis ........................................................................................................................................ 10 
Table of Contents ........................................................................................................................ 18 
List of Tables ............................................................................................................................... 21 
List of Figures .............................................................................................................................. 22 
List of Abbreviations .................................................................................................................. 23 
1. 
Introduction ...................................................................................................................... 25 
2. 
Background Information................................................................................................. 25 
2.1 
Investigational Product:  Tarloxotinib ............................................................................ 25 
2.2 
Study Diseases ................................................................................................................ 26 
2.2.1 
Non-Small Cell Lung Cancer.................................................................................. 26 
2.2.2 
Advanced Solid Tumors ......................................................................................... 30 
2.3 
Summary of Nonclinical Studies and Clinical Trials Using Tarloxotinib ..................... 34 
2.3.1 
Nonclinical Studies ................................................................................................. 34 
2.3.2 
Clinical Trials .......................................................................................................... 40 
2.4 
Rationale for Selection of the RAIN-701 Study Population .......................................... 42 
2.4.1 
NSCLC with EGFR Exon 20 Insertion Mutation or HER2-Activating Mutation .. 42 
2.5 
Rationale for Dose Selection and QT Prolongation Mitigation ..................................... 44 
2.6 
Potential Risks ................................................................................................................ 45 
3. 
Trial Objectives and Purpose ......................................................................................... 45 
3.1 
Primary Objective .......................................................................................................... 46 
3.2 
Secondary Objectives ..................................................................................................... 46 
3.3 
Exploratory Objectives ................................................................................................... 46 
4. 
Trial Design ...................................................................................................................... 46 
4.1 
Trial Design Overview ................................................................................................... 46 
4.2 
Endpoints and Criteria for Evaluation ............................................................................ 48 
4.2.1 
Primary Endpoint .................................................................................................... 48 
4.2.2 
Secondary Endpoints .............................................................................................. 48 
4.2.3 
Exploratory Endpoints ............................................................................................ 49 
4.3 
Measures Taken to Minimize/Avoid Bias ...................................................................... 49 


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4.4 
Duration of Study Treatment.......................................................................................... 49 
5. 
Selection and Withdrawal of Patients ............................................................................ 49 
5.1 
Inclusion Criteria ............................................................................................................ 51 
5.2 
Exclusion Criteria ........................................................................................................... 52 
5.3 
Patient Withdrawal Criteria ............................................................................................ 54 
6. 
Treatment of Patients ...................................................................................................... 56 
6.1 
Patient Enrollment .......................................................................................................... 56 
6.2 
Tarloxotinib Administration ........................................................................................... 57 
6.2.1 
Tarloxotinib Dose Calculation ................................................................................ 57 
6.2.2 
Tarloxotinib Infusion Duration ............................................................................... 57 
6.2.3 
Tarloxotinib Administration Schedule .................................................................... 57 
6.3 
Premedication ................................................................................................................. 58 
6.4 
Potassium Supplementation ........................................................................................... 59 
6.5 
Treatment and Retreatment Criteria ............................................................................... 59 
6.6 
Treatment Beyond Progression ...................................................................................... 60 
6.7 
Tarloxotinib Dose Modifications ................................................................................... 60 
6.7.1 
Treatment Guidelines for QTc Prolongation .......................................................... 61 
6.7.2 
Treatment Guidelines for Infusion-related Reactions ............................................. 63 
6.7.3 
Treatment Guidelines for Other Non-Hematologic Toxicity .................................. 64 
6.8 
Compliance ..................................................................................................................... 64 
6.9 
Study Visits .................................................................................................................... 65 
6.9.1 
Screening Period/Baseline Assessments ................................................................. 65 
6.9.2 
Treatment Period ..................................................................................................... 66 
6.9.3 
End-of-Treatment Visit ........................................................................................... 69 
6.9.4 
Safety Follow-up Visit ............................................................................................ 69 
6.10 Concomitant Medications and Treatments ..................................................................... 70 
6.10.1 Prohibited Medications ........................................................................................... 70 
7. 
Assessment of Efficacy ..................................................................................................... 70 
7.1 
Primary Efficacy:  Objective Response ......................................................................... 71 
7.2 
Secondary Efficacy ........................................................................................................ 71 
8. 
Assessment of Safety and Exploratory Variables ......................................................... 71 
8.1 
Adverse Events ............................................................................................................... 71 


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8.1.1 
Adverse Events Definitions .................................................................................... 71 
8.2 
Adverse Events Reporting .............................................................................................. 73 
8.2.1 
Adverse Event Term ............................................................................................... 73 
8.2.2 
Adverse Event Severity........................................................................................... 73 
8.2.3 
Adverse Event Duration .......................................................................................... 74 
8.2.4 
Adverse Event Causality ......................................................................................... 74 
8.3 
Serious Adverse Events Reporting ................................................................................. 75 
8.4 
Reporting Infusion-related Reactions ............................................................................. 75 
8.5 
Reporting QTc Prolongation .......................................................................................... 76 
8.6 
Reporting Disease Progression and Death ..................................................................... 77 
8.7 
Electrocardiogram Monitoring ....................................................................................... 77 
8.8 
Vital Sign Assessments .................................................................................................. 78 
8.9 
Clinical Laboratory Assessments ................................................................................... 78 
8.10 Pregnancy Testing and Contraception ............................................................................ 79 
8.11 Physical Examinations ................................................................................................... 79 
8.12 Eastern Cooperative Oncology Group ........................................................................... 80 
8.13 Pharmacokinetics ........................................................................................................... 80 
8.14 Tumor Tissue.................................................................................................................. 80 
8.15 Biomarker Analysis ........................................................................................................ 81 
9. 
Statistics ............................................................................................................................ 81 
9.1 
Determination of Sample Size ........................................................................................ 81 
9.2 
Patient Disposition ......................................................................................................... 82 
9.2.1 
Disposition of Patients ............................................................................................ 82 
9.2.2 
Protocol Deviations ................................................................................................. 82 
9.2.3 
Analysis Sets ........................................................................................................... 82 
9.3 
General Considerations .................................................................................................. 82 
9.4 
Baseline Characteristics and Concomitant Medications ................................................ 83 
9.5 
Treatment Compliance ................................................................................................... 83 
9.6 
Efficacy Analyses ........................................................................................................... 83 
9.6.1 
Primary Efficacy Analysis ...................................................................................... 83 
9.6.2 
Secondary Efficacy Analyses ................................................................................. 84 
9.7 
Safety Analyses .............................................................................................................. 85 


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9.7.1 
Cardiac Safety ......................................................................................................... 85 
9.8 
Other Analyses ............................................................................................................... 86 
9.8.1 
Pharmacokinetic Analyses ...................................................................................... 86 
9.8.2 
Tumor Tissue .......................................................................................................... 86 
9.8.3 
Biomarker Analyses ................................................................................................ 86 
10. 
Quality Control and Quality Assurance ........................................................................ 86 
10.1 Data Quality Assurance .................................................................................................. 86 
10.1.1 Database Management and Quality Control ........................................................... 87 
11. 
Ethics ................................................................................................................................. 87 
11.1 Informed Consent ........................................................................................................... 87 
11.2 Protocol Approval and Amendment ............................................................................... 87 
11.3 Duration of the Study ..................................................................................................... 88 
11.4 Premature Termination of the Study .............................................................................. 88 
11.5 Confidentiality ................................................................................................................ 88 
12. 
Data Handling and Record Keeping .............................................................................. 89 
12.1 Case Report Forms and Source Documentation ............................................................ 89 
12.1.1 Data Collection ....................................................................................................... 89 
12.2 Access to Source Data .................................................................................................... 90 
12.3 Data Processing .............................................................................................................. 90 
12.4 Archiving Study Records ............................................................................................... 90 
13. 
Publication Policy............................................................................................................. 90 
14. 
References ......................................................................................................................... 91 
Appendix A:  Packaging, Labeling, and Storage of Study Drug ............................................ 96 
Appendix B:  QT-Prolonging Drugs with a Known Risk for Torsade de Pointes ................ 97 
Declaration of the Investigator .................................................................................................. 99 
 
LIST OF TABLES 
Table 1: 
Comparative Cellular ERBB Kinase Inhibitory Activity of Tarloxotinib-E ...34 
Table 2: 
Tarloxotinib-E Potency in Ba/F3 Cell Lines ...................................................35 
Table 3: 
Number of Patients by Cohort .........................................................................47 
Table 4: 
Eligible Mutations/Gene Fusions .....................................................................50 
Table 5: 
Potassium Supplementation Guidelines ...........................................................59 
Table 6: 
Tarloxotinib Dose Reductions .........................................................................61 
Table 7: 
Treatment Guidelines for QTc Prolongation ...................................................62 


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Table 8: 
Treatment Guidelines for Infusion-Related Reactions ....................................63 
Table 9: 
Treatment Guidelines for Tarloxotinib-Related Non-Hematologic Toxicity ..64 
Table 10: 
Severity Grading Guideline for Adverse Events Not Listed in NCI CTCAE .74 
Table 11: 
Severity Grading Guideline for Infusion-Related Reactions ...........................76 
Table 12: 
NCI CTCAE Grading of ECG QTc Prolongation (Medical Dictionary of 
 
Regulatory Activities Code:  10014383) .........................................................77 
Table 13: 
Clinical Laboratory Assessments .....................................................................79 
Table 14: 
ECOG Performance Status Scale .....................................................................80 
Table 15: 
Censoring Rules for Progression-Free Survival ..............................................84 
 
LIST OF FIGURES 
Figure 1: 
Structure of the Prodrug Tarloxotinib and Mechanism of Activation to 
 
Tarloxotinib-E ..................................................................................................26 
Figure 2: 
EGFR and Downstream Signaling ...................................................................27 
Figure 3: 
Schematic Representation of the Structure of EGFR with the Locations and 
 
Regions of Commonly Occurring Mutations in the EGFR Tyrosine Kinase 
 
Domain Shown in the Exon Boundary Map ....................................................28 
Figure 4: 
EGFR and HER2 Exon 20 Mutations ..............................................................29 
Figure 5: 
NRG1-Fusion Signaling...................................................................................33 
Figure 6: 
Comparative Activity of Tarloxotinib, Cetuximab, and Afatinib Against 
 
EGFR exon 20 Insertion (ASV)-Driven CUTO-14 Tumors ............................36 
Figure 7: 
Activity of Tarloxotinib in Mice-bearing Large CUTO-14 EGFR exon 20 
 
Insertion (ASV)-Driven Tumors ......................................................................37 
Figure 8: 
Comparative Activity of Tarloxotinib (Tarlox), Cetuximab, Afatinib and 
 
Osimertinib Against EGFR exon 20 Insertion (NPH)-Driven CUTO-17 
 
Tumors .............................................................................................................38 
Figure 9: 
Comparative Activity of Tarloxotinib (Tarlox) and Afatinib Against CLU-
 
NRG1-Driven OV-10-0050 Tumors ................................................................39 
Figure 10: 
Plasma and Tumor Pharmacokinetics of a Single Dose of Tarloxotinib in OV-
 
10-0050 (CLU-NRG1) Tumor-bearing Mice Depicting the Profiles of 
 
Tarloxotinib and Tarloxotinib-E when Tarloxotinib Was Administered at 
 
48 mg/kg (A) or 26 mg/kg (B) .........................................................................39 
Figure 11: 
Sustained Downregulation of Multiple Cancer Signaling Pathways in OV-10-
 
0050 (CLU-NRG1) PDX Model Using nCounter® Vantage 3D™ Protein 
 
Solid Tumor Panel After Single Dose of Tarloxotinib (48 mg/kg) .................40 
Figure 12: 
Study Schema...................................................................................................48 
Figure 13: 
Sample Patient Identification Number .............................................................56 


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LIST OF ABBREVIATIONS 
Abbreviation or Specialist Term 
Explanation 
ADC 
Antibody-drug conjugate 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
BOR 
Best overall response 
BSA 
Body surface area 
CI 
Confidence interval 
Cmax 
Maximum peak plasma concentration 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
Central nervous system 
COVID-19  
Coronavirus disease 2019  
CR 
Complete response 
CT 
Computed tomography 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EOI 
End of infusion 
EOT 
End-of-Treatment Visit 
FDA 
Food and Drug Administration 
FUP 
Follow-up Visit 
HED 
Human effective dose 
HER 
Human epidermal growth factor receptor 
IC50 
50% inhibitory concentration 
IEC 
Independent ethics committee 
ILD 
Interstitial lung disease 
IND 
Investigational New Drug 
IP 
Intraperitoneal 
IRB 
Institutional review board 
IRR 
Infusion-related reactions 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NRG1 
Neuregulin 1 
NSCLC 
Non-small cell lung cancer 


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Abbreviation or Specialist Term 
Explanation 
ORR 
Objective response rate 
PD 
Progressive disease 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PR 
Partial response 
QTc 
Corrected QT interval 
QTcB 
Corrected QTc interval as calculated according to Bazett's formula 
QTcF 
Corrected QTc interval as calculated according to Fridericia’s 
formula 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCC 
Squamous cell carcinoma 
SD 
Stable disease  
SEM 
Standard error of the mean 
STEAP4 
Six transmembrane epithelial antigen of the prostate, family 
member 4 
T790M 
Mutation within exon 20 of EGFR substituting methionine for 
threonine at position 790  
TdP 
Torsade de Pointes  
T-DXd 
Trastuzumab deruxtecan 
TGF-α 
Transforming growth factor alpha 
TKI 
Tyrosine kinase inhibitor 
ULN 
Upper limit of normal 
US 
United States 
WOCBP 
Women of childbearing potential 
WT 
Wild type 
 
 
 


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1. INTRODUCTION 
Tarloxotinib was designed and initially developed at the University of Auckland, New Zealand.  
The program was subsequently evaluated in the clinic by Proacta Inc. (as PR610) and later by 
Threshold Pharmaceuticals, Inc. (as TH-4000).  Rain Therapeutics, Inc. is now developing 
tarloxotinib for the treatment of patients with advanced solid tumors with qualifying genetic 
mutations and/or fusions.   
The first-in-human Phase 1 clinical trial investigated the safety and pharmacokinetics of 
tarloxotinib administered as a weekly 1-hour infusion to 27 patients with advanced solid tumors.  
Tarloxotinib doses ranged from 10 to 200 mg/m2.  A maximum tolerated dose (MTD) of 
150 mg/m2 was declared for the 1-hour infusion duration.  A 24-hour duration was also evaluated 
for an improved toxicity profile, but none was observed with this extended infusion.  The most 
common treatment-related adverse events (AEs) appeared to be dose-dependent and included 
skin rash, diarrhea, nausea and vomiting, QTc prolongation, and infusion-related reactions (see 
Section 2.3.2). 
Two Phase 2 open-label studies were subsequently performed to evaluate the safety and 
preliminary efficacy of tarloxotinib administered as a 150 mg/m2 weekly 1-hour infusion in 
patients with epidermal growth factor receptor (EGFR)-mutant, T790M-negative, advanced 
non-small cell lung cancer (NSCLC) that was resistant to EGFR tyrosine kinase inhibitors 
(TKIs), and in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head 
and neck or skin.  These studies failed to show significant antitumor activity.  Both trials enrolled 
a patient population unlikely to respond to EGFR inhibition (see Section 2.3.2).  However, 
results from preclinical models with qualifying genetic mutations or fusions have suggested the 
potential for therapeutic benefit from tarloxotinib treatment in human cancers with few effective 
available therapies. 
2. BACKGROUND INFORMATION  
2.1 
Investigational Product:  Tarloxotinib 
Tarloxotinib is a hypoxia-activated prodrug of a pan-ERBB (EGFR, HER2, and HER4) TKI.  It 
is classified as a pan-ERBB TKI based on results of isolated enzyme kinase inhibition studies.  
Tarloxotinib is designed to be inactive under normal oxygen conditions (normoxia) but 
undergoes fragmentation under low oxygen conditions (hypoxia) to release the potent 
irreversible active metabolite (tarloxotinib-E) that has activity against both the normal/wild-type 
(WT) and mutant versions of the ERBB family.   
Solid tumors demonstrate significant areas of hypoxia, which can lead to resistance to 
radiotherapy and chemotherapy (Muz 2015).  Tarloxotinib was designed to exploit this 
characteristic to generate a therapeutic window; the prodrug selectively fragments under hypoxic 
conditions to release its active metabolite tarloxotinib-E, an irreversible EGFR/HER2 inhibitor 
(Figure 1).  Tarloxotinib-E, once produced, may then diffuse to surrounding hypoxic and 
normoxic tumor tissue alike to exert its pharmacological action.  A single reductase, STEAP4, is 
responsible for the first reduction step of the fragmentation process and is highly expressed in 
tumors that are also EGFR positive (Figure 1). 


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Figure 1: 
Structure of the Prodrug Tarloxotinib and Mechanism of Activation to 
Tarloxotinib-E 
 
 
Selective production of tarloxotinib-E from tarloxotinib under hypoxic conditions in the tumor 
may allow delivery of higher, more effective concentrations of tarloxotinib-E to the tumor tissue 
with significantly reduced systemic tarloxotinib-E levels.  Diminished systemic exposure of 
tarloxotinib-E is anticipated to lead to reduced WT EGFR inhibition and reduced WT 
EGFR-mediated toxicities than standard EGFR TKIs.  This strategy is expected to broaden the 
therapeutic window translating to both improved efficacy and tolerability for patients, with 
minimal tarloxotinib-E generated in the gastrointestinal tract, skin, and other normoxic healthy 
tissues.   
See Appendix A for tarloxotinib packaging, labeling, and storage instructions.   
2.2 
Study Diseases 
2.2.1 
Non-Small Cell Lung Cancer 
Lung cancer is one of the most common solid tumors and is the leading cause of cancer-related 
death worldwide (World Health Organization 2018).  In 2018, it is expected that there will be 
approximately 234,000 new cases of lung cancer, and approximately 154,000 deaths in the 
United States (US) (American Cancer Society 2018).  NSCLC is the most common subtype, 
accounting for approximately 85% of all lung cancers (Heuvers 2012).  Although early stages of 
the disease are potentially curable with surgery or chemoradiation, most lung carcinomas are 
diagnosed at an advanced stage, leading to a poor prognosis (Howington 2013).  Treatment of 
advanced disease is in part segmented by the presence of certain molecular drivers that are 
targetable by approved drugs (e.g., EGFR-sensitizing mutations, anaplastic lymphoma kinase 
(ALK) fusions, ROS1 fusions, and BRAF V600E mutations).  Therapy for patients in the 
EGFR-mutated segment of NSCLC has been well established over the past decade and will be 
further discussed in the following sections.   


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2.2.1.1 
The ERBB Family of Receptors and Their Role in Cancer 
The EGFR is a 170-kDa transmembrane protein that is widely expressed in several malignancies, 
including lung cancer (Doebele 2010).  EGFR, also known as HER1 (ERBB1), is a member of a 
family of 4 closely related receptor tyrosine kinases that also include HER2/NEU (ERBB2), 
HER3 (ERBB3), and HER4 (ERBB4) (Gazdar 2009, Doebele 2010).   
The ERBB (HER) family of receptors share important structural similarities across 
4 extracellular domains (I through IV), a transmembrane domain, and intracellular domains 
consisting of a kinase domain and tyrosine phosphorylation sites in the carboxy-terminal tail 
(Doebele 2010).   
Multiple ligands bind to the ERBB family of receptors with varying specificity (Figure 2), 
inducing ERBB receptor homodimerization (e.g., EGFR–EGFR) or heterodimerization 
(e.g., EGFR–HER2).  HER2 has no known ligand but is the preferred binding partner of EGFR 
and the other ERBB family members (Doebele 2010). 
Figure 2: 
EGFR and Downstream Signaling  
 
Ligand-bound receptors form functionally active homodimers or heterodimers, resulting in the activation of 
downstream signaling pathways that promote cellular proliferation and survival.  No known ligand exists for HER2, 
and HER3 has no functional TK activity.  Other receptor TKs (e.g., IGF-1R, MET) can modulate EGFR 
downstream pathways. 
EGFR = epidermal growth factor receptor; HB-EGF = heparin-binding epidermal growth factor; 
IGF-1R = insulin-like growth factor receptor-1; NRG = neuregulin; RTK = receptor tyrosine kinase; 
TGFα = transforming growth factor alpha; TK = tyrosine kinase. 
Adapted from Doebele 2010 
 
EGFR mutations shift the equilibrium of protein structures from an inactive to an active state, 
resulting in the increased and sustained phosphorylation of EGFR and other ERBB family 


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proteins without ligand stimulation (Kobayashi 2016).  Downstream signaling networks 
controlled by ERBB family activation consist of several interconnected and overlapping 
pathways that regulate many physiological events including cell proliferation, apoptosis, 
angiogenesis, cell adhesion and motility, embryonic development, and organogenesis 
(Jacobi 2017).  A broad range of cancers, including lung, breast, stomach, colorectal, head and 
neck cancers, have been associated with hyperactivation of these pathways via mutation or 
increased expression of members of the ERBB family of receptors (Jacobi 2017, 
Roskoski 2014). 
2.2.1.2 
EGFR and HER2 Mutations in NSCLC 
Activating mutations in the EGFR kinase domain occur in 10% to 15% of patients with NSCLC 
in North American and European populations and in up to 40% among Asian populations 
(Lindeman 2013, Kobayashi 2016).  Most mutations are present in the first 4 exons (18 to 21) 
that encode a portion of the EGFR kinase domain (Figure 3).  Deletions in exon 19 and the 
L858R mutation in exon 21 are the most common, accounting for approximately 85% to 90% of 
all EGFR mutations (Kobayashi 2016, Takeda 2018).  These “oncogene-addicted” tumors 
depend on the growth and survival signaling emanating from the EGFR.   
Figure 3: 
Schematic Representation of the Structure of EGFR with the Locations 
and Regions of Commonly Occurring Mutations in the EGFR Tyrosine 
Kinase Domain Shown in the Exon Boundary Map 
 
Adapted from Doebele 2010 
 
Insertions in exon 20 are the third most common family of EGFR mutations and account for 
approximately 5% to 9% of EGFR mutations (Oxnard 2013, Takeda 2018, Arcila 2013).  They 
represent a combination of in-frame insertions and/or duplications of 3 to 21 base pairs, 
predominantly clustered between codons 767 and 774 (Figure 4) (Arcila 2013). 


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Figure 4: 
EGFR and HER2 Exon 20 Mutations  
Adapted from Robichaux 2018 
 
Mutations of the HER2 gene have also been identified as oncogenic drivers in NSCLC with a 
frequency of 2% to 3% (Takeda 2018).  The most common mutations are in-frame insertions in 
exon 20 such as YVMA as well as substitutions at L755 and S310 (Chmielecki 2015).  They are 
typically mutually exclusive with mutations in EGFR, KRAS, and BRAF, and rearrangements 
involving ALK and ROS1 (Lindeman 2018).  The most common HER2 mutations consist of a 
12-base pair duplication of codons 775 to 778 in-frame insertion encoding amino acids YVMA 
(Takeda 2018).  They are more commonly observed in younger patients and patients with no 
smoking history (Lindeman 2018).   
Together, EGFR exon 20 insertion and HER2 mutations are found in approximately 4% to 5% of 
all patients with NSCLC (Robichaux 2018). 
2.2.1.3 
Treatment of NSCLC Patients with Activating Mutations 
International treatment guidelines now recommend molecular testing for all patients with 
NSCLC to assess the presence of EGFR-activating mutations (Lindeman 2018).  The most 
recently updated guidelines published in 2018 recommend testing of EGFR, ALK, and ROS1 as 
an absolute minimum.  A second group of genes including BRAF, MET, RET, ERBB2 (HER2) 
should be included in any expanded panel that is offered for lung cancer patients.  KRAS testing 
may also be offered as a single-gene test to exclude patients from expanded panel testing 
(Lindeman 2018). 


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Successful oncogene-targeted therapies have been developed and approved for NSCLC that 
harbor the more common EGFR-activating mutations such as exon 19 deletions and exon 21 
L858R mutations; however, there are currently no approved targeted therapies for patients with 
lung cancer harboring EGFR exon 20 insertion or HER2-activating mutations. 
TKIs such as erlotinib, gefitinib, dacomitinib, afatinib, and osimertinib are directed at sensitizing 
mutations (and the T790M resistance mutation for osimertinib) in the EGFR gene by binding to 
the adenosine triphosphate (ATP)-binding pocket of EGFR and preventing ATP binding to this 
site (Kobayashi 2016).  Approximately 70% of patients treated with TKIs experience an 
objective response, improved progression free-survival (PFS), and improved quality of life 
compared to those treated with chemotherapy alone (Robichaux 2018, Mok 2009, Rosell 2012, 
Soria 2018).  Patients with HER2-activating mutations (most of which are located in exon 20) 
have shown responses to TKI (afatinib) treatment with an objective response rate (ORR) of 19% 
and disease control rate (DCR) of 69%; time to failure was 2.9 months (Peters 2018).  
The structural changes of EGFR exon 19 and 21 mutations enable higher binding affinity of 
EGFR inhibitors as compared to WT EGFR.  Additionally, EGFR exon 19 and 21 mutations are 
associated with lower binding affinity for ATP as compared to WT EGFR (Yasuda 2013).  
However, TKIs have been associated with dose-limiting toxicities due to simultaneous inhibition 
of WT EGFR (Sullivan 2017).  Toxicities associated with WT EGFR inhibition in normal tissues 
include adverse skin and gastrointestinal events (Sullivan 2017).   
Exon 20 EGFR insertion mutations are generally resistant to EGFR TKIs.  In contrast to EGFR 
exon 19 and 21 mutations, EGFR exon 20 insertion mutations present binding affinity for ATP 
and for EGFR inhibitors more similar to WT EGFR (Yasuda 2013).  In vitro, in vivo, and clinical 
data support the conclusion that standard first- and second-generation EGFR inhibitors such as 
erlotinib, gefitinib, and afatinib have suboptimal efficacy against the exon 20 insertion class of 
EGFR mutations; ORRs of approximately 3% to 8% have been reported to first-line therapy 
(Robichaux 2018).  TKIs targeting HER2, such as afatinib, lapatinib, neratinib, and dacomitinib, 
also have limited activity in patients with HER2-mutant tumors, demonstrating ORRs of 12% or 
below in many studies (Robichaux 2018). 
Approved treatment options for patients with exon 20 mutations in the first-line setting are 
limited to platinum-containing chemotherapy with or without bevacizumab or immune-
checkpoint inhibitors.  Single-agent pembrolizumab in first-line therapy, or other checkpoint 
inhibitors in second-line therapy, have emerged as treatment options especially in patients whose 
expression levels of the programmed cell death protein 1 ligand is elevated, however, EGFR 
mutations appear to be a negative predictive factor for clinical benefit (Garassino 2018, Gainor 
2016).  It is yet not known if the same negative correlation exists in patients with uncommon 
mutations (including exon 20 insertions).  Retrospective data suggest patients with EGFR or 
HER2 exon 20 mutations are less likely to benefit from nivolumab therapy (Takeda 2018).  Only 
1 of 7 patients achieved a partial response (PR) despite seeing tumor proportion score of 50% in 
2 patients, and 10%, 5%, 0% in 3 patients, respectively, while 2 patients had unknown scores. 
2.2.2 
Advanced Solid Tumors  
Cancer is a leading cause of death worldwide, accounting for an estimated 9.6 million deaths in 
2018.  The most common cancers are:  lung (2.09 million cases), breast (2.09 million cases), 


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colorectal (1.80 million cases), prostate (1.28 million cases), skin cancer (non-melanoma) 
(1.04 million cases), and stomach (1.03 million cases) (World Health Organization 2018).  The 
molecularly targeted cancer therapies have resulted in improving the lives of a large number of 
cancer patients due to their specificity toward cancer cells while sparing toxicity to off-target 
cells (Gerber 2008). 
Structural gene rearrangements resulting in gene fusions are frequent events in solid tumors.  
Gene fusions arise as a result of genomic rearrangements, including chromosomal inversions, 
interstitial deletions, duplications, or translocations, and can drive both the development and 
progression of the cancer.  Using contemporary sequencing techniques, at least 1 gene fusion can 
be identified in up to 17% of solid tumors.  Many of these fusions lead to a state of oncogene 
addiction and their products are ideal targets of anticancer drugs (Schram 2017).  Many of these 
events, such as fusions involving ALK, ROS1, RET, NTRK1/2/3, FGFR1/2/3, and PDGFB, are 
clinically actionable and targeted therapies are highly effective (Schram 2017, Drilon 2018a). 
2.2.2.1 
HER-Family Gene Fusions in Cancer 
Fusions involving HER-family receptor tyrosine kinases, i.e., EGFR, HER2, and HER4, are 
reported in multiple cancers.  EGFR fusions were detected in glioblastoma, glioma 
(EGFR/SEPT14) (Stransky 2014) and in lung adenocarcinoma (EGFR-RAD51 and 
EGFR-PURB, 0.05%) (Konduri 2016).   
Kinase fusions commonly share a mechanism of activation whereby the fusion partner drives 
dimerization of the kinase and leads to ligand-independent activation.  EGFR-RAD51 fusion is 
oncogenic in Ba/F3 cells and activates downstream oncogenic signaling via the PI3K/AKT and 
MAPK pathways.  EGFR-RAD51 fusion proteins could be activated by RAD51 oligomerization 
and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies 
(Konduri 2016).  EGFR kinase domain duplications represent a novel form of EGFR–EGFR 
gene fusion in which a second EGFR kinase domain is fused in tandem to a full-length EGFR 
gene.  These alterations have been demonstrated to be functionally activated oncogenes, 
potentially targetable by EGFR inhibitors, and identified in multiple different tumor types 
including lung, sarcoma, and gliomas (Gallant 2015). 
ZNF207-HER2, and MDK-HER2 fusions have been detected in gastric cancer.  The HER2 
fusions were oncogenic and led to aberrant activation of the HER2 pathway (Yu 2015).  Gene 
rearrangement generating ERBB2-GRB7 fusions have been reported in breast and bladder 
cancers and provide a novel mode of activation by directly tethering a dominant SH2 adaptor 
protein directly to the HER2 kinase domain (Ross 2013; Chmielecki 2015).  EZR-ERBB4 fusion 
was detected in invasive mucinous adenocarcinoma of the lung.  The EZR-ERBB4 fusion protein 
contains the EZR coiled-coil domain, which functions in protein dimerization, and activates 
downstream signaling.  NIH3T3 cells expressing ERZ-ERBB4 fusion is oncogenic and form 
tumors in nude mice (Nakaoku 2014). 
Overall, the HER-family gene fusions occur at low frequency and represent actionable oncogenic 
drivers. 


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2.2.2.1.1 
Treatment of Patients with Solid Tumors Harboring HER-Family Gene 
Fusions 
Responses to EGFR fusions have been observed with EGFR TKIs.  Four patients with 
EGFR-RAD51 and EGFR-PURB fusions demonstrated antitumor responses from treatment with 
the EGFR TKI erlotinib (Konduri 2016).  Response to erlotinib has also been reported recently in 
a Chinese patient with EGFR-RAD51 fusion (Zhu 2018). 
2.2.2.2 
NRG1 Gene Fusion in Cancer  
Gene fusions involving the neuregulin-1 gene (NRG1) were identified in NSCLC in lung 
adenocarcinomas (Fernandez-Cuesta 2014).  NRG1 fusions are particularly enriched in invasive 
mucinous adenocarcinomas of the lung, where they are found in 27% to 31% of cases.  These are 
often mutually exclusive with KRAS mutations, a driver known to be enriched in mucinous 
adenocarcinomas (Fernandez-Cuesta 2014, Trombetta 2018).  NRG1 rearrangements were 
detected across a variety of other cancers, including breast (0.01%), head and neck (0.49%), 
renal (0.19%), ovarian (0.24%), pancreatic (0.55%), prostate (0.3%), and uterine (1.75%) 
cancers, using MSK-IMPACT and the MSK solid fusion assays (Drilon 2018b).  NRG1 fusions 
were also reported in cholangiocarcinoma (0.8%), thyroid (0.7%), ovarian (0.5%), pancreatic 
(0.4%), NSCLC (0.3%), breast (0.2%), sarcoma (0.2%), and other (0.1%) cancers using 
ArcherDx fusion assay with an overall incidence of 0.2% in solid tumors (Jonna 2019). 
NRG1 gene fusions are drivers of cancer growth.  NRG1 encodes several isoforms that contain 
an EGF-like domain that serves as the ligand of the receptor HER3 (Fernandez-Cuesta 2015).  
Chimeric transmembrane proteins encoded by NRG1 fusions are predicted to maintain this 
extracellular domain, thus activating HER3 in a para/juxtacrine or autocrine fashion (Schaefer 
1997).  NRG1 binding to HER3 results in heterodimerization with HER2, activation of 
downstream signaling, including the MAPK, PI3K-AKT, and NF-κB pathways, and increased 
tumor cell proliferation and growth.  CD74-NRG1 fusion activates HER3 as well as PI3K-AKT 
signaling promoting anchorage-independent growth of NIH-3T3 cells, and the signaling could be 
suppressed by clinically approved kinase inhibitors afatinib and lapatinib (Nakaoku 2014).  
Numerous N-terminal partners have been reported for NRG1 fusions which retain an EGF-like 
domain (Drilon 2018b, Jonna 2019). 


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Figure 5: 
NRG1-Fusion Signaling 
 
Graphic depiction of DNA splice site and protein fusion products solute carrier family 3 member 2 
(SLC3A2-NRG1) (A) and CD74 molecule (CD74)-NRG1 (B) along with depiction of how they drive 
ERBB-mediated cellular proliferation through overactive autocrine and paracrine signaling through the EGF-like 
domain.  
CRD = cysteine rich domain; HER2 = receptor tyrosine-protein kinase erbB-2; HER3/4 = receptor tyrosine-protein 
kinase erbB-3/4; NRG1 = neuregulin 1; PI3K = phosphoinositide 3-kinase; mTOR = mammalian target of 
rapamycin; MHC = major histocompatibility complex; TM = transmembrane domain. 
Adapted from Gay 2017  
 
HER3 Networks and NRG Signaling in NRG1-Rearranged Lung Tumors 
NRG1 proteins act as ligands of HER3 receptors.  The interaction NRG1-HER3 triggers the 
receptor, inducing its heterodimerization with HER2 and the consequent activation of the PI3K-
AKT and MAPK pathway, both in autocrine (cell-1) and juxtacrine (cell-2) ways, resulting in 
irregular cell proliferation and tumor growth.  Mechanisms of evasion of the apoptosis are 
activated too.  In the NRG1 fused protein, the part belonging to the 5’ partner gene is colored in 
blue (Trombetta 2017). 


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2.2.2.2.1 
Treatment of Patients with Solid Tumors Harboring NRG1 Gene Fusions 
Clinical responses to various HER-directed therapies have been reported for NRG1 gene fusions.  
Afatinib displayed responses in 2 patients with SDC4-NRG1 (lung adenocarcinoma) and 
ATP1B1-NRG1 (cholangiocarcinoma) (Jones 2017) and SLC3A2-NRG1 (lung adenocarcinoma) 
fusions (Gay 2017).  GSK2849330, HER3 monoclonal antibody demonstrated durable response 
in CD74-NRG1 (lung invasive mucinous adenocarcinoma) fusion (Drilon 2018b).  The 
combination of lumretuzumab and erlotinib showed stable disease (SD) in a patient harboring 
SLC3A2-NRG1 fusion (Han 2017).  These initial reports of activity provide clinical concept 
validation to target NRG1 gene fusions. 
2.3 
Summary of Nonclinical Studies and Clinical Trials Using Tarloxotinib 
2.3.1 
Nonclinical Studies  
Tarloxotinib and tarloxotinib-E inhibitory activity were compared directly against gefitinib, 
afatinib, and osimertinib across patient-derived cell lines harboring EGFR exon 20 insertion 
mutations, HER2 amplification, and HER2 exon 20 insertion mutations along with various 
EGFR and HER2 mutations in Ba/F3 cells under normoxic conditions (Table 1). 
• For cell lines with EGFR exon 20 insertion mutations, tarloxotinib-E tended to be the 
most potent inhibitor with 1.5-, 4.6-, and 5.3-fold higher potency in CUTO-14, 
CUTO-17, and CUTO-18 cell lines, respectively, than afatinib. 
• Tarloxotinib (prodrug) was > 63-fold less potent than tarloxotinib-E (active metabolite) 
in CUTO-14, CUTO-17, and CUTO-18 patient-derived cell lines. 
• In ERBB2/HER2 amplification cell lines H-2170 and CALU-3, tarloxotinib-E was the 
most potent compared to the tested drugs.  Tarloxotinib-E was 130.8- and 162.5-fold 
more potent than tarloxotinib, respectively. 
• Tarloxotinib-E was 53-fold more potent than tarloxotinib in H-1781 cell line containing 
HER2 exon 20 insertion mutation and was more potent than afatinib. 
• Tarloxotinib-E was potent across various EGFR/HER2 mutations and fusions in Ba/F3 
cells (Suda 2019). 
 
Table 1: 
Comparative Cellular ERBB Kinase Inhibitory Activity of 
Tarloxotinib-E 
NSCLC Cellular Anti-Proliferative Assay IC50 (nM) ±SEM 
Cell Line 
Kinase 
Gefitinib 
Afatinib Osimertinib Tarloxotinib 
Tarloxotinib-
E 
N 
CUTO-14 
EGFR 
A767_V769dupASV 
3741 ± 1.4 
111 ± 5 
303 ± 1.9 
4645 ± 5.5 
72 ± 5.2 
3 
CUTO-17 
EGFR 
N771_H773dupNPH 
4197 ± 1.4 220 ± 2.6 
426 ± 3 
3090 ± 1.6 
48 ± 1.3 
3 
CUTO-18 
EGFR 
S768_D770dupSVD 
> 10000 
841 ± 3 
647 ± 3 
> 10000 
158 ± 1.3 
3 


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NSCLC Cellular Anti-Proliferative Assay IC50 (nM) ±SEM 
Cell Line 
Kinase 
Gefitinib 
Afatinib Osimertinib Tarloxotinib 
Tarloxotinib-
E 
N 
PC9 
EGFR Del 746_L750 
30 ± 1.5 
< 1 
- 
18 ± 1.2 
< 1 
3 
H3255 
EGFR L858R 
0.80 ± 2.3 
< 1 
- 
3.54 ± 1.3 
< 1 
3 
H2170 
ERBB2 amplification 
1156.1 ± 2.4 11.4 ± 1.3 112.7 ± 1.4 
588.8 ± 1.9 
4.5 ± 4.7 
3 
Calu-3 
ERBB2 amplification 
1324 ± 1.9 31.1 ± 3.4 187.9 ± 20.2 
325 ± 1.5 
2 ± 1.2 
3 
H1781 
ERBB2 p.G776Ins 
V_G/C 
4168 ± 5 
66 ± 4 
406.4 ± 17.1 
816 ± 1.2 
15.4 ± 4.4 
3 
MDA-MB-
175 
DOC4-NRG1 
404 
1.2 
37 
307 
0.3 
3 
EGFR = epidermal growth factor receptor; IC50 = 50% inhibitory concentration; NSCLC = non-small cell lung 
cancer; SEM = standard error of the mean 
 
Table 2: 
Tarloxotinib-E Potency in Ba/F3 Cell Lines  
Ba/F3 Cellular Anti-Proliferative Assay IC50 (nM) 
Cell Line 
Kinase 
Gefitinib 
Afatinib Osimertinib Tarloxotinib 
Tarloxotinib-
E 
N 
Ba/F3 HER2  
A775_G776insYVMA  
- 
8.1 
68.3 
122.9 
0.7 
3 
Ba/F3 HER2 
G776delinsVC  
- 
2.1 
7.2 
22.2 
0.03 
3 
Ba/F3 HER2 
P780_Y781insGSP  
- 
6.5 
88.45 
73.53 
0.87 
3 
Ba/F3 HER2 
V659E 
- 
6.09 
22.2 
407.2 
0.80  
3 
Ba/F3 HER2 
L755A 
- 
21.4 
67.0 
595.2 
4.52 
3 
Ba/F3 HER2 
L755P 
- 
7.58 
27.6 
162.8 
0.90 
3 
Ba/F3 EGFR 
A763insFQEA 
- 
0.7 
14.6 
15.2 
<0.5 
3 
Ba/F3 EGFR 
V769insASV 
- 
35.5 
118.4 
675.9 
7.6 
3 
Ba/F3 EGFR 
D770insSVD 
- 
86.0 
184.7 
990.1 
7.3 
3 
Ba/F3 EGFR 
H773insNPH 
- 
35.8 
61.9 
714.0 
9.9 
3 
Ba/F3 EGFR 
H773insH 
- 
325 
77.7 
>1000 
73.1 
3 
Ba/F3 EGFR–
EGFR  
EGFR kinase domain 
duplication 
228 
0.015 
2.4 
4.6 
0.015 
2 
Ba/F3 EGFR-
RAD51 
EGFR-RAD51 fusion 
4.5 
0.024 
8.6 
6.6 
0.026 
3 
EGFR = epidermal growth factor receptor; HER2 = human epidermal growth factor receptor 2; IC50 = 50% 
inhibitory concentration.  
 


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Tarloxotinib was evaluated in the CUTO-14 patient-derived xenograft, a model of EGFR 
exon 20 insertion (ASV)-driven cancer and compared to cetuximab, cetuximab with afatinib, and 
afatinib.  Tarloxotinib dosed at a once a week intraperitoneal (IP) dosing schedule resulted in 
tumor regression and was more effective than the comparator agents when dosed at 48 mg/kg, a 
dose providing a similar unbound plasma area under the curve in mice as is achieved in humans 
at the MTD of 150 mg/m2 (comparator agents were dosed at approximately their human effective 
dose [HED]; Figure 6).  Treatments were associated with modest (< 5%) changes in body 
weight. 
Figure 6: 
Comparative Activity of Tarloxotinib, Cetuximab, and Afatinib Against 
EGFR exon 20 Insertion (ASV)-Driven CUTO-14 Tumors 
 
EGFR = epidermal growth factor; i.p. intraperitoneal; p.o. = oral; q3d = every 3 days; q.d. = every day 


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Tarloxotinib activity was evaluated in mice with large tumors by using the vehicle group bearing 
CUTO-14 tumors with average tumor size of 573 mm3 (range 120 to 1623 mm3).  Tarloxotinib 
was dosed at the same dose of 48 mg/kg once a week on Day 23 for a total of 4 doses.  Rapid 
tumor regression was observed in these mice despite large tumors at the start dose and the tumor 
regression persisted for 2 weeks after the last dose (Figure 7). 
Figure 7: 
Activity of Tarloxotinib in Mice-bearing Large CUTO-14 EGFR exon 20 
Insertion (ASV)-Driven Tumors 
 
EGFR = epidermal growth factor; qw = every week 
 
CUTO-17 patient-derived xenograft, a model of EGFR exon 20 insertion (NPH)-driven cancer 
was used to test tarloxotinib and compare to cetuximab and osimertinib.  Tarloxotinib dosed at a 
once a week, IP dosing of 48 mg/kg schedule resulted in tumor volume reduction and was more 
effective than the comparator agents dosed at approximately their HEDs (Figure 8). 


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Figure 8: 
Comparative Activity of Tarloxotinib (Tarlox), Cetuximab, Afatinib and 
Osimertinib Against EGFR exon 20 Insertion (NPH)-Driven CUTO-17 
Tumors 
 
i.p. = intraperitoneal; p.o. = oral; q3d = every 3 days; q.w. = every week 
 
OV-10-0050 ovarian cancer patient-derived xenograft, a model of CLU-NRG1 fusion-driven 
cancer was used to test tarloxotinib and to compare to afatinib.  Tarloxotinib dosed at a once a 
week, IP dosing of 48 mg/kg and 26 mg/kg schedules led to significant tumor volume regression 
at both doses, while afatinib dosed at approximately the HED was not effective (Figure 9).  
Tarloxotinib and tarloxotinib-E exhibited sustained tumor exposure in the OV-10-0050 tumors 
for up to 168 hours (Figure 10) and demonstrated sustained inhibition of multiple pathways 
downstream of HER2/HER3 signaling (Figure 11).  


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Figure 9: 
Comparative Activity of Tarloxotinib (Tarlox) and Afatinib Against 
CLU-NRG1-Driven OV-10-0050 Tumors 
 
IP = intraperitoneal; PO = oral; QW = every week 
 
 
Figure 10: 
Plasma and Tumor Pharmacokinetics of a Single Dose of Tarloxotinib in 
OV-10-0050 (CLU-NRG1) Tumor-bearing Mice Depicting the Profiles of 
Tarloxotinib and Tarloxotinib-E when Tarloxotinib Was Administered at 
48 mg/kg (A) or 26 mg/kg (B) 
 


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Figure 11: 
Sustained Downregulation of Multiple Cancer Signaling Pathways in 
OV-10-0050 (CLU-NRG1) PDX Model Using nCounter® Vantage 3D™ 
Protein Solid Tumor Panel After Single Dose of Tarloxotinib (48 mg/kg) 
 
h = hour(s) 
Please refer to the Tarloxotinib Investigator’s Brochure for additional nonclinical information. 
2.3.2 
Clinical Trials  
Study PR610-1001 
A first-in-human Phase 1 clinical trial (Study PR610-1001) evaluated tarloxotinib administered 
as either a 1-hour or a 24-hour weekly intravenous (IV) infusion.  The study was designed to 
determine the MTD and dose-limiting toxicities (DLTs) of tarloxotinib in patients with locally 
advanced or metastatic solid tumors.  Twenty-seven patients received tarloxotinib administered 
weekly as a 1-hour infusion at doses ranging from 10 mg/m2 to 200 mg/m2 and 6 patients 
received tarloxotinib administered weekly as a 24-hour infusion at doses of 200 mg/m2 or 
335 mg/m2.  Of the patients who received tarloxotinib administered as a weekly 1-hour infusion, 
6 patients received tarloxotinib at the recommended Phase 2 dose of 150 mg/m2 tarloxotinib.   


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DLTs with the 1-hour infusion included Grade 3 infusion-related reaction (150 mg/m2), Grade 3 
facial pain (200 mg/m2), and Grade 4 QTc prolongation (200 mg/m2).  An MTD of 150 mg/m2 
was declared for the 1-hour infusion duration.  Other treatment-related AEs observed in the 
Phase 1 study included perioral paresthesia, musculoskeletal pain, nausea and vomiting, and dose 
dependent signs and symptoms of EGFR inhibition, notably skin rash, and diarrhea.   
After the DLTs of Grade 3 facial pain (1) and Grade 4 QTc prolongation (1) were observed at 
200 mg/m2 administered as a 1-hour infusion, a 24-hour infusion duration was evaluated to 
determine if a reduced maximum peak plasma concentration (Cmax) would reduce toxicities and 
allow higher weekly dosing.  Three patients each were treated with a 24-hour infusion of 
tarloxotinib at 200 mg/m2 or 335 mg/m2.  Treatment-related AEs were similar to those observed 
with the 1-hour infusion including nausea and diarrhea, skin rash and QT prolongation.  A DLT 
of Grade 3 QTc prolongation was reported in 1 patient at 335 mg/m2 at the 24-hour infusion 
duration.   
Pharmacokinetic (PK) samples were collected from patients after administration of the first dose 
in Cycles 1 and 2.  No accumulation of tarloxotinib was observed on Cycle 2 Day 1 as compared 
to Cycle 1 Day 1 for any PK parameter.  The data obtained across all dose levels were consistent 
with linear pharmacokinetics for both tarloxotinib and tarloxotinib-E.  The mean elimination 
half-life of tarloxotinib was approximately 5 hours at the 150 mg/m2 dose level, and mean Cmax 
was 20.54 μg/mL.  Across the range of doses, plasma concentrations of tarloxotinib-E averaged 
about 1% of those of tarloxotinib.   
Study TH-CR-601 and Study TH-CR-602 
Two Phase 2, open-label studies were subsequently performed to evaluate tarloxotinib 
administered as a 150 mg/m2 weekly 1-hour IV infusion in patients with EGFR-mutant, 
T790M-negative, advanced NSCLC that was resistant to EGFR TKIs (Study TH-CR-601), and 
in patients with recurrent or metastatic SCC of the head and neck or skin (Study TH-CR-602).  
These studies failed to show significant antitumor activity.  It is believed that both trials enrolled 
a study population unlikely to respond to EGFR inhibition.  Tumors lacking EGFR T790M as 
their EGFR TKI resistance mechanism are not likely to be EGFR dependent due to enrichment 
for tumors with bypass signaling or other non-EGFR-dependent signaling mechanisms; 
therefore, no EGFR inhibitor, including tarloxotinib, would be expected to show benefit in this 
population.  Additionally, SCC is not known to be dependent on EGFR signaling.  Data from 
these 2 studies are in the process of being analyzed and should be considered preliminary and 
subject to change. 
Study TH-CR-601 enrolled 21 subjects.  A total of 223 AEs related to tarloxotinib were reported 
in 21 subjects during the study.  Of these, 17 subjects (81%) experienced Grade 3 AEs, and 
1 subject (5%) experienced a Grade 4 AE.  QTc prolongation accounted for most of the Grade 3 
toxicities (10 subjects, 48%).  This was mainly due to corrected QTc interval as calculated 
according to Fridericia’s formula (QTcF) change from baseline of > 60 msec (38%) while 2 
subjects (10%) developed QTcF ≥ 501 msec.  None were associated with clinically significant 
arrhythmia.  Other Grade 3 toxicities included hypertension in 2 subjects and various other 
events in 1 subject each.  Grade 4 events related to tarloxotinib included 1 event of 
cerebrovascular accident, while no one experienced Grade 5 toxicity. 


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Study TH-CR-602 enrolled 30 patients.  In combining the results of both studies, the most 
common AE was ECG QT prolongation, which occurred in 35/51 (68.6%) of the patients and in 
these 35 patients, 19 (54.3%) were Grade 3 severity and 16 (45.7%) less than Grade 3.  Skin and 
subcutaneous tissue disorders were experienced by patients and the most frequent were 
dermatitis acneiform 13/51 (25.5%), rash 7/51 (13.7%), and pruritus 5/51 (9.8%) and most were 
≤ Grade 2 in severity.  The other most common treatment-related AEs were diarrhea (35.3%, 
18/51) and fatigue (17/51, 33.3%).   
Special emphasis was placed on QT monitoring in both studies.  This included Holter monitoring 
during Cycle 1 Day 1 and calibrated ECG machines with central reading of ECG measurements 
throughout the study duration.  Holter monitoring was used to record and extract triplicate QT 
measurements at 9 predefined time points during the first 24 hours of Cycle 1 Day 1 in both 
studies.  The mean maximum QTcF change from baseline was 51 msec occurring 3 hours after 
the end of infusion and 55 msec occurring 2 hours after the end of infusion in Study TH-CR-601 
and Study TH-CR-602, respectively.  Across the 2 studies, 10 patients (21%) developed QTcF 
values ≥ 501 msec and 16 patients (34%) developed a QTcF change from baseline of > 60 msec.  
The time-matched PK and QTcF data suggest a QT prolongation hysteresis of up to 2 to 3 hours 
after the tarloxotinib Cmax which occurs at the end of infusion.  T-wave segmentation analysis 
suggests that tarloxotinib is a hERG channel blocker and that it does not possess mitigating 
multichannel blocking properties. 
Please refer to the Tarloxotinib Investigator’s Brochure for the most current safety assessment.  
2.4 
Rationale for Selection of the RAIN-701 Study Population 
2.4.1 
NSCLC with EGFR Exon 20 Insertion Mutation or HER2-Activating Mutation 
The selection of patients with NSCLC that harbor EGFR exon 20 insertion or HER2-activating 
mutations is based on the hypothesis that tarloxotinib will overcome the inherent resistance of 
tumors harboring these mutations to standard EGFR, HER2 or pan-HER TKIs.   
Preclinical in vitro evidence from 3 patient-derived cell lines, which harbor the 3 most common 
EGFR exon 20 insertion variants, has demonstrated that the active metabolite (tarloxotinib-E) 
causes potent tumor cell proliferation inhibition compared to US Food and Drug Administration 
(FDA)-approved EGFR inhibitors afatinib or gefitinib.  These cell lines depend on EGFR 
signaling for their proliferation and are resistant to approved EGFR inhibitors compared to 
sensitizing EGFR mutations in exon 19 and 21.   
Preclinical in vitro evidence from Ba/F3 cells harboring HER2 mutations and 3 cell lines, which 
harbor HER2 amplification and HER2 exon 20 insertion (ERBB2 p.G776Ins V_G/C), has 
demonstrated that the active metabolite (tarloxotinib-E) causes potent tumor cell proliferation 
inhibition compared to FDA-approved EGFR inhibitors afatinib, osimertinib, or gefitinib.  These 
cell lines depend on HER2 signaling for their proliferation and are resistant to approved ERBB 
inhibitors compared to sensitizing EGFR mutations in exon 19 and 21. 
In vitro, the active metabolite (tarloxotinib-E) inhibits HER2 downstream signaling and 
proliferation of HER2 exon 20 insertion mutation cell lines.  Nonclinical data demonstrated that 
tarloxotinib can significantly inhibit growth of xenograft tumors in vivo and reduce tumor 


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volume.  Additionally, tarloxotinib has 30- to 70-fold lower activity in vitro under normoxic 
conditions compared to tarloxotinib-E, depending on the cell line.  As such, administration of 
tarloxotinib may selectively deliver higher concentrations of the active irreversible TKI, 
tarloxotinib-E, to the hypoxic tumor relative to normoxic normal tissues, thereby achieving 
inhibition of EGFR or HER2 signaling without high incidence of dose-limiting side effects.  
Standard EGFR inhibitors such as erlotinib, gefitinib, and afatinib are not effective against 
NSCLC harboring the exon 20 insertions, these patients have no other known effective therapy 
other than standard chemotherapy.  Other investigational agents currently being tested in this 
patient population include poziotinib, TAK788, and osimertinib.  Results from 2 ongoing studies 
reported an ORR of 14.8% and 43% for poziotinib and TAK788, respectively, which provides 
important proof-of-concept information that an oral ERBB-selective TKI is able to produce 
relevant tumor responses in the target population (Heymach 2018, Doebele 2018, Le 2020, Riely 
2020).  However, approximately 65% of the patients receiving poziotinib required dose reduction 
due to typical EGFR-related toxicities, such as skin rash and diarrhea, suggesting poziotinib 
lacks adequate exon 20 selectivity over the WT EGFR receptor, which is consistent with in vitro 
data showing that poziotinib/HM781-36b has greater selectivity for WT EGFR than EGFR exon 
20 mutations. 
Additionally, because HER2 inhibitors such as lapatinib and neratinib are not effective against 
NSCLC harboring the exon 20 insertions, these patients have no other known effective therapy 
other than standard chemotherapy.  Other investigational agents currently being tested in this 
patient population include trastuzumab deruxtecan (T-DXd), TAK-788, and poziotinib.  
Preliminary results from an ongoing study reported an ORR of 61.9% for T-DXd, which 
provides important proof-of-concept information that a HER2 targeted antibody-drug conjugate 
(ADC) is able to produce relevant tumor responses in the target population (Smit 2020).  
However, 64.3% patients had ≥ Grade 3 treatment-emergent AEs including decreased neutrophil 
count (26.2%), anemia (16.7%) and drug-related interstitial lung disease (ILD, 11.9%); 59.5% of 
the patients receiving T-DXd required dose interruption, 38.1% dose reduction and 23.8% 
treatment discontinuation.  Results from a TAK-788 Phase 2 trial in HER2 exon 20 insertion 
cohort have not been reported yet, but Phase 1 results demonstrated a confirmed ORR of 8%.  
Poziotinib demonstrated an ORR of 27.8% of NSCLC with HER2 mutations, but with significant 
≥ Grade 3 treatment-emergent AEs including rash and diarrhea (Socinski 2020).  
Antibody therapies (including ADCs) bind to the extracellular domain of HER2 leading to 
internalization of the HER2-monoclonal antibody/ADC complex and intracellular release of the 
chemotoxic payload.  In addition to the cytotoxic effects of the payload, antibody-dependent 
cell-mediated cytotoxicity also contributes to the efficacy of the ADC.  While resistance 
mechanisms have not been reported for T-DXd, multiple resistance mechanisms are reported for 
another HER2-ADC complex, T-DM1.  These include altered internalization of HER2-ADC 
complex, reduced T-DM1 binding, dependence on alternate receptor tyrosine kinases such as 
EGFR and HER3, intra-tumoral heterogeneity of HER2 expression, altered lysosomal 
catabolism, and impaired lysosomal release of the payload (Hunter 2020).  Most of these 
mechanisms are involved in the binding and processing of ADC and present a favorable 
environment for a small molecule TKI-dependent activity based on direct binding to the HER2 
kinase domain, suggesting that patients who progressed on antibody therapies may benefit from a 
TKI therapy.  


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2.5 
Rationale for Dose Selection and QT Prolongation Mitigation 
This study will evaluate tarloxotinib 150 mg/m2 as a weekly 1-hour IV infusion (the MTD 
declared in the first-in-human Phase 1 study (Patterson 2013) and the dose level explored in the 
2 Phase 2 studies).  Preclinical xenograft studies utilizing weekly doses of tarloxotinib at human 
equivalent of the clinically assessed dose (48 mg/kg intraperitoneally weekly equivalent to 150 
mg/m2 IV weekly) induced marked tumor shrinkage and marked inhibition of EGFR 
phosphorylation for 7 days suggesting protracted tumor residence time for tarloxotinib-E.  
Furthermore, this dose was associated with low-grade skin rash and diarrhea, suggesting limited 
systemic EGFR inhibition, indicating an on-target pharmacodynamic effect in man.  It is 
expected that enhanced activation in the tumor compared to normal tissue may offer a 
therapeutic advantage over standard TKIs in terms of the potential for enhanced intra-tumoral 
blockade of EGFR signaling with acceptable tolerability. 
Tarloxotinib was associated with Grade 1 or Grade 2 QTc prolongation starting at a dose of 
40 mg/m2 and more consistent QTc prolongation at 150 mg/m2 suggesting a dose-dependent 
effect.  However, extending the infusion duration from 1 hour to 24 hours, which reduced the 
tarloxotinib Cmax approximately 6-fold, did not appear to have an impact on QTc prolongation at 
the 200 mg/m2 dose of tarloxotinib in the 2 patients evaluated.  Time-matched assessment of 
QTc changes from baseline with tarloxotinib plasma concentrations after a 150 mg/m2 dose from 
the Phase 2 studies did not suggest an exposure correlation.  What is evident, is that there was a 
time-delay of the maximum QTc prolongation from baseline from the time to maximum 
tarloxotinib exposure of about 3 hours (QT prolongation hysteresis).  During this period, patients 
are at greatest risk of developing QT-related cardiac arrhythmias, such as Torsade de Pointes 
(TdP).  The QT prolongation risk mitigation strategy includes several layers of precautions, as 
follows: 
• Eligibility criteria that exclude patients at increased risk, such as:   
o History of long QT syndrome, TdP, or family history of sudden death 
o Receiving medication that prolongs QTc interval  
o Baseline QTcF ≥ 450 msec  
o Significant cardiovascular disease 
• Repeated ECG measurements during the study (prior to and following the infusion) 
• Potassium supplementation prior to dosing, as needed (Section 6.4)  
• All patients are under direct supervision of qualified personnel with immediate 
availability of appropriate resuscitation equipment.  Patients will therefore be under 
intense monitoring and supervision during the entire period they are at risk for QT 
prolongation.  
• Patients will not be discharged unless they have ≤ Grade 2 QTcF. 
In the prior Phase 1 and 2 Phase 2 studies, the main identified risk of tarloxotinib treatment (QT 
prolongation) was observed primarily within a 3- to 4-hour period following the start of infusion.   


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Given the absence of effective treatment options for NSCLC patients with EGFR exon 20 
insertion or HER2-activating mutations and based upon the manageability of observed risks 
associated with tarloxotinib, the risk-to-benefit ratio for participants in this study is acceptable.  
This risk of QT prolongation is mitigated in this study by the medical supervision of patients 
during first 3 to 4 hours of drug administration, when the risk of an event is greatest, with 
additional guidance on management of QT prolongation provided in the protocol and the 
Tarloxotinib Investigator’s Brochure. 
2.6 
Potential Risks  
Cancers harboring the mutations and fusions under evaluation in study RAIN-701 have been 
generally refractory to currently available therapies.  Tarloxotinib is an investigational agent with 
no proven clinical benefits.  As of the start of this clinical trial, tarloxotinib had been 
administered to 84 adults with a variety of cancer types.  In the combined dataset of Studies 
TH-CR-601 and TH-CR-602 (n = 51), where tarloxotinib was administered as a 1-hour weekly 
IV infusion at a dose level of 150 mg/m2, the most commonly reported AEs included ECG QT 
prolongation, diarrhea, fatigue, dermatitis, rash, pruritus, nausea, and cough.  Infusion-related 
reactions characterized by flushing, urticarial skin rash, pruritus, and hypotension have been 
observed during and immediately following infusion of tarloxotinib.  All patients receiving 
tarloxotinib should be instructed to seek immediate medical care in the event allergic symptoms 
develop.   
Prolongation of the QT interval have been observed up to 4 hours following completion of 
tarloxotinib infusion.  At the recommended dose of 150 mg/m2, AEs of QT prolongation were 
reported by 35/51, 68.6% (19 of these patients experienced Grade 3 QTc prolongation).  There 
was 1 patient who experienced a Grade 3/Grade 4 event at the 335 mg/m2 dose level in the 
Phase 1 study).  QT prolongation can infrequently lead to serious (rarely fatal) fast and irregular 
heart rhythms and other symptoms, such as severe dizziness and/or fainting, seizure, and 
palpitations.  Patient eligibility criteria and monitoring have been implemented based on these 
past findings.  
Due to the possibility of phototoxicity, patients should be instructed to avoid prolonged exposure 
to sunlight while on study treatment and when exposure cannot be avoided to use a 
broad-spectrum sunscreen.   
Please refer to the most recent version of the Tarloxotinib Investigator’s Brochure for the most 
current understanding and management of the potential risks associated with the use of 
tarloxotinib.   
3. TRIAL OBJECTIVES AND PURPOSE  
The purpose of this study is to evaluate the safety and efficacy of tarloxotinib when administered 
to patients with NSCLC whose tumors harbors either an EGFR exon 20 insertion or a 
HER2-activating mutation (including exon 20 insertions) or patients with advanced solid tumors 
expressing NRG1/ HER-family gene fusions or a HER2-activating mutation (including exon 20 
insertions).  All patients will have received at least 1 prior platinum-based 
chemotherapy-containing regimen in the advanced/metastatic setting (Cohorts A, B, and B1) or 
standard of care for cancer (Cohorts C and D).  Patients in Cohorts C  and D must have received 


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all standard therapy appropriate for their tumor type and stage of disease, or, in the opinion of the 
Investigator, would be unlikely to tolerate or derive clinically meaningful benefit from 
appropriate standard-of-care therapy. 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the ORR of tarloxotinib according to Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 
3.2 
Secondary Objectives 
Secondary objectives are: 
• To evaluate further measures of antitumor activity of tarloxotinib including best overall 
response (BOR), duration of response (DOR), DCR, progression-free survival (PFS), 
and overall survival (OS)  
• To investigate the pharmacokinetics (PK) of tarloxotinib and tarloxotinib-E using 
population PK (PopPK) methods and explore correlations between PK, exposure, 
response, and/or safety findings 
• To evaluate the safety and tolerability of tarloxotinib in this population including to 
determine whether there is an association between plasma exposure to tarloxotinib and 
effects on cardiac repolarization 
3.3 
Exploratory Objectives 
Exploratory objectives are: 
• To evaluate the concordance of EGFR mutation, ERBB2 (HER2) mutation, and NRG1, 
EGFR, ERBB2 (HER2), and ERBB4 (HER4) fusion detection between tissue and 
plasma using circulating tumor deoxyribonucleic acid (ctDNA) 
• To evaluate exploratory biomarkers of hypoxia in tumor tissue including STEAP4 
expression and ERBB family and cancer cell signaling pharmacodynamic markers 
• To evaluate the pharmacokinetics of tarloxotinib and tarloxotinib-E in tumor tissue 
4. TRIAL DESIGN  
4.1 
Trial Design Overview 
This is a Phase 2 multicenter, open-label study to evaluate the antitumor effect of tarloxotinib in 
patients with: 
• Previously treated advanced/metastatic NSCLC who have a tumor harboring one of the 
following: 
o An EGFR exon 20 insertion (Cohort A) 
o A HER2-activating mutation (including HER2 exon 20 insertions) who have not 
received prior HER2-directed therapy (Cohort B) 


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o A HER2-activating mutation (including HER2 exon 20 insertions) who have received 
prior HER1 antibodies or ADCs (Cohort B1) 
• Previously treated advanced solid tumors harboring: 
o NRG1 or ERBB HER-family gene fusions (Cohort C)  
o HER2-activating mutations (including HER2 exon 20 insertions), excluding NSCLC 
(Cohort D) 
Cohorts B1 and/or D may not be pursued, at the discretion of the Sponsor.  All cohorts will use a 
Simon’s 2-stage design.  In the first stage, 21 patients will be accrued.  If more than 3 patients in 
a cohort have a partial or complete response, up to 22 additional patients may be enrolled to the 
cohort, for up to a total of 43 patients per cohort. However, if there are 3 or fewer responses 
among these 21 patients, the cohort will be stopped based on futility.   
Table 3: 
Number of Patients by Cohort  
Cohort 
Description 
N 
A: 
• 
Patients with advanced NSCLC harboring an EGFR exon 20 insertion mutation 
o 
At least 1 prior platinum-based chemotherapy-containing regimen 
43 
B: 
• 
Patients with advanced NSCLC with a HER2 activating mutation  
• 
Patients who have received at least 1 prior platinum-based 
chemotherapy-containing regimen 
43  
B1*: 
• 
Patients with advanced NSCLC harboring a HER2-activating mutation 
• 
Patients who have received at least 1 platinum-based chemotherapy-containing 
regimen 
• 
Patients who have received prior HER2-directed therapy 
43 
C: 
• 
Patients with advanced solid tumors who have failed standard therapies 
appropriate for their tumor type and stage of disease, or, in the opinion of the 
Investigator, would be unlikely to tolerate or derive clinically meaningful 
benefit from appropriate standard-of-care therapy 
• 
Patients with tumors harboring an NRG1 gene fusion, EGFR gene fusion, 
EGFR kinase domain duplication, ERBB2 gene fusion, or ERBB4 gene fusion 
43 
D* 
• 
Patients with advanced solid tumors who have failed all standard therapies 
appropriate for their tumor type and stage of disease, or, in the opinion of the 
Investigator, would be unlikely to tolerate or derive clinically meaningful 
benefit from appropriate standard-of-care therapy 
• 
Patients with tumors (excluding NSCLC) harboring a HER2-activating 
mutation 
43 
 
Total 
215 
*Cohorts B1 and/or D may not be pursued, at the discretion of the Sponsor. 
Patients who are not evaluable for tumor response assessment may be replaced; accordingly, the 
study is expected to enroll approximately 248 patients to yield 215 evaluable patients.  
Prior to screening, potential patients will have tested positive for an EGFR exon 20 insertion 
mutation (Cohort A) or a HER2-activating mutation (Cohort B, B1, and D) or tumors harboring 
NRG1 or other HER-family gene fusions (Cohort C) using a CLIA-certified test (or similar 
accredited laboratory for non-US sites) to determine their eligibility for treatment with 


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tarloxotinib.  Results will be reviewed by the Medical Monitor (or designee) and participants will 
be assigned to one of the cohorts based on disease and mutation type.   
Based on the determined recommended Phase 2 dose, all patients will receive tarloxotinib 
150 mg/m2 administered as a weekly 1-hour IV infusion on Days 1, 8, 15, and 22 of each 28-day 
cycle until disease progression or unacceptable toxicity (e.g., hepatotoxicity meeting Hy’s law 
criteria or serious arrhythmias of ventricular origin).  Radiographic tumor assessment including 
computed tomography (CT) scans or magnetic resonance imaging (MRI) of chest and abdomen 
will be performed every 8 weeks (± 5 days) from Cycle 1 Day 1, using the same imaging 
modality per patient (Section 7).  Safety assessments will be performed on an ongoing basis. 
Figure 12: 
Study Schema 
                                
    
                                  
  
Treatment Period 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
   
Screening  
  
Cycles 1 to 3 
  
Additional Cycles  
  EOT   
Safety 
FUP 
  
   
 
 
 
 
  
   
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  Tarloxotinib Infusion1 X 
X 
X X 
 
X 
X 
X 
X 
 
  
 
 
 
 
  
  Tumor Assessment2 
<----------------------------------X2----------------------------> 
        
  
  
  
1 Days 1, 8, 15, and 22 of every 28-day cycle  
  
  
2 Every 8 weeks (± 5 days) from Cycle 1 Day 1 
  
                                
    
                                  
EOT = End-of-Treatment Visit; FUP = Follow-up Visit 
Note:  This schematic is not to scale.  
 
4.2 
Endpoints and Criteria for Evaluation 
4.2.1 
Primary Endpoint 
The primary efficacy endpoint is ORR based on patients who had PR or complete response (CR) 
with confirmation at least 8 weeks after initial documentation.  Tumor response will be assessed 
by the investigators in accordance with RECIST v1.1.  If disease progression according to 
RECIST v1.1 is documented at any time, no further disease response assessment will be 
required.  Patients who are alive with no objective documentation of disease progression by the 
data cut-off date for ORR analysis will be censored at the date of their last evaluable tumor 
assessment. 
4.2.2 
Secondary Endpoints  
Secondary efficacy endpoints include:  
• BOR defined as best response during the study SD, PR, or CR 
• DOR defined as the time from date of first response to date of disease progression or 
death   


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• DCR defined as CR, PR, or SD at least 2 cycles (8 weeks) recorded in the period 
between first study drug dose and disease progression or death to any cause   
• PFS defined as the time from the date of first dose to the earliest date of the first 
objective documentation of radiographic disease progression or death due to any cause   
• OS as measured from the date of first dose to the date of death by any cause 
Safety endpoints include the incidence of treatment-emergent AEs; changes in clinical laboratory 
parameters (hematology, serum chemistry, urinalysis, and serum pregnancy test), vital signs, and 
ECG parameters (especially QT); physical examination results; and use of concomitant 
medications. 
4.2.3 
Exploratory Endpoints  
Archived tumor samples or samples from newly obtained tumor tissue will be collected prior to 
baseline and will be used to confirm mutation status retrospectively in all patients and to assess 
STEAP4 expression and other biomarkers in consenting patients.   
Blood samples will be collected for biomarker analysis (e.g., ctDNA) at Cycle 1 Day 1, Cycle 2 
Day 1, and end of treatment.  Tumor tissue will be collected for retrospective concordance 
mutation testing and correlation with biomarkers.  An optional tumor tissue biopsy will be 
collected for measurements of tarloxotinib and the active metabolite (tarloxotinib-E) in 
consenting patients. 
Blood samples for tarloxotinib and tarloxotinib-E PK analyses will be collected in all patients 
and correlated with response and safety parameters including QTcF. 
4.3 
Measures Taken to Minimize/Avoid Bias  
If a patient withdraws from the study, the data (including tested and untested samples) collected 
to the point of withdrawal will remain part of the study database and will not be removed.   
Response criteria are based on objective measurements as defined in RECIST v1.1 by site 
radiologists.  All responses will be source verified; copies of tumor assessment scans will be 
collected and provided to an independent third party for evaluation, as necessary.   
4.4 
Duration of Study Treatment 
Patients will continue to receive tarloxotinib until documented disease progression or 
unacceptable toxicity (e.g., hepatotoxicity meeting Hy’s law criteria).  See Section 6.6 for 
treatment beyond progression.   
5. SELECTION AND WITHDRAWAL OF PATIENTS  
Cohorts A, B, and B1: 
To be considered for inclusion, the patient’s cancer must have recurred or progressed following 
at least 1 standard-of-care chemotherapy regimen (platinum-based chemotherapy).  This would 
include regimens that may also contain biologic agents, such as bevacizumab, or immunotherapy 
agents, such as pembrolizumab, nivolumab, atezolizumab, or durvalumab.   


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Cohorts C and D: 
To be considered for inclusion, the patient’s cancer must have failed standard therapies 
appropriate for their tumor type and stage of disease, or, in the opinion of the Investigator, would 
be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard-of-care 
therapy 
Potential patients must have a tumor with one of the following (see Table 4 for examples):  
• An EGFR exon 20 insertion mutation (Cohort A)  
• A HER2-activating mutation (Cohort B, B1 and D) 
• An NRG1/HER-family fusion (Cohort C) 
Mutation testing will be performed in a CLIA-certified laboratory (US sites) or similar 
accredited laboratory (non-US sites) using tissue and/or plasma.   
Table 4: 
Eligible Mutations/Gene Fusions 
Example Mutations and Gene Fusions (See Footnote) 
Cohort A 
Cohorts B, B1, and D 
Cohort C 
EGFR 
Exon 20 
HER2 (ERBB2) 
Mutations 
NRG1 
Fusions 
EGFR 
Fusions 
HER2 
(ERBB2) 
Fusions 
ERBB4 
(HER4) 
Fusions 
A763X 
S310F/Y 
CD74-NRG1
† 
EGFR–EGFR 
(KDD) 
ZNF207-
ERBB2 
EZR-ERBB4 
Y764X 
V659E/D 
DOC4-NRG1 
EGFR-RAD51 
MDK-ERBB2 
IKZF2-
ERBB4 
V765X 
G660D 
SLC3A2-
NRG1 
EGFR-PURB 
NOS2-ERBB2 
BGALT-
ERBB4 
M766X 
L755P/S 
RBPMS-
NRG1 
EGFR-SHC1 
ERBB2-GRB7 
A767X 
Del755-759 
SDC4-NRG1 
SEC61G–
EGFR 
ERBB2-CTTN 
S768X 
D769H/Y 
RAB2IL1-
NRG1 
ERBB2-
PPP1R1B 
V769X 
V773L 
VAMP2-
NRG1 
ERBB2-
PSMB3 
D770X 
A775_G776insYVMA* 
KIF13B-
NRG1 
N771X 
G776V/L, Cins 
ATP1B1-
NRG1 
P772X 
V777L 
CDH6-NRG1 
H773X 
P780_Y781insGSP 
AKAP13-
NRG1 
V774X 
V842I 
THBS1-NRG1 
X = insertion, duplication, or mutation  
* Most common HER2 mutation in NSCLC; note there are multiple nomenclature designations for 
insertions/duplications. 
† Most common NRG1 fusion; CD74-NRG1 is the only NRG1 fusion detected by Foundation Medicine. 
Note:  These are examples and not meant to be a comprehensive list.  Patients who have failed standard therapies but 


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have other gene alterations not specifically mentioned in this table, may still be eligible.  Please discuss with the 
Medical Monitor the eligibility of patients with other scientifically supported gene alterations. 
 
 
Potential patients with a qualifying mutation must meet all the following eligibility criteria.   
5.1 
Inclusion Criteria 
Potential patients must meet all the following criteria to be considered for inclusion: 
1. ≥ 18 years old 
2. Signed and dated written informed consent  
3. Histologically and/or cytologically confirmed primary diagnosis of cancer  
a. Cohorts A, B and B1:  NSCLC (Stage IV, Stage IIIB, or III C) not amenable to 
definitive curative-intent therapy, or recurrent disease after prior diagnosis of 
Stage I-III disease  
Note:  NSCLC staging according to American Joint Committee on Cancer, 8th 
edition, lung cancer staging criteria 
b. Cohort C and D:  Locally advanced or metastatic solid tumor  
4. Progression of disease on or after a platinum-based chemotherapy regimen (Cohorts A, 
B, and B1) or after standard of care (Cohorts C and D)  
a. Cohorts C and D:  Must have received all standard therapy appropriate for their 
tumor type and stage of disease, or, in the opinion of the Investigator, would be 
unlikely to tolerate or derive clinically meaningful benefit from appropriate 
standard-of-care therapy 
Note: If it is determined by the Investigator that a patient would be unlikely to 
tolerate or derive clinically meaningful benefit from standard-of-care therapy, the 
specific reason(s) for such a determination will be documented in the electronic 
case report form (eCRF). 
5. CLIA diagnosis of eligible cancer mutation or fusion  
a. Cohort A:  EGFR exon 20 insertion mutation  
b. Cohorts B, B1 and D:  HER2-activating mutation  
c. Cohort C:  NRG1 or ERBB/HER-family gene fusions 
6. Must have at least 1 target lesion evaluable by RECIST v1.1 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
8. Minimum life expectancy of 3 months or more 
9. Clinical laboratory values meeting the following criteria within the 7 days prior to 
Cycle 1 Day 1 
a. Calculated creatinine clearance ≥ 30 mL/min using Cockcroft-Gault equation 
b. Total bilirubin  
• ≤ 1.5 x ULN or  
• ≤ 3 x ULN in the presence of liver metastases 
c. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)  
• ≤ 2.5 x ULN or 


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•  ≤ 5 x ULN, in the presence of liver metastases 
d. Absolute neutrophil count ≥ 1,500 cells/μL 
e. Hemoglobin ≥ 9 g/dL or 5.6 mmol/L 
f. Platelet count ≥ 100,000/μL 
10. Adequate cardiac function meeting all of the following ECG criteria:  
a. No evidence of second- or third-degree atrioventricular block  
b. No clinically significant arrhythmia (i.e., pauses of > 4 seconds, ventricular 
tachycardia of any duration, supraventricular tachycardia > 4 beats/minute)  
c. QRS interval ≤ 110 msec  
d. QTc interval of < 450 msec as calculated according to Fridericia’s formula 
(QTcF = QT/[R to R interval]0.33)  
e. PR interval ≤ 200 msec (does not apply to people with chronic stable atrial 
fibrillation or atrial flutter as determined by the Investigator)  
11. Adequate pretreatment tumor sample (125 µm of formalin-fixed paraffin embedded 
(FFPE) block or at least 8 prepared slides) 
Note:  Tumor tissue should be from the most recent pretreatment biopsy; if only 
archival tissue from the initial biopsy is available, it is acceptable  
12. All toxicities from prior therapy (except alopecia and neuropathy) must have resolved to 
baseline or to ≤ Grade 2 according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) v5.0 prior to Cycle 1 Day 1 
13. For women of childbearing potential (WOCBP), documentation of negative serum 
pregnancy test (β-human chorionic gonadotropin) within 7 days prior to Cycle 1 Day 1   
Note:  WOCBP is defined as fertile, following menarche and until becoming 
post-menopausal (no menses for 12 months without an alternative medical cause) 
unless permanently sterile (had a hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy) 
14. For WOCBP, agreement to use a highly effective method of contraception during the 
study and for at least 90 days after the last dose of study treatment   
Note:  Highly effective birth control includes a) intrauterine device; b) oral, 
implantable or injectable combined hormonal (estrogen and progestogen 
containing) or progestogen-only contraceptive associated with inhibition of 
ovulation; c) intrauterine hormone-releasing system; or d) bilateral tubal 
occlusion, vasectomized partner, sexual abstinence 
15. For male patients, agreement to use a condom and a highly effective method of 
contraception during the study and for at least 30 days after the last dose of study 
treatment.  Male patients should also refrain from sperm donation during this time period.  
16. Willingness and ability to comply with scheduled visits and study procedures 
5.2 
Exclusion Criteria 
Potential patients who meet any of the following criteria will be excluded: 
1. Has another known activating oncogene-driver mutation, including, but not limited to 
KRAS, ALK, ROS1, RET, BRAF, NTRK1/2/3, MET, MEK1, NRAS and HRAS.  


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Note:  If another mutation is present but is deemed to be a tumor suppressor 
mutation or a variant of unknown significance then the patient may be enrolled 
with Sponsor approval of the mutation report. 
2. Cohorts A, B, B1 and D only:  Previously received anti-EGFR or anti-HER2 TKIs 
including but not limited to erlotinib, gefitinib, afatinib, dacomitinib, osimertinib, 
poziotinib, TAK788, nazartinib, lapatinib, or neratinib   
3. Cohorts A and B only:  Previously received anti-EGFR or anti-HER2 monoclonal 
antibodies or EGFR or HER2 antibody-drug conjugates including but not limited to 
cetuximab, necitumumab, panitumumab, trastuzumab, trastuzumab emtansine (TDM-1), 
or pertuzumab 
4. Received other recent antitumor therapy including: 
a. Investigational therapy administered within the 21 days prior to Cycle 1 Day 1 or 
5 half-lives, whichever is shorter.  
Note:  Exceptions may be made with Medical Monitor approval for 
investigational therapies where the half-life is unknown or shorter than 5 half-
lives have passed between last dose of investigational therapy and Cycle 1 Day 1. 
b. Any standard chemotherapy or radiation within 14 days prior to Cycle 1 Day 1   
Note:  Adequate time must have passed from the last treatment to first scheduled 
treatment in this study to clear the timeframe for actual or anticipated toxicities of 
such treatment 
c. Any immunotherapy (e.g., pembrolizumab, nivolumab, atezolizumab, or 
durvalumab) within 21 days prior to Cycle 1 Day 1 
5. Clinically active or symptomatic ILD or interstitial pneumonitis. 
Note:  A patient with documented resolution of prior clinically significant ILD or 
radiation pneumonitis will be eligible for enrollment.  
6. Has any of the following within 28 days prior to the first dose of study drug: 
• ALT and AST > 3 × ULN if no hepatic metastases are present; > 5 × ULN if 
hepatic metastases are present 
• Total bilirubin > 1.5 × ULN; > 3 × ULN with direct bilirubin > 1.5 × ULN in the 
presence of Gilbert’s syndrome 
7. Untreated central nervous system (CNS) metastases and/or untreated/treated 
leptomeningeal disease  
Note:  Patients who require steroid for CNS metastases must be on a stable or tapering 
dose of corticosteroids for at least 2 weeks prior to Cycle 1 Day 1 to be eligible for the 
trial.  If applicable, patients must complete stereotactic radiosurgery 7 days prior to Cycle 
1 Day 1 and whole brain radiotherapy 21 days prior to Cycle 1 Day 1. 
8. Receiving medication that prolongs QT interval, with a risk of TdP per protocol 
Appendix B, unless one of the following criteria are met: 
a. Enrollment is allowed if discontinuation of such medication occurs at least 
5 half-lives before Cycle 1 Day 1 OR 


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b. The patient is on a stable dose of a concomitant medication listed in Appendix B 
prior to study entry and Sponsor approval is obtained 
Note:  Exceptions may be made with Medical Monitor approval (e.g., for medications 
where the half-life is unknown or for QT prolonging medications not listed in 
Appendix B). 
9. Personal or familial history of Long QT Syndrome, sudden death, or TdP   
10. History of significant cardiovascular disease, including: 
a. Cardiac failure New York Heart Association class III or IV or LVEF < 55% 
b. Myocardial infarction, severe or unstable angina within 6 months prior to 
enrollment 
c. TdP, ventricular arrhythmia (i.e., ventricular tachycardia or ventricular 
fibrillation) 
d. Clinically significant thrombotic or embolic events within 3 months prior to 
enrollment  
Note:  Significant thrombotic or embolic events include but are not limited to 
stroke or transient ischemic attack.  Catheter-related thrombosis is not a cause for 
exclusion.  Diagnosis of deep vein thrombosis or pulmonary embolism is allowed. 
e. Any uncontrolled or severe cardiovascular disease 
11. Known concurrent malignancy that is expected to require active treatment within 2 years 
or may interfere with the interpretation of the efficacy and safety outcomes of this study 
in the opinion of the treating Investigator and confirmed by the Medical Monitor   
Note:  Prior malignancy that is at a low risk of progression or recurrence 
(e.g., superficial bladder cancer, non-melanoma skin cancers, or low-grade 
prostate cancer not requiring therapy) may be allowed after discussion and 
approval of the Medical Monitor 
12. Major surgery within 4 weeks prior to Cycle 1 Day 1  
13. Infection requiring systemic treatment within 7 days prior to Cycle 1 Day 1   
14. History of severe allergic or anaphylactic reactions or hypersensitivity to compounds of 
similar chemical or biologic composition as tarloxotinib 
15. Known human HIV infection or active hepatitis B or C   
16. Women who are pregnant or breastfeeding 
17. Any other medical condition (e.g., alcohol abuse) or psychiatric condition that, in the 
opinion of the Investigator, might interfere with the patient’s participation in the trial or 
interfere with the interpretation of trial results   
 
5.3 
Patient Withdrawal Criteria  
All patients are free to discontinue study treatment or withdraw from the study at any time.  All 
patients wishing to discontinue from study treatment or withdraw from the study will be queried 
to determine the reason for withdrawal while respecting the privacy of the patient.  The reason a 
patient decided to withdraw from study treatment will be recorded.    


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In the event of consent withdrawal, the Investigator should make every effort to ensure that the 
patient is followed for AEs for a minimum of 30 days after their last dose of study treatment, 
with documented patient agreement.   
Patients will be discontinued from study treatment if any of the following events occurs:  
• Any unacceptable toxicity attributable to study treatment (e.g., hepatotoxicity meeting 
Hy’s Law criteria)  
• Progressive disease according to RECIST v1.1 at any time during the study  
o Unless approved by the Medical Monitor (See Section 6.6) 
• Clinical progression (e.g., symptomatic deterioration) not meeting the RECIST v1.1 
criterion for progressive disease but considered by the Investigator to require withdrawal 
from study treatment 
• Patient is unable to tolerate dosing after more than 2 dose reductions  
• Patient misses 2 doses  
o Exception:  Patients who miss 2 doses may continue study treatment following 
agreement between the Investigator and the Medical Monitor. 
• Significant deviation from the protocol or eligibility criteria.  These patients may 
continue study treatment following a discussion and agreement between the Investigator 
and the Medical Monitor and subsequent approval by the institutional review board 
(IRB) or independent ethics committee (IEC). 
• Pregnancy  
• Patient withdrawal of consent and/or election to discontinue study treatment 
• Termination of the study by the Sponsor 
• Any other reason which, in the opinion of the Investigator, would justify removing the 
patient from the study treatment  
A patient may also be withdrawn from study treatment by the Sponsor, Regulatory Authorities, 
or IECs/IRBs.   
If a patient discontinues study treatment due to the ongoing coronavirus disease 2019 
(COVID-19) global pandemic, information should be captured on the eCRF so that this can be 
summarized in the clinical study report at the end of the study, in line with the FDA Guidance 
(FDA 2020).  The reason for discontinuation should be recorded in the eCRF as COVID-19, if 
applicable, and include as many details as possible.  For example, specific reasons may include, 
but are not limited to: 
• The patient exhibits symptoms consistent with COVID-19. 
• The patient has a positive test result for COVID-19. 
• The patient has neither symptoms nor a positive test for COVID-19 but has decided to 
discontinue treatment due to personal choice related to COVID-19 concerns. 


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Patients who are discontinued from study treatment for reasons other than progressive disease by 
RECIST v1.1 should undergo scans for tumor assessment according to the original tumor 
assessment schedule (every 8 weeks [± 5 days] from Cycle 1 Day 1) until any of the following 
occurs, whichever comes first:  
• Progressive disease (PD) by RECIST v1.1,  
• Initiation of new anticancer treatment, or  
• Discontinuation from the study (death, withdrawal of consent, or loss to follow-up).   
After discontinuation from study treatment, all patients will have an End-of-Treatment Visit 
(EOT).  All patients, including those discontinued due to PD, will undergo a post-treatment 
Safety Follow-up Visit at 30 days (± 7 days) after last tarloxotinib infusion.   
Withdrawal from the study should be in a step-wise fashion.  As mentioned above, patients may 
withdraw or be withdrawn from study treatment.  Any patient who withdraws or is withdrawn 
from study treatment should be encouraged to complete all planned safety and follow-up 
assessments.  If the patient wished to withdraw from all study assessments, permission should be 
requested to contact the patient, a designated contact person, or the patient’s primary care 
provider.  If the patient does not wish any direct follow-up, permission should be requested to 
conduct periodic medical record review and/or contact the patient’s medical care provider.   
6. TREATMENT OF PATIENTS  
6.1 
Patient Enrollment  
Prior to any study-related assessments, all potential patients will provide written informed 
consent.  Informed consent can be obtained any time prior to Cycle 1 Day 1.  All patients who 
provide informed consent will be assigned a unique patient identification number consisting of 
6 digits, the first 3 digits will represent investigational site and the second 3 digits will identify 
the patient within that site (Figure 13); patient numbering within sites will begin with the number 
“– 201.”  Once a patient identification number has been assigned, it will be used to identify the 
patient throughout the study and it cannot be reassigned to another patient.   
Figure 13: 
Sample Patient Identification Number  
 
 
All potential patients must be approved by the Medical Monitor prior to enrollment.  
Investigational sites will provide the Medical Monitor with a completed Eligibility Checklist and 
relevant redacted source documents.  The Medical Monitor (or designee) will review the 
provided documentation and confirm the patient’s preliminary eligibility.  The Medical Monitor 


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(or designee) should be able to respond within 1 business day.  Following review of the provided 
documentation, the Medical Monitor (or designee) will notify the investigational site if the 
patient appears eligible.  Patients who meet eligibility criteria may be enrolled.  Patients will be 
considered enrolled after receiving any tarloxotinib.  
6.2 
Tarloxotinib Administration 
Tarloxotinib will be administered as an IV infusion using an IV infusion or syringe pump and a 
0.2-micron inline filter.  Tarloxotinib may be infused with latex-free polyvinyl chloride or 
polyolefin containers and equipment.   
6.2.1 
Tarloxotinib Dose Calculation  
Tarloxotinib will be administered at a dose level of 150 mg/m2.  The dose administered will be 
based on the patient’s body surface area (BSA) determined on Day 1 of each cycle or within 
7 days (e.g., Day 21 of the prior cycle).  The DuBois and DuBois formula for BSA calculation is:  
BSA = (W 0.425 x H 0.725) x 0.007184 
Investigational sites are instructed to use the DuBois and DuBois formula but may also use the 
formula/method in current institutional practice if accurate dose calculation can be assured.   
Tarloxotinib doses within a cycle do not need to be adjusted unless there is a > 10% change in 
weight.   
6.2.2 
Tarloxotinib Infusion Duration  
Tarloxotinib infusions must be at least 1 hour (60 minutes) in duration.  The tarloxotinib infusion 
can be slowed or interrupted in the event of infusion-related reactions.  If the tarloxotinib 
infusion is interrupted, it should be restarted at one-half the infusion rate after the symptoms of 
the infusion-related reaction have resolved.   
6.2.3 
Tarloxotinib Administration Schedule  
Tarloxotinib will be administered on Day 1, Day 8, Day 15, and Day 22 of every 28-day cycle.  
All infusions after Cycle 1 Day 1 will be administered 7 days ± 1 day after the prior infusion.  
Investigators are instructed to avoid dose schedule modifications whenever possible, especially 
within the first 3 cycles of study treatment.  The reason for the dose schedule modification 
should be recorded in the eCRF. 
Dose Delays 
All dose schedule modifications of > 1 day must be discussed with the Medical Monitor (or 
designee).  Intentional cycle delays of > 1 day (e.g., patient vacation, physician requested “drug 
holiday”) must be approved by the Medical Monitor (or designee).  Study visits will align with 
tarloxotinib infusion days.  If a tarloxotinib dose must be delayed > 3 days, this will be 
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Missed Doses 
If a patient misses a dose due to hospitalization or any other reason, the next dose received will 
be referred to as the next scheduled dose (e.g., If a patient misses their Cycle 1 Day 22 infusion, 
the next dose will be administered at their Cycle 2 Day 1 visit.).  If a patient must miss their 
Cycle 2 Day 1 dose, the assessments that were planned for this visit (e.g. PK assessments and 
ECGs) should be collected at the Cycle 2 Day 8 visit to ensure adequate data is collected for 
these endpoints.  For other missed visits, any assessments that were part of the missed visit, but 
are not part of the next visit (i.e., no need to duplicate tests) should be collected, if possible, at 
the next visit. Radiographic tumor assessments should continue per the Study Schedule (i.e., 
every 8 weeks [± 5 days] from Cycle 1 Day 1) regardless of changes to the dosing schedule.   
If there is an unavoidable delay of an infusion due to COVID-19, the Medical Monitor should be 
informed as soon as possible.  The infusion should be rescheduled based on Investigator 
judgment, taking into consideration the patient’s safety.   
6.3 
Premedication 
All patients may receive steroid or anti-emetics premedication prior to tarloxotinib infusions.  
The premedication regimen will be determined by the Investigator and may be adjusted at 
subsequent infusions based on the signs and symptoms observed during or after prior infusions.  
Additionally, patients may be discharged with take-home prophylactic medications.   
The tarloxotinib Phase 1 and 2 studies demonstrated that tarloxotinib is associated with 
non-hematologic toxicities.  These included mainly low-grade skin rash and diarrhea typical of 
that observed with EGFR TKIs.  For this reason, prophylaxis and treatment for these toxicities 
should be considered following institutional guidelines, similar to another EGFR TKI such as 
erlotinib or afatinib.   
Infusion-related reactions were observed in patients receiving tarloxotinib.  These reactions were 
characterized by flushing, urticarial skin rash, pruritus, and hypotension occurring during or 
immediately following the infusion of tarloxotinib.  Patients who experienced an infusion 
reaction with the first dose of tarloxotinib received prophylactic steroids prior to subsequent 
doses, which reduced the severity of infusion reactions.  Therefore, prophylaxis for drug 
hypersensitivity reactions that may include a glucocorticoid and an anti-histamine may be 
considered prior to each tarloxotinib dose according to institutional guidelines. 
Nausea and vomiting have occurred in patients in the Phase 1 and 2 studies; therefore, anti-
emetic prophylaxis for minimally to moderately emetogenic regimens should be considered after 
Cycle 1 Day 1 according to institutional guidelines.  Prophylaxis against nausea and vomiting in 
the tarloxotinib studies was based on metoclopramide as a single agent.  If a 5-HT3 antagonist is 
required, palonosetron should be employed, if possible, as it is considered to have the least 
potential among 5-HT3 antagonists for QT prolongation.   


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6.4 
Potassium Supplementation 
Serum electrolytes (including potassium) will be checked prior to each tarloxotinib infusion.  
• Tarloxotinib will not be administered if the serum potassium level is < 3.5 mEq/L.  
• Patients with a serum potassium of < 3.5 mEq/L will receive potassium replacement per 
institutional policy (IV and/or oral) and have the scheduled tarloxotinib infusion delayed 
at least 24 hours and potassium levels rechecked within 1 hour prior to the rescheduled 
infusion.  
All patients who present with a serum potassium level of ≥ 3.5 mEq/L will be given potassium 
supplementation prior to tarloxotinib infusion based on pre-infusion serum potassium result 
(Table 5).  
Table 5: 
Potassium Supplementation Guidelines  
Pre-infusion 
Serum Potassium 
(mEq/L) 
Potassium 
Supplement Strategy 
< 3.5 
• 
Hold tarloxotinib  
• 
Administer potassium replacement per institutional policy (IV and/or PO) 
• 
Delay the scheduled tarloxotinib infusion delayed at least 24 hours and potassium 
levels rechecked within 1 hour prior to the rescheduled infusion 
3.5 to 4.0 
• 
All patients will be supplemented daily with 20 mEq of potassium (IV or PO).  
> 4.0 
• 
Administer potassium replacement per institutional policy (IV and/or PO) 
IV = intravenous; PO = oral 
6.5 
Treatment and Retreatment Criteria 
The result of tumor assessments is not required for the initiation of subsequent cycles, but 
patients must meet the following criteria before receiving each tarloxotinib infusion.  Note:  all 
ECG dose modifications will be based on the average manually measured QTcF.   
• No QTcF of ≥ 601 msec during any previous infusion 
Note:  Patients with QTcF of ≥ 501 msec and < 601 msec during or following the prior 
infusion MUST be dose reduced.  If QTcF prolongation is ≥ Grade 3, an ECG may need to 
be repeated more frequently during a patient’s visit as indicated in Table 7, depending on the 
degree of the prolongation  and per institutional standards. 
• Check serum electrolytes 
o Pre-infusion magnesium and calcium in normal range, unless an exception is 
approved by the Medical Monitor. 
o If other electrolytes (eg, sodium, chloride) are outside of the normal range, patient can 
receive tarloxotinib infusion if it is deemed safe per Investigator discretion. 
o Pre-infusion serum potassium must be ≥ 3.5 mEq/L.  
• Pre-infusion ECG  


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o No evidence of second- or third-degree atrioventricular block  
o QTcF interval of < 450 msec  
• Skin rash of ≤ Grade 2  
• Gastrointestinal toxicity of ≤ Grade 2  
• Any other clinically significant tarloxotinib-related toxicity must return to at least 
Grade 2.   
All patients not meeting retreatment criteria must be discussed with the Medical Monitor (or 
designee) and possible dose/schedule modification and/or study treatment discontinuation 
discussed.   
6.6 
Treatment Beyond Progression 
Patients with disease progression may continue to receive tarloxotinib if, in the opinion of the 
Investigator, the patient is still benefiting (e.g., asymptomatic systemic progression or local 
symptomatic progression) following discussion with and approval by the Medical Monitor (or 
designee).  The IRB/IEC will be notified of any planned treatment beyond progression.  Patients 
may receive palliative radiation to disease sites of progression, including brain metastases, 
following discussion with and approval by the Medical Monitor (or designee).  
6.7 
Tarloxotinib Dose Modifications 
All patients will begin study treatment with a dose level of 150 mg/m2 based on the body weight 
measured on Day 1 of each cycle (or within 7 days prior [e.g., Day 22 of the prior cycle]).  As 
described above, tarloxotinib dose calculations do not need to be adjusted within a cycle unless 
the patient has a > 10% change in body weight.  Other dose modifications may be required based 
on QTc prolongation, infusion-related reactions, and other tarloxotinib-related toxicity as 
described in: 
• Table 7:  Treatment Guidelines for QTcF Prolongation 
• Table 8:  Treatment Guidelines for Infusion-related Reactions 
• Table 9:  Treatment Guidelines for Tarloxotinib-related Non-Hematologic Toxicity 
Dose level reductions will be in a step-wise fashion.  The dose level reductions are presented in 
Table 6.  If a patient requires more than 2 dose level reductions, tarloxotinib will be permanently 
discontinued.   


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Table 6: 
Tarloxotinib Dose Reductions  
Dose Level Reduction 
Tarloxotinib Dose 
(mg/m2) 
Grade 3 QTc prolongation  
based on a QTcF ≥ 501 msec 
IRR and/or hematologic/ 
non-hematologic toxicity 
1 
100 
120 
2 
75 
3 
Discontinue tarloxotinib 
IRR = infusion-related reaction; QTc = corrected QT interval; QTcF = corrected QTc interval as calculated 
according to Fridericia’s formula 
 
Hematologic toxicity has not been associated with tarloxotinib administration to date.  However, 
if Grade 3 or 4 neutropenia or thrombocytopenia considered related to tarloxotinib occurs, then 
the treatment guidelines for non-hematologic toxicity described in Table 9 should be followed.  
Dose modifications for anemia (any grade) or for Grade 2 or less neutropenia or 
thrombocytopenia are not required.   
If a tarloxotinib-related toxicity results in a treatment delay of more than 3 weeks (withholding 
more than 2 doses of tarloxotinib), patients will be removed from study treatment unless 
otherwise approved by the Medical Monitor.   
6.7.1 
Treatment Guidelines for QTc Prolongation 
Immediate medical management of patients will be based on the following:  
1. Baseline:  A pre-infusion (baseline) ECG will be obtained on all patients, if the 
automated measurements indicate a QTcF of ≥ 450 msec 
a. The single QTcF will be verified by manually measuring at least 3 complexes within 
the ECG and determining the average QTcF 
b. All patients must have a pre-infusion QTcF of < 450 msec by either: 
 
Calculation using the automated measurements of the first ECG or  
 
The manual measurement of a single ECG 
If it is determined that the manually read QTcF ≥ 450 msec, the Medical Monitor should 
be contacted to discuss the clinical significance of the reading and to determine if it is 
appropriate to move forward with the infusion. 
2. During treatment:  Grade 3 QTc prolongation (any QTcF that is ≥ 501 msec 
OR > 60 msec QTcF increase relative to pre-infusion) will be manually verified by 
measuring at least 3 complexes with the ECG and determining the average QTcF.  If 
QTcF prolongation is ≥ Grade 3, an ECG may need to be repeated more frequently 
during a patient’s visit, depending on the degree of the prolongation, as indicated in 
Table 7 and per institutional standards. 
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If the Investigator has any question regarding the local automated reading, a local cardiologist 
should be consulted.  Treatment guidelines for patients experiencing QTc prolongations are 
provided in (Table 7).   
Patients who experience ≥ Grade 3 QTc prolongation must be assessed by the Investigator (or 
qualified designee) prior to discharge.  
Table 7: 
Treatment Guidelines for QTc Prolongation 
QTc Prolongation 
After Tarloxotinib Administration 
Grade 1 
450 to 480 msec QTcF 
• Cycle 1 and Cycle 2 Day 1 
o 
May be discharged if the 4-hour (or later) post-infusion QTcF is Grade 1 or 
lower and asymptomatic  
• After Cycle 2 Day 1 
o 
Obtain pre-infusion and 2-hour post-infusion ECGs 
o 
May be discharged if the 2-hour (or later) post-infusion QTcF is ≤ Grade 1 
and the patient is asymptomatic  
• Continue the same tarloxotinib dose for subsequent cycles  
Grade 2 
481 to 500 msec QTcF 
• Cycle 1 and Cycle 2 Day 1 
o 
May be discharged if the 4-hour (or later) post-infusion QTcF is ≤ Grade 2 
and the patient is asymptomatic  
• After Cycle 2 Day 1 
o 
Obtain pre-infusion and 2-hour post-infusions ECGs 
o 
May be discharged if the 2-hour or later post-infusion QTcF is ≤ Grade 2 
and the patient is asymptomatic  
• Continue the same tarloxotinib dose for subsequent cycles  
Grade 3 
≥ 501 msec QTcF 
• Obtain ECGs every 15 to 30 minutes until QTcF is ≤ Grade 2 and then obtain 
ECGs every 1 hour 
• May be discharged home if 2 subsequent measurements (at least 15 minutes apart) 
after the 4-hour post-infusion QTcF is ≤ Grade 2 and no significant arrhythmias 
• If QTcF is ≥ 601 msec, permanently discontinue tarloxotinib  
• If QTcF ≥ 501 msec and ≤ 600 msec   
o 
Resume tarloxotinib dosing with dose reduction  
▪ 
1st occurrence:  reduce to 100 mg/m2 
▪ 
2nd occurrence:  reduce to 75 mg/m2 
▪ 
3rd occurrence:  permanently discontinue tarloxotinib  
• Obtain ECGs prior to and hourly (for at least 4 hours) following the next 
tarloxotinib infusion  
Grade 3 
> 60 msec increase from 
pre-infusion QTcF AND 
≤ 500 msec QTcF 
• Obtain ECGs every 15-30 minutes until QTcF is ≤ Grade 2 and then obtain ECGs 
every 1 hour 
• May be discharged home if 2 subsequent measurements (at least 15 minutes apart) 
after the 4-hour post-infusion QTcF is ≤ Grade 2 and no significant arrhythmias 
• Obtain ECGs prior to and hourly (for at least 4 hours) following the next 
tarloxotinib infusion 
Grade 4 
TdP or polymorphic 
ventricular tachycardia, 
signs/symptoms of serious 
arrhythmia 
• Place patient on telemetry and obtain ECGs as clinical indicated 
• Obtain Cardiologist consult and admit to hospital for extended observation on 
telemetry  
• Permanently discontinue tarloxotinib  
ECG = electrocardiogram; msec = millisecond; QTcF = corrected QT interval as calculated according to Fridericia’s 
formula; TdP = Torsade de Pointes  
Note:  If QTcF prolongation is ≥ Grade 3, an ECG may need to be repeated more frequently during the patient’s 


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visit depending on the degree of the prolongation and per institutional standards. 
 
Treatment and retreatment guidelines in this study are based on absolute QTcF observations that 
vary from the NCI CTCAE.  Importantly, dose reductions are not based on the QTcF change 
from baseline, only the absolute QTcF.  For example, if a patient has a change > 60 msec from 
baseline but has an absolute QTcF ≤ 500 msec, no dose reduction is required. 
6.7.2 
Treatment Guidelines for Infusion-related Reactions 
Treatment and management of infusion-related reactions will be based on the severity and type 
of symptom(s) experienced.  Treatment guidelines for infusion-related reactions are presented in 
Table 8.   
Table 8: 
Treatment Guidelines for Infusion-Related Reactions 
Grade 
(CTCAE v5.0) 
Definition 
Treatment Guideline 
Grade 1 
• Mild transient reaction 
• Infusion interruption not indicated  
• Intervention not indicated  
• Monitor for at least 2 hours after the end of the 
infusion 
• Provide patient instructions and prophylactic 
medications at discharge as appropriate  
• Consider adjusting premedication based on 
symptoms for subsequent infusions  
Grade 2 
• Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment  
• Prophylactic medications indicated 
for ≤ 24 hours 
• Administration of medications 
(e.g., anti-histamines, steroids, NSAIDs and 
IV fluids), as appropriate 
• Monitor for at least 2 hours after the end of the 
infusion  
• Consider adjusting premedication based on 
symptoms for subsequent infusions 
Grade 3 
• Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion)  
• Recurrence of symptoms following 
initial improvement, 
hospitalization indicated for 
clinical sequelae  
• Administration of medications 
(e.g., anti-histamines, steroids, NSAIDs and 
IV fluids), as appropriate 
• Hospitalization for medical care and 
observation  
• Reduce tarloxotinib dose to 120 mg/m2 for 
subsequent doses*, or consider slowing 
infusion rate, and/or adjusted premedication 
after discussion with the Medical Monitor 
• If Grade 3 infusion reaction recurs after this 
initial dose reduction, then reduce the 
tarloxotinib dose to 75 mg/m2 for subsequent 
doses*  
Grade 4 
• Life-threatening consequences 
• Urgent intervention indicated  
• Hospitalization for urgent medical treatment  
• Discontinue tarloxotinib permanently  
CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NSAID = nonsteroidal 
anti-inflammatory drug 
* Dose re-escalation may be permitted following discussion and approval by the Medical Monitor 
 


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6.7.3 
Treatment Guidelines for Other Non-Hematologic Toxicity 
Table 9 provides treatment guidelines for treating tarloxotinib non-hematologic toxicities other 
than QT prolongation and infusion-related reactions.   
Table 9: 
Treatment Guidelines for Tarloxotinib-Related Non-Hematologic 
Toxicity 
Toxicity 
(CTCAE v5.0) 
Details 
Hold Dose 
Dose Levels After Recovery 
to ≤ Grade 2 or Baseline 
Grade 2 
Intolerable  
Intolerable skin toxicity or 
diarrhea  
Hold dose until resolution 
to Grade 0 or 1 or Grade 2 
tolerable  
If symptoms are intolerable, 
recurrent, or not controlled by 
supportive care, hold dose until 
symptoms improve and reduce 
to next lower dose level 
Grade 2 
ALT or AST > 3 x ULN 
Hold dose until resolution 
to < Grade 2 or baseline 
150 mg/m2 (no reduction)  
ALT or AST > 3 x ULN 
(Grade 2) AND a total 
bilirubin ≥ 2 x ULN (patients 
without liver metastasis)** 
Treatment to be 
discontinued  
Not applicable 
Grade 3  
Except nausea and vomiting*  
Hold dose until resolution 
to Grade 0 or 1 or Grade 2 
tolerable 
120 mg/m2; if recurs, then 
second reduction to 75 mg/m2  
Grade 4  
Life-threatening conditions  
Treatment to be 
discontinued  
Not applicable 
Grade 4  
Except fatigue and 
non-life-threatening 
pulmonary embolism that are 
adequately treated  
Hold dose until resolution 
to Grade 0 or 1  
120 mg/m2; if recurs, then 
second reduction to 75 mg/m2  
ALT = alanine aminotransferase; ASP = aspartate aminotransferase; CTCAE = Common Terminology Criteria 
for Adverse Events; ULN = upper limit of normal 
* May hold or reduce if nausea/vomiting continues despite optimized anti-emetic treatment 
** Tarloxotinib-related toxicity meeting the definition of Hy’s Law, tarloxotinib will be discontinued 
permanently 
 
6.8 
Compliance 
Investigators are required to conduct the study in compliance with the protocol.  Compliance 
with the protocol will be closely monitored.  Important aspects of compliance with this clinical 
trial include:  
• Eligibility,  
• Tarloxotinib administration, including: 
o Dose calculation 
o Dose modification 
o Infusion duration 
• Performance of protocol-specified assessments,  


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• ECG monitoring, and  
• AE reporting 
Protocol deviations are defined as any departure from the protocol or associated instructions and 
will be monitored.  Deviations from the protocol, including violations of inclusion/exclusion 
criteria, will be assessed as “minor” or “major.”  Protocol deviations at investigational sites will 
be discussed with the Investigator and additional training will be provided as needed to secure 
Investigator compliance.   
Study staff will receive additional training as needed to prevent non-compliance.  
6.9 
Study Visits  
Protocol-required assessments scheduled for each study visit are summarized in the Schedule of 
Events and described below.  All assessments with a time point relative to study treatment 
infusion may be performed in the 5 minutes prior to and following the protocol-specified time.  
Any assessment that is not able to be collected at the protocol-specified time (e.g., blood sample 
for pharmacokinetic testing) should be obtained as soon as practicable and the actual date/time of 
collection recorded.  
6.9.1 
Screening Period/Baseline Assessments 
Patients may be screened anytime during the 28 days prior to Cycle 1 Day 1.  Unless otherwise 
specified, baseline assessments may be done anytime following consent and prior to the first 
study drug administration.  Patients who are determined not to meet eligibility criteria at any 
time prior to Cycle 1, Day 1 will not receive study drug.  The following will be assessed or 
measured at screening/baseline: 
• Informed consent  
• Eligibility (including tumor assessment) 
• Medical/Disease history 
• Smoking history:  Smoking history should be documented in the eCRF page as “never”, 
“former” (with quit date), or “current” (document pack years). 
• Demographics  
• Physical examination  
• Weight  
• ECOG 
• Vital signs  
• ECG (12-lead) 
• Hematology panel  
• Serum chemistry panel  


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• Urinalysis  
• Pregnancy test  
o Serum pregnancy test within 3 to 7 days of Cycle 1 Day 1 
• Tumor tissue  
o FFPE block from newly obtained biopsy or archive tissue of at least 8 to 10 slides  
Note:  Adequacy must be confirmed by local pathologist. 
• Concomitant medications 
o Record all concomitant medications use after 14 days prior to Cycle 1 Day 1 
o Special attention should be accorded to medications that are known to cause 
prolongation of QTc or deplete potassium 
• Conduct baseline radiographic tumor assessment 
o Perform according to institutional practice; include CT or MRI of the chest and 
abdomen, brain scan, and bone scan.  The baseline radiographic tumor assessment is 
required within 28 days prior to the first dose of tarloxotinib.  Brain and bone scans 
do not need to be repeated for patients with no brain or bone metastases at baseline.  
A recently completed negative positron emissions tomography (PET) scan can be 
substituted for the baseline bone scan.   
6.9.2 
Treatment Period  
The following will be assessed or measured at the indicated study days: 
Day 1 
• Complete physical examination  
• ECOG (Cycle 1) 
• Weight 
• Vital signs  
o Pre-infusion  
o End of infusion (EOI) 
o 30, 60, and 90 minutes after EOI (± 10 minutes) 
• ECG (12-lead)  
o Cycle 1  
▪ Pre-infusion  
▪ EOI 
▪ 1, 2, 3, and 4 hours after EOI (± 10 minutes) 
▪ Hourly thereafter as needed (see Section 6.9.2.1)  
o Cycle 2  
▪ Pre-infusion  


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▪ EOI 
▪ 1, 2, 3, and 4 hours after EOI (± 10 minutes) 
▪ Hourly thereafter as needed (see Section 6.9.2.1) 
o Cycles 3+ 
▪ Pre-infusion  
▪ 2 hours after EOI (± 10 minutes) 
▪ 4 hours after EOI (patients with QTcF ≥ 501 msec) (± 10 minutes) 
▪ Hourly thereafter as needed (see Section 6.9.2.1)   
• Hematology panel  
• Serum chemistry panel  
• Serum potassium (Cycles 1 and 2 only) 
o EOI  
o 3 hours after EOI (± 10 minutes) 
• Urinalysis  
• Pregnancy test  
o Urine (dipstick allowed) 
• PK samples (Cycles 1 and 2 only) 
o Pre-infusion (± 5 minutes) 
o EOI (± 5 minutes) 
o 3 hours after EOI (± 10 minutes) 
o 7 hours after EOI (in a subset of patients on Cycle 1 Day 1 only) (± 10 minutes) 
• Blood sample for biomarkers (e.g., ctDNA) (Cycles 1 and 2) 
• Ensure that all electrolytes are within normal ranges  
• Potassium supplementation, if applicable (See Table 5) 
• Premedication, as applicable per local institutional guideline 
• Tarloxotinib infusion (at least 1 hour in duration) 
• Concomitant medications 
• Assess AEs 
Days 8, 15, and 22  
• Vital signs  
o Pre-infusion  
o EOI 
o 30, 60, and 90 minutes after EOI (± 10 minutes) 
• ECG (12-lead)  


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o Cycle 1 
▪ Pre-infusion  
▪ EOI 
▪ 1, 2, 3, and 4 hours after EOI (± 10 minutes) 
▪ Hourly thereafter as needed (see Section 6.9.2.1) 
o Cycles 2+ 
▪ Pre-infusion  
▪ 2 hours after EOI (± 10 minutes) 
▪ 4 hours after EOI (patients with ≥ Grade 3 QTcF prolongation) (± 10 minutes) 
▪ Hourly thereafter as needed (see Section 6.9.2.1) 
• Serum chemistry panel  
• Urinalysis (Cycle 1 only) 
• Optional tumor biopsy  
o Day 15 after EOI (preferred) or Day 16 (within 24 hours of any EOI) 
o Plasma samples for PK and biomarkers should be obtained as close to the time of 
biopsy as possible 
• Ensure that all electrolytes are within normal ranges  
• Potassium supplementation, if applicable (See Table 5) 
• Premedication, as applicable per local institutional guideline 
• Tarloxotinib infusion (at least 1 hour in duration) 
• Concomitant medications 
• Assess AEs 
Note:  Pre-infusion assessments scheduled for Day 1 of Cycles 2 and later cycles are considered 
Day 29 of the prior cycle.  If any patient is not proceeding to an additional cycle, the assessments 
scheduled for the EOT should be performed within ± 7 days of their last dose of tarloxotinib.   
Every 8 weeks (± 5 days) From Cycle 1 Day 1 
• Radiographic tumor assessments 
o The first post-baseline radiographic tumor assessment will occur 8 weeks after the 
Cycle 1 Day 1 visit.  The same imaging modality used for baseline imaging (i.e., CT 
or MRI) must be used for subsequent radiographic tumor assessments. 
6.9.2.1 
Electrocardiogram Guidance for QT Prolongation During the Treatment 
Period 
In the event of QTcF prolongation (≥ 501 msec or > 60 msec increase compared to pre-infusion), 
repeat ECG every 15 to 30 minutes until resolved to Grade 2 (481 to 500 msec) or lower 
(≤480 msec) and then obtain ECGs every hour.  For patients who have had a Grade 3 event of 


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QTcF prolongation at a previous infusion ECGs should be conducted hourly for the 4 hours 
following the subsequent infusion. 
6.9.3 
End-of-Treatment Visit  
The EOT should be completed within ± 7 days of the last dose of tarloxotinib.  The following 
will be assessed or measured at EOT:  
• Complete physical examination  
• Weight 
• Vital signs  
• ECG (12-lead) 
• Hematology panel  
• Serum chemistry panel  
• Pregnancy test 
• Urine (dipstick acceptable) 
• Blood sample for biomarkers (e.g., ctDNA)  
• Concomitant medications 
• Assess AEs 
• Record the date and reason for the decision to discontinue study treatment 
6.9.4 
Safety Follow-up Visit  
All patients will return to the investigational site 30 days (± 7 days) following the last 
tarloxotinib infusion for the Safety Follow-up Visit.  At this visit, the following will be assessed 
or measured:  
• Physical examination  
• Weight  
• Vital signs  
• ECG (12-lead) 
• Hematology panel  
• Serum chemistry panel  
• Urinalysis  
• Assess AEs 


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6.10 
Concomitant Medications and Treatments  
All medications (prescription and over-the-counter) and blood products taken within 14 days of 
Cycle 1 Day 1 until the EOT will be recorded.  The reason(s) for treatment, dose, and dates of 
treatment will be recorded.  In addition, concomitant medications used to treat AEs occurring up 
to 30 days after the last dose of tarloxotinib will be recorded.   
6.10.1 
Prohibited Medications  
Concomitant medications and therapies excluded during the conduct of this trial include: 
• Any other anticancer treatment including non-palliative radiation, chemotherapy, 
monoclonal antibodies, or TKIs  
• Hormonal therapy for cancer  
Note:  Female patients who have been on hormone replacement therapy for menopausal 
symptoms for a period of at least 2 months will not be excluded from the study provided the 
planned hormone replacement therapy regimen remains largely unchanged during the 
conduct of the study 
• Other tumor-targeted therapies  
• Limited-field palliative radiotherapy to non-target lesions and bone-targeted agents, such 
as zoledronic acid and denosumab, are permitted.  
o Tarloxotinib should be delayed during radiotherapy and resumed upon completion of 
radiotherapy, if deemed appropriate by the treating physician after discussion with the 
Medical Monitor.   
• Medications that prolong QT interval and have a risk of TdP (See Appendix B) 
Patients should avoid all herbal remedies during study treatment; however, if herbal remedies are 
used, they should be documented as a concomitant medication.  Patients and study staff should 
be instructed to notify all care providers that they are participating in a clinical study that has 
identified prohibited medications.  
7. ASSESSMENT OF EFFICACY  
Tumor assessment and imaging will be performed according to institutional practice and will 
include CT or MRI of the chest and abdomen, brain scan, and bone scan at baseline.  The 
baseline radiographic tumor assessment is required within 28 days prior to the first dose of 
tarloxotinib.  Brain and bone scans do not need to be repeated for patients with no brain or bone 
metastases at baseline.  Recently completed negative positron emissions tomography (PET) 
scans can be substituted for baseline bone scans.  Subsequent radiographic tumor assessments 
will be every 8 weeks (±5 days) with respect to Cycle 1 Day 1, until unequivocal PD is 
documented.  The same imaging modality used for baseline imaging (i.e., CT or MRI) must be 
used for subsequent tumor assessments in each patient.  In accordance with RECIST v1.1, 
response (PR and CR) must be confirmed by a second tumor assessment at least 8 weeks after 
the initial observed response.  The scheduling of subsequent tumor assessments may be adjusted 
based on the date of the most recent imaging.  Investigators are instructed to ensure that original 


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images (or high-quality copies) of all baseline and on-study scans are filed and available for 
transmission to the Sponsor (or designee) for a future possible central reading.   
Efficacy assessment will be according to the local Investigator.   
7.1 
Primary Efficacy:  Objective Response 
The primary efficacy variable, ORR, is defined as a CR or PR according to RECIST v1.1 
recorded from baseline until disease progression or death due to any cause. 
7.2 
Secondary Efficacy 
Secondary efficacy variables include:  
• BOR as measured by CR, PR, and SD 
• DOR as measured from the date of first response to date of disease progression or death 
• DCR based on patients who had CR or PR or SD for at least 2 cycles (8 weeks) 
• PFS as measured from the date of first study drug dose to the date of the first objective 
documentation of radiographic disease progression or death due to any cause 
• OS as measured from the date of first study drug dose to the date of death by any cause  
8. ASSESSMENT OF SAFETY AND EXPLORATORY VARIABLES 
8.1 
Adverse Events  
Investigators will collect information related to AEs will be collected throughout this clinical 
trial.  The terms and definitions are consistent with the US DHHS guidance (2012).   
All AEs occurring in all patients will be collected following exposure to study treatment 
(treatment emergent) until approximately 30 days after the last study treatment.  Changes in the 
patient’s medical condition that occur prior to the first exposure to study treatment will be 
reported as medical history.  At each post-treatment visits, patients will be asked about any 
possible AEs in a non-leading manner.  An example of a non-leading method of eliciting AE 
information is “Have there been any changes in your health since you were here last?”  Patients 
should also be asked about the severity and/or persistence of any AEs that were ongoing at the 
time of their last visit.   
All AEs will be followed until stabilization or resolution.   
8.1.1 
Adverse Events Definitions 
8.1.1.1 
Adverse Events (21 CFR 312.32(a)) 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  An AE (also referred to as an adverse 
experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug and does not imply any 
judgment about causality.  An AE can arise with any use of the drug (e.g., off-label use, use in 


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combination with another drug) and with any route of administration, formulation, or dose, 
including an overdose. 
8.1.1.2 
Suspected Adverse Reaction (21 CFR 312.32(a))  
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE.  For the purposes of IND safety reporting, “reasonable possibility” means 
there is evidence to suggest a causal relationship between the drug and the AE.  A suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which 
means any AE caused by a drug. 
8.1.1.3 
Unexpected (21 CFR 312.32(a)) 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed; or, if 
an Investigator’s Brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as amended.  
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the Investigator’s Brochure referred only to elevated hepatic enzymes or hepatitis.  
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the Investigator’s Brochure listed only cerebral vascular accidents.  
"Unexpected," as used in this definition, also refers to AEs or suspected adverse reactions that 
are mentioned in the Investigator’s Brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug but are not specifically mentioned as occurring 
with the particular drug under investigation.   
8.1.1.4 
Serious Adverse Event (21 CFR 312.32(a))  
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  
• Death  
• Life-threatening AE  
• Inpatient hospitalization or prolongation of existing hospitalization  
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• Congenital anomaly/birth defect.   
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 


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8.1.1.5 
Serious Unexpected Suspected Adverse Reaction  
A suspected adverse reaction that is both serious and unexpected will be reported in an expedited 
manner.   
Rain Therapeutics (or designee) will report all serious unexpected suspected adverse reactions 
(serious, related, and unexpected AEs) to the regulatory agencies in the countries where this 
study is conducted per local country requirements. 
• Regulatory agencies will be notified (e.g., by telephone, facsimile transmission, or in 
writing) of all fatal and/or life-threatening suspected adverse drug reactions as soon as 
possible but no later than 7 calendar days after first knowledge by the Sponsor that a case 
qualifies, followed by as complete a report as possible within 8 additional calendar days. 
• Serious, unexpected suspected adverse reactions that are not fatal or life-threatening must 
be filed as soon as possible but no later than 15 calendar days after first knowledge by the 
Sponsor that the case meets the minimum criteria for expedited reporting.   
8.2 
Adverse Events Reporting  
8.2.1 
Adverse Event Term  
AEs must be reported using standard medical terminology.  The use of abbreviations (standard 
and nonstandard) should be avoided to help ensure a clear understanding of the event.  An 
example of a standard abbreviation that may have several meanings is “MI” which could mean 
“myocardial infarction” or “mitral insufficiency.”  All AE terms will be coded using a 
standardized dictionary (i.e., Medical Dictionary for Regulatory Activities [MedDRA®]).  
Generally, when reporting a well-known and understood condition, it is preferable to report the 
overall diagnosis rather that the individual signs and symptoms; the exception to this rule in this 
study is when the patient experiences an infusion reaction (i.e., infusion-related reaction).  The 
term “intermittent” should be avoided as the duration and incidence of events helps in 
understanding the safety profile of the study drug.   
8.2.2 
Adverse Event Severity  
AEs will be reported at the highest experienced.  AE severity will be graded according to NCI 
CTCAE v5.0.  A copy of the document will be provided to investigational sites and an electronic 
version is available at:  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf  
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Table 10: 
Severity Grading Guideline for Adverse Events Not Listed in NCI 
CTCAE  
Adverse Events Not Listed in NCI CTCAE v5.0 
Grade 
Description 
1 
Mild; 
Asymptomatic or mild symptoms; 
Clinical or diagnostic observations only; 
Intervention not indicated 
2 
Moderate; 
Minimal, local or noninvasive intervention indicated; 
Limiting age-appropriate instrumental activities of daily living* 
3 
Severe or medically significant but not immediately life-threatening; 
Hospitalization or prolongation of hospitalization indicated; 
Disabling; 
Limiting self-care activities of daily living** 
4 
Life-threatening consequences; 
Urgent intervention indicated 
5 
Death related to adverse event 
Adapted from NCI CTCAE v5.0 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events 
*Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care activities of daily living refer to bathing, dressing, and undressing, feeding self, using the toilet, 
taking medications, and not bedridden.  
Note:  A semicolon indicates “or” within the description of the grade. 
 
8.2.3 
Adverse Event Duration  
The start date (the date that the event was first noticed) and the end date (the date that the event 
had completely resolved or returned to baseline) will be recorded.  If the exact date is not known, 
the best estimate should be reported.   
All AEs will be followed until stabilization or resolution.   
8.2.4 
Adverse Event Causality  
Where the determination of the relationship of the AE to study drug rests on medical judgment, 
the determination must be made with the appropriate involvement of the Investigator, or, if the 
Investigator is not a physician, a designated sub-investigator who is a physician. 
Using the following criteria, Investigators will assess whether there is a reasonable possibility 
that the study drug caused or contributed to the AE. 
Related 
• The time sequence between the onset of the AE and study drug administration is 
consistent with the event being related to study drug; and/or  


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• There is a possible biologic mechanism for study drug causing or contributing to the AE; 
and the AE may or may not be attributed to concurrent/underlying illness, other drugs, or 
procedures. 
Not Related   
• Another cause of the AE is most likely; and/or  
• The time sequence between the onset of the AE and study drug administration is 
inconsistent with a causal relationship; and/or  
• A causal relationship is considered biologically unlikely.  
8.3 
Serious Adverse Events Reporting  
Suspected adverse reactions that meet the definition of serious (see Section 8.1.1.5) require 
accelerated reporting.   
To enable Rain Therapeutics to meet the expedited reporting requirements, Investigators must 
report all SAEs regardless of causality immediately (within 24 hours of learning of the event).  
SAEs will be reported by submitting a Serious Adverse Events Report to:  
RainDrugSafety@rainthera.com 
An event that results in hospitalization or prolongs an existing hospitalization will not be 
considered an SAE, if the only reason for that hospitalization or prolongation is: 
• Administration of study treatment 
• Administration of study procedures 
• Placement of permanent intravenous catheter 
• Hospice placement due to PD 
8.4 
Reporting Infusion-related Reactions  
Infusion-related reactions (IRRs) are defined as “a disorder characterized by adverse reaction to 
the infusion of pharmacological or biological substances.”  The incidence and severity or IRRs 
will be collected in the eCRF designed to collected tarloxotinib infusion details; individual signs 
and symptoms of IRRs will be reported as AEs.  Investigators will indicate which reported AEs 
were part of an IRR.   


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Table 11: 
Severity Grading Guideline for Infusion-Related Reactions  
Infusion-Related Reactions 
Grade 
Description 
1 
Mild transient reaction;  
infusion interruption not indicated;  
intervention not indicated  
2 
Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (e.g., 
antihistamines, nonsteroidal anti-inflammatory drugs, narcotics, intravenous fluids); prophylactic 
medications indicated for ≤ 24 hours   
3 
Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae  
4 
Life-threatening consequences;  
Urgent intervention indicated  
5 
Death 
Adapted from National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 
Note:  A semicolon indicates “or” within the description of the grade. 
 
8.5 
Reporting QTc Prolongation  
QT prolongation is not unexpected but it is an AE of special interest (AESI).  Grade 3 AESIs 
require expedited reporting to the Sponsor.  ECGs will be obtained throughout the study and will 
be read locally at the investigational sites.  Grade 3 QTc prolongation (absolute QTcF of ≥ 501 
msec or QTcF increase of > 60 msec relative to pre-infusion) or Grade 4 QTc prolongation will 
be reported as an AESI.   
Any apparent Grade 3 AESIs should be verified by manually measuring at least 3 complexes 
within the ECG and determining the average QTcF.   
AESIs will be reported by submitting an AESI Report to:  
RAIN701@ncgs.com 
All events of Grade 3 QTc prolongation (absolute QTcF of ≥ 501 msec or QTcF increase of 
> 60 msec relative to pre-infusion) or Grade 4 QTc prolongation will be reported as an AESI 
unless the event met the criteria of serious (see Section 8.1.1.4) in which case it will be reported 
as an SAE.   


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Table 12: 
NCI CTCAE Grading of ECG QTc Prolongation (Medical Dictionary of 
Regulatory Activities Code:  10014383) 
ECG QTc Prolongation NCI CTCAE Grade 
1 
2 
3 
4 
5 
Average QTc 
450 to 480 msec 
Average QTc 
481 to 500 msec 
Average 
QTc ≥ 501 msec 
OR 
> 60 msec change 
from baseline* 
Torsade de Pointes 
OR 
polymorphic 
ventricular 
tachycardia 
OR 
signs/symptoms of 
serious arrhythmia 
Not applicable 
Adapted from NCI CTCAE v5.0 
ECG = electrocardiogram; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events; QTc = corrected QT interval; QTcF = corrected QTc interval as calculated according to Fridericia’s 
formula  
Definition of QTc prolongation: A finding of a cardiac dysrhythmia characterized by an abnormally long QTc 
* Although a Grade 3 event (≥ 501 msec OR > 60 msec change from baseline) is reportable as an adverse event 
of special interest, dose reductions are not required for patients with absolute QTcF ≤ 500 msec and a ≤ 60 msec 
QTcF change from baseline. 
 
8.6 
Reporting Disease Progression and Death 
PD, also referred to a disease progression, and death due to disease progression are study 
endpoints and information related to these events will collected in eCRFs specifically designed 
to collect these data.  These events will not be reported as AE/SAEs unless the Investigator feels 
that these are accelerated, atypical, or related to study treatment.  Deaths occurring within the 
30 days after the last study treatment will be recorded.  Any death that the Investigator feels is 
related to study treatment must be reported to the Sponsor as an SAE within 1 business day of 
first becoming aware of the death.  Deaths occurring more than 30 days after study completion 
that are not considered related to study treatment may be reported cumulatively on a quarterly 
basis.  Reports of all deaths must be communicated as soon as possible to the appropriate 
IRB/IEC and/or reported in accordance with local laws and regulations. 
If an autopsy is performed, a copy of the report will be requested and provided to the Sponsor, if 
available.   
8.7 
Electrocardiogram Monitoring  
Standard 12-lead ECGs will be performed locally using a calibrated digital ECG machine 
capable of providing automated measurements.  All ECG tracings will be acquired with the 
patient in the supine position after the patient has been resting for at least approximately 
5 minutes.  ECG tracings will be measured and interpreted locally by a cardiologist or other 
qualified health care professional in accordance with institutional standard of care.   
Immediate medical management of patients will be based on the automated reading obtained at 
the investigational site (all clinically significant ECG readings should be manually verified by a 
qualified individual).  If the Investigator has any question regarding the local automated read, a 
local cardiologist should be consulted.   


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For patients with QT prolongation during tarloxotinib infusion, ECGs may need to be conducted 
more frequently than indicated in the Schedule of Events, depending on the degree of 
prolongation (see Section 6.9.2.1). 
Rain will review all reported ECG measurements at least quarterly.   
8.8 
Vital Sign Assessments  
The following vital signs will be assessed after the patient has been sitting for approximately 
5 minutes.  Vital signs will be obtained at each visit and prior to and following the start of each 
tarloxotinib infusion.  Vital signs to be measured include: 
• Blood pressure (systolic and diastolic; mmHg) 
• Heart rate (beats per minute) 
• Body temperature (°C) 
• Respiration rate (breaths per minute) 
8.9 
Clinical Laboratory Assessments  
Clinical laboratory assessments will be performed by each institution’s local laboratory.  The 
following laboratory variables (Table 13) will be collected in accordance with the Schedule of 
Events.  All clinically significant unscheduled laboratory results will be recorded and all 
clinically significant laboratory results (scheduled and unscheduled) obtained during the study 
period will be reported as AEs (e.g., ≥ Grade 2 AST, ALT, or serum bilirubin).  


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Table 13: 
Clinical Laboratory Assessments 
Serum Chemistry: 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Calcium 
Magnesium 
Phosphorous 
Glucose 
Blood urea nitrogen 
Creatinine 
Bilirubin 
Aspartate aminotransferase increased  
Alanine aminotransferase increased 
Alkaline phosphatase 
Albumin 
Total protein 
Hematology: 
Hematocrit  
Hemoglobin  
White blood cell count with differential (reported as absolute counts)  
• 
Total neutrophils  
• 
Lymphocytes  
• 
Monocytes  
• 
Eosinophils  
• 
Basophils  
Platelet count  
Urinalysis: 
Protein 
Glucose 
Ketones 
Urobilinogen 
Occult blood 
Microscopic sediment evaluation, as clinically indicated 
Pregnancy Test: 
In women with childbearing potential only:  serum β-human chorionic gonadotropin 
pregnancy test, urine, or urine dipstick 
 
8.10 
Pregnancy Testing and Contraception 
Patients who are WOCBP will have a serum pregnancy test performed within the 3 to 7 days 
prior to Cycle 1 Day 1 and a urine pregnancy test performed on Day 1 (pre-infusion) of all cycles 
and at EOT.  Additional pregnancy testing may be performed according to institutional practice.   
Patients who are WOCBP and male patients whose partners are WOCBP will be counseled on 
the importance of avoiding pregnancy during the study and must agree to the use of at least 
1 highly effective method of contraception, in the opinion of the Investigator.  WOCBP must use 
a highly effective method of contraception during the study and for at least 90 days after the last 
dose of study treatment.  Male patients must use a condom and refrain from sperm donation 
during the study and for at least 30 days after the last dose of study treatment.  All patients will 
be instructed to report any suspected pregnancies in themselves or their partner up to 90 days 
after the last infusion.   
8.11 
Physical Examinations  
Complete physical examinations, including a review of all body systems, will be performed at 
the Screening Visit, Day 1 of all cycles, and the EOT as shown in the Schedule of Events.  
Clinically significant findings observed during physical examination will be reported as medical 
history (pretreatment) or AEs (post-treatment).  


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8.12 
Eastern Cooperative Oncology Group 
All patients will be assessed at Cycle 1 Day 1 using the ECOG Performance Status Scale.  An 
ECOG performance score of 0 to 1 is required for study entry but is not a criterion for 
retreatment or study treatment discontinuation.   
Table 14: 
ECOG Performance Status Scale 
ECOG Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more 
than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
ECOG = Eastern Cooperative Oncology Group 
*Oken M, Creech R, Tormey D, et al.  Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5:649-655. 
 
8.13 
Pharmacokinetics 
Blood samples for tarloxotinib and tarloxotinib-E plasma concentrations will be collected prior 
to and following tarloxotinib infusion on Cycle 1 Day 1 and Cycle 2 Day 1.  Serum potassium 
samples will also be collected after the infusion.  Refer to the Laboratory Manual for sample 
collections, processing, and shipping instructions.  All blood samples may be collected within the 
5 or 10 minutes (see Schedule of Events) prior to or following the protocol-specified time point.  
Samples that cannot be collected with the sample collections window should be collected as soon 
as practicable and the actual date/time of collection reported.  
8.14 
Tumor Tissue 
All patients will have tumor tissue collected at baseline.  Tumor tissue may come from archived 
samples or from a recent pretreatment biopsy.  Formalin-fixed paraffin embedded blocks are 
preferred, but if FFPE tissue is not available patients must have 8 to 10 prepared slides available.  
Mutation status will be confirmed after enrollment; these results will not be used to determine 
eligibility. 
Tumor samples obtained during screening may also be used to determine levels of the reductase, 
STEAP4, which is responsible for generating the unstable intermediate species from the prodrug 
tarloxotinib to the pharmacologically active tarloxotinib-E under hypoxic conditions.  As a third 
priority, if there is enough material, the samples will be used to for a hypoxia gene signature, 
phosphor-EGFR, and detection of EGFR homodimers by proximity ligation assay. 
In addition to the above-mentioned tumor sample, an optional tumor tissue sample for 
measurement of the active metabolite (tarloxotinib-E) and tarloxotinib will collected from 
consenting patients on Cycle 1 Day 15 after infusion along with a blood sample for PK.  If the 


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biopsy (and associated PK sample) is not able to be performed on Cycle 1 Day 15, it should be 
collected within the 24 hours after the tarloxotinib infusion or after another infusion day.   
Refer to the Laboratory Manual for samples collection, processing, and shipping instructions.   
8.15 
Biomarker Analysis 
Blood samples will be collected for biomarker assessment (e.g., ctDNA) according to the 
Schedule of Events.  Refer to the Laboratory Manual for samples collection, processing, and 
shipping instructions. 
Biomarker assessment may include ctDNA mutation analysis and evaluation of the concordance 
of EGFR and HER2 mutation identification between blood and tumor tissue. 
9. STATISTICS  
The primary objective of this study is to evaluate the ORR of tarloxotinib according to 
RECIST v1.1. 
ORR will be estimated with precision using the 95% exact binomial confidence interval (CI) 
limits.  The analyses of time-to-event endpoints (DOR, PFS, and OS) will follow standard 
methodology by employing Kaplan-Meier and Cox proportional hazard model methodology.   
Safety data will be summarized descriptively.  AEs will be summarized by severity, seriousness, 
and relationship to study drug.  Laboratory data will be compared to baseline values.   
Additional exploratory data analyses will be conducted as appropriate. 
Details of the statistical analyses presented below will be provided in the study’s statistical 
analysis plan (SAP).  A change to the data analysis methods described in the protocol will 
require a protocol amendment only if it alters a principal feature of the protocol.  The SAP will 
be finalized prior to database lock.  Any changes to the methods described in the plan will be 
described and justified in the final clinical study report. 
9.1 
Determination of Sample Size 
The primary objective of this study is to determine if tarloxotinib provides a clinically significant 
tumor response to patients in each cohort.  This will be investigated by assessing if the true ORR 
is at least above some desirable target level following therapy with tarloxotinib. 
Currently approved EGFR or HER2 TKIs are, in general, ineffective against EGFR or HER2 
exon 20 mutations and only associated with ORR of 12% or less (Robichaux 2018).  Other 
treatment options for this population includes docetaxel, however, the ORR is no better than 15% 
(Hanna 2017).   
For all cohorts, a Simon’s 2-stage minimax design (Simon 1989) will be used.  The null 
hypothesis that the true response rate is 15% will be tested against a one-sided alternative.  In the 
first stage, 21 patients will be accrued.  If there are 3 or fewer responses among these 21 patients, 
the cohort will be stopped.  Otherwise, 22 additional patients may be accrued for a total of 


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43 patients in each cohort.  The null hypothesis will be rejected if 11 or more responses are 
observed in 43 patients.  This design yields a type I error rate of 0.0454 and power of 0.8014 
when the true response rate is 31%.  The probability of early termination at the end of the first 
stage is 0.61 if the true response rate is 15% (Ivanova 2012). 
9.2 
Patient Disposition 
9.2.1 
Disposition of Patients 
An accounting of the study patients will be tabulated.  Patients not meeting the eligibility criteria 
will be identified.  Patients not completing the study will be listed along with the reason for their 
premature discontinuation.  Reasons for premature discontinuation will be summarized. 
9.2.2 
Protocol Deviations 
Deviations from the protocol including violations of inclusion/exclusion criteria will be assessed 
as “minor” or “major” in cooperation with the Sponsor.  Deviations will be defined prior to 
database lock.  Handling of major deviations in statistical analyses will be defined in the SAP. 
9.2.3 
Analysis Sets 
The primary efficacy analysis population includes all patients who received at least 1 dose of 
tarloxotinib.  The Safety Population will consist of all patients who received at least 1 dose of 
tarloxotinib.  The Safety Population will be the analysis population for the safety and primary 
efficacy analyses. 
The Per Protocol (PP) Population is defined as patients who did not have a major protocol 
deviation that may affect interpretation of results.  Efficacy will also be analyzed using the PP 
Population.  A detailed specification of the PP Population will be provided prior to the database 
lock.  
All enrolled patients who receive study treatment, have a baseline tumor assessment with 
documentation of measurable disease, have at least 1 on-study tumor assessment, whether or not 
this occurs at the specified imaging interval, and have no major protocol violations including 
inclusion/exclusion criteria or prohibited concomitant medication while on study, will be 
considered evaluable for response.  Patients with a confirmed objective response (CR or PR) per 
RECIST criteria will be considered responders.  Patients without a confirmed objective response, 
SD, or PD will be considered to be non-responders. 
Patients who are treated and removed from the study prior to on-study tumor assessments 
because of clinical disease progression will be considered non-responders.  Patients who are 
treated and removed from study prior to on-study tumor assessments for reasons other than 
clinical progression will be considered unevaluable for response and may be replaced.  In 
addition, if a patient is enrolled without central laboratory confirmation of the specific gene 
alteration, and then is subsequently found not to have the specific gene alteration by central 
review, this patient will be considered unevaluable for response and may be replaced. 
9.3 
  General Considerations 
Efficacy variables will be assessed without adjustment for multiple comparisons. 


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Continuous data will be summarized by cohort using descriptive statistics (number of patients, 
number of missing information, mean, median, standard deviation, minimum, and maximum).  
Categorical data will be summarized by cohort using frequency tables (frequency counts and 
percentages).  
The statistical test for primary efficacy endpoint ORR will be performed by cohort using an 
exact binomial test for single proportion at the 5% one-sided significance level, unless otherwise 
stated.   
9.4 
Baseline Characteristics and Concomitant Medications 
Demographic data, medical history, concomitant disease, and concomitant medication will be 
summarized by means of descriptive statistics (n, mean, standard deviation, median, minimum, 
and maximum) or frequency tables by cohort. 
9.5 
Treatment Compliance 
Study drug administration will be described in terms of the total number of cycles administered, 
the median (range) of cycles administered, and dose intensity. 
9.6 
Efficacy Analyses 
9.6.1 
Primary Efficacy Analysis 
9.6.1.1 
Hypothesis to be Tested 
The study is designed to test the null hypothesis that the true ORR is 15% versus the alternative 
hypothesis that the true ORR is 42% for tarloxotinib in each cohort. 
9.6.1.2 
Statistical Methods 
The primary efficacy endpoint is confirmed ORR. 
Objective response is defined as a CR or PR according to RECIST v1.1 recorded from baseline 
until disease progression or death due to any cause.  Response assessment will be according to 
the local Investigator.   
A patient will be considered to have achieved an objective response if the patient has a 
confirmed CR or PR according to RECIST v1.1.  Additionally, patients with inadequate data for 
tumor assessment (e.g., no baseline assessment or no follow-up assessments) will be considered 
non-evaluable in the ORR analysis. 
The ORR in each cohort will be estimated as the number of patients with confirmed objective 
response (CR or PR) divided by the number of evaluable patients in the respective cohort 
(“response rate”).  The ORR will be summarized by cohort along with the corresponding 2-sided 
95% CI.  The best response rate will also be summarized similarly. 


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9.6.2 
Secondary Efficacy Analyses 
9.6.2.1 
Duration of Response  
The DOR is defined as the date of first documentation of OR according to RECIST v1.1 to date 
of disease progression or death to any cause.  The DOR will be summarized using the 
Kaplan-Meier method and displayed graphically when appropriate.  Median event times and the 
corresponding 2-sided 95% CI will be provided.   
9.6.2.2 
Disease Control Rate 
The DCR is defined as CR, PR, or SD for at least 2 cycles (8 weeks) according to RECIST v1.1 
recorded in the period between first study drug dose and disease progression or death to any 
cause. 
The DCR for each cohort will be estimated by dividing the number of patients with CR, PR, or 
SD for at least 2 cycles (8 weeks) by the number of patients enrolled in each cohort.  Similar 
analysis as for ORR will be performed for DCR. 
9.6.2.3 
Progression-free Survival  
The PFS, which is defined as the time from the date of first tarloxotinib dose to the date of the 
first objective documentation of radiographic disease progression or death due to any cause, 
whichever occurs first.  For the analysis, PFS data will be censored according to Table 15 for 
patients who are alive with no objective documentation of (radiographic) disease progression by 
the data cut-off date for PFS analysis. 
Table 15: 
Censoring Rules for Progression-Free Survival 
Situation 
Date of Censoring 
No baseline radiologic assessment 
Date of first study drug dose 
No post-baseline radiologic assessment (and no death 
prior to first scheduled radiologic assessment) 
Date of first study drug dose 
No progression or death on study 
Date of last radiologic assessment 
Documented progression or death after 2 or more 
consecutive missing radiologic assessments 
Date of last radiologic assessment 
New anticancer therapy started prior to progression 
Date of last radiologic assessment prior to new 
anticancer therapy 
 
The PFS will be summarized using the Kaplan-Meier method and displayed graphically when 
appropriate.  Median event times and the corresponding 2-sided 95% CI will be provided.   
9.6.2.4 
Overall Survival  
OS as measured from the date of first tarloxotinib dose to the date of death by any cause.  In the 
absence of confirmation of death, survival time will be censored to last date the patient is known 
to be alive.  The OS will be summarized using the Kaplan-Meier method and displayed 
graphically when appropriate.  Median event times and the corresponding 2-sided 95% CI will 
be provided.   


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9.7 
Safety Analyses 
MedDRA will be used to map the AE verbatim to lowest level term, preferred term, and system 
organ class for summary purposes.  All AEs including the AE verbatim term and the associated 
AE MedDRA preferred term will be provided in the patient data listings.  Incidence of 
treatment-emergent AEs and use of concomitant medications will be summarized descriptively 
by cohort and total.  Results for clinical laboratory parameters, vital signs, ECGs, and physical 
examinations will be summarized by cohort and combined and by study visits.  Descriptive 
summary statistics in observed values as well as changes from baseline will be presented.  In 
addition, thresholds of marked laboratory abnormalities based on NCI CTCAE v5.0 will be 
predefined for specific safety parameters.  Incidence of marked laboratory abnormalities and 
shift tables will be presented. 
9.7.1 
Cardiac Safety 
Electrocardiogram parameters (PR interval, QRS interval, QT interval corrected for heart rate by 
Fridericia’s formula [QTcF] and Bazett’s formula [QTcB], and heart rate) will be presented as 
actual values and as changes from the baseline values by summary statistics (number, mean, 
standard deviation, median, minimum, and maximum).  Each of these will be presented at each 
scheduled ECG time, along with their 2-sided upper 90% CI, using a mixed effects analysis of 
variance.  The primary statistical model will include the effects of patient and ECG time.  The 
numbers and percentages of patients who meet categorical analyses such as the following criteria 
at each scheduled ECG time point will be presented. 
• Absolute QTc interval: 
o QTc interval < 450  
o QTc interval 451 to 480 msec 
o QTc interval 481 to 500 msec  
o QTc interval ≥ 501 msec 
• Change from predose baseline in QTc interval:  
o ≤ 30 msec 
o 31 to 60 msec 
o > 60 msec  
The numbers and percentages of patients meeting each criterion will be summarized for each 
ECG time point, as well as for each patient overall at any time.  In addition, a central tendency 
analysis of the ECG parameters will be performed.   
Abnormal ECG findings not present at the predose baseline will be summarized as the number of 
patients with each finding at 1 or more ECG times.  Descriptive waveform morphology changes 
will be provided.  Additional ECG analyses may be conducted and will be provided in a separate 
SAP. 


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9.8 
Other Analyses 
9.8.1 
Pharmacokinetic Analyses 
Pharmacokinetic samples for tarloxotinib and tarloxotinib-E will be collected for patients on 
Cycle 1 Day 1 and Cycle 2 Day 1.  Exploratory analysis (via graphical displays and/or 
population PK/pharmacodynamics) will be conducted to examine the relationship of exposure to 
tarloxotinib and tarloxotinib-E and specific safety parameters including QTc interval and, if 
possible, to efficacy endpoints (e.g., ORR) and support PK analyses.  Details of the planned 
analyses and the results of these analyses will be described in a separate PK data analysis plan.   
9.8.2 
Tumor Tissue 
Tumor tissue will be analyzed based on the following priority: 
1. Archived tumor samples or newly obtained pretreatment samples is mandatory for all 
patients and will be used for concordance analyses against the test used for patient 
enrollment.  The companion diagnostic platform used for these analyses remains to be 
determined. 
2. Tumor STEAP4 will be analyzed and correlated with disease-outcome parameters to 
determine the predictive value.  This analysis will only be performed if the patient 
provided consent. 
3. Exploratory analyzes of phosphor-EGFR, EGFR proximity ligation assay and a hypoxia 
gene signature will be performed if the patient provided consent. 
An optional tissue sample will be obtained at post-infusion from consenting patients will be 
analyzed for tarloxotinib and tarloxotinib-E levels.   
9.8.3 
Biomarker Analyses 
Blood samples will be collected for biomarker (e.g., ctDNA mutation) analysis at baseline and at 
several time points throughout the study.  Details of the analysis for biomarker and other 
ancillary data will be provided in the SAP. 
10. QUALITY CONTROL AND QUALITY ASSURANCE  
10.1 
Data Quality Assurance 
The Sponsor or Sponsor’s designee will conduct a site visit to verify the qualifications of each 
Investigator, inspect the site facilities, and inform the Investigator of responsibilities and the 
procedures for ensuring adequate and correct documentation. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant.  All information recorded in the electronic data capture (EDC) system for this study 
must be consistent with the patients’ source documentation (i.e., medical records). 


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10.1.1 
Database Management and Quality Control 
All data generated by the site personnel will be captured electronically at each study center using 
an EDC system.  Data from external sources (such as laboratory data) will be entered into the 
database.  Once the EDC clinical data have been submitted to the central server at the 
independent data center, corrections to the data fields will be captured in an audit trail.  The 
reason for change, the name of the person who performed the change, together with the time and 
date will be logged to provide an audit trail.   
If additional corrections are needed, the responsible monitor or data manager will raise a query in 
the EDC application.  The appropriate staff at the study site will answer queries sent to the 
Investigator.  The name of the staff member responding to the query and time and date stamp 
will be captured to provide an audit trail.  Once all source data verification is complete and all 
queries are closed, the monitor will freeze the EDC. 
The specific procedures to be used for data entry and query resolution using the EDC system will 
be provided to study sites in a training manual.  In addition, site personnel will receive training 
on the EDC system. 
11. ETHICS  
11.1 
Informed Consent 
Before each patient is admitted to the study, written informed consent will be obtained from the 
patient according to the regulatory and legal requirements of the participating country.  This 
consent form must be dated and retained by the Investigator as part of the study records.  The 
Investigator will not undertake any investigation specifically required only for the clinical study 
until valid consent has been obtained.  The terms of the consent and when it was obtained must 
also be documented in the EDC system. 
Patients may elect to provide optional tumor or plasma samples for DNA biomarker analysis and 
correlative studies.  These samples will be collected only if the patient provides additional 
consent. 
If a protocol amendment is required, the informed consent form may need to be revised to reflect 
the changes to the protocol.  If the consent form is revised, it must be reviewed and approved by 
the appropriate IEC/IRB and signed by all patients subsequently enrolled in the study as well as 
those currently enrolled in the study. 
11.2 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements.  The 
Sponsor or Sponsor’s designee must ensure that all ethical and legal requirements have been met 
before the first patient is enrolled in the study. 
This protocol is to be followed exactly.  To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate).   


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Administrative changes (not affecting the patient benefit/risk ratio) may be made without the 
need for a formal amendment.  All amendments will be distributed to all protocol recipients with 
appropriate instructions. 
11.3 
Duration of the Study 
The total study duration is estimated to be 36 months, including approximately 24 months for 
accrual and approximately 12 months for follow-up after the last patient is enrolled.  Patients are 
expected to receive up to 10 cycles of treatment.  The end of the study is defined as the last 
patient visit or contact, including telephone contacts, for collection of any study-related data.   
11.4 
Premature Termination of the Study 
If the Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions or events 
that suggest a possible hazard to patients if the study continues, the study may be terminated 
after appropriate consultation between the relevant parties.  The study may also be terminated 
early at the Sponsor’s discretion in the absence of such a finding. 
Conditions that may warrant termination include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled 
in the study 
• Failure to enroll patients at an acceptable rate 
• A decision on the part of the Sponsor to suspend or discontinue development of the drug 
11.5 
Confidentiality 
All goods, materials, information (oral or written) and unpublished documentation provided to 
the Investigator (or any company acting on their behalf), inclusive of this protocol, the patient 
eCRFs, and the Tarloxotinib Investigator's Brochure are the exclusive property of the Sponsor.  
Documents and information provided to the Investigator by the Sponsor may not be given or 
disclosed by the Investigator or by any person within his authority in part or in totality to any 
unauthorized person without the prior written formal consent of the Sponsor. 
It is specified that the submission of this protocol and other necessary documentation to the IRB 
or IEC is expressly permitted, the IRB or IEC members having the same obligation of 
confidentiality. 
The Investigator shall consider as confidential and shall take all necessary measures to ensure 
that there is no breach of confidentiality in respect of all information accumulated, acquired or 
deduced during the trial, other than that information to be disclosed to a third party mandated by 
applicable law.   
Any language relating to these issues appearing in the Clinical Trial Agreement will supersede 
that which is outlined in this section. 
The anonymity of participating patients must be maintained.  Patients will be identified in the 
EDC system and other documents submitted to the Sponsor or Sponsor’s designee by their 


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patient number, initials, and/or birth date, not by name.  Documents not to be submitted to the 
Sponsor or Sponsor’s designee that identify the patient (e.g., the signed informed consent) must 
be maintained in confidence by the Investigator.   
12. DATA HANDLING AND RECORD KEEPING  
12.1 
Case Report Forms and Source Documentation 
All data obtained during this study should be entered in the EDC system promptly.  All source 
documents from which EDC entries are derived should be placed in the patient’s medical 
records.  Measurements for which source documents are usually available include laboratory 
assessments, ECG recordings, CT scans, MRI, and X-rays.  EDC entries may be checked against 
source documents at the study site or remotely by the Sponsor or Sponsor’s designee site 
monitor.  After review by the site monitor, completed EDC entries will be uploaded and 
forwarded to the Sponsor (or designee).  Instances of missing or uninterpretable data will be 
discussed with the Investigator for resolution.   
The specific procedures to be used for data entry and query resolution using the EDC system will 
be provided to study sites in a training manual.  In addition, site personnel will receive training 
on the EDC system. 
12.1.1 
Data Collection  
The investigators (and appropriately authorized staff) will be given access to an online 
web-based EDC) system which is 21 CFR Part 11 compliant.  This system is specifically 
designed for the collection of the clinical data in electronic format.  Access and right to the EDC 
system will be carefully controlled and configured according to everyone’s role throughout the 
study.  In general, only the Investigator and authorized staff will be able to enter data and make 
corrections in the eCRFs. 
The eCRF should be completed for each patient included in the study and should reflect the latest 
observations on the patients participating in the study.  Therefore, the eCRFs are to be completed 
as soon as possible during or immediately after the patient’s visit or assessment.  The 
Investigator must verify that all data entries in the eCRF are accurate and correct. 
Computerized data-check programs and manual checks will identify any clinical data 
discrepancies for resolution.  Corresponding queries will be loaded into the system and the site 
will be informed about new issues to be resolved on-line.  All discrepancies will be solved 
on-line directly by the Investigator or by authorized staff.  Off-line edit checks will be done to 
examine relationships over time and across panels to facilitate quality data. 
After completion, the Investigator will be required to electronically sign off the clinical data.  
Data about all study drug dispensed or administered to the patient and any dosage changes will 
be tracked on the eCRF.   


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12.2 
Access to Source Data 
During the study, a monitor will make site visits or conduct remote monitoring to review 
protocol compliance, compare EDC entries and individual patient’s medical records, and ensure 
that the study is being conducted according to pertinent regulatory requirements.  EDC entries 
will be verified with source documentation.  The review of medical records will be performed in 
a manner to ensure that patient confidentiality is maintained. 
Checking of the EDC entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study.  Moreover, Regulatory 
Authorities of certain countries, IRBs, IECs, and/or the Sponsor’s Clinical Quality Assurance 
Group may wish to carry out such source data checks and/or on-site audit inspections.  Direct 
access to source data will be required for these inspections and audits; they will be carried out 
giving due consideration to data protection and medical confidentiality.  The Investigator assures 
the Sponsor (or designee) the necessary access at all times. 
12.3 
Data Processing 
All data will be entered by site personnel into the EDC system.  The data-review and 
data-handling document, to be developed during the initiation phase of the study, will include 
specifications for consistency and plausibility checks on data and will also include data-handling 
rules for obvious data errors.  Query/correction sheets for unresolved queries will be sent to the 
study monitors for resolution with the Investigator.  The database will be updated based on 
signed corrections.   
Concomitant medications will be coded using the WHODrug Global, which employs the 
Anatomical Therapeutic Chemical classification system.  Medical history, current medical 
conditions, and AEs will be coded using MedDRA terminology.  The versions of the coding 
dictionaries will be provided in the clinical study report. 
12.4 
Archiving Study Records 
Per 21 CFR 312.62(c), investigators shall retain records required to be maintained under this part 
for a period of 2 years following the date a marketing application is approved for the drug for the 
indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified.  However, documents may be retained for a longer period if 
required by the applicable legal requirements. 
Rain Therapeutics will maintain archive copies of all records for a period of no less than 
25 years.  
13. PUBLICATION POLICY 
By signing the study protocol, the Investigator agrees with the use of results of the study for the 
purposes of national and international registration, publication, and information for medical and 
pharmaceutical professionals.  If necessary, Regulatory Authorities will be notified of the 
Investigator's name, address, qualifications, and extent of involvement. 


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An Investigator shall not publish any data (poster, abstract, paper, etc.) without discussion with 
and approval by the Sponsor. 
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Gerber DE. Targeted therapies:  a new generation of cancer treatments. Am Fam 
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mucinous non-small cell lung cancer harboring an NRG1 fusion gene. J Thoracic Oncol. 
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Hanna N, Johnson D, Temin S, et al. Systemic therapy for stage IV non-small-cell lung cancer:  
American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 
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Heuvers ME, Hegmans JP, Stricker BH, et al. Improving lung cancer survival; time to move on. 
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Hunter FW, Barker HR, Lipert B, et al. Mechanisms of resistance to trastuzumab emtansine (T-
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http://cancer.unc.edu/biostatistics/program/ivanova/SimonsTwoStageDesign.aspx 
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treatment strategy for metastatic cancer. Ann Oncol. 2017;28(12):3092-3097. 
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Kobayashi Y, Mitsudomi T. Not all epidermal growth factor receptor mutations in lung cancer 
are created equal:  Perspectives for individualized treatment strategy. Cancer Sci. 
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cancer. Cancer Discov. 2016;6(6):601-611. 
Le X, Goldman J, Clarke J, et al. Abstract CT081: Poziotinib activity and durability of responses 
in previously treated EGFR exon 20 NSCLC patients-a Phase 2 study. 
Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection 
of lung cancer patients for treatment with targeted tyrosine kinase inhibitors:  Guideline from the 
College of American Pathologists, the International Association for the Study of Lung Cancer, 
and the Association for Molecular Pathology. J Thorac Oncol. 2018;13(3):323-358.  
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cancer patients for EGFR and ALK tyrosine kinase inhibitors:  Guideline from the College of 
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inhibitor in phase I clinical trial. Mol Cancer Ther. 2013;12(11 Suppl):B278.  
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patients with ERBB2 mutation-positive advanced NSCLC:  Findings from a global named 
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mobocertinib (TAK-788) in NSCLC with EGFR exon 20 insertions (exon20ins). Annals of 
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APPENDIX A:  PACKAGING, LABELING, AND STORAGE OF STUDY DRUG   
Study drug will be bulk packaged by the Sponsor according to all local legal requirements.  
Study drug will be bulk labeled in accordance with applicable regulatory requirements.  Consult 
the Pharmacy Manual for additional details. 
Tarloxotinib will be supplied frozen (–20°C ± 5°C) in 20-mL vials containing a minimum of 
100 mg tarloxotinib in at least 10 mL of a sterile, preservative-free solution containing 
40% 2-hydroxypropyl-beta-cyclodextrin, 20 mM citrate, disclosing minimally the product name, 
strength, lot number, route of administration, required storage conditions, Sponsor’s name, 
manufacturers name and address, and precautionary labeling as required by US federal law 
and/or international and local laws.   
Storage 
Tarloxotinib must be stored in a secure area with limited access under controlled conditions 
at -20°C ± 5°C. 
Dose Preparation 
Tarloxotinib vials are stored at -20°C ± 5°C and are thawed at room temperature prior to use.  
Complete thawing at room temperature could take up to 2 hours.  Once thawed, tarloxotinib vials 
should be diluted into 5% Dextrose in Water (D5W) within 12 hours.  D5W for dilution of 
tarloxotinib will be obtained from commercial source and will be stored at room temperature.  
The final tarloxotinib concentration for the prepared tarloxotinib/D5W solution should be no less 
than 0.15 mg/mL and no more than 1 mg/mL.   
Method of Administration 
Once diluted in D5W for infusion, tarloxotinib is stable at room temperature exposed to light for 
up to 24 hours.  Tarloxotinib should be administered as a 1-hour IV infusion, through a 0.2-μm 
in-line filter.   
Drug Accountability 
The Investigator is responsible for the control of drugs under investigation.  Adequate records of 
the receipt and disposition of all tarloxotinib shipped to the site must be maintained.  Records 
will include dates, lots received, quantities received, quantities dispensed, quantities damaged (if 
applicable), storage conditions, and the identification codes of the patients who received 
tarloxotinib.  The individual administering the tarloxotinib or designee will write the study 
number, patient number, lot number, number of vials, date, and start/stop times of each 
administration, and the destruction of all tarloxotinib on the Drug Accountability Record, as 
appropriate.  The Investigator is responsible for returning or destroying all unused study drug to 
the Sponsor or designee and must verify that no remaining supplies are in the Investigator’s 
possession at the end of the study, unless otherwise instructed by the Sponsor.  Further 
instructions can be found in the Pharmacy Manual. 
 
 


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APPENDIX B:  QT-PROLONGING DRUGS WITH A KNOWN RISK FOR TORSADE 
DE POINTES  
It is the responsibility of each Investigator to check this list periodically for new additions. 
Please refer to the following website for the most recent information: 
https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf  
Antiarrhythmics  
• 
Amiodarone (Cordarone, Pacerone)  
• 
Bepridil (Vascor)  
• 
Disopyramide (Norpace)  
• 
Dofetilide (Tikosyn)  
• 
Dronedarone (Multaq)  
• 
Flecainide (Tambocor)  
• 
Hydroquinidine (Serecor) 
• 
Ibutilide (Corvert)  
• 
Nifekalant (Shinbit) 
• 
Procainamide (Pronestyl, Procan)  
• 
Quinidine (Cardioquin, Quinaglute)  
• 
Sotalol (Betapace)  
 
Antibiotics  
• 
Azithromycin (Zithromax)  
• 
Ciprofloxacin (Cipro, Otiprio, Ciloxan) 
• 
Clarithromycin (Biaxin)  
• 
Erythromycin (Erythrocin, EES)  
• 
Gatifloxacin (Tequin) 
• 
Grepafloxacin (Raxar) 
• 
Levofloxacin (Levaquin, Tavanic)  
• 
Moxifloxacin (Avelox)  
• 
Pentamidine (NebuPent, Pentam)  
• 
Roxithromycin (Rulide) 
• 
Sparfloxacin (Zagam)  
 
Antidepressant  
• 
Citalopram (Celexa)  
• 
Escitalopram (Cipralex)  
 
Anti-emetics  
• 
Chlorpromazine (Thorazine, Largactil, 
Megaphen) 
• 
Domperidone (Motilium)  
• 
Droperidol (Inapsine)  
• 
Ondansetron (Zofran) 
Anticancer 
• 
Aclarubicin (Aclacin) 
• 
Oxiplatin (Eloxatin) 
• 
Vandetanib (Caprelsa) 
 
Antifungal 
• 
Fluconazole (Diflucan, Trican) 
• 
Pentamidine (Pentam) 
 
Antihistamine  
• 
Astemizole (Hismanal)  
• 
Terfenadine (Seldane)  
 
Anticholesterolemic  
• 
Probucol (Lorelco)  
 
Antimalarials  
• 
Chloroquine (Aralen)  
• 
Halofantrine (Halfan)  
• 
Hydroxychloroquine (Plaquenil) 
 
Antipsychotics  
• 
Chlorpromazine (Thorazine)  
• 
Chlorprothixene (Truxal) 
• 
Haloperidol (Haldol)  
• 
Levomepromazine (Nosinan, Levoprome) 
• 
Levosulpiride (Lesuride, Eliva) 
• 
Mesoridazine (Serentil)  
• 
Pimozide (Orap)  
• 
Sulpiride (Dogmatil) 
• 
Sultopride (Barnetil, Barnotil, Topral) 
• 
Thioridazine (Mellaril)  
 
Gastrointestinal Stimulant  
• 
Cisapride (Propulsid)  
 
Opiate Agonists  
• 
Levomethadyl acetate (Orlaam)  
• 
Methadone (Dolophine, Methadose) 


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Other  
• 
Anagrelide (Agrylin)  
• 
Arsenic trioxide (Trisenox)  
• 
Cesium chloride 
• 
Cocaine 
• 
Cilostazol (Pletal) 
• 
Donepezil (Aricept) 
• 
Ibogaine 
• 
Papaverine hydrochloride (intracoronary) 
• 
Propofol (Diprivan)Sevoflurane (Ultane) 
• 
Terlipressin (Teripress, Glypressin) 
• 
Terodiline (Micturin) 
 
 
 


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DECLARATION OF THE INVESTIGATOR 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence.  This documentation includes this study 
protocol, Tarloxotinib Investigator's Brochure, electronic data capture system, and other 
scientific data.  I have read and understood and agree to abide by all the conditions and 
instructions contained in this protocol and agree to: 
• Conduct the study in accordance with the relevant, current protocol and will only make 
changes in a protocol after notifying the Sponsor, except when necessary to protect the safety, 
rights, or welfare of subjects.   
• Personally, conduct or supervise the described investigation.   
• Inform any patients, or any persons used as controls, that the drugs are being used for 
investigational purposes and I will ensure that the requirements relating to obtaining informed 
consent in 21 CFR Part 50 and IRB)/IEC review and approval in 21 CFR Part 56 are met.   
• Report to the Sponsor adverse experiences that occur in the course of the investigation(s) in 
accordance with 21 CFR 312.64. I have read and understand the information in the protocol 
and Tarloxotinib Investigator’s Brochure, including the potential risks and side effects of the 
drug.   
• Ensure that all associates, colleagues, and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments.   
• Maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make those 
records available for inspection in accordance with 21 CFR 312.68.   
• Ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible 
for the initial and continuing review and approval of the clinical investigation. I also agree to 
promptly report to the IRB all changes in the research activity and all unanticipated problems 
involving risks to human subjects or others.  Additionally, I will not make any changes in the 
research without IRB approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.   
• Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements in 21 CFR Part 312. 
 
 
Responsible Investigator 
 
 
 
Signature 
 
Date 
Name (Printed) 
 
 
Title (Printed) 
 

SAP_001.pdf: 
Page 1 of 61
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2 Study of Tarloxotinib in Patients with Select 
Gene Alterations and Non-Small Cell Lung Cancer or 
Other Advanced Solid Tumors
Study Number:
RAIN-701
Investigational Drug:
Tarloxotinib bromide
Indication:
Treatment of Non-Small Cell Lung Cancer or Other 
Advanced Solid Tumors
Investigators:
Multicenter
IND Number:
112290
Sponsor:
Rain Therapeutics Inc.
8000 Jarvis Ave Suite 204
Newark, CA, 94560 
Plan Version:
1.0, 14 October 2022
Plan Prepared by:
Inka Leprince, MS
Statistical Consultant
PharmaStat, LLC
CONFIDENTIAL
This document is confidential and property of Rain Therapeutics Inc. It may not be copied 
or provided to any other party without the express written consent of 
Rain Therapeutics Inc.
©2022 Rain Therapeutics Inc.
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STATISTICAL ANALYSIS PLAN
RAIN-701
A Phase 2 Study of Tarloxotinib in Patients with Select Gene Alterations and Non-Small Cell 
Lung Cancer or Other Advanced Solid Tumors
Plan Version:
1.0, 14 October 2022
Plan version reviewed:
14 October 2022
Signature Page
Author:
Inka Leprince, MS
Statistician and Data Analyst
PharmaStat, LLC
Date
Reviewer:
Lucio Tozzi
SVP, Head of Clinical Operations
Rain Therapeutics Inc.
Date
Reviewer:
Robert C Doebele, MD, PhD
President and Chief Scientific Officer
Rain Therapeutics Inc.
Date
Reviewer:
Feng Xu
VP, Biometrics
Rain Therapeutics Inc.
Date
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Table of Contents
1 
REVISION HISTORY ............................................................................................. 9 
2 
RELATED DOCUMENTS: PROTOCOL AND CASE REPORT FORMS ........... 9 
3 
COMMITMENT TO GOOD STATISTICAL PRACTICE..................................... 9 
3.1 
Definition of Good Statistical Practice..................................................................... 9 
3.2 
Use of Standards....................................................................................................... 9 
4 
PURPOSE OF THE ANALYSIS PLAN................................................................ 10 
5 
STUDY OBJECTIVE............................................................................................. 11 
5.1 
Efficacy Objectives and Endpoints......................................................................... 11 
5.1.1 
Primary Efficacy..................................................................................................... 11 
5.1.2 
Secondary Efficacy................................................................................................. 11 
5.1.3 
Exploratory Efficacy............................................................................................... 12 
5.2 
Safety Objective...................................................................................................... 12 
6 
STUDY DESIGN ................................................................................................... 12 
6.1 
Overall Study Design.............................................................................................. 12 
6.2 
Study Medication.................................................................................................... 14 
6.2.1 
Tarloxotinib ............................................................................................................ 14 
6.2.2 
Potassium Supplementation.................................................................................... 14 
6.2.3 
Premedication ......................................................................................................... 15 
6.3 
Assessments............................................................................................................ 15 
6.3.1 
Efficacy Assessments ............................................................................................. 15 
6.3.2 
Safety Assessments................................................................................................. 16 
6.3.3 
Pharmacokinetic Measurements ............................................................................. 17 
6.3.4 
Tumor Tissue.......................................................................................................... 17 
6.3.5 
Biomarker Analysis ................................................................................................ 17 
7 
SAMPLE SIZE AND POWER .............................................................................. 20 
8 
ANALYSIS SETS .................................................................................................. 20 
8.1 
Intent-To-Treat Analysis Set .................................................................................. 20 
8.2 
Primary Analysis Set .............................................................................................. 20 
9 
GENERAL CONSIDERATIONS.......................................................................... 20 
9.1 
Presentation of Summary Statistics ........................................................................ 20 
9.2 
Definitions and Derived Variables ......................................................................... 21 
9.2.1 
Screened and Enrolled Subjects.............................................................................. 21 
9.2.2 
Study Day ............................................................................................................... 21 
9.2.3 
End of Study Treatment Definition ........................................................................ 22 
9.2.4 
End of Study Definition.......................................................................................... 22 
9.2.5 
Date Last Known Alive .......................................................................................... 22 
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9.2.6 
Age.......................................................................................................................... 22 
9.2.7 
Body Mass Index .................................................................................................... 22 
9.2.8 
Baseline Values ...................................................................................................... 22 
9.2.9 
Sum of Target Lesions............................................................................................ 22 
9.2.10 
Evaluable Subjects.................................................................................................. 23 
9.2.11 
RECIST Response Assessment .............................................................................. 23 
9.2.12 
Duration of Response ............................................................................................. 24 
9.2.13 
Disease Control Rate .............................................................................................. 24 
9.2.14 
Progression-Free Survival ...................................................................................... 25 
9.2.15 
Overall Survival...................................................................................................... 25 
9.2.16 
Study Drug Exposure Variables ............................................................................. 25 
9.2.17 
Prior, Concomitant and Post treatment Medications.............................................. 26 
9.2.18 
Adverse Events ....................................................................................................... 26 
9.3 
Analysis Windows.................................................................................................. 28 
10 
STATISTICAL AND ANALYSIS ISSUES .......................................................... 29 
10.1 
Adjustments for Covariates .................................................................................... 29 
10.2 
Handling Dropouts or Missing Data....................................................................... 29 
10.2.1 
Handling of Laboratory Data.................................................................................. 29 
10.2.2 
Handling of Safety Data ......................................................................................... 30 
10.3 
Multicenter Considerations..................................................................................... 31 
10.4 
Multiple Comparisons, Multiplicity ....................................................................... 31 
10.5 
Active-Control Studies ........................................................................................... 31 
10.6 
Examination of Subgroups ..................................................................................... 31 
11 
STUDY SUBJECTS............................................................................................... 31 
11.1 
Subject Enrollment and Disposition....................................................................... 31 
11.1.1 
Enrolled Subjects.................................................................................................... 31 
11.2 
Protocol Deviations ................................................................................................ 32 
11.3 
Demographics and Baseline Characteristics........................................................... 32 
11.3.1 
Key Baseline Demographics................................................................................... 32 
11.4 
Medical History ...................................................................................................... 32 
12 
STUDY DRUG AND OTHER MEDICATIONS .................................................. 33 
12.1 
Exposure to Study Drug and Study Treatment Compliance................................... 33 
12.2 
Prior and Concomitant Medications ....................................................................... 33 
13 
EFFICACY ANALYSES....................................................................................... 34 
13.1 
Primary Analysis .................................................................................................... 34 
13.2 
Primary Efficacy..................................................................................................... 34 
13.3 
Secondary Efficacy................................................................................................. 34 
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13.3.1 
Duration of Response ............................................................................................. 35 
13.3.2 
Survival Reporting.................................................................................................. 35 
13.4 
Exploratory Objectives ........................................................................................... 35 
13.5 
Subgroup Analyses ................................................................................................. 35 
14 
SAFETY ANALYSES ........................................................................................... 36 
14.1 
Adverse Events ....................................................................................................... 36 
14.1.1 
Overall Summary of TEAEs................................................................................... 36 
14.1.2 
Summary of TEAEs by System Organ Class and Preferred Term......................... 37 
14.1.3 
Summary of TEAEs by Preferred Term ................................................................. 37 
14.2 
Clinical Laboratory Evaluation............................................................................... 37 
14.3 
Vital Signs .............................................................................................................. 38 
14.4 
12-Lead Electrocardiogram .................................................................................... 39 
15 
CHANGES RELATIVE TO THE PROTOCOL-SPECIFIED ANALYSIS.......... 40 
16 
References............................................................................................................... 42 
17 
Appendix A: Local Laboratory Units and Reference Ranges by Site and 
Parameter ................................................................................................................ 43 
18 
Appendix B:............................................................................................................ 58 
List of Tables
Table 1 
RAIN-701 Number of Subjects by Cohort................................................................... 12 
Table 2 
Study RAIN-701 Protocol Schedule Events (Protocol [Amendment 3] 24 October 
2020) ............................................................................................................................ 18 
Table 3 
Response Evaluation Criteria in Solid Tumours Guidelines........................................ 23 
Table 4 
Censoring Rules for Progression-Free Survival........................................................... 24 
Table 5 
Severity Grading Guideline for Adverse Events.......................................................... 27 
Table 6 
Visit Analysis Windows (Clinic visits only)................................................................ 28 
Table 7 
Clinical Laboratory Parameters ................................................................................... 38 
Table 8 
Site 101 Units and Reference Ranges by Parameter.................................................... 43 
Table 9 
Site 102 Units and Reference Ranges by Parameter.................................................... 44 
Table 10 Site 103 Units and Reference Ranges by Parameter.................................................... 45 
Table 11 Site 104 Units and Reference Ranges by Parameter.................................................... 46 
Table 12 Site 105 Units and Reference Ranges by Parameter.................................................... 47 
Table 13 Site 107 Units and Reference Ranges by Parameter.................................................... 48 
Table 14 Site 110 Units and Reference Ranges by Parameter.................................................... 49 
Table 15 Site 111 Units and Reference Ranges by Parameter.................................................... 51 
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Table 16 Site 113 Units and Reference Ranges by Parameter.................................................... 52 
Table 17 Site 116 Units and Reference Ranges by Parameter.................................................... 53 
Table 18 Site 117 Units and Reference Ranges by Parameter.................................................... 55 
Table 19 Site 122 Units and Reference Ranges by Parameter.................................................... 56 
Table 20 Common Terminology Criteria for Adverse Events v5.0, November 27, 2017.......... 58 
List of Figures
Figure 1 Schema of Study RAIN-701........................................................................................... 14 
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List of Abbreviations and Definition of Terms
Abbreviation
Description
ADaM
analysis data model
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
Anatomical / Therapeutic / Chemical
BOR
best overall response
CI
confidence interval
CDISC
Clinical Data Interchange Standards Consortium
CM
concomitant medication
CR
complete response
CSR
clinical study report
CT
computed tomography
ctDNA
circulating tumor deoxyribonucleic acids
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EGFR
epidermal growth factor receptor
EOI
End of infusion
EOT
End-of-Treatment Visit
ERBB2
v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2
ERBB4
erb-b2 Receptor tyrosine kinase 4
FDA
Food and Drug Administration
HER
human epidermal growth factor receptor
HR 
heart rate
ICH
International Council for Harmonisation
IV
intravenous
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NRG1
neuregulin 1
NSCLC
non-small cell lung cancer
ORR
objective response rate
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Abbreviation
Description
OS
overall survival
PAS
Primary analysis set
PD
progressive disease
PET
positron emissions tomography
PFS
progression-free survival
PK
pharmacokinetic
PO
oral
PR
partial response
QTc
corrected QT interval
QTcF
corrected QTc interval as calculated according to Fridericia’s formula
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease (tumor response)
SD
standard deviation (statistics)
SOC
system organ class
STEAP4
six transmembrane epithelial antigen of the prostate, family member 4
TEAE
treatment-emergent adverse event
TLF
tables, listings, and figures
WHO
World Health Organization
WOCBP
women of childbearing potential
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1
REVISION HISTORY
Version
Date
Document 
Owner
Revision Summary
1.0
14 October 
2022
Inka Leprince
Initial version
2
RELATED DOCUMENTS: PROTOCOL AND CASE REPORT FORMS
Version
Date
Initial Protocol
14Dec2018
Protocol (Amendment 1)
06Mar2019
Protocol (Amendment 2)
17Jun2019
Protocol (Amendment 2.1)
11Nov2019
Protocol (Amendment 3)
24Oct2020
Case Report Forms
22Mar2019
3
COMMITMENT TO GOOD STATISTICAL PRACTICE
3.1
Definition of Good Statistical Practice
The International Council for Harmonisation Guideline on Statistical Principles for Clinical 
Trials (ICH E9) implicitly defines good statistical practice. Good statistical practice includes 
both appropriate statistical designs to minimize bias and maximize precision of analysis plus 
operational excellence to assure credibility of results. The scientific design associated with any 
clinical trial is found in the protocol and a more detailed, pre-specified statistical analysis plan 
such as this one presents the final statistical methods.
We interpret the operational side of good statistical practice as a transparent, reproducible, and 
validated approach to acquiring and analyzing clinical trial data. Reproducible research depends 
upon process transparency and also provides auditability of the statistical analysis. Analysis 
transparency requires that a navigable electronic process chain exists from defining the objective 
of the analysis to creating the results.
3.2
Use of Standards
Data standards are foundational for creating an environment where tools can be leveraged at 
different points in the analysis process. Data standards for clinical development of drugs have 
been defined and are maturing under various initiatives through the Clinical Data Interchange 
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Standards Consortium (CDISC). RAIN Therapeutics uses raw, source data sets and Analysis 
Data Model (ADaM) statistical analysis files for producing analysis results. Other applicable 
standards include regulatory guidance from the Food and Drug Administration (FDA) and ICH:
x
ICH Guideline on the Structure and Content of Clinical Study Reports (ICH E3)
x
ICH Guideline for Good Clinical Practice (ICH E6)
4
PURPOSE OF THE ANALYSIS PLAN
This statistical analysis plan (SAP) pre-specifies the statistical analysis methods for supporting 
the completion of the abbreviated clinical study report (CSR) of Study RAIN-701 for 
investigational product tarloxotinib, a novel drug candidate designed to treat subjects with 
advanced solid tumors with qualifying genetic mutations and/or fusions. The study intended to 
enroll up to 215 subjects across 5 cohorts but was discontinued early on the basis of a business 
decision made by the sponsor. At the time of the database lock for RAIN-701 (23 April 2021), 
41 subjects were enrolled. This SAP will be used to conduct a comprehensive safety analysis and 
summarize the available efficacy data collected during the study. The primary, secondary, and 
efficacy analyses planned in the protocol may not be appropriate or possible based on the 
available data. The planned analyses identified in this SAP may be included in future 
manuscripts.
The analysis methods described in this plan are considered a posterior, in that they have been 
defined after the clinical database lock. Exploratory analyses that are not defined in this SAP 
may be performed to support the clinical development program. Any post-hoc or unplanned 
analyses that are performed for the CSR, but not defined in this SAP, will be documented in the 
CSR. Changes from the planned analyses stated in the study protocol are described in Section 15.
Should the SAP and the protocol be inconsistent with respect to any further planned analyses, the 
language of the SAP is governing.
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5
STUDY OBJECTIVE
This study was planned to evaluate the safety and efficacy of tarloxotinib 150 mg/m2 as a weekly 
1-hour intravenous (IV) infusion of up to 40 weeks when administered to subjects with non-
small cell lung cancer (NSCLC) whose tumors harbor either an epidermal growth factor receptor 
(EGFR) exon 20 insertion or a human epidermal growth factor receptor 2 (HER2)-activating 
mutation (including exon insertions).
5.1
Efficacy Objectives and Endpoints
The primary, secondary, and efficacy analyses planned in the protocol may not be appropriate or 
possible based on the available data. Additionally, efficacy analyses are unlikely to be significant 
because the sample size is small and the analyses will be underpowered. In place of formal 
efficacy analyses, selected efficacy endpoints will be summarized descriptively.
5.1.1
Primary Efficacy
The analysis of the primary objective as outlined in the study protocol will not be performed for 
the abbreviated CSR, but will instead be summarized descriptively and listed where possible.
The primary objective of this study was the evaluation of the objective response rate (ORR),
based on subjects who had complete response or partial response, of tarloxotinib according to 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
5.1.2
Secondary Efficacy
The analyses of the secondary objectives as outlined in the study protocol will not be performed 
for the abbreviated CSR, but will instead be summarized descriptively and listed where possible.
Secondary objectives include evaluation of the antitumor effect of tarloxotinib on: best overall 
response (BOR), duration of response (DOR), disease control rate (DCR), progression-free 
survival (PFS), and overall survival (OS) as measured from the date of first study drug dose to 
the date of death by any cause. Additional secondary efficacy endpoints such as the exploration 
of pharmacokinetics of tarloxotinib and tarloxotinib-E; and the determination of whether there is 
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an association between plasma exposure to tarloxotinib and effects on cardiac repolarization will 
not be performed because of the limited data basis.
5.1.3
Exploratory Efficacy
The analyses of the exploratory objectives as outlined in the study protocol will not be performed 
for the abbreviated CSR because of the limited data basis. Exploratory objectives are described 
in Protocol Section 4.2.3.
5.2
Safety Objective
The safety objective of the study is to evaluate the safety of tarloxotinib subjects with NSCLC
using safety assessments described in Section 6.3.2. Safety endpoints include the incidence of 
treatment-emergent adverse events (TEAEs); changes in clinical laboratory parameters 
(hematology, serum chemistry, and urinalysis), vital signs, and electrocardiogram (ECG)
parameters; physical examination results; and use of concomitant medications (CMs).
6
STUDY DESIGN
6.1
Overall Study Design
This was a Phase 2 multicenter, open-label study to evaluate the antitumor effect of tarloxotinib 
in subjects with NSCLC whose tumors harbors either an EGFR exon 20 insertion or a HER2-
activating mutation (including exon 20 insertions) or subjects with advanced solid tumors 
expressing NRG1/HER-family gene fusions or a HER2-activating. All subjects have received at 
least 1 prior platinum-based chemotherapy-containing regimen in the advanced/metastatic setting 
(Cohorts A, B, and B1) or standard of care for cancer (Cohorts C and D). Cohorts B1 and D were 
not be pursued at the discretion of the Sponsor.
Table 1
RAIN-701 Number of Subjects by Cohort
Cohort
Description
Planned 
N
Enrolled
N
A: 
x Subjects with advanced NSCLC harboring an EGFR exon 20 
insertion mutation o At least 1 prior platinum-based 
chemotherapy-containing regimen
43
11
B: 
x Subjects with advanced NSCLC with a HER2 activating 
mutation
43
22
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x Subjects who have received at least 1 prior platinum-based 
chemotherapy-containing regimen
B1*
x Subjects with advanced NSCLC harboring a HER2-activating 
mutation
x Subjects who have received at least 1 platinum-based 
chemotherapy-containing regimen
x Subjects who have received prior HER2-directed therapy
43
0
C:
x Subjects with advanced solid tumors who have failed standard 
therapies appropriate for their tumor type and stage of disease, 
or, in the opinion of the Investigator, would be unlikely to 
tolerate or derive clinically meaningful benefit from 
appropriate standard-of-care therapy
x Subjects with tumors harboring an NRG1 gene fusion, EGFR 
gene fusion, EGFR kinase domain duplication, ERBB2 gene 
fusion, or ERBB4 gene fusion
43
8
D*:
x Subjects with advanced solid tumors who have failed all 
standard therapies appropriate for their tumor type and stage of 
disease, or, in the opinion of the Investigator, would be unlikely 
to tolerate or derive clinically meaningful benefit from 
appropriate standard-of-care therapy
x Subjects with tumors (excluding NSCLC) harboring a HER2-
activating mutation
43
0
Total
215
41
Approximately 248 subjects were planned for enrollment on the study to yield 215 evaluable 
subjects, 43 subjects per cohort. A total of 41 subjects were enrolled in cohorts A, B and C. No 
subjects were enrolled on cohorts C and D. All cohorts used a Simon’s 2-stage design. In the first 
stage, 21 subjects were accrued. If more than 3 subjects in a cohort had a partial or complete 
response, up to 22 additional subjects could have been enrolled to the cohort, for up to a total of 
43 subjects per cohort. However, if there were 3 or fewer responses among these 21 subjects, the 
cohort would be stopped based on futility.
Subjects received taroxontinib 150 mg/m2 administered as a weekly 1-hour IV infusion on 
Days 1, 8, 15, and 22 of each 28-day cycle until disease progression or unacceptable toxicity 
(e.g., hepatotoxicity meeting Hy’s law criteria or serious arrhythmias of ventricular origin).
* Cohorts B1 and/or D were not pursued, at the discretion of the Sponsor
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Subjects were expected to receive up to 10 cycles of treatment. The total study duration was 
estimated to be 36 months, including approximately 24 months for accrual and approximately 
12 months for follow-up after the last subject was enrolled. Upon completion of the end of 
treatment visit, subjects returned to the clinic within 30 days following their last dose for a 
Follow-up visit. Clinical visits during the Treatment Period and Follow-up Period included
efficacy, biomarkers, safety, and pharmacokinetic (PK) assessments. Figure 1 depicts study visits 
from Screening Period to Follow-up Period. The maximum duration of Study RAIN-701 per 
subject was expected to be up to 338 days (i.e., a maximum of 28-day Screening Period, a
Treatment Period consisting of a maximum of ten 28-day treatment cycles, and a 30-day safety 
Follow-up Period). Assessments and procedures for evaluation of safety, efficacy, PK, and 
biomarkers were conducted per the protocol-specified schedule (see Table 2).
Figure 1 Schema of Study RAIN-701
6.2
Study Medication
6.2.1
Tarloxotinib
Tarloxotinib 150 mg/m2 was administered as a 1-hour IV infusion weekly until progressive 
disease (PD) or unacceptable toxicity. Tarloxotinib was administered on Day 1, Day 8, Day 15,
and Day 22 of every 28-day cycle. All infusions after Cycle 1 Day 1 were administered 7 days ±
1 day after the prior infusion.
6.2.2
Potassium Supplementation
Serum electrolytes (including potassium) were checked prior to each tarloxotinib infusion. 
Subjects with a pre-infusion serum potassium of < 3.5 mEq/L received potassium replacement 
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per institutional policy (IV and/or oral [PO]) and have the scheduled tarloxotinib infusion 
delayed at least 24 hours and potassium levels rechecked within 1 hour prior to the rescheduled 
infusion. All subjects with a pre-infusion serum potassium levels  3.5 mEq/L DQG 5.0 mEq/L
were supplemented daily with 40 mEq/L of potassium replacement per institutional policy (IV 
and/or PO). 
6.2.3
Premedication
All subjects may have received steroid or anti-emetics premedication prior to tarloxotinib 
infusions. The premedication regimen was determined by the Investigator and may be adjusted at 
subsequent infusions based on the signs and symptoms observed during or after prior infusions.
6.3
Assessments
Table 2 shows the schedule of events for the study.
6.3.1
Efficacy Assessments
Tumor assessment and imaging was performed according to institutional practice and included
computerized tomography (CT) or magnetic resonance imaging (MRI) of the chest and 
abdomen, brain scan, and bone scan at baseline. The baseline radiographic tumor assessment was 
required within 28 days prior to the first dose of tarloxotinib, at the Screening assessment. Brain 
and bone scans did not need to be repeated for subjects with no brain or bone metastases at 
baseline. Recently completed negative positron emissions tomography (PET) scans could be 
substituted for baseline bone scans. Subsequent radiographic tumor assessments were every 
8 weeks (± 5 days) with respect to Cycle 1 Day 1 (e.g., Cycle 3 Day 1, Cycle 5 Day 1, etc.), until 
unequivocal PD was documented. The same imaging modality used for baseline imaging (i.e., 
CT or MRI) was used for subsequent tumor assessments in each subject. In accordance with 
RECIST v1.1, response (partial response [PR] and complete response [CR]) was confirmed by a 
second tumor assessment at least 4 weeks after the initial observed response. The scheduling of 
subsequent tumor assessments may have been adjusted based on the date of the most recent 
imaging. 
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6.3.2
Safety Assessments
The objective of the safety assessments was to evaluate the safety and tolerability of tarloxotinib 
in this population, including to determine whether there is an association between plasma 
exposure to tarloxotinib and effects on cardiac repolarization. Safety was assessed by repeated 
clinical evaluations including adverse events (AEs), suspected adverse reactions, unexpected 
events, serious AEs (SAEs), serious unexpected suspected adverse reactions, vital signs, physical 
examination, ECGs, clinical laboratory tests (serum chemistry, hematology, and urinalysis).
6.3.2.1
Adverse Events
Investigators collected information related to AEs throughout this clinical trial. All AEs 
occurring in all subjects were collected following exposure to study treatment (treatment 
emergent) until approximately 30 days after the last study treatment.
6.3.2.2
Vital Signs
Vital signs were obtained at each visit and prior to and following the start of each tarloxotinib 
infusion. Vital signs measured include: blood pressure (systolic and diastolic; mmHg); heart rate 
(beats per minute); body temperature (°C); respiration rate (breaths per minute); and weight (kg).
6.3.2.3
Physical Examinations
Complete physical examinations, including a review of all body systems, was performed at the 
Screening, Day 1 of all cycles, and the end of treatment (EOT) visits as shown in Table 2.
Clinically significant findings observed during physical examination were reported as medical 
history (pre-treatment) or AEs (post-treatment).
6.3.2.4
Electrocardiograms
All 12-lead ECG tracings were performed once at the following visits: Screening, EOT, and 
Safety Follow-up. During Cycle 1, ECGs were performed at five time points (preinfusion, end of 
infusion [EOI], 1 hour after EOI, 2 hours after EOI, 3 hours after EOI, 4 hours after EOI), and 
hourly thereafter as needed. After Cycle 1, all treatment visits have ECGs performed at a
minimum of three time points (preinfusion, 2 hours after EOI, 4 hours after EOI) and hourly 
thereafter as needed, as shown in Table 2.
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6.3.3
Pharmacokinetic Measurements
Blood samples for tarloxotinib and tarloxotinib-E plasma concentrations were collected prior to 
and following tarloxotinib infusion on Cycle 1 Day 1 and Cycle 2 Day 1. Serum potassium 
samples were also collected after the infusion. All blood samples may be collected within the 5 
or 10 minutes (see Table 2) prior to or following the protocol-specified time point. 
Plasma samples were collected for evaluation of the pharmacokinetics of tarloxotinib and 
tarloxotinib-E in tumor tissue. Plasma sample were collected at approximately at pre-infusion, 
EOI, 3 hours after EOI, and 7 hours after EOT (Cycle 1 Day 1 only) for measurement of 
tarloxotinib and tarloxotinib-E concentrations at each Cycle 1 Day 1 and Cycle 2 Day 1 visits as 
indicated in Table 2. An optional tumor biopsy may have been conducted at Cycle 1 Day 15.
6.3.4
Tumor Tissue
All subjects had tumor tissue collected at baseline. Tumor samples obtained during screening 
may have also been used to determine levels of the reductase, six transmembrane epithelial 
antigen of the prostate, family member 4 (STEAP4). In addition to the above-mentioned tumor 
sample, an optional tumor tissue sample for measurement of the active metabolite (tarloxotinib-
E) and tarloxotinib may have been collected from consenting subjects on Cycle 1 Day 15 after 
infusion along with a blood sample for PK. If the biopsy (and associated PK sample) was not 
able to be performed on the Cycle 1 Day 15 visit, it should have been collected within the 
24 hours after the tarloxotinib infusion or after another infusion day.
6.3.5
Biomarker Analysis
Blood samples were collected for biomarker assessment (e.g., circulating tumor 
deoxyribonucleic acid [ctDNA]) at the Cycle 1 Day 1, Cycle 2 Day 2, and End of Treatment 
visits. Biomarker assessment may include ctDNA mutation analysis and evaluation of the 
concordance of EGFR and HER2 mutation identification between blood and tumor tissue.
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Table 2
Study RAIN-701 Protocol Schedule Events (Protocol [Amendment 3] 24 October 2020)
Schedule of Events
SCR
Cycle 1 (Day)
Cycle 2 (Day)
Cycles 3+ (Day)
OBX
EOT1
FUP
1
8
15
22
1
8
15
22
1
8
15
22
Informed Consent
X
Eligibility
X
Medical/Disease History/ 
Smoking History
X
Demographics
X
Physical Examination
X
X
X
X
X
X
ECOG
X
X
Weight
X
X
X
X
X
X
Vital Signs
X
X
X
Pre-infusion
X
X
X
X
X
X
X
X
X
X
X
X
EOI
X
X
X
X
X
X
X
X
X
X
X
X
30, 60, and 90 min after EOI2
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram (12-lead)3
X
X
X
Pre-infusion
X
X
X
X
X
X
X
X
X
X
X
X
EOI
X
X
X
X
X
1 h after EOI2
X
X
X
X
X
2 h after EOI2
X
X
X
X
X
X
X
X
X
X
X
X
3 h after EOI2
X
X
X
X
X
4 h after EOI2
X
X
X
X
X
X
X
X
X
X
X
X
hourly thereafter as needed2
X
X
X
X
X
X
X
X
X
X
X
X
Hematology Panel
X
X
X
X
X
X
Serum Chemistry Panel
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1 Day 1 of Cycles 2+ and EOT Visit are Day 28 of the prior cycle
2 For subjects with Grade 3 QTcF prolongation ( 501 msec or 60 msec increase compared to pre-infusion), repeat ECG every 15 to 30 minutes until resolved to Grade 2 (481 to 
500 msec) or lower ( 499 msec) and then obtain ECGs every hour. If QTcF prolongation is  Grade 3, an ECG may need to be repeated more frequently during a subject’s
visit as indicated in Table 6 , depending on the degree of the prolongation and per institutional standards.
3 For subjects with  Grade 3 (500 msec) QTcF prolongation with current or prior infusion
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Schedule of Events
SCR
Cycle 1 (Day)
Cycle 2 (Day)
Cycles 3+ (Day)
OBX
EOT1
FUP
1
8
15
22
1
8
15
22
1
8
15
22
Serum Potassium
X
X
EOI
3 h after EOI2
X
X
Urinalysis
X
X
X
X
X
X
X
X
Pregnancy Test4
X
X
X
X
X
PK Samples
X5
Pre-infusion6
X
X
EOI6
X
X
3 h after EOI6
X
X
7 h after EOI6
X7
at optional tumor biopsy
Biomarker Sample
X
X
X5
X
Potassium Supplementation8
X
X
X
X
X
X
X
X
X
X
X
X
Tarloxotinib Infusion
X
X
X
X
X
X
X
X
X
X
X
X
Tumor Tissue
X
Optional Tumor Biopsy
X5
X5
X9
Tumor Assessment
X
ĸ(YHU\ZHHNVGD\VIURP&\FOH'D\ĺ
Concomitant Medications
X
ĸ(YHU\9LVLWĺ
X
X
Adverse Events Assessment
ĸ(YHU\9LVLWĺ
X
X
X
Abbreviations: CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; EOT = End-of-Treatment Visit; FUP = Follow-up Visit; 
MRI = magnetic resonance imaging; OBX = optional biopsy; PET = positron emissions tomography; PK = pharmacokinetic; QTcF = corrected QT interval as calculated 
according to Fridericia’s formula; SCR = Screening Period
4 Serum pregnancy at baseline, then urine dipstick, for women of childbearing potential.
5 Collect blood (plasma samples for PK and biomarker including ctDNA) at time of biopsy
6 Can be made ±5 minutes of scheduled event.
7 In a subset of subjects.
8 If applicable, see Section 6.2.2.
9 Collect blood (plasma sample for biomarker) at time of biopsy
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7
SAMPLE SIZE AND POWER
The primary objective of this study is to determine if tarloxotinib provides a clinically significant 
tumor response to subjects in each cohort, investigated by assessing if the true ORR is at least 
above some desirable target level following therapy with tarloxotinib.
According to the protocol, a Simon’s 2-stage minimax design (Simon 1989) was used for all 
cohorts. The null hypothesis that the true response rate is 15% was tested against a one-sided 
alternative. In the first stage, 21 subjects were accrued. If there were 3 or fewer responses among 
these 21 subjects, the cohort was stopped for futility. Otherwise, 22 additional subjects may be 
accrued for a total of 43 subjects in each cohort. The null hypothesis will be rejected if 11 or 
more responses are observed in 43 subjects. This design yields a type I error rate of 0.0454 and 
power of 0.8014 when the true response rate is 31%. The probability of early termination at the 
end of the first stage is 0.61 if the true response rate is 15%.
8
ANALYSIS SETS
8.1
Intent-To-Treat Analysis Set
The Intent-To-Treat (ITT) Analysis Set will include all enrolled subjects regardless of Treatment 
Period eligibility or completion. The ITT Analysis Set will be the basis for demographics and 
baseline characteristics. Since enrolled subjects are subjects who received at least one dose of 
tarloxotinib, the ITT Analysis Set is functionally the same as the Primary Analysis Set.
8.2
Primary Analysis Set
The Primary Analysis Set (PAS), referred to as the Safety Population in the protocol, is defined 
as all subjects who subjects who received at least 1 dose of tarloxotinib. The Primary Analysis 
Set will be the analysis population for the safety and efficacy analyses.
9
GENERAL CONSIDERATIONS
9.1
Presentation of Summary Statistics
For most summary statistics, data will be analyzed and displayed in tabular format. Continuous 
and categorical data will be summarized by cohort and overall.
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Continuous variables will be summarized using a 6-point descriptive summary (n, mean, 
standard deviation [SD], median, minimum, and maximum) unless otherwise specified. The 
same number of decimal places as in the observed value will be presented when reporting 
minimum and maximum; 1 additional decimal place than in the observed value will be presented 
when reporting mean, median, 95% confidence interval (CI); 2 additional decimal places than in 
the observed value will be presented when reporting stable disease (SD).
All categorical/qualitative data will be presented using the frequency of events and percentages. 
All percentages will be presented to 1 decimal place, unless otherwise specified. Percentages 
equal to 100 will be presented as 100% and percentages will not be presented for zero 
frequencies. For summaries of AEs and CMs, the percentages will be based on the number of 
subjects who received study drug.
The statistical test for efficacy endpoints will not be performed.
Results of statistical analyses will be reported using summary tables, listings, and figures (TLFs).
The ICH of Technical Requirements for Pharmaceuticals for Human Use numbering convention 
will be used for all TLFs.
All analyses and summaries will be produced using SAS® version 9.4 or higher.
9.2
Definitions and Derived Variables
9.2.1
Screened and Enrolled Subjects
9.2.1.1
Screened Subjects
Subjects who signed an informed consent form are considered Screened Subjects
9.2.1.2
Enrolled Subjects
Subjects who received at least one dose of tarloxotinib, are considered Enrolled Subjects.
9.2.2
Study Day
Study Day, which follows the CDISC Study Data Tabulation Model standard, is defined 
as (Assessment date - date of first study drug dosing + 1 day), where the assessment date is on or 
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after the date of first study drug dosing; (Assessment date - date of first study drug dosing), 
where the assessment date is before the date of first study drug dosing.
9.2.3
End of Study Treatment Definition
A subject is considered to have completed study treatment if the subject has completed the End 
of Treatment Visit.
9.2.4
End of Study Definition
A subject is considered to have completed the study if the subject has completed final safety
follow-up visit. The end of the study is defined as the date of the last follow up visit of the last 
subject in the study.
9.2.5
Date Last Known Alive
If a subject died, the date last known alive is the subject’s date of death. Otherwise, the date last 
known alive is the date of last contact with the subject in the study (e.g., the most recent date of 
any in-clinic visit, date of telephone contact, date of withdrawal of consent, date of study 
completion date, etc.).
9.2.6
Age
Age (years) will be calculated as the number of years between date of birth and date of the 
earliest informed consent, rounded down to the largest to a whole number less than or equal to 
the age at measurement.
9.2.7
Body Mass Index
Body mass index (kg/m2) is derived as weight (kg) / [height (m) × height (m)].
9.2.8
Baseline Values 
Baseline values are defined as the last, non-missing assessment prior to the first dose of study 
drug.
9.2.9
Sum of Target Lesions
The sum of target lesions is defined as the sum of the longest diameters for non-nodal lesions 
and the short axis for lymph nodes.
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9.2.10 Evaluable Subjects
A subject is classified as response evaluable if they have at least one response assessment or if 
they discontinue from treatment due to death prior to obtaining at least one response assessment. 
Subjects discontinuing treatment for disease progression must have a disease assessment 
performed documenting the progression
9.2.10.1 Responder
All enrolled subjects who receive study treatment, have a baseline tumor assessment with 
documentation of measurable disease, have at least 1 on-study tumor assessment, whether or not 
this occurs at the specified imaging interval, will be considered evaluable for response. Subjects 
will be considered responders if they have a confirmed objective response of CR or PR 
according to RECIST v1.1 recorded from baseline until disease progression or death due to any 
cause.
9.2.11 RECIST Response Assessment
Table 3
Response Evaluation Criteria in Solid Tumours Guidelines
Response assessment
RECIST guideline, version 1.1
Target lesions
Complete Response
Disappearance of all target lesions and reduction in the short axis measurement 
of all pathologic O\PSKQRGHVWRPP
Partial Response
GHFUHDVHLQWKHVXPRIWKHORQJHVWGLDPHWHURIWKHWDUJHWOHVLRQVFRPSDUHG
with baseline
Progressive Disease
LQFUHDVHRIDWOHDVWPPLQWKHVXPRIWKHORQJHVWGLDPHWHURIWKHWDUJHW
lesions compared with the smallest sum of the longest diameter recorded
OR
The appearance of new lesions, including those detected by fludeoxyglucose 
PET
Stable Disease
Neither partial response nor progressive disease
Non-target lesions
Complete Response
Disappearance of all non-target lesions and normalization of tumor marker 
levels
Incomplete Response; 
Stable Disease
Persistence of 1 or more non-target lesions and/or the maintenance of tumor 
marker levels above normal limits
Progressive Disease
The appearance of 1 or more new lesions or unequivocal progression
If subject has measurable disease, an increase in the overall level or substantial 
worsening in non-target lesions, such that tumor burden has increased, even if 
there is stable disease or partial response in target lesions
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If no measurable disease, an increase in the overall tumor burden comparable in 
magnitude with the increase that would be required to declare progressive 
disease in measurable disease (eg, an increase in pleural effusions from trace to 
large, or an increase in lymphangitic disease from localized to widespread)
9.2.11.1 Overall Response Rate
The overall response rate in each cohort will be estimated as the number of subjects with a
confirmed objective response (CR or PR) divided by the number of enrolled subjects (defined in 
Section 9.2.10) in each respective cohort.
9.2.11.2 Best Overall Response Rate
Best overall response rate is calculated the same as the ORR (Section 9.2.11.1), but subjects are 
summarized at their best response level. Best to worst response is as follows: CR, PR, SD, and 
then PD.
9.2.12 Duration of Response
DOR as measured from the date of first objective response (CR or PR) to date of disease 
progression or death is documented. DOR data will be censored according to Table 4 for subjects
who are alive with no objective documentation of (radiographic) disease progression by the data 
cut-date.
Table 4
Censoring Rules for Progression-Free Survival
Situation 
Date of Censoring 
No baseline radiologic assessment 
Date of first study drug dose 
No post-baseline radiologic assessment (and 
no death prior to first scheduled radiologic 
assessment) 
Date of first study drug dose. 
No progression or death on study 
Date of last radiologic assessment 
Documented progression or death after 2 or 
more consecutive missing radiologic 
assessments 
Date of last radiologic assessment 
New anticancer therapy started prior to 
progression 
Date of last radiologic assessment prior to 
new anticancer therapy 
9.2.13 Disease Control Rate
Disease control rate is defined as the number of subjects who have CR, PR, or SD for at least 
2 cycles (8 weeks) according to the RECIST v1.1 recorded in the period between first study drug 
dose and disease progression or death to any cause. The DCR on each cohort will be estimated 
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by dividing the number of subjects with CR, PR, or SD for at least 2 cycles (8 weeks) by the 
number of subjects enrolled in each cohort.
9.2.14 Progression-Free Survival
Progression-free survival is defined as the time from the date of first tarloxotinib dose to the date 
of the first objective documentation of radiographic disease progression or death due to any 
cause, whichever occurs first. PFS data will be censored according to Table 4 for subjects who 
are alive with no objective documentation of (radiographic) disease progression by the data cut-
date.
9.2.15 Overall Survival
Overall survival as measured from the date of first tarloxotinib dose to the date of death by any 
cause. In the absence of confirmation of death, survival time will be censored to last date the 
subject is known to be alive. 
9.2.16 Study Drug Exposure Variables
9.2.16.1 Total Tarloxotinib Dose (mg) Taken
Total tarloxotinib dosage (mg) is defined as the cumulative dosage of tarloxotinib actually 
received over the Treatment Period, calculated as follows:
ܶ݋ݐ݈ܽ ܶܽݎ݈݋ݔ݋ݐܾ݅݊݅ ܦ݋ݏ݁= ෍(ܣܿݐݑ݈ܽ ܶܽݎ݈݋ݔ݋ݐܾ݅݊݅ ܦ݋ݏ݁)௜
௞
௜ୀଵ
where 
ȈUHSUHVHQWVWKHVXPPDWLRQRSHUDWRUDQGWKHYDOXHLQSDUHQWKHVHVLVVXPPHGRYHUWKHVHTXHQFHi = 1 to k, where
k = number of tarloxotinib infusions subject received.
9.2.16.2 Actual Number of Infusions Administered
The number of infusions a subject received. Interrupted infusions also count as one infusion.
9.2.16.3 Actual Number of Cycles Administered
The number of cycles a subject initiated. This includes receiving infusions at each scheduled 
visit of the cycle (Day 1, Day 8, Day 15, and Day 22).
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9.2.16.4 Actual Dose Intensity
Actual dose intensity (mg/day) is calculated as total cumulative dose received divided by actual 
number of infusions administered.
9.2.16.5 Treatment Duration
Treatment duration (days) is defined as (Last Dose Date – First Dose Date + 1 day). Treatment 
duration indexed by the 28-day cycles is defined as ([Last Dose Date – First Dose Date + 1 
day]/28 days), rounded to one decimal place.
9.2.17 Prior, Concomitant and Post treatment Medications
All medication verbatim terms reported on the electronic case report form (eCRFs) will be 
mapped according to the World Health Organization (WHO) Drug Dictionary (WHO DD March 
2020 B3). The medications will be mapped to Anatomical/Therapeutic/Chemical (ATC) class 
and preferred names.
A prior medication is considered to be any medication that is taken within a year prior to the first 
study drug dosing.
A concomitant medication is considered to be any medication that is continued from Screening 
and continued after the first study drug dosing (i.e., a prior medication can also be a CM if it 
continued after the first dose of study drug) or any medication with start dates or stop dates 
within the Treatment Period. Specifically, CMs are medications: that are continued from 
Screening and continued after the first study drug dosing, or with start dates or stop dates within 
the first dose date through last dose date + 24 hours, missing CM end date, or ongoing) with the
study drug administration.
Post medications is considered to be any medication taken after the last study drug dose date + 
24 hours, missing CM end date, or ongoing.
9.2.18 Adverse Events 
All AE verbatim terms reported on the eCRFs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA® version 22.0). AE severity will be graded according to 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE 
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2017) version 5. MedDRA will be used to map the AE verbatim to lowest level term, preferred 
term, and system organ class for summary purposes.
Table 5
Severity Grading Guideline for Adverse Events
Grade 
Description 
1
Mild; Asymptomatic or mild symptoms; Clinical or 
diagnostic observations only; Intervention not indicated 
2
Moderate; Minimal, local or noninvasive intervention 
indicated; Limiting age-appropriate instrumental 
activities of daily living*
3
Severe or medically significant but not immediately 
life-threatening; Hospitalization or prolongation of 
hospitalization indicated; Disabling; Limiting self-care 
activities of daily living†
4
Life-threatening consequences; Urgent intervention 
indicated 
5
Death related to adverse event 
9.2.18.1 Treatment-Emergent Adverse Events
Treatment-emergent adverse events are defined as any AEs, regardless of relationship to study 
drug, that have an onset or worsening in severity on or after the first dose of study drug until 
30 days after the final dose of study drug (safety follow-up visit).
Related TEAEs are those reported by investigators as related to the study drug.
9.2.18.2 Serious Adverse Events
Serious AEs are defined according to the NCI CTCAE v5.0, as described in Protocol 
Section 8.2.2 Adverse Event Severity.
9.2.18.3 Severe Adverse Events
Severe AEs are defined as events with a severity of Grade 3 or higher.
* Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.
† Self-care activities of daily living refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications,
and not bedridden
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9.2.18.4 Serious Unexpected Suspected Adverse Reaction
A serious AE deemed related to the study drug (adverse reaction) is considered “unexpected” if 
it is not listed in the Investigator’s Brochure (i.e., ECG QT prolonged, Hypertension, Rash [rash, 
infusion site rash and rash erythematous]) or is not listed at the specificity or severity that has 
been observed.
9.3
Analysis Windows
Clinical visits may occur outside protocol-specified windows. Therefore, instead of relying 
solely on visit labels in the clinical database, analysis visits and their windows are defined using 
Study Day (See Section 9.2.2). For the purposes of data analysis and summary, assessments 
and/or measurements will be flagged based on the collection date/time that is closest to the 
protocol-scheduled time point (or target Study Day). Analysis visit windows are presented in by 
type of assessments and/or measurements.
Table 6
Visit Analysis Windows (Clinic visits only)
Protocol 
Specified Visit
Target Study Day
Start (days)
Stop (days)
Screening
-114
low
-1
Cycle 1 Day 1
1
1
4
Cycle 1 Day 8
8
5
11
Cycle 1 Day 15
15
12
18
Cycle 1 Day 22
22
19
25
Cycle 2 Day 1
29
26
32
Cycle 2 Day 8
36
33
39
Cycle 2 Day 15
43
40
46
Cycle 2 Day 22
50
47
53
Cycle 3 Day 1
57
54
60
Cycle 3 Day 8
64
61
67
Cycle 3 Day 15
71
68
74
Cycle 3 Day 22
78
75
81
Cycle 4 Day 1
85
82
88
Cycle 4 Day 8
92
89
95
Cycle 4 Day 15
99
96
102
Cycle 4 Day 22
106
103
109
Cycle 5 Day 1
113
110
116
Cycle 5 Day 8
120
117
123
Cycle 5 Day 15
127
124
130
Cycle 5 Day 22
134
131
137
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Protocol 
Specified Visit
Target Study Day
Start (days)
Stop (days)
Cycle 6 Day 1
141
138
144
Cycle 6 Day 8
148
145
151
Cycle 6 Day 15
155
152
158
Cycle 6 Day 22
162
159
165
Cycle 7 Day 1
169
166
172
Cycle 7 Day 8
176
173
179
Cycle 7 Day 15
183
180
186
Cycle 7 Day 22
190
187
193
Cycle 8 Day 1
197
194
200
Cycle 8 Day 8
204
201
207
Cycle 8 Day 15
211
208
214
Cycle 8 Day 22
218
215
221
Cycle 9 Day 1
225
222
228
Cycle 9 Day 8
232
229
235
Cycle 9 Day 15
239
236
242
Cycle 9 Day 22
246
243
249
Cycle 10 Day 1
253
250
256
Cycle 10 Day 8
260
257
263
Cycle 10 Day 15
267
264
270
Cycle 10 Day 22
274
271
277
End of Treatment
Treatment End 
Date
Study Day <=
(ADSL.TRTEDT -
ADSL.TRTSDT + 1)
Follow-up
Treatment End 
Date + 30 Days (± 7 
days)
Study Day >
(ADSL.TRTEDT -
ADSL.TRTSDT + 1)
high
10
STATISTICAL AND ANALYSIS ISSUES
10.1 Adjustments for Covariates
No adjustments for covariates will be performed in the study.
10.2 Handling Dropouts or Missing Data
Missing data will not be imputed. Every effort will be made by the Sponsor to ensure 
completeness of data collection.
10.2.1 Handling of Laboratory Data
A retest value will be used if the first test is invalidated, e.g., specimen hemolyzed.
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10.2.2 Handling of Safety Data
10.2.2.1 Adverse Events
If the time of onset (before or after intake of study drug) cannot be determined whether an AE is 
treatment-emergent because of a partial onset date, the event will be counted as a TEAE.
Adverse events with incomplete start dates will be considered TEAEs, if:
x
Day and month are missing and the year is equal to or after the year of the first date of study 
drug dosing; 
x
Month is missing and the year is after the year of the first date of study drug dosing; 
x
Day is missing and the year is equal to the year of the first date of study drug dosing and the 
month is equal to or after the month of the first date of study drug dosing; or
x
Year is missing.
If severity or relationship of an AE to study drug is not recorded, the severity or relationship will 
be imputed as “severe” or relationship as “possibly related,” for analysis purposes.
10.2.2.2 Concomitant Medications
If start date of a medication is missing, the medication will be considered to have started prior to 
the study. Such a medication may also be considered concomitant, depending on the stop date or 
lack thereof. If the stop date of a concomitant medication is missing, then the medication will be 
treated as ongoing. If the start date of a medication is missing, the stop date will be used to 
determine whether or not it is concomitant. Medications with other incomplete start dates or end 
dates will be imputed as follows:
Incomplete medication start date/time:
x
If only have a YEAR, impute as Jan. 1.
x
Else if only have YEAR and MONTH, impute as Day 1 of month.
x
Otherwise missing, no imputation.
Incomplete medication end date/time:
x
If only have a YEAR, impute as December 31.
x
Else if only have YEAR and MONTH, then impute to last day of the month.
x
Otherwise missing, no imputation.
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10.3 Multicenter Considerations
This trial will be conducted at 14 study centers in the United States, Canada, and other regions.
Data from all study centers will be pooled for efficacy and safety analyses. Because the number 
of subjects at each center is likely to be small, no analyses will be performed by center. Subjects 
from all centers will be pooled for all analyses.
10.4 Multiple Comparisons, Multiplicity
Efficacy variables will be assessed without adjustment for multiple comparisons.
10.5 Active-Control Studies
There is no comparator in this study as all subjects are treated with tarloxotinib.
10.6 Examination of Subgroups
Efficacy variables will be assessed without examination of subgroups.
11 STUDY SUBJECTS
11.1 Subject Enrollment and Disposition
11.1.1 Enrolled Subjects
An accounting of the study subjects will be tabulated. Subjects not completing the study will be 
listed along with the reason for their premature discontinuation. Reasons for premature 
discontinuation will be summarized.
Enrolled (Section 9.2.1) subjects will be summarized by cohort and overall.
Treatment Periods
x
Number of subjects enrolled (ITT)
o
Number (%) of subjects who discontinued from the study treatment
¾ The primary reason for withdrawal from the study treatment
o
Number (%) of subjects who completed the study
o
Number (%) of subjects who discontinued from the study
¾ The primary reason for withdrawal from the study
The percentages will be based on the total subjects who are enrolled (ITT).
A listing of disposition will be provided for all enrolled subjects.
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11.2 Protocol Deviations
Protocol deviations will be neither listed nor summarized because RAIN-701 was discontinued 
and this SAP will support an abbreviated clinical study report, which does not include protocol 
deviations per FDA guidance (Food and Drug Administration, 1999).
11.3 Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized and listed for all treated subjects 
(ITT). Demographic characteristics will include age, sex, race, and ethnicity. A subject listing of 
demographics will be provided.
11.3.1 Key Baseline Demographics
The following parameters from each of the individual baseline and historical summaries will be 
summarized in a single summary:
x
Age
x
Age group, n (%)
x
Sex, n (%)
x
Race, n (%)
x
Ethnicity, n (%)
x
Smoking status, n (%)
x
Baseline weight (kg)
x
ECOG performance status, n(%)
x
Mutation status, n (%)
x
Stage at time of disease, n (%)
x
Stage at time of study entry, n (%)
11.4 Medical History
Medical history and current medical conditions will be mapped to preferred terms and system 
organ classes using the MedDRA® Dictionary (version 23.0) Medical history will be summarized 
by system organ class (SOC) and preferred term (PT) by cohort and overall for ITT subjects. A
subject listing of general medical history will include start date/end date, verbatim medical 
history term, SOC, PT, and ongoing status (Yes, No). Additional subject listings of prior 
radiation therapy and prior surgeries will contain the start date and end date (if available) and 
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type of procedure. The subject listing of prior systemic therapies will include at a start date, end 
date, medication, reason the therapy ended, and best overall response.
12 STUDY DRUG AND OTHER MEDICATIONS
12.1 Exposure to Study Drug and Study Treatment Compliance
Summaries of study drug exposure and compliance will be summarized overall and by cohort.
The source for study drug dosing and compliance is drug exposure.
The summaries will include total number of cycles initiated, the median (range) of cycles 
administered, and dose intensity (see definitions in Section 9.2.11) by cohort and overall. The 
denominators for percentages will be the number of subjects who received the study treatment.
12.2 Prior and Concomitant Medications
Prior and concomitant medications (see definition in Section 9.2.10), will be summarized using 
WHO DD ATC class and preferred name. The summary results will be presented by cohort. 
Prior medications will be summarized by cohort. Concomitant medications will be summarized 
by cohort and overall.
These summaries will present the number and percentage of subjects using each medication. 
Subjects may have more than one medication within an ATC class and preferred name. At each 
summary level subjects are counted once if they reported one or more medications at that level. 
Each summary will be ordered by descending frequency of incidence of ATC class and preferred 
name within each ATC class.
All medications will be provided in a subject listing with flags indicating study drug dose level.
The variables include, but not limited to: Start date/end date/ongoing, medication name, ATC 
class and preferred name, indication, dose, unit, form, frequency, and route.
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13
EFFICACY ANALYSES
13.1 Primary Analysis
The primary analysis was planned after all subjects stop tarloxotinib treatment until documented 
disease progression or unacceptable toxicity. The primary analysis will not be performed because 
RAIN-701 was discontinued and this SAP supports an abbreviated clinical study report.
Additionally, efficacy analyses are unlikely to be significant because the sample size is small and 
the analyses will be underpowered. In place of formal primary analyses, selected efficacy 
endpoints will be summarized descriptively.
13.2 Primary Efficacy 
The primary objective of this study is to evaluate the ORR of tarloxotinib as defined as a CR or 
PR according to RECIST v1.1 recorded from baseline until disease progression or death due to 
any cause.
The numbers and percentages of subjects meeting each response will be summarized, and the 
ORR will be summarized by cohort along with the corresponding 2-sided 95% CI calculated 
using the binomial exact method. All treatment responses and all tumor assessments will be 
listed.
The maximum percent reduction from baseline in the sum of target lesions will be displayed as a 
waterfall plot. The waterfall plot will have a y-axis that will be the maximum percent change 
from baseline in the sum of target lesions, and the x-axis will be each cohort and overall.
The best overall response (Section 13.3) will be reported similarly.
13.3 Secondary Efficacy
The secondary efficacy objective is to evaluate further measures of antitumor activity of 
tarloxotinib including:
x
Best overall response (Reporting as described in Section 13.2),
x
Duration of response (Section 13.3.1),
x
Disease control rate (Section 13.2),
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x
Progression-free survival (Section 13.3.2), and 
x
Overall survival (Section 13.3.2)
The additional secondary objectives of exploratory biomarkers of hypoxia in tumor tissue and
plasma exposure to tarloxotinib and effects on cardiac repolarization will not have analyses or 
descriptive summarization of these endpoints due to the limited data basis.
13.3.1 Duration of Response
DOR will be summarized using descriptive statistics (Section 9.1) for each cohort and overall.
The DOR data will be listed for each subject.
13.3.2 Survival Reporting
The PFS and OS will be summarized using the Kaplan-Meier method and displayed graphically
by cohort and overall: Median event times and the corresponding 2-sided 95% CI will be 
provided. The number and % of subjects with disease progression or death will be provided. The 
number and % of subjects censored as well as reasons for censoring will be provided. A listing of 
survival data will be provided.
13.4 Exploratory Objectives
The exploratory objectives are:
x
To evaluate the concordance of EGFR mutation, HER2 mutation, and NRG1, EGFR, 
HER2, and HER4 fusion detection between tissue and plasma using ctDNA
x
To evaluate exploratory biomarkers of hypoxia in tumor tissue including 6 
transmembrane epithelial antigen of the STEAP4 expression and ERBB family and 
cancer cell signaling pharmacodynamic markers
x
To evaluate the pharmacokinetics of tarloxotinib and tarloxotinib-E in tumor tissue
Analysis and descriptive summary of these exploratory endpoints are outside the scope of this 
SAP.
13.5 Subgroup Analyses
No examination of subgroups is planned.
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14
SAFETY ANALYSES
One of the study objectives is to assess the safety of tarloxotinib. Safety will be assessed by 
repeated clinical evaluations including adverse events (AEs), serious AEs (SAEs), suspected 
serious unexpected suspected adverse reactions, vital signs, physical examination, 
electrocardiograms (ECGs), clinical laboratory tests (serum chemistry, hematology, and 
urinalysis). All analyses of the safety data will be performed using the primary analysis set. All 
descriptive statistics (described in Section 9.1) will be presented by cohort and overall.
14.1 Adverse Events
Safety will be assessed by repeated clinical evaluations including adverse events (AEs), serious 
AEs (SAEs), serious unexpected suspected adverse reactions (SUSARs), and deaths.
Safety data will be summarized descriptively. AEs will be summarized by severity, seriousness, 
and relationship to study drug. All AEs including the AE verbatim term and the associated AE 
MedDRA preferred term will be provided in the subject data listings. Incidence of treatment-
emergent AEs will be summarized descriptively by cohort and total.
TEAEs are defined in Section 9.2.18.1. All reported AEs (including non-TEAEs) will be listed.
Separate listings will be provided for suspected adverse reactions, unexpected events, SAEs, and 
serious unexpected suspected adverse reactions. All TEAE summary tables will present the 
number and percentages of subjects reporting TEAEs, unless otherwise specified. A summaries 
of TEAEs by severity, seriousness, and relation to study drug will be tabulated.
14.1.1 Overall Summary of TEAEs
Overall summary of TEAEs will be presented by cohort and overall. Subjects will be counted 
only once at the highest severity when summarizing TEAE by severity. The overall summary 
will include the following:
x
Number (%) of subjects with any TEAEs
x
Number (%) of subjects with any TEAEs by severity 
x
Number (%) of subjects with any serious TEAEs
x
Number (%) of subjects with any related TEAEs
x
Number (%) of subjects with any serious unexpected suspected adverse reactions
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x
Number (%) of subjects with any TEAEs leading to study drug discontinuation 
x
Number (%) of subjects with any AEs leading to death
14.1.2 Summary of TEAEs by System Organ Class and Preferred Term
AEs will be summarized by MedDRA SOC and PT. Subjects can experience more than one AE 
per SOC and PT. At each level of subject summarization (SOC or PT or severity), subjects will 
be counted once if they reported at least one AE at that level (SOC or PT or severity). Each 
summary will be ordered by SOC alphabetically and by PT in descending order of the total 
incidence within each SOC. Summary tables will be created for each of the following types of 
AEs:
x
TEAEs
x
6HYHUH Grade 3) TEAEs
x
Related TEAEs
x
TEAEs leading to study drug discontinuation
x
Serious TEAEs
x
Serious unexpected suspected adverse reactions
x
TEAEs leading to death
14.1.3 Summary of TEAEs by Preferred Term
AEs will be summarized by MedDRA preferred term (PT). Subjects can experience more than 
one AE per PT. At each preferred term, subjects will be counted once if they reported at least one 
AE at that level (PT). Each summary will be ordered by PT in descending order of the incidence. 
Summary tables will be created for each of the following types of AEs:
x
TEAEs
x
6HYHUH Grade 3) TEAEs
x
Related TEAEs
x
TEAEs leading to study drug discontinuation
x
Serious TEAEs
x
Serious unexpected suspected adverse reactions
x
TEAEs leading to death
14.2 Clinical Laboratory Evaluation
Results for clinical laboratory parameters (serum chemistry and hematology), vital signs, ECGs, 
and physical examinations will be summarized by cohort and combined and by study visits. 
Descriptive summary statistics in observed values as well as changes from baseline will be 
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presented. In addition, thresholds of marked laboratory abnormalities based on NCI CTCAE v5.0 
will be summarized by worst grade shift from baseline (see Appendix B).
Table 7 shows clinical laboratory assessments (hematology, chemistry, and urinalysis) that were 
performed performed. Chemistry and hematology laboratory parameters will be summarized by 
cohort and scheduled visit. Urinalysis assessments will be listed but not summarized due to their 
qualitative nature.
Table 7
Clinical Laboratory Parameters
Chemistry
Hematology
Urinalysis
Sodium
Creatinine
Hematocrit
Specific gravity
Potassium
Total Bilirubin
Hemoglobin
Protein
Chloride
AST/SGOT
WBC count
Glucose
Bicarbonate
ALT/SGPT
Neutrophils
Ketones
Calcium
ALP‡
Lymphocytes
Urobilinogen
Magnesium
Albumin
Monocytes
Occult blood
Phosphorous
Total protein
Eosinophils
Microscopic sediment 
evaluation‡
Glucose
Basophils
Blood urea nitrogen
Platelet count
WOCBP only:
ȕ-HCG§
ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; HCG = ȕ-human chorionic 
gonadotropin pregnancy; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic pyruvic 
transaminase; WBC = white blood count; WOCBP = women of child-bearing potential
Numeric results will be summarized using (6-point) descriptive statistics at baseline and at each 
scheduled post-baseline time point, unless otherwise specified. Changes from baseline will also 
be summarized by scheduled time point, where available. Selected laboratory results will be 
listed with CTCAE reference ranges.
14.3 Vital Signs
Descriptive statistics for pulse rate, respiratory rate, temperature, weight, and blood pressure 
(systolic and diastolic) including baseline values and change from baseline values, will be 
summarized by cohort and scheduled time point. All vital signs parameters will be listed.
‡ Alkaline phosphatase and microscopic sediment evaluation will neither be listed nor summarized due to lack of data
§ ȕ-HCG pregnancy test may be collected as a serum, urine, or urine dipstick assessment
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14.4 12-Lead Electrocardiogram
Electrocardiogram (ECG) data, such as clinical interpretation of ECGs, heart rate (HR) values, 
and interval assessments of QRS duration, PR interval, QT interval, and the Fridericia's corrected 
value of the interval between the Q and T waves on the ECG tracing (QTcF) will be listed. 
Descriptive statistics for observed values and change from baseline at each scheduled time point 
will be presented for these 12-lead ECG interval and HR assessments will be presented as actual 
values and as changes from the baseline values by 6-point descriptive summary statistics (n, 
mean, SD, median, minimum, and maximum). The numbers and percentages of subjects who 
meet categorical analyses such as the following criteria at each scheduled ECG time point will be 
presented.
x
Absolute QTcF interval:
o
QTcF interval < 450
o
QTcF interval 451 to 480 msec
o
QTcF interval 481 to 500 msec
o
47F)LQWHUYDOPVHF
x
Change from predose baseline in QTcF interval:
o
PVHF
o
31 to 60 msec
o
60 msec
The numbers and percentages of subjects meeting each criterion will be summarized for each 
ECG time point, as well as for each subject overall at any time. 
Abnormal ECG findings not present at the pre-dose baseline will be summarized as the number 
of subjects with each finding at 1 or more ECG times. Descriptive waveform morphology 
changes will be provided.
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15 CHANGES RELATIVE TO THE PROTOCOL-SPECIFIED ANALYSIS
Protocol Section 9.2.3 states "Deviations will be defined prior to database lock. Handling of 
major deviations in statistical analyses will be defined in the SAP” and further defines a Per-
Protocol analysis set excludes subjects with certain, pre-specified deviations. RAIN-701 was 
terminated and the analysis will support an abbreviated clinical study report, which does not 
include protocol deviations per FDA guidance for industry, Submission of Abbreviated Reports 
and Synopses in Support of Marketing Applications. Analysis will be performed on the safety 
population which includes all subjects who received at least 1 dose of tarloxotinib. Analysis of a 
Per Protocol (PP) population where subjects with major protocol deviations are removed is not 
necessary for the aCSR. The abbreviated CSR will provide a comprehensive safety analysis for 
all subjects receiving at least 1 dose of tarloxotinib. Additionally, the primary efficacy analysis 
of ORR will include all treated subjects. Efficacy analyses are not interpretable as RAIN-701
was terminated and did not enroll the intended sample size to support statistical analyses.
Protocol Section 7 states, “In accordance with RECIST v1.1, response (PR and CR) must be 
confirmed by a second tumor assessment at least 8 weeks after the initial observed response.” 
SAP Section 6.3.1 text instead states that the confirmation assessment must be at least 4 weeks 
after the initial observed response, which is aligned with the true RECIST v1.1 criteria. The 
efficacy endpoint (Section 9.2.13) still follows the protocol text in defining the disease control 
for at least 8 weeks (2 cycles).
Protocol Table 12 states "Microscopic sediment evaluation, as clinically indicated" as a 
urinalysis assessment, but these microscopic sediment urinalysis assessments were not collected. 
Similarly, Protocol Table 12 lists ALP as a serum chemistry assessment, but it was not collected.
Units and reference ranges of the local laboratory assessments were not collected. The Sponsor 
has assigned units and lab normal ranges for each parameter (e.g., lower limit of normal, upper 
limit of normal) based on available information and Harrison's Principles of Internal Medicine
(Appendix A).
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Adverse events were coded with MedDRA version 22.0 and medical history events were coded 
with MedDRA version 23.0.
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16 References
Cancer Therapy Evaluation Program. (2017, November 27). Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5.0. National Institutes of Health National Cancer 
Institute, U.S. Department of Health and Human Services. Retrieved from CTEP: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_8.5x11.pdf
Food and Drug Administration. (1999, September 13). Submission of Abbreviated Reports and 
Synopses in Support of Marketing Applications. Centers for Drug Evaluation and 
Research (CDER) and Biologics Evaluation and Research (CBER), U.S. Department of 
Health and Human Services. Rockville, MD: Federal Register. doi:99-23663
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use. (1996, July). Structure and Content of Clinical Study Reports (ICH E3).
Center for Drug Evaluation and Research (CDER), U.S. Department of Health and 
Human Services. Rockville, MD: Federal Register. doi:96-18000
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use. (1998, September). Statistical Principles for Clinical Trials (ICH E9).
Centers for Drug Evaluation and Research (CDER) and Biologics Evaluation and 
Research (CBER), U.S. Department of Health and Human Services. Rockville, MD: 
Federal Register. doi:98-24754
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17
Appendix A: Local Laboratory Units and Reference Ranges by Site and Parameter
When a reference range is followed by an asterisk, it is sourced from Harrison's Principles of 
Internal Medicine, 19th edition.
Table 8
Site 101 Units and Reference Ranges by Parameter
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
101
Chemistry
Albumin
g/dL
3.5
5
101
Chemistry
ALP
/L
45
117
101
Chemistry
ALT/SGPT
/L
15
41
101
Chemistry
AST/SGOT
/L
3
34
101
Chemistry
Bicarbonate
mmol/L
18
23
101
Chemistry
Blood urea 
nitrogen
M
mg/dL
9
20
101
Chemistry
Blood urea 
nitrogen
F
mg/dL
7
17
101
Chemistry
Calcium
mmol/L
1.12
1.32
101
Chemistry
Chloride
mmol/L
98
107
101
Chemistry
Creatinine
M
mg/dL
0.66
1.5
101
Chemistry
Creatinine
F
mg/dL
0.52
1.04
101
Chemistry
Glucose
mg/dL
65
140
101
Chemistry
Magnesium
mg/dL
1.6
2.3
101
Chemistry
Phosphorous
mg/dL
2.5
4.5
101
Chemistry
Potassium
mmol/L
3.5
5.1
101
Chemistry
Sodium
mmol/L
137
145
101
Chemistry
Total Bilirubin
mg/dL
0.2
1.3
101
Chemistry
Total protein
g/dL
6.3
8.2
101
Hematology
Basophils
k/uL
0
0.2
101
Hematology
Eosinophils
k/uL
0
0.7
101
Hematology
Hematocrit
M
%
37.5
49.5
101
Hematology
Hematocrit
F
%
34.5
44
101
Hematology
Hemoglobin
M
g/dL
12.5
16.5
101
Hematology
Hemoglobin
F
g/dL
11
14.5
101
Hematology
Lymphocytes
k/uL
0.6
4.9
101
Hematology
Monocytes
k/uL
0.1
1.3
101
Hematology
Neutrophils
k/uL
1.7
8.1
101
Hematology
Platelet count
k/uL
145
400
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SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
101
Hematology
WBC count
k/uL
4
10.8
101
Urinalysis
Glucose
Normal
101
Urinalysis
Ketones
Negative
101
Urinalysis
Occult blood
Negative
101
Urinalysis
Protein
Negative
101
Urinalysis
Specific gravity
1.003
1.03
101
Urinalysis
Urobilinogen
mg/dL
< 2.0
Table 9
Site 102 Units and Reference Ranges by Parameter
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
102
Chemistry
Albumin
g/dL
3.5*
5.5*
102
Chemistry
ALP
102
Chemistry
ALT/SGPT
U/L
7*
41*
102
Chemistry
AST/SGOT
U/L
12*
38*
102
Chemistry
Bicarbonate
meq/L
22*
30*
102
Chemistry
Blood urea nitrogen
mg/dL
7*
20*
102
Chemistry
Calcium
mg/dL
8.7*
10.2*
102
Chemistry
Chloride
meq/L
102*
109*
102
Chemistry
Creatinine
F
mg/dL
0.5*
0.9*
102
Chemistry
Creatinine
M
mg/dL
0.6*
1.2*
102
Chemistry
Glucose
mg/dL
65*
95*
102
Chemistry
Magnesium
mg/dL
1.5*
2.3*
102
Chemistry
Phosphorous
mg/dL
2.7
4.5
102
Chemistry
Potassium
meq/L
3.5*
5*
102
Chemistry
Sodium
meq/L
136*
146*
102
Chemistry
Total Bilirubin
mg/dL
0.1
1.3
102
Chemistry
Total protein
g/dL
6.7*
8.6*
102
Hematology
Basophils
10^9/L
0
0.2
102
Hematology
Eosinophils
10^9/L
0
0.4
102
Hematology
Hematocrit
M
%
39.2
50.2
102
Hematology
Hematocrit
F
%
35.7
46.7
102
Hematology
Hemoglobin
M
g/dL
14.3
18.1
102
Hematology
Hemoglobin
F
g/dL
12.1
16.3
102
Hematology
Lymphocytes
10^9/L
1
4.8
102
Hematology
Monocytes
10^9/L
0.2
0.9
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 45 of 61
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
102
Hematology
Neutrophils
10^9/L
1.8
6.6
102
Hematology
Platelet count
10^9/L
150
400
102
Hematology
WBC count
10^9/L
4
11.1
102
Urinalysis
Glucose
NEGATIVE
102
Urinalysis
Ketones
NEGATIVE
102
Urinalysis
Occult blood
NEGATIVE
102
Urinalysis
Protein
NEGATIVE
102
Urinalysis
Specific gravity
1.001
1.035
102
Urinalysis
Urobilinogen
mg/dL
< 2.0
Table 10 Site 103 Units and Reference Ranges by Parameter
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
103
Chemistry
Albumin
g/dL
3.4
5
103
Chemistry
ALP
IU/L
38
126
103
Chemistry
ALT/SGPT
M
IU/L
17
63
103
Chemistry
ALT/SGPT
F
IU/L
14
54
103
Chemistry
AST/SGOT
IU/L
15
41
103
Chemistry
Bicarbonate
mmol/L
21
31
103
Chemistry
Blood urea 
nitrogen
mg/dL
8
26
103
Chemistry
Calcium
mg/dL
8.4
10.2
103
Chemistry
Chloride
mmol/L
98
107
103
Chemistry
Creatinine
mg/dL
0.5
1.4
103
Chemistry
Glucose
mg/dL
65*
95*
103
Chemistry
Magnesium
mg/dL
1.6
2.3
103
Chemistry
Phosphorous
mg/dL
2.5
4.6
103
Chemistry
Potassium
mmol/L
3.5
5
103
Chemistry
Sodium
mmol/L
136
146
103
Chemistry
Total Bilirubin
mg/dL
0.3
1.5
103
Chemistry
Total protein
g/dL
6.3
7.7
103
Hematology
Basophils
10^9/L
0
0.06
103
Hematology
Eosinophils
10^9/L
0
0.4
103
Hematology
Hematocrit
M
%
38
48.8
103
Hematology
Hematocrit
F
%
34.1
43.3
103
Hematology
Hemoglobin
M
g/dL
12.9
16.9
103
Hematology
Hemoglobin
F
g/dL
11.6
14.6
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 46 of 61
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
103
Hematology
Lymphocytes
10^9/L
0.8
3.65
103
Hematology
Monocytes
10^9/L
0.3
0.9
103
Hematology
Neutrophils
× 109/L
1.42*
6.34*
103
Hematology
Platelet count
× 109/L
165*
415*
103
Hematology
WBC count
10^9/L
3.8
10.6
103
Urinalysis
Glucose
Negative
103
Urinalysis
Ketones
Negative
103
Urinalysis
Occult blood
Negative
103
Urinalysis
Protein
Negative
103
Urinalysis
Specific gravity
1.001
1.035
103
Urinalysis
Urobilinogen
Normal
Table 11 Site 104 Units and Reference Ranges by Parameter
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
104
Chemistry
Albumin
M
g/dL
3.7
5.3
104
Chemistry
Albumin
F
g/dL
4.2
5.5
104
Chemistry
ALP
U/L
34
104
104
Chemistry
ALT/SGPT
U/L
7
52
104
Chemistry
AST/SGOT
U/L
13
39
104
Chemistry
Bicarbonate
mmol/L
21
31
104
Chemistry
Blood urea 
nitrogen
mg/dL
7
25
104
Chemistry
Calcium
mg/dL
8.6
10.3
104
Chemistry
Chloride
mmol/L
98
107
104
Chemistry
Creatinine
M
mg/dL
0.7
1.3
104
Chemistry
Creatinine
F
mg/dL
0.6
1.2
104
Chemistry
Glucose
low -
50
mg/dL
70
115
104
Chemistry
Glucose
51 -
high
mg/dL
85
125
104
Chemistry
Magnesium
mg/dL
1.9
2.7
104
Chemistry
Phosphorous
mg/dL
2.5
5
104
Chemistry
Potassium
mmol/L
3.5
5.1
104
Chemistry
Sodium
mmol/L
136
145
104
Chemistry
Total Bilirubin
mg/dL
0
1.4
104
Chemistry
Total protein
g/dL
6
8.3
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 47 of 61
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
104
Hematology
Basophils
THOUS/MCL
0
0.2
104
Hematology
Eosinophils
THOUS/MCL
0
0.5
104
Hematology
Hematocrit
%
39.5
50
104
Hematology
Hemoglobin
g/dL
13.5
16.9
104
Hematology
Lymphocytes
THOUS/MCL
0.9
3.3
104
Hematology
Monocytes
THOUS/MCL
0
0.8
104
Hematology
Neutrophils
THOUS/MCL
2
8.1
104
Hematology
Platelet count
THOUS/MCL
150
400
104
Hematology
WBC count
THOUS/MCL
4
10.5
104
Urinalysis
Glucose
mg/dL
Negative
104
Urinalysis
Ketones
mg/dL
Negative
104
Urinalysis
Occult blood
/HPF
2
104
Urinalysis
Protein
mg/dL
Negative
104
Urinalysis
Specific gravity
1.003
1.03
104
Urinalysis
Urobilinogen
mg/dL
< 2
Table 12 Site 105 Units and Reference Ranges by Parameter
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
105
Chemistry
Sodium
mEq/L
135
145
105
Chemistry
Potassium
mEq/L
3.6
5.2
105
Chemistry
Chloride
mEq/L
98
108
105
Chemistry
Bicarbonate
mEq/L
22
32
105
Chemistry
Calcium
mg/dL
8.9
10.2
105
Chemistry
Phosphorous
mg/dL
2.5
4.5
105
Chemistry
Magnesium
mg/dL
1.8
2.4
105
Chemistry
Blood urea 
nitrogen
mg/dL
8
21
105
Chemistry
Albumin
g/dL
3.5
5.2
105
Chemistry
ALP
U/L
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 48 of 61
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
105
Chemistry
ALT/SGPT
M
0 -<
50
U/L
10
64
105
Chemistry
ALT/SGPT
M
50 -
high
U/L
10
48
105
Chemistry
ALT/SGPT
F
U/L
7
33
105
Chemistry
AST/SGOT
U/L
9
38
105
Chemistry
Creatinine
M
mg/dL
0.51
1.18
105
Chemistry
Creatinine
F
mg/dL
0.38
1.02
105
Chemistry
Glucose
mg/dL
62
125
105
Chemistry
Total Bilirubin
mg/dL
0.2
1.3
105
Chemistry
Total protein
g/dL
6
8.2
105
Hematology
Hematocrit
M
%
38
50
105
Hematology
Hematocrit
F
%
36
45
105
Hematology
Hemoglobin
M
g/dL
13
18
105
Hematology
Hemoglobin
F
g/dL
11.5
15.5
105
Hematology
Neutrophils
thou/uL
1.8
7
105
Hematology
Lymphocytes
thou/uL
1
4.8
105
Hematology
Monocytes
thou/uL
0
0.8
105
Hematology
Eosinophils
thou/uL
0
0.5
105
Hematology
Basophils
thou/uL
1.8
7
105
Hematology
Platelet count
thou/uL
150
400
105
Hematology
WBC count
x10^3/uL
20
1000
105
Urinalysis
Glucose
Negative
105
Urinalysis
Ketones
Negative*
105
Urinalysis
Occult blood
1.005
1.03
105
Urinalysis
Protein
negative
105
Urinalysis
Specific gravity
105
Urinalysis
Urobilinogen
negative
Table 13 Site 107 Units and Reference Ranges by Parameter
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
107
Chemistry
Albumin
g/L
38
50
107
Chemistry
ALP
U/L
40
150
107
Chemistry
ALT/SGPT
U/L
7
40
107
Chemistry
AST/SGOT
U/L
5
34
107
Chemistry
Bicarbonate
mmol/L
23
29
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 49 of 61
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
107
Chemistry
Blood urea 
nitrogen
mmol/L
2.5*
7.1*
107
Chemistry
Calcium
mmol/L
2.2
2.62
107
Chemistry
Chloride
mmol/L
100
110
107
Chemistry
Creatinine
M
ȝPRO/
64
110
107
Chemistry
Creatinine
F
ȝPRO/
50
98
107
Chemistry
Glucose
mmol/L
3.8
7
107
Chemistry
Magnesium
mmol/L
0.7
1.1
107
Chemistry
Phosphorous
mmol/L
0.81*
1.4*
107
Chemistry
Potassium
mmol/L
3.2
5
107
Chemistry
Sodium
mmol/L
135
145
107
Chemistry
Total Bilirubin
ȝPRO/
low
< 23
107
Chemistry
Total protein
g/L
65
80
107
Hematology
Hematocrit
L/L
0.42
0.54
107
Hematology
Hematocrit
L/L
0.33
0.47
107
Hematology
Hemoglobin
M
g/L
140
180
107
Hematology
Hemoglobin
F
g/L
120
160
107
Hematology
Neutrophils
10^9/L
2
7.5
107
Hematology
Lymphocytes
10^9/L
1.5
4
107
Hematology
Monocytes
10^9/L
0.2
0.8
107
Hematology
Eosinophils
10^9/L
0.04
0.4
107
Hematology
Basophils
10^9/L
0
0.2
107
Hematology
Platelet count
10^9/L
150
400
107
Hematology
WBC count
10^9/L
4
11
107
Urinalysis
Glucose
Negative
107
Urinalysis
Ketones
Negative
107
Urinalysis
Occult blood
Negative
Trace
107
Urinalysis
Protein
Negative
Trace
107
Urinalysis
Specific gravity
1.005
1.03
107
Urinalysis
Urobilinogen
umol/L
low
< 17
Table 14 Site 110 Units and Reference Ranges by Parameter
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
110
Chemistry
Albumin
g/L
39
50
110
Chemistry
ALP
M
U/L
42
110
110
Chemistry
ALP
F
U/L
32
93
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 50 of 61
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
110
Chemistry
ALP
F
U/L
47
124
110
Chemistry
ALT/SGPT
M
U/L
8
58
110
Chemistry
ALT/SGPT
F
16 -
50
U/L
7
36
110
Chemistry
ALT/SGPT
F
51 -
high
U/L
8
45
110
Chemistry
AST/SGOT
M
U/L
15
38
110
Chemistry
AST/SGOT
F
16 -
50
U/L
14
30
110
Chemistry
AST/SGOT
F
51 -
high
U/L
15
37
110
Chemistry
Bicarbonate
mmol/L
21
31
110
Chemistry
Blood urea 
nitrogen
M
16 -
30
mmol/L
2.5
6.3
110
Chemistry
Blood urea 
nitrogen
M
31 -
40
mmol/L
3.1
8
110
Chemistry
Blood urea 
nitrogen
M
41 -
50
mmol/L
3.6
7.8
110
Chemistry
Blood urea 
nitrogen
M
50 -
high
mmol/L
3
8.8
110
Chemistry
Blood urea 
nitrogen
F
16 -
40
mmol/L
2.5
6.4
110
Chemistry
Blood urea 
nitrogen
F
41 -
50
mmol/L
2.8
6.7
110
Chemistry
Blood urea 
nitrogen
F
50 -
high
mmol/L
2.9
8
110
Chemistry
Calcium
16 -<
59
mmol/L
2.11
2.55
110
Chemistry
Calcium
59 -
high
mmol/L
2.24
2.63
110
Chemistry
Chloride
mmol/L
100
109
110
Chemistry
Creatinine
M
umol/L
67
109
110
Chemistry
Creatinine
F
umol/L
49
882
110
Chemistry
Glucose
mmol/L
3.6*
5.3*
110
Chemistry
Magnesium
mmol/L
0.66
1.07
110
Chemistry
Phosphorous
mmol/L
0.88
1.45
110
Chemistry
Potassium
mmol/L
3.6
5
110
Chemistry
Sodium
mmol/L
136
148
110
Chemistry
Total Bilirubin
umol/L
4
23
110
Chemistry
Total protein
g/L
67
87
110
Hematology
Hematocrit
M
0.395
0.488
110
Hematology
Hematocrit
F
0.347
0.449
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 51 of 61
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
110
Hematology
Hemoglobin
M
g/dL
13.3
17.1
110
Hematology
Hemoglobin
F
g/dL
11.5
14.8
110
Hematology
Neutrophils
x10^9/L
2.01
7.42
110
Hematology
Lymphocytes
x10^9/L
1.06
3.61
110
Hematology
Monocytes
x10^9/L
0.26
0.85
110
Hematology
Eosinophils
x10^9/L
0.02
0.45
110
Hematology
Basophils
x10^9/L
0.02
0.09
110
Hematology
Platelet count
x10^9/L
167
396
110
Hematology
WBC count
x10^9/L
3.89
9.93
110
Urinalysis
Glucose
mg/dL
Negative
110
Urinalysis
Ketones
mg/dL
Negative
110
Urinalysis
Occult blood
Negative
110
Urinalysis
Protein
mg/dL
Negative
110
Urinalysis
Specific gravity
1.005
1.03
110
Urinalysis
Urobilinogen
E.U./dL
0.2
1
Table 15 Site 111 Units and Reference Ranges by Parameter
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
111
Chemistry
Albumin
g/dL
3.4
5
111
Chemistry
ALP
U/L
46
116
111
Chemistry
ALT/SGPT
U/L
12
78
111
Chemistry
AST/SGOT
U/L
15
37
111
Chemistry
Bicarbonate
mEq/L
21
32
111
Chemistry
Blood urea 
nitrogen
mg/dL
7
18
111
Chemistry
Calcium
mg/dL
8.5
10.4
111
Chemistry
Chloride
mEq/L
98
107
111
Chemistry
Creatinine
mg/dL
0.51
1.17
111
Chemistry
Glucose
mg/dL
70
110
111
Chemistry
Magnesium
mg/dL
1.8
2.4
111
Chemistry
Phosphorous
mg/dL
2.5
4.9
111
Chemistry
Potassium
mEq/L
3.5
5.1
111
Chemistry
Sodium
mEq/L
136
145
111
Chemistry
Total Bilirubin
mg/dL
0
1
111
Chemistry
Total protein
g/dL
6.4
8.2
111
Hematology
Hematocrit
M
%
38
50
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 52 of 61
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
111
Hematology
Hematocrit
F
%
34
45
111
Hematology
Hemoglobin
M
g/dL
13
17.5
111
Hematology
Hemoglobin
F
g/dL
11.6
15.4
111
Hematology
Neutrophils
K/uL
1.5
8
111
Hematology
Lymphocytes
K/uL
1
4
111
Hematology
Monocytes
K/uL
0.2
1
111
Hematology
Eosinophils
K/uL
0
0.6
111
Hematology
Basophils
K/uL
0
0.2
111
Hematology
Platelet count
K/uL
140
390
111
Hematology
WBC count
K/uL
3.5
10.5
111
Urinalysis
Glucose
NEGATIVE
111
Urinalysis
Ketones
NEGATIVE
111
Urinalysis
Occult blood
NEGATIVE
111
Urinalysis
Protein
mg/dL
< 10
111
Urinalysis
Specific gravity
1.005
1.035
111
Urinalysis
Urobilinogen
EU/dL
0.2
1
Table 16 Site 113 Units and Reference Ranges by Parameter
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
113
Chemistry
Albumin
Apr-
60
g/dL
3.4
4.2
113
Chemistry
Albumin
61 -
70
g/dL
2.5
5.5
113
Chemistry
Albumin
71 -
80
g/dL
3.6
4.8
113
Chemistry
Albumin
81 -
90
g/dL
3.5
4.8
113
Chemistry
Albumin
90 -
high
g/dL
3.2
4.6
113
Chemistry
ALP
IU/L
113
Chemistry
ALT/SGPT
M
IU/L
0
44
113
Chemistry
ALT/SGPT
F
IU/L
0
32
113
Chemistry
AST/SGOT
IU/L
0
40
113
Chemistry
Bicarbonate
mmol/L
20
29
113
Chemistry
Blood urea 
nitrogen
18 -
39
mg/dL
6
20
113
Chemistry
Blood urea 
nitrogen
40 -
59
mg/dL
6
24
113
Chemistry
Blood urea 
nitrogen
60 -
89
mg/dL
8
27
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 53 of 61
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
113
Chemistry
Blood urea 
nitrogen
90 -
high
mg/dL
10
36
113
Chemistry
Calcium
mg/dL
4.5
5.6
113
Chemistry
Chloride
mmol/L
97
106
113
Chemistry
Creatinine
mg/dL
0.76
1.27
113
Chemistry
Creatinine
mg/dL
0.57
1
113
Chemistry
Glucose
ng/mL
65
199
113
Chemistry
Magnesium
mg/dL
1.6
2.3
113
Chemistry
Phosphorous
mg/dL
2.5
4.5
113
Chemistry
Potassium
mmol/L
3.5
5.2
113
Chemistry
Sodium
mmol/L
134
144
113
Chemistry
Total Bilirubin
mg/dL
0
1.2
113
Chemistry
Total protein
g/dL
6
8.5
113
Hematology
Hematocrit
%
43.5
53.7
113
Hematology
Hemoglobin
g/dL
14.1
18.1
113
Hematology
Neutrophils
x10E3/uL
1.4
7
113
Hematology
Lymphocytes
x10E3/uL
0.7
3.1
113
Hematology
Monocytes
x10E3/uL
0.1
0.9
113
Hematology
Eosinophils
x10E3/uL
0
0.4
113
Hematology
Basophils
x10E3/uL
0
0.2
113
Hematology
Platelet count
x10E3/uL
150
450
113
Hematology
WBC count
x10E3/uL
3.4
10.8
113
Urinalysis
Glucose
Negative
113
Urinalysis
Ketones
Negative
113
Urinalysis
Occult blood
Negative
113
Urinalysis
Protein
Negative
113
Urinalysis
Specific gravity
1
1.035
113
Urinalysis
Urobilinogen
Normal
Table 17 Site 116 Units and Reference Ranges by Parameter
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
116
Chemistry
Albumin
20 -
60
g/L
35
52
116
Chemistry
Albumin
61 -
90
g/L
32
46
116
Chemistry
ALP
U/L
40
150
116
Chemistry
ALT/SGPT
U/L
< 56
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 54 of 61
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
116
Chemistry
AST/SGOT
U/L
5
34
116
Chemistry
Bicarbonate
mmol/L
22
29
116
Chemistry
Blood urea 
nitrogen
M
mmol/L
3.2
7.4
116
Chemistry
Blood urea 
nitrogen
F
mmol/L
2.5
6.7
116
Chemistry
Calcium
mmol/L
2.1
2.55
116
Chemistry
Chloride
mmol/L
98
107
116
Chemistry
Creatinine
M
umol/L
63.6
110.5
116
Chemistry
Creatinine
F
umol/L
50.4
98.1
116
Chemistry
Glucose
mmol/L
3.6*
5.3*
116
Chemistry
Magnesium
mmol/L
0.66
1.07
116
Chemistry
Phosphorous
mmol/L
0.74
1.52
116
Chemistry
Potassium
mmol/L
3.5
5.1
116
Chemistry
Sodium
mmol/L
136
145
116
Chemistry
Total Bilirubin
umol/L
5.1
20.5
116
Chemistry
Total protein
g/L
64
83
116
Hematology
Hematocrit
M
%
37
52
116
Hematology
Hematocrit
F
%
35
47
116
Hematology
Hemoglobin
M
g/dL
12.5
17.5
116
Hematology
Hemoglobin
F
g/dL
11.5
16
116
Hematology
Neutrophils
K/uL
1.7
88
116
Hematology
Lymphocytes
K/uL
1
4.5
116
Hematology
Monocytes
K/uL
0.2
1
116
Hematology
Eosinophils
K/uL
0
0.5
116
Hematology
Basophils
K/uL
0
0.2
116
Hematology
Platelet count
K/uL
150
400
116
Hematology
WBC count
× 109/L
3.54*
9.06*
116
Urinalysis
Glucose
Negative
116
Urinalysis
Ketones
Negative
116
Urinalysis
Occult blood
Negative
116
Urinalysis
Protein
Negative
116
Urinalysis
Specific gravity
1.001
1.035
116
Urinalysis
Urobilinogen
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 55 of 61
Table 18 Site 117 Units and Reference Ranges by Parameter
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
117
Chemistry
Albumin
18 -
59
g/dL
3.7
4.8
117
Chemistry
Albumin
60 -
89
g/dL
3.2
4.6
117
Chemistry
Albumin
90 -
high
g/dL
2.9
4.5
117
Chemistry
ALP
15 -
20
IU/L
50
180
117
Chemistry
ALP
20 -
high
IU/L
40
140
117
Chemistry
ALT/SGPT
7*
41*
117
Chemistry
AST/SGOT
12*
38*
117
Chemistry
Bicarbonate
meq/L
22*
30*
117
Chemistry
Blood urea 
nitrogen
mg/dL
10
25
117
Chemistry
Calcium
mg/dL
8.6
10.4
117
Chemistry
Chloride
mmol/L
98
111
117
Chemistry
Creatinine
M
mg/dL
< 1.28
117
Chemistry
Creatinine
F
mg/dL
< 1.16
117
Chemistry
Glucose
mg/dL
50
140
117
Chemistry
Magnesium
mg/dL
1.8
2.3
117
Chemistry
Phosphorous
mg/dL
2.5
4.5
117
Chemistry
Potassium
mmol/L
3.5
5
117
Chemistry
Sodium
mmol/L
135
145
117
Chemistry
Total Bilirubin
mg/dL
< 1.2
117
Chemistry
Total protein
g/dL
6
8.3
117
Hematology
Hematocrit
M
%
41
53
117
Hematology
Hematocrit
F
%
36
46
117
Hematology
Hemoglobin
M
g/dL
13.5
17
117
Hematology
Hemoglobin
F
g/dL
12
15
117
Hematology
Neutrophils
K/uL
1.8
7.7
117
Hematology
Lymphocytes
K/uL
1.1
4
117
Hematology
Monocytes
K/uL
0
0.8
117
Hematology
Eosinophils
K/uL
0
0.7
117
Hematology
Basophils
K/uL
0
0.2
117
Hematology
Platelet count
K/uL
150
450
117
Hematology
WBC count
K/uL
3.8
10.6
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 56 of 61
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
117
Urinalysis
Glucose
Negative
117
Urinalysis
Ketones
Negative
117
Urinalysis
Occult blood
Negative
117
Urinalysis
Protein
Negative
117
Urinalysis
Specific gravity
1.005
1.03
117
Urinalysis
Urobilinogen
U/dL
< 2.0
Table 19 Site 122 Units and Reference Ranges by Parameter
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
122
Chemistry
Albumin
g/dL
3.5
5.2
122
Chemistry
ALP
M
U/L
40
130
122
Chemistry
ALP
F
U/L
35
105
122
Chemistry
ALT/SGPT
M
U/L
low
41
122
Chemistry
ALT/SGPT
F
U/L
low
33
122
Chemistry
AST/SGOT
M
U/L
low
40
122
Chemistry
AST/SGOT
F
U/L
low
32
122
Chemistry
Bicarbonate
meq/L
22*
30*
122
Chemistry
Blood urea 
nitrogen
18 -<
60
mg/dL
6
20
122
Chemistry
Blood urea 
nitrogen
60 -
90
mg/dL
8
23
122
Chemistry
Blood urea 
nitrogen
> 90
mg/dL
8.6
10
122
Chemistry
Calcium
18 -<
60
mg/dL
8.6
10
122
Chemistry
Calcium
60 -
90
mg/dL
8.8
10.2
122
Chemistry
Calcium
> 90
mg/dL
8.2
9.6
122
Chemistry
Chloride
mmol/L
98
107
122
Chemistry
Creatinine
M
mg/dL
0.7
1.2
122
Chemistry
Creatinine
F
mg/dL
0.5
0.9
122
Chemistry
Glucose
mg/dL
74
109
122
Chemistry
Magnesium
20 -<
60
mg/dL
1.6
2.6
122
Chemistry
Magnesium
60 -
90
mg/dL
1.6
2.4
122
Chemistry
Phosphorous
mg/dL
2.5
4.5
122
Chemistry
Potassium
mmol/L
3.4
4.5
122
Chemistry
Sodium
mmol/L
136
145
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 57 of 61
SITE
NUMBER
PANEL
PARAMETER
SEX
AGE
UNITS
REFERENCE 
LOW
REFERENCE 
HIGH
122
Chemistry
Total Bilirubin
mg/dL
low
1.2
122
Chemistry
Total protein
g/dL
6.4
8.3
122
Hematology
Hematocrit
M
%
40.1
51
122
Hematology
Hematocrit
F
%
34.1
44.9
122
Hematology
Hemoglobin
M
g/dL
13.7
17.5
122
Hematology
Hemoglobin
F
g/dL
11.2
15.7
122
Hematology
Neutrophils
k/uL
2.3
7.1
122
Hematology
Lymphocytes
k/uL
0.8
3.5
122
Hematology
Monocytes
k/uL
0.2
0.8
122
Hematology
Eosinophils
k/uL
0.1
0.4
122
Hematology
Basophils
k/uL
0
0.1
122
Hematology
Platelet count
k/uL
150
450
122
Hematology
WBC count
k/uL
4
10.5
122
Urinalysis
Glucose
Negative
122
Urinalysis
Ketones
Negative
122
Urinalysis
Occult blood
Negative
122
Urinalysis
Protein
Negative
122
Urinalysis
Specific gravity
1.001
1.03
122
Urinalysis
Urobilinogen
Normal
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 58 of 61
18
Appendix B: Common Terminology Criteria for Adverse Events for Laboratory Parameters
Table 20
Common Terminology Criteria for Adverse Events v5.0, November 27, 2017
Panel
Parameter
CTCAE Term
Definition
Grade 1
Grade 2
Grade 3
Grade 4
Grade5
Chemistry
Sodium
Hypernatremia
A disorder characterized by 
laboratory test results that indicate 
an elevation in the concentration 
of sodium in the blood.
>ULN - 150
mmol/L
>150 - 155 
mmol/L; 
intervention 
initiated
>155 - 160 
mmol/L; 
hospitalization 
indicated
>160 mmol/L;
life-threatening 
consequences
Death
Chemistry
Sodium
Hyponatremia
A disorder characterized by 
laboratory test results that indicate 
a low concentration of sodium in 
the blood.
<LLN - 130
mmol/L
125-129 mmol/L 
and asymptomatic
125-129 mmol/L 
symptomatic; 120-
124 mmol/L 
regardless of 
symptoms
<120 mmol/L; 
life-threatening 
consequences
Death
Chemistry
Potassium
Hyperkalemia
A disorder characterized by 
laboratory test results that indicate 
an elevation in the concentration 
of potassium in the blood; 
associated with kidney failure or 
sometimes with the use of diuretic 
drugs
>ULN - 5.5 
mmol/L
>5.5 - 6.0 mmol/L; 
intervention 
initiated
>6.0 - 7.0 mmol/L; 
hospitalization 
indicated
>7.0 mmol/L; life-
threatening 
consequences
Death
Chemistry
Potassium
Hypokalemia
A disorder characterized by 
laboratory test results that indicate 
a low concentration of potassium 
in the blood.
<LLN - 3.0 
mmol/L
Symptomatic with 
<LLN - 3.0 
mmol/L; 
intervention 
indicated
<3.0 - 2.5 mmol/L; 
hospitalization 
indicated
<2.5 mmol/L; life-
threatening 
consequences
Death
Chemistry
Calcium
Hyper-calcemia
A disorder characterized by 
laboratory test results that indicate 
an elevation in the concentration 
of calcium (corrected for 
albumin) in blood.
>ULN - 2.9 
mmol/L
>2.9 - 3.1 mmol/L; 
symptomatic
>3.1 - 3.4 mmol/L; 
hospitalization 
indicated
>3.4 mmol/L; life-
threatening 
consequences
Death
Chemistry
Calcium
Hypocalcemia
A disorder characterized by 
laboratory test results that indicate 
a low concentration of calcium 
(corrected for albumin) in the 
blood.
<LLN - 2.0 
mmol/L
<2.0 - 1.75 
mmol/L; 
symptomatic
<1.75 - 1.5 
mmol/L; 
hospitalization 
indicated
<1.5 mmol/L; life-
threatening 
consequences
Death
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 59 of 61
Panel
Parameter
CTCAE Term
Definition
Grade 1
Grade 2
Grade 3
Grade 4
Grade5
Chemistry
Magnesium
Hypermagnesemia
A disorder characterized by 
laboratory test results that indicate 
an elevation in the concentration 
of magnesium in the blood.
>ULN - 3.0 
mg/dL; >ULN -
1.23 mmol/L
>3.0 - 8.0 mg/dL; 
>1.23 - 3.30 
mmol/L
>8.0 mg/dL; >3.30 
mmol/L; life-
threatening 
consequences
Death
Chemistry
Magnesium
Hypomagnesemia
A disorder characterized by 
laboratory test results that indicate 
a low concentration of 
magnesium in the blood.
<LLN - 1.2 
mg/dL; <LLN -
0.5 mmol/L
<1.2 - 0.9 mg/dL; 
<0.5 - 0.4 mmol/L
<0.9 - 0.7 mg/dL; 
<0.4 - 0.3 mmol/L
<0.7 mg/dL; <0.3 
mmol/L; 
lifethreatening 
consequences
Death
Chemistry
Glucose
Hypoglycemia
A disorder characterized by 
laboratory test results that indicate 
a low concentration of glucose in 
the blood.
<LLN - 55
mg/dL; <LLN -
3.0 mmol/L
<55 - 40 mg/dL; 
<3.0 - 2.2 mmol/L
<40 - 30 mg/dL; 
<2.2 - 1.7 mmol/L
<30 mg/dL; <1.7 
mmol/L;
lifethreatening 
consequences; 
seizures
Death
Chemistry
Creatinine
Creatinine 
increased
A finding based on laboratory test 
results that indicate increased 
levels of creatinine in a biological 
specimen.
>ULN - 1.5 x 
ULN
>1.5 - 3.0 x 
baseline; >1.5 -
3.0 x ULN
>3.0 x baseline; 
>3.0 - 6.0 x ULN
>6.0 x ULN
Chemistry
Total 
Bilirubin
Blood bilirubin 
increased
A finding based on laboratory test 
results that indicate an abnormally 
high level of bilirubin in the 
blood. Excess bilirubin is 
associated with jaundice.
>ULN - 1.5 x 
ULN if baseline 
was normal; > 1.0 
- 1.5 x baseline if 
baseline was 
abnormal
>1.5 - 3.0 x ULN 
if baseline was 
normal; >1.5 - 3.0 
x baseline if 
baseline was 
abnormal
>3.0 - 10.0 x ULN 
if baseline was 
normal; >3.0 -
10.0 x baseline if 
baseline was 
abnormal
>10.0 x ULN if 
baseline was 
normal; >10.0 x 
baseline if baseline 
was abnormal
Chemistry
AST/SGOT
Aspartate 
aminotransferase 
increased
A finding based on laboratory test 
results that indicate an increase in 
the level of aspartate 
aminotransferase (AST or SGOT) 
in a blood specimen.
>ULN - 3.0 x 
ULN if baseline 
was normal; 1.5 -
3.0 x baseline if 
baseline was 
abnormal
>3.0 - 5.0 x ULN 
if baseline was 
normal; >3.0 - 5.0 
x baseline if 
baseline was 
abnormal
>5.0 - 20.0 x ULN 
if baseline was 
normal; >5.0 -
20.0 x baseline if 
baseline was 
abnormal
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 60 of 61
Panel
Parameter
CTCAE Term
Definition
Grade 1
Grade 2
Grade 3
Grade 4
Grade5
Chemistry
ALT/SGPT
Alanine 
aminotransferase 
increased
A finding based on laboratory test 
results that indicate an increase in 
the level of alanine 
aminotransferase (ALT or SGPT) 
in the blood specimen.
>ULN - 3.0 x 
ULN if baseline 
was normal; 1.5 -
3.0 x baseline if 
baseline was 
abnormal
>3.0 - 5.0 x ULN 
if baseline was 
normal; >3.0 - 5.0 
x baseline if 
baseline was 
abnormal
>5.0 - 20.0 x ULN 
if baseline was 
normal; >5.0 -
20.0 x baseline if 
baseline was 
abnormal
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal
Chemistry
ALP
Alkaline 
phosphatase 
increased
A finding based on laboratory test 
results that indicate an increase in 
the level of alkaline phosphatase 
in a blood specimen.
>ULN - 2.5 x 
ULN if baseline 
was normal; 2.0 -
2.5 x baseline if 
baseline was 
abnormal
>2.5 - 5.0 x ULN 
if baseline was 
normal; >2.5 - 5.0 
x baseline if 
baseline was 
abnormal
>5.0 - 20.0 x ULN 
if baseline was 
normal; >5.0 -
20.0 x baseline if 
baseline was 
abnormal
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal
Chemistry
Albumin
Hypoalbuminemia
A disorder characterized by 
laboratory test results that indicate 
a low concentration of albumin in 
the blood.
<LLN - 3 g/dL; 
<LLN - 30 g/L
<3 - 2 g/dL; <30 -
20 g/L
<2 g/dL; <20 g/L
Life-threatening 
consequences; 
urgent intervention 
indicated
Death
Hematology
Hemoglobin
Anemia
A disorder characterized by a 
reduction in the amount of 
hemoglobin in 100 ml of blood. 
Signs and symptoms of anemia 
may include pallor of the skin and 
mucous membranes, shortness of 
breath, palpitations of the heart, 
soft systolic murmurs, lethargy, 
and fatigability.
<LLN - 10.0 
g/dL; <LLN - 6.2 
mmol/L; <LLN -
100 g/L
<10.0 - 8.0 g/dL; 
<6.2 - 4.9 mmol/L; 
<100 - 80g/L
<8.0 g/dL; <4.9 
mmol/L; <80 g/L;
transfusion 
indicated
Life-threatening 
consequences; 
urgent intervention 
indicated
Death
Hematology
Hemoglobin
Hemoglobin 
increased
A finding based on laboratory test 
results that indicate increased 
levels of hemoglobin above 
normal.
Increase in >0 - 2
g/dL
Increase in >2 - 4
g/dL
Increase in >4 
g/dL
Hematology
Neutrophils
Neutrophil count 
decreased
A finding based on laboratory test 
results that indicate a decrease in 
number of neutrophils in a blood 
specimen.
<LLN -
1500/mm3; <LLN 
- 1.5x 10e9 /L
<1500 -
1000/mm3; <1.5 -
1.0x 10e9 /L
<1000 - 500/mm3; 
<1.0 - 0.5 x10e9 
/L
<500/mm3; <0.5 x 
10e9 /L
	



Rain Therapeutics Inc.
RAIN-701 SAP
Version 1.0, 14 October 2022
Page 61 of 61
Panel
Parameter
CTCAE Term
Definition
Grade 1
Grade 2
Grade 3
Grade 4
Grade5
Hematology
Lymphocytes
Lymphocyte count 
decreased
A finding based on laboratory test 
results that indicate a decrease in 
number of lymphocytes in a blood 
specimen.
<LLN - 800/mm3; 
<LLN - 0.8 x 
10e9/L
<800 - 500/mm3; 
<0.8 - 0.5 x 
10e9/L
<500 - 200/mm3; 
<0.5 - 0.2 x 
10e9/L
<200/mm3; <0.2 x 
10e9/L
Hematology
Eosinophils
Eosinophilia
A disorder characterized by 
laboratory test results that indicate 
an increased number of 
eosinophils in the blood.
>ULN and 
>Baseline
Steroids initiated
Hematology
Platelet 
count
Platelet count 
decreased
A finding based on laboratory test 
results that indicate a decrease in 
number of platelets in a blood 
specimen.
<LLN - 75.0 x 
10e9/L
<75.0 - 50.0 x 
10e9/L
<50.0 - 25.0 x 
10e9/L
<25.0 x 10e9/L
	
